Ryuzo Kawahara

Multi-institutional study on the teratogenicity and fetal toxicity of antiepileptic drugs: a report of a collaborative study group in Japan.

Summary: A multi‐institutional collaborative study was conducted concerning the course of pregnancy and delivery and the incidence of abnormal infants delivered of epileptic women. Of 657 women receiving antiepileptic drugs, 73% delivered live infants, 14% had miscarriage or stillbirth, and 13% underwent induced abortion. In contrast to the above findings, 80% of 162 patients not receiving antiepileptic drugs delivered live infants and 4% had miscarriage or stillbirth. The latter outcome was significantly increased in the medicated patients. In this series, 63 (9.9%) of 638 live births were malformed, 55 (11.5%) being from medicated mothers and 3 (2.3%) from nonmedicated mothers. The incidence of fetal malformation in medicated mothers was thus five times as high as that in nonmedicated mothers. Cleft lip and/or palate and malformations involving the cardiovascular system were found frequently in the infants from medicated mothers. General background factors that might exert teratogenic effects on pregnant patients with epilepsy were studied, and the potential toxicity of antiepileptic drugs to the fetus was also analyzed. In this regard, consideration should be given to whether the patient has partial epileptic seizures, whether the patient herself exhibits any malformation, or whether her previous pregnancy resulted in an abnormal outcome. The incidence of fetal malformation was the highest (12.7%) in the medicated patients who had epileptic seizures during the pregnancy. It is presumed on the basis of the results of analysis of the data that a combination of more than three drugs and a daily dose greater than a certain minimal level is likely to produce malformed infants.

Visual hallucinations as REM sleep behavior disorders in patients with Parkinson's disease

To clarify whether visual hallucinations in patients with Parkinsons disease (PD) are related to rapid eye movement (REM) sleep, nocturnal polysomnographic variables were compared between a group with hallucinations (hallucinators, n = 14) and a group without hallucinations (nonhallucinators, n = 8). A multiple sleep latency test (MSLT) was performed on 3 hallucinators, and the content of dreams during daytime REM sleep was investigated. The efficacy of clonazepam, a standard treatment choice for REM sleep behavior disorders, was investigated in 8 hallucinators. Nocturnal polysomnograms of the hallucinators showed a higher amount of stage 1–REM sleep with tonic electromyogram (stage 1–REM) than the nonhallucinators, and the reported occurrences of nocturnal hallucinations corresponded with the periods of stage REM or stage 1–REM in most hallucinators. The frequency of sleep onset REM periods (SOREMP) on the MSLT were pathologically high in the hallucinators, and the content of the dreams during the MSLT period was quite similar to their hallucinations. During clonazepam treatment, the frequency of hallucinatory symptoms decreased in 5 of 8 hallucinators. These results indicate that visual hallucinations in PD are likely to be related to a REM sleep disorder manifested as the appearance of both stage 1–REM during the night and SOREMP in the daytime.

Autonomic function in the early stage of panic disorder: Power spectral analysis of heart rate variability

Previous studies of autonomic nervous system (ANS) function in panic disorder (PD) patients have yielded conflicting results. We speculate that these differences might result from the variety of clinical stages of PD. In order to investigate this, we compared ANS activity in untreated patients in the early stage of PD with control subjects using power spectral analysis of electrocardiogram R‐R intervals (PSR‐R) in supine rest and during head‐up tilt, which was performed according to the maximum entropy method (MEM). It recognizes two main components: high‐frequency power (HF), which mainly reflects cardiac parasympathetic activity, and low‐frequency power (LF), which reflects both cardiac sympathetic and parasympathetic activity. The patients with PD had significantly higher values for all components of PSR‐R only in tilt position total power (TP), LF, and HF than did the control subjects (P < 0.01, < 0.01, < 0.02, respectively). However, the LF/HF ratio which indicated sympathovagal balance did not differ significantly between the two groups in tilt position. Our findings suggest that patients with PD in the early stage of illness have co‐activation of sympathetic and parasympathetic nervous systems, which might act to maintain a balance between the two autonomic systems.

Relationships between serum magnesium levels and clinical background factors in patients with mood disorders

We measured serum magnesium (Mg) levels in 71 in‐patients and out‐patients with mood disorders and in 30 healthy controls and investigated the relationships between serum Mg levels and clinical background factors. Serum Mg levels were found to be significantly higher in patients with mood disorders than in controls. Serum Mg levels showed no significant correlation with patient sex, age, diagnosed subtype and disease phase in the mood disorder group. Serum Mg levels in patients with major depressive disorder who were taking psychotropic drugs were not significantly different from levels seen in patients with major depressive disorder who were not taking psychotropic drugs. These results suggest that the high serum Mg levels noted in patients with mood disorder are related to the underlying disorder itself and are not influenced by clinical background factors.

Clinical efficacy and indication of acetazolamide treatment on sleep apnea syndrome.

The efficacy and indication of acetazolamide treatment on patients with sleep apnea syndrome (SAS) were discussed from assessing the changes of polysomnographic findings with the treatment in 75 SAS patients. For the patients as a whole, respiratory disorder variables improved significantly during the treatment. However, the number of acetazolamide treatment responders who showed a decrease of apnea hypopnea index (AHI) to 50% or less of the pretreatment value numbered only 34 (45.3%). The lower values of body mass index and AHI in the responder group indicated that monotherapy with acetazolamide is the treatment choice only for mild SAS cases without obesity. However, combined treatment with acetazolamide and uvulopalatopharyngoplasty was thought to be beneficial for severe cases.

Treatment of periodic leg movement disorder and restless leg syndrome with talipexole.

In order to investigate the bedtime dose of talipexole, a D2 and α2 stimulant, on patients with periodic leg movement disorder (PLMD) and restless leg syndrome (RLS), we made a comparison of polysomnographic findings and subjective symptom ratings before and during 4 weeks of the treatment on five cases with RLS and PLMD. A significant decrease in both the frequencies of periodic leg movements and subjective symptom ratings and significant improvement of sleep composition were recognized during the treatment. We speculate that the combination of the agonistic action of D2 and α2 receptor with the drug might not only suppress PLMD and RLS but also improve sleep quality.

Mechanism of action and therapeutic indication of prosthetic mandibular advancement in obstructive sleep apnea syndrome.

Abstract Prosthetic mandibular advancement (PMA) was applied to nine patients with obstructive sleep apnea syndrome (OSAS) and its therapeutic usefulness, mechanism of action, and clinical indication were discussed based on polysomnographic findings and serial examination of upper airway before and during PMA treatment. Apnea hypopnea index significantly decreased during PMA treatment compared with the value before treatment (P < 0.01) and the rate of the treatment responder counted 78.1%. Cephalometric variables indicated forward and inferior advancement of mandible in our subjects. Magnetic resonance imaging of the upper airway during sleep revealed a marked improvement of velopharyngeal obstruction in most subjects. In addition, intraesophageal negative pressure during sleep decreased significantly. Our results confirmed the high therapeutic efficacy of PMA for OSAS and indicated forward advancement of the mandible and decrease of negative pressure loading on upper airway with PMA might suppress velopharyngeal collapse. Thus, PMA was regarded as one of the treatments of choice for OSAS occurring based on with velopharyngeal narrowing.

Relationship between hypersomnia and respiratory disorder during sleep in Prader–Willi syndrome

Abstract To assess whether hypersomnia in Prader–Willi syndrome (PWS) patients is related to the respiratory disorder during sleep (RDDS), we made a systematic evaluation regarding the relationship between the two disorders in three patients. All patients showed hypersomnia manifested as the long duration of night sleep and shortened sleep latencies of multiple sleep latency test. Although magnetic resonance imaging and laboratory studies revealed obstruction of the upper airway and mild increase of esophageal pressure during sleep, the number of other apneic episodes or awakenings was not as frequent. From the above results, we speculate that the mechanism of excessive daytime sleepiness in PWS is not caused by RDDS and quite resembles that of essential hypersomnia.

Age-specific effects of noradrenergic alpha-2 agonist clonidine on the development of amygdaloid kindling in developing rats

The effects of clonidine on the development of amygdaloid kindling were studied in rats of various ages (14, 21, 28 and 70 postnatal days). Administration of clonidine (0.2, 0.5 mg/kg i.p.) caused a significant retardation of kindling development in the 28-day-old rats as well as in the adult rats, whereas, in the 14-day-old rats, the development of kindling was significantly facilitated by clonidine. No significant effect of clonidine was observed in the 21-day-old rats. These results indicate that in rats the effects of clonidine on the development of amygdaloid kindling vary during development.

Chemical kindling with Met-enkephalin and transfer between chemical and electrical kindling

The role played by Met-enkephalin (ME) in epileptic seizures was investigated, using 57 ME kindled rats and 10 saline injected control rats. Repeated microinjection of 10 micrograms ME into the right amygdala (AM) of male Wistar rats led to development of generalized convulsions. One week after the completion of ME kindling, 1 or 2 electrical stimulations (200-400 microA, 60 Hz, 1 sec) of the right AM of ME kindled rats resulted in generalized convulsions in 5 rats. The duration of after-discharge (AD) in the first generalized convulsion induced by electrical AM stimulation in the ME kindled rats was significantly longer than that in the first generalized convulsion induced by electrical stimulation in the saline treated control rats (P less than 0.05). One week after the completion of ME kindling, naloxone (10 or 20 mg/kg, i.p.) given 10 min before the infusion of ME into the other 3 ME kindled rats attenuated both convulsive behavior and electrographical seizures. With the progress of convulsive behavior, the frequency of wet-dog shakes (WDS) tended to decrease and was significantly lower after ME injection in the first stage 5 seizures than after the first ME injection (P less than 0.01). These results strongly suggest that ME has a potent epileptogenic effect on the rat brain which is caused by the opioid receptors. There are some differences between chemical kindling with ME and electrical kindling as indicated by the development of the AD duration and the WDS frequency.