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The Clozapine Plus Working Group is frequently consulted for advice on measures in case of infection with SARSCoV-2 and on vaccination against COVID-19 in patients receiving clozapine.pAIM: Inform about risks of infection with SARS-CoV-2 in patients with severe mental illness (SMI), patients with schizophrenia spectrum disorders (SSD), and patients treated with clozapine. Advise on monitoring of clozapine plasma levels and white blood cell count and differential in COVID-19 and after vaccination, as well as measures to be taken.pMETHOD: Literature research and case studies.pRESULTS: SMI patients and in particular SSD patients have an increased risk of infection with SARS-CoV-2 with more hospitalizations and higher mortality than non-psychiatric patients. Patients using clozapine may be at greater risk of infection. SARS-CoV-2 infection may cause a dangerous increase of clozapine plasma levels and generally mild and short-term granulocytopenia and lymphocytopenia, which are usually not a result of clozapine treatment.pCONCLUSION: In case of COVID-19 extra alertness is required in patients with SMI and especially SSD. In clozapine users, in case of COVID-19, reduction in dose by half to three quarters of the original dose is recommended. When patients develop granulocytopenia, SARS-CoV-2 should be considered as the cause and not immediately clozapine. SMI patients and clozapine users in particular belong to a high risk group with a medical indication for early vaccination.

Reactions on 'The effectiveness of monoamine oxidase inhibitors in treatment-resistant depressive disorders in clinical practice; a retrospective open-label study'.

There is no national protocol for the use of light therapy in bipolar depression.br/AIM: The chronotherapy collaboration group of the Foundation for Bipolar Disorders intended to write a protocol for light therapy in bipolar depressive episodes.br/METHOD: Narrative review of several systematic reviews, two clinician's guides and deliberation with the sub-commission Guidelines of the Dutch Ophthalmologic Society.br/RESULTS: The following indication was established: depressive episode, with or without seasonal features, in bipolar I or II disorder, including subsyndromal (depressive) seasonal complaints. The list of relative contra-indications (pre-existent retinal illnesses, systemic illnesses with effect on the retina and use of photosensitive medication) was shortened. In this case the medical professional discusses the possibility of an ophthalmologic consultation with the patient. Use of a mood stabilizer/antimanic medication in order to prevent mania or a mixed episode is only necessary in a depressive episode in bipolar I, but not in bipolar II disorder. Standard treatment is 10.000 lux white light during 30 minutes in the morning.br/CONCLUSION: There is sufficient evidence to propose light therapy in a bipolar depressive episode with or without seasonal features.

To test whether: (1) psychiatrists will prescribe clozapine more often if they can delegate the monitoring tasks to an advanced nurse practitioner (ANP), (2) clozapine monitoring by an ANP is at least as safe as monitoring by a psychiatrist. Patients from 23 Dutch outpatient teams were assessed for an indication for clozapine. ANPs affiliated to these teams were randomized to Condition A: clozapine monitoring by an ANP, or Condition B: monitoring by the psychiatrist. The safety of monitoring was evaluated by determining whether the weekly neutrophil measurements were performed. Staff and patients were blinded regarding the first hypothesis. Of the 173 patients with an indication for clozapine at baseline, only seven in Condition A and four in Condition B were prescribed clozapine (Odds Ratio = 2.24, 95% CI 0.61–8.21; p = 0.225). These low figures affected the power of this study. When we considered all patients who started with clozapine over the 15-month period (N = 49), the Odds Ratio was 1.90 (95% CI 0.93–3.87; p = 0.078). With regard to the safety of the monitoring of the latter group of patients, 71.2% of the required neutrophil measurements were performed in condition A and 67.3% in condition B (OR = 0.98; CI = 0.16–3.04; p = 0.98). Identifying patients with an indication for clozapine does not automatically lead to improved prescription rates, even when an ANP is available for the monitoring. Clozapine-monitoring performed by an ANP seemed as safe as that by a psychiatrist. Electronic supplementary material The online version of this article (10.1007/s10488-020-01031-4) contains supplementary material, which is available to authorized users.

Aims To systematically review the literature on the efficacy and tolerability of the major chronotherapeutic treatments of bipolar disorders (BD)-bright light therapy (LT), dark therapy (DT), treatments utilizing sleep deprivation (SD), melatonergic agonists (MA), interpersonal social rhythm therapy (IPSRT), and cognitive behavioral therapy adapted for BD (CBTI-BP)-and propose treatment recommendations based on a synthesis of the evidence. Methods PRISMA-based systematic review of the literature. Results The acute antidepressant (AD) efficacy of LT was supported by several open-label studies, three randomized controlled trials (RCTs), and one pseudorandomized controlled trial. SD showed rapid, acute AD response rates of 43.9%, 59.3%, and 59.4% in eight case series, 11 uncontrolled, studies, and one RCT, respectively. Adjunctive DT obtained significant, rapid anti-manic results in one RCT and one controlled study. The seven studies on MA yielded very limited data on acute antidepressant activity, conflicting evidence of both antimanic and maintenance efficacy, and support from two case series of improved sleep in both acute and euthymic states. IPSRT monotherapy for bipolar II depression had acute response rates of 41%, 67%, and 67.4% in two open studies and one RCT, respectively; as adjunctive therapy for bipolar depression in one RCT, and efficacy in reducing relapse in two RCTs. Among euthymic BD subjects with insomnia, a single RCT found CBTI-BP effective in delaying manic relapse and improving sleep. Chronotherapies were generally safe and well-tolerated. Conclusions The outcome literature on the adjunctive use of chronotherapeutic treatments for BP is variable, with evidence bases that differ in size, study quality, level of evidence, and non-standardized treatment protocols. Evidence-informed practice recommendations are offered.

BackgroundDysfunction of neuroplasticity due to N-methyl-d-aspartate (NMDA) receptor hypofunction may be a causal factor for memory and executive dysfunctioning in schizophrenia. Deregulation of NMDA transmission in the prefrontal cortex may also explain negative and positive symptoms. Clozapine augmentation with memantine targets altered NMDA receptor-mediated neurotransmission in schizophrenia and showed substantial beneficial effects on several symptom domains in a small proof-of-concept study. We evaluate effects of memantine add-on treatment to clozapine for memory and executive function, and negative and positive symptoms in schizophrenia.MethodClozapine-treated patients with refractory schizophrenia were randomly assigned to 12 weeks of double-blind adjunctive treatment with memantine (n = 26) or placebo (n = 26). Crossover occurred after a 2-week placebo wash-out period. Primary endpoints were change from baseline to 12 weeks treatment and 14 weeks to 26 weeks treatment on memory and executive function using the Cambridge Neuropsychological Test Automated Battery (CANTAB), Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression Severity Scale (CGI-S). Side effects were assessed using the Liverpool University Neuroleptic Side-Effect Rating Scale.ResultsWhen compared with placebo, memantine improved a composite memory score comprising verbal recognition memory and paired associates learning task scores on the CANTAB (effect size = 0.30) and PANSS negative subscale score (effect size = 0.29). Side effects were mild and transient.ConclusionsIn patients with clozapine-treated refractory schizophrenia, memantine addition significantly improved verbal and visual memory and negative symptoms without serious adverse effects. These results justify further investigations on long-term memantine augmentation to clozapine in treatment-resistant schizophrenia.

BACKGROUND Patients with epilepsy who use anticonvulsants frequently show low levels of folate and vitamin B12 and high levels of homocysteine. Patients with bipolar disorder use some anticonvulsants as mood stabilisers.br/AIM: To determine whether some anticonvulsants lower folate and vitamin B12 and raise homocysteine levels.br/METHOD: Systematic literature search to determine the relation between the anticonvulsants valproic acid, carbamazepine, lamotrigine and topiramate on the one hand and blood levels of folate, vitamin B12 and homocysteine on the other hand.br/RESULTS: The vast majority of studies in adults and children showed a correlation between use of anticonvulsant carbamazepine and decrease of the folate level. Hardly any of the studies that examined the effect of valproic acid on folate levels found a correlation. There was next to no evidence of a correlation between the use of carbamazepine and a low vitamin B12 level in adults or children. In adults and children the use of valproic acid was found to correlate with a higher vitamin B12 level. Nearly all studies found an increase in homocysteine in adults and children using carbamazepine. Among the users of valproic acid, it was only children who showed a clear association with a rise in homocysteine level. The results for adults were contradictory. We were unable to make any clear statement about topiramate or lamotrigine because there have been very few publications about these anticonvulsants.br/CONCLUSION: In adults and children with epilepsy use of carbamazepine is associated with a decrease of folate, valproic acid with a rise in the vitamin B12 level, and carbamazepine with an increase in homocysteine. Valproic acid showed only in children an association with the rise of the homocysteine level. Psychiatrists may find it advisable to control the levels of folate and homocysteine in adults and children who are taking carbamazepine and to measure homocysteine level in children taking valproic acid.

Clozapine is an effective drug for treating psychosis in Parkinson's disease (PDP) and is registered as such in the Netherlands. However, clozapine can have adverse effects, including agranulocytosis. The new drug pimavanserin was recently registered in the United States for the treatment of PDP.br/AIM: To review the literature on pimavanserin and discuss the position it currently occupies in the Netherlands as a potential treatment for PDP.br/METHOD: Systematic search of the literature.br/RESULTS: We found reports on four randomised controlled trials (RCTs), one review and six articles about the pharmacokinetics and pharmacodynamics of pimavanserin. Pimavanserin is an effective treatment for PDP, and, like clozapine, it has very few negative effects on motor skills. However, all of the RCTs were funded by the manufacturer of pimavanserin and the trials were conducted in a very selective patient population. This means that results cannot be generalised. Long-term results are not yet available. In earlier trials clozapine was shown to have a greater and faster antipsychotic effect. Many clinicians and psychiatrists have a great deal of experience with this drug. Another important point is that no-one has yet conducted a trial comparing clozapine and pimavanserin.br/CONCLUSION: Given that the current second drug of choice, namely quetiapine, has not been found to be effective for PDP, we are of the opinion that - if pimavanserin is registered in the Netherlands - pimavanserin could be used when the current drug of choice, clozapine, is not completely effective or is poorly tolerated. For patients who have cognitive impairments in addition to psychosis, we advise testing the patient's reaction to a cholinesterase inhibitor before starting the patient on a course of antipsychotics.

Lithium is associated with adverse effects on cognitive functioning. However, there are published trials that have investigated the protective effects of lithium in cognitive decline.br/AIM: To review studies that investigate the potentially protective effects of lithium on cognitive disorders.br/METHOD: We studied English-language and Dutch reports on controlled, clinical trials published up to October 2016.br/RESULTS: We found four relevant articles. Two studies indicated that cognitive functioning remained more stable when patients were given lithium than when they were given a placebo. One study, however, could not detect any difference between the effects of lithium and the effects of placebos. The fourth study, which examined patients' ability to tolerate lithium, could not find any difference in the cognitive functioning of patients.br/CONCLUSION: The reported results indicate that the cognitive functioning of patients with pre-stage Alzheimer's disease remains more stable after patients have taken lithium than after they have taken a placebo.

IntroductionIn a recent placebo-controlled, double blind crossover trial (n = 52), we found significant beneficial effects on memory (d = 0.30) and negative symptoms (d = 0.29) after 12 weeks memantine augmentation in patients with clozapine-refractory schizophrenia.AimsIn this open-label 1 year extension study, we report the long-term effects and tolerability of memantine add-on therapy to clozapine.MethodsCompleters of the first trial who experienced beneficial effects during 12 weeks of memantine treatment received memantine for one year. Primary endpoints were memory and executive function using the Cambridge neuropsychological test automated battery (CANTAB), the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impression Severity Scale (CGI-S).ResultsOf 31 RCT completers who experienced beneficial effects from memantine, 24 received memantine for one year. The small improvement in memory found in the memantine condition in the placebo-controlled trial remained stable in the extension study. Executive function did not improve. After 26 weeks of memantine add-on therapy to clozapine, PANSS negative symptoms (r = 0.53), PANSS positive symptoms (r = 0.50), and PANSS total symptoms (r = 0.54) significantly improved. Even further significant improvement in all these measures was observed between 26 weeks and 52 weeks memantine, with effect sizes varying from 0.39 to 0.51. CGI-S showed a non-significant moderate improvement at 26 weeks (r = 0.36) and 52 weeks (r = 0.34). Memantine was well tolerated without serious adverse effects.ConclusionsIn the one-year extension phase, the favorable effect of adjunctive memantine on memory was sustained and we observed further improvement of positive, negative and overall symptoms of schizophrenia.Disclosure of interestP.F.J.S. reports personal fees from H. Lundbeck A/S, outside the submitted work and he is a board member of the Dutch Clozapine Collaboration Group. L.d.H., has received investigator-led research grants or recompense for presenting his research from Eli Lilly, Bristol-Myers Squibb, Janssen-Cilag and AstraZeneca.

IntroductionIn a recent 26-week placebo-controlled, crossover trial (n = 52) we found significant positive effects on verbal and visual memory, and negative symptoms in clozapine-treated patients with refractory schizophrenia.ObjectivesIn this 1-year extension study, we report the long-term effects and tolerability of memantine add-on therapy to clozapine.AimsTo evaluate the persistence of improvements in cognitive functioning and symptoms of memantine add-on therapy to clozapine in schizophrenia.MethodsCompleters of the first trial who experienced a beneficial effect of memantine after 12 weeks continued memantine for one year. Primary endpoints were change from baseline to 26 weeks treatment and 26 weeks to 52 weeks treatment on memory and executive function using the Cambridge Neuropsychological Test Automated Battery (CANTAB), Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression Severity Scale (CGI-S). Secondary endpoints were change on the Health of the Nation Outcome Scales (HoNOS) and Liverpool University Neuroleptic Side Effect Rating Scale (LUNSERS).ResultsOf 32 completers who experienced a beneficial effect of memantine 23 patients continued memantine for one year. Memory improvement was sustained, verbal recognition memory improved even further between t = 26 weeks and t = 52 weeks. Continued treatment with memantine add-on to clozapine was associated with significantly improved PANSS positive, negative and overall score, CGI-S and HoNOS scores.ConclusionsIn the extension phase the positive effect of memantine add-on therapy on verbal memory sustained and positive, negative and overall symptoms of schizophrenia, clinical global status and psychosocial functioning significantly improved. Memantine was well tolerated without serious adverse effects.Disclosure of interestThe authors have not supplied their declaration of competing interest.

The addition of fluvoxamine to clozapine induces a rise of plasma concentrations of clozapine. This enables the prescription of a lower number of clozapine tablets, yet it attains sufficient clozapine plasma concentrations, and facilitates treatment adherence.Providing practical advice for the practical implementation of the addition of fluvoxamine to clozapine.A review of the literature with Ovid Medline and the presentation of a case series (N=7).Addition of 25 or 50 mg fluvoxamine induces a mean rise of plasma concentrations of clozapine with a factor 2-3, probably even higher with the addition of 100 mg. However, the range of this factor varies considerably between individuals. The use of clozapine and fluvoxamine at the same time possibly has a favourable impact on the metabolic side-effects of clozapine.Addition of fluvoxamine to clozapine can lead to a dangerous rise of clozapine plasma concentrations. However, it can also be used to prescribe a lower number of clozapine tablets and to facilitate treatment adherence. A sufficient safety margin should be taken and regular control of clozapine plasma concentrations is mandatory.

In the last five years seven independently financed studies comparing first and second generation antipsychotics (FGAS and SGAS) have been published. Most of these studies were conducted among patients attending regular psychiatric practices. The results show that very few or no advantages are to be gained from using SGAS rather than FGAS. In general, the clinical effectiveness is not increased, but the side-effects are different. The effectiveness studies in fact definitely justify the selection of FGAS (particularly those of low and medium potency) if a change in medication is indicated.

Introduction Itzhaky (2012) found significantly lower vitamin D level in patients with schizophrenia than in healthy controls. Objective Measurement of vitamine-D in bipolar and schizophrenia/schizoaffective outpatients. Aims Determining the prevalence of vitamin D deficiency in outpatients with bipolar disorder, schizophrenia or schizoaffective disorder in the Netherlands. Method Outpatients in the Alkmaar region aged 18w65 years with a bipolar disorder, Schizophrenia/schizoaffective disorder were asked to add vitamin D levels determination to the annual standard blood sample taking. Results 111 patients, 54 with schizophrenia/schizoaffective disorder and 57 with bipolar disorder, participated. 58 (53%) was male, mean age 47 (SD 9.9) years. 64 (58%) showed vitamin-D insufficiency ( 50 had a serum level between 30–50 nmol/l. No significant differences were found between bipolar disorder and schizophrenia/schizoaffective disorder. Conclusion To prevent osteoporosis, vitamin D supplementation is advised with vitamin D-levels below 30nmol/l or below 50 in women >50 years and men >70 years, (Dutch Health Council). Using to this criterion 39 patients (35%) of the study-population needed vitamine-D supplement. If confirmed, addition of vitamine-D levels to the annual somatic screening of patients with bipolar disorder, schizophrenia/schizoaffective disorder is indicated. Limitation: the impact of the season on vitamine-D levels was not corrected for in either population.

Methods Adult patients with schizophrenia or schizoaffective disorder who had been treated with clozapine for 5 years or longer were eligible to participate in the study (index group). The end point of observation was death, loss to follow-up or 1 January 2010. The control group consisted of patients never treated with clozapine, matched on age, diagnosis and gender. Results During the study period we identified 94 patients in each group. The mean follow-up in the index and control group was 12.3 and 13.5 years respectively. The vast majority of patients continued clozapine until the end of the follow-up period (mean duration of therapy: 10.7 years). The cumulative incidence of diabetes in the clozapine group was 22.3% compared to 16.0% in the control group (NS). The absolute risk difference was 6.3% (95%CI: −4.9% to 17.5%). The hazard ratio for time to new-onset diabetes was 1.54 (95%CI: 0.80–3.00) (see Fig 1 for Kaplan-Meier curve). Discussion To the best of our knowledge, this study has the longest follow-up of a sizeable cohort of clozapine users in comparison to matched controls. The absolute risk difference was 6.3% and not significant despite an adequate power and extended follow-up of more than 13 years. Our result is in agreement with four randomized studies with a follow-up varying from 14 weeks up to 9 years. A case-control study matched 7,227 cases of newly treated diabetes by year of birth and gender to 6,780 controls and found no significant association between the incidence of new-onset diabetes and clozapine. Download : Download full-size image [Kaplan-Meier curve: time to new-onset diabetes]

Recent research shows that in first episode schizophrenia the chance of response to an antipsychotic trial decreases from 75% in the first trial to 17% in the second. A subsequent trial with clozapine has a response rate of 75% again. Studies show a significant higher response rate at clozapine plasma trough levels above a therapeutic threshold of 350–400 ng/ml. The absolute risk difference is about 40%. In children and adolescents with therapy-resistant early onset schizophrenia spectrum disorder clozapine appears to be superior to olanzapine and haloperidol. Clozapine has a superior effect on aggression in patients with psychotic disorders. Case series point to an anti-aggressive effect in non-psychotic disorders too. Comparison of patients on clozapine to patients on other antipsychotics shows decreased rates of suicide and suicide attempts. A randomised controlled trial in patients with schizophrenia or schizoaffective disorder and a high risk for suicidality shows an absolute risk difference of 2,9% of suicide attempts per year in the clozapine group versus the olanzapine group. In observational studies more patients on clozapine get into remission and maintain remission of alcohol and substance abuse or dependance than on other antipsychotics. Thus clozapine has a place beyond therapy resistance in schizophrenic patients with aggression, suicidality or alcohol and substance abuse/dependance.

Polygraphic recordings were made on 10 preterm infants recovering from respiratory distress syndrome and 12 healthy preterm control infants at 40, 52, and 64 weeks' conceptual age to study the influence of respiratory distress syndrome on the development of the sleep apnoea profile. Two significant differences were found: infants with respiratory distress syndrome not only had a lower incidence of non-obstructive apnoea and periodic breathing at 40 weeks but also a persistently higher incidence of obstructive and mixed apnoea at 52 and 64 weeks' conceptual age; the latter finding being related to non-rapid eye movement sleep only. While the lower incidence of both types of apnoea at 40 weeks suggests an advanced maturation of respiratory drive, the persistence of obstructive and mixed apnoea related to non-rapid eye movement sleep may reflect the impact of respiratory distress syndrome on airway structures.

A considerable number of high risk brain tumours require an interdisciplinary approach with surgery, radiation and chemotherapy rather than one single therapeutic regimen. Children with a medulloblastoma must be subdivided into four different risk groups depending on the size of the tumour, on the age of the child and on cerebral spinal fluid cytology findings. The treatment protocol for ependymomas depends on the location of the tumour and on histological grading. Pineal region tumours can be successfully removed; further therapy depends on the type of the tumour. Children with hemispheric high grade astrocytomas gain substantially from local radiation therapy. The GPO (Gesellschaft für Pädiatrische Onkologie) has most recently taken the initiative to found a pediatric neuro-oncology working group in order to establish and to evaluate different treatment modalities.

1. Bei parathyreoidektomierten, hypocalcamischen Katzen zeigen Receptoren aus Haut, Muskel, Herz, Gefassystem, Lunge und die Chemoreceptoren des Glomus caroticum typische Veranderungen der Entladungsfolge: 2. Die Bedeutung dieser durch Hypocalcamie veranderten afferenten Zustrome wird diskutiert

By means of polygraphic recordings complete independence of the sequence of sleeping and waking and of the two sleep states (REM and NREM) could be demonstrated in twins extensively conjoined at the skulls. Functionally important connections in the circulation of the two babies were found during subsequent preoperative investigations. These observations are at variance with the hypothesis of an extraneuronal humoral sleep-inducing factor based on crossed-circulation experiments in animals; moreover they raise a new question about the transportation of the sleepregulating biogenic amines.

The effects of hypocalcemia induced by excision of the parathyroid glands upon the function of spinal motoneurones and peripheral receptors were investigated in decerebrate cats.

In dieser Arbeit wurde die neuromuskulare Erregungsubertragung elektromyographisch untersucht: 1. Wie bei der bleibenden Myasthenia gravis alterer Kinder und Erwachsener fanden wir im Elektromyogramm myasthenischer Neugeborener die Zeichen des kompetitiven Endplattenblocks: 2. Die neuromuskulare Erregungsubertragung des reifen Neugeborenen ist funktionell noch nicht vollstandig entwickelt. Hochfrequente, rhythmische Nervenreize wurden nach langer Seriendauer nicht mehr vollstandig auf den Muskel ubertragen. Der Verlust war groser als bei gesunden Erwachsenen. 3. Eine solche Funktionsschwache konnte bedingt sein

The incidence of periodic breathing, apnea and bradycardia in 8 otherwize “normal” preterm infants was correlated to sleep states by means of long term polygraphio surveillance (EMG, EEG, respiration, eye movements, spontaneous motor and monosynaptic reflex activity). There was a significant coincidence between episodes of bradycardia and periodic breathing or apnea. Periodic breathing (recurrent pauses 10 sec) and episodes of bradycardia with and without respiratory arrest occurred predominantly in active or EEM (rapid eye movement) sleep, when monosynaptic reflex responses were reduced, indicating brain stem inhibitory influence to spinal motoneurones. In preterm infants during their long lasting REM sleep periods descending inhibition on respiratory and other spinal motoneurones and their proprioceptive control as well as the reduction of preganglionic sympathic activity facilitate apneic spells and/or bradycardia. Under the influence of barbiturates the amount of REM sleep decreases together with a reduction of apneic spells.

For characterization of mixed and obstructive apnea persisting in infants after severe IRDS we obtained polygraphic recordings incl. submental and diaphragmatic EMG by surface electrodes in 2 wks intervals from 40-46 and at 52 wks postconc age RESULTS: Pt 40 wks mixed apnea was found to be the predominant type of apnea with preponderance in NON-REM sleep decreasing in number towards 52 wks. 80% of these events had the sequence; inactive-obstructive and were almost regularly characterized by the following EMG pattern: In 80% the inactive part was initiated by a sigh with simultaneous phasic increase of both submental and diaphragma EMG. The following obstructive component showed in 54% a rhythmic diaphragma activity with a short phasic activation of the submental EMG which, however, did not terminate the apnea. Only a synchronous phasic activation of both submental and diaphragma EMG (likely to reflect active exspiration) resolved airway obstruction. Arousal didn't occur. Bradycardia frequently accompanied the obstruction and in one mixed apnea with hypoxemia the synchronous EMG activation was lacking and asystoly occurred which could be terminated by atactile stimulation alone. CONCLUSION: Mixed apnea often accompanied by bradycardia present a regular pattern of synchronicity of submental and diaphragmatic muscle activation for terminating the apnea. Hypoxemia might be responsible for disturbing this synchronicity and thus leading to life threatening events.

In order to assess the occurrance of feeding related abnormal breathing patterns and hypoxemia beyond the neonatal period polygraphia recordings incl.tcpO2 were obtained in 23 infants during feeding and sleep also: 18 preterms, gest. age 30(27-36)wks., 14 after resp. distress syndrom(ROS) and 4 after apnoea of prematurity(AOP) as well as 5 fullterms after a life threatening event related to feeding in 4 infants,postnatal age 1-13 wks.

The mortality of premature infants has decreased over the last two decades with significantly more high risk infants surviving. Different results exist concerning the neurological outcome of these infants. Most follow-up studies were performed only with patients of single neonatal care units. In 1983 a prospective multicenter follow-up study of VLBW-infants (< 1500 g) was initiated for the whole region of Hamburg, West Germany. In the first year 125 of the surviving 147 VLBW-infants could be followed up to at least 18 months of age. In 94 % of these cases a cerebral ultrasound was performed at 64 weeks conceptual age. Major changes from periventricular leucomalacia were seen in 18 %. At 18 months of age 14 cases (11.2 %) had cerebral palsy. 9 % had signs of minimal brain dysfunction, 17 % were developmentally retarded without any neurological signs. Compared with AGA more SGA-infants were retarded at follow-up, but only one had cerebral palsy. Major changes at ultrasound examination coincided with neurological abnormalities in 90 %, 52 % had cerebral palsy. Compared with previous studies from single neonatal centers, our results are less favourable probably because of our multi-center approach covering the entire region. Permanent major periventricular changes visualized by ultrasound are of important prognostic value.