Extracerebral Abnormalities Research Articles

Anomalies of Midbrain/Hindbrain Development and Related Disabilities: Pontocerebellar Hypoplasia, Congenital Disorders of Glycosylation, and Cerebellar Hemisphere Hypoplasia

AbstractRecent progress in developmental biology, molecular genetics, and neuroimaging has enabled a more profound comprehension of developmental disorders affecting the embryonic midbrain and hindbrain, which manifest clinically. The purpose of this review is to describe anomalies of the midbrain/hindbrain such as pontocerebellar hypoplasia (PCH), congenital disorders of glycosylation (CDG), cerebellar hemisphere hypoplasia. PCH is a group of disorders that is both clinically and genetically diverse. These disorders are identified by the hypoplasia and degeneration of the cerebellum and ventral pons. A total of 18 distinct clinical subtypes of PCH, each linked to pathogenic variants in 19 different genes, have been documented, like mutations in TSEN54 (coding a subunit of tRNA splicing endonucleases complex) and TBC1D23 which display moderate-to-severe intellectual disability (ID) and microcephaly. CDG represent a set of inherited conditions marked by impaired glycosylation of proteins and lipids. The most prevalent subtype among CDG is PMM2-CDG, inherited in a recessive manner, causing reduced activity of phosphomannomutase. Its phenotype varies from mild to severe, involving the central nervous system and affecting many other organs as well. Patients who are severely affected also exhibit visceral symptoms alongside severe ID and other neurological manifestations. Cerebellar hypoplasia (CH) is characterized by a cerebellum of diminished volume while maintaining its shape. CH exhibits a diverse range of neuroradiologic features, etiologies, clinical characteristics, and neurodevelopmental involvement. Cerebello–oculo–facio–genital syndrome is linked to a recessive MAB21L1 mutation. Jubert's syndrome, associated with a rare autosomal recessive mutation, is identified on magnetic resonance imaging by cerebellar worm hypoplasia and midbrain malformations. The rhombencephalosynapsis, characterized by vermian agenesis or hypogenesis with the fusion of the cerebellar hemispheres, emerges during embryogenesis. It can manifest alone or in conjunction with other and/or extracerebral abnormalities.

Congenital lymphocytic choriomeningitis virus: A review.

Lymphocytic choriomeningitis virus (LCMV) uses rodents such as mice and hamsters as its principal reservoir. When women acquire LCMV during pregnancy because of contact with rodents, it can lead to congenital LCMV infection, which is associated with high mortality and morbidity. Although the number of cases reported in the literature is increasing, LCMV is rarely mentioned because a history of exposure to rodents is uncommon and mostly unknown. The main objective of this article was to summarize all morphological, antenatal, and postnatal abnormalities that may suggest a congenital LCMV infection. We reviewed PubMed case reports and case series where an antenatal and/or a postnatal description of at least one case of congenital LCMV infection was documented. We found 70 cases of congenital LCMV infection, 68 of which had antenatal or postnatal brain abnormalities, which were mainly chorioretinitis (59/70), hydrocephaly (37/70), microcephaly (22/70), ventriculomegaly (11/70) and periventricular calcifications (11/70). Antenatal and postnatal extracerebral abnormalities were mainly small for gestational age, ascites, cardiomegaly or anemia. Other organ damage was rare, but could include skin abnormalities, hydrops or hepatosplenomegaly. Seventy percent (49/70) of cases had major cerebral abnormalities that could have been detected by antenatal ultrasound examination. Congenital LCMV infection is associated with a significant mortality rate (30%) and survivors often have severe neurologic sequelae. LCMV is a rare congenital infection, but awareness of the various prenatal ultrasound morphological abnormalities should be improved, and LCMV should be considered when first-line etiological explorations are negative, especially when the mother's medical history indicates exposure to rodents.

Regional brain development in fetuses with Dandy-Walker malformation: A volumetric fetal brain magnetic resonance imaging study.

Dandy-Walker malformation (DWM) is a common prenatally diagnosed cerebellar malformation, characterized by cystic dilatation of the fourth ventricle, upward rotation of the hypoplastic vermis, and posterior fossa enlargement with torcular elevation. DWM is associated with a broad spectrum of neurodevelopmental abnormalities such as cognitive, motor, and behavioral impairments, which cannot be explained solely by cerebellar malformations. Notably, the pathogenesis of these symptoms remains poorly understood. This study investigated whether fetal structural developmental abnormalities in DWM extended beyond the posterior fossa to the cerebrum even in fetuses without apparent cerebral anomalies. Post-acquisition volumetric fetal magnetic resonance imaging (MRI) analysis was performed in 12 fetuses with DWM and 14 control fetuses. Growth trajectories of the volumes of the cortical plate, subcortical parenchyma, cerebellar hemispheres, and vermis between 18 and 33 weeks of gestation were compared. The median (interquartile range) gestational ages at the time of MRI were 22.4 (19.4–24.0) and 23.9 (20.6–29.2) weeks in the DWM and control groups, respectively (p = 0.269). Eight of the 12 fetuses with DWM presented with associated cerebral anomalies, including hydrocephalus (n = 3), cerebral ventriculomegaly (n = 3), and complete (n = 2) and partial (n = 2) agenesis of the corpus callosum (ACC); 7 presented with extracerebral abnormalities. Chromosomal abnormalities were detected by microarray analysis in 4 of 11 fetuses with DWM, using amniocentesis. Volumetric analysis revealed that the cortical plate was significantly larger in fetuses with DWM than in controls (p = 0.040). Even without ACC, the subcortical parenchyma, whole cerebrum, cerebellar hemispheres, and whole brain were significantly larger in fetuses with DWM (n = 8) than in controls (p = 0.004, 0.025, 0.033, and 0.026, respectively). In conclusion, volumetric fetal MRI analysis demonstrated that the development of DWM extends throughout the brain during the fetal period, even without apparent cerebral anomalies.

VP24.06: Unilateral microphthalmia and CNS‐associated anomalies: management and prognosis

We present the case of a fetus with a normal nuchal scan at 13 weeks with low risk for chromosomal abnormalities and then diagnosed with microphtalmia at the time of the anomaly scan at 22 weeks with no other cerebral or extracerebral abnormalities except one left ventricular hyperechogenic focus. After counselling about the future visual and esthetic disturbances and the possible association with several fetal syndromes the mother decided for continuation of the pregnancy and follow-up, the first step recommended being amniocentesis for arrayCGH. At 24 weeks we received the result of a normal karyiotype. In the 3rd trimester, at 28+5 weeks of pregnancy scan we noticed more cerebral anomalies: a much smaller left orbit with cataract and obvious facial dysmorphism, a nonlinear cerebral falx at the level of the anterior complex that was displaced towards left, high cerebral lateral ventricles inequality with the larger ventricle being the left (9.8mm), an appearance and suspicion of smooth cerebral surface and polyhydramnios with normal fetal growth and no other abnormalities. The mother declines other genetic tests (WES) and accepted to perform fetal cerebral MRI at 32 weeks that confirmed the US abnormalities described earlier plus gyration abnormalities and severe hypoplasia of the left frontal lobe and left ophthalmic nerve. Following this result she decided for TOP.

Cytomegalovirus infection in pregnancy – An update

Cytomegalovirus (CMV) is a ubiquitous DNA virus with a global seroprevalence of 83 %. It is the most common pathogen causing teratogenic congenital infection. It is therefore a major public health concern. Maternal infection is associated with congenital CMV (cCMV), the leading cause of non-genetic sensorineural hearing loss. cCMV also causes impairment of cognitive development and cerebral palsy. Transmission of CMV occurs through direct contact with bodily fluids such as saliva, urine or semen from someone who is actively shedding the virus. Transmission rates are higher after primary infection with the rate of transmission increasing with gestational age. Severe fetal effects are however more common when infection occurs before 20weeks. Past infection does not confer immunity to mother or protect the fetus. cCMV may present with cerebral or extracerebral abnormalities on ultrasound, fetal growth restriction and fetal loss. Diagnosis of primary maternal CMV in pregnancy should be based on seroconversion in pregnancy (de novo appearance of virus‐specific immunoglobulin G (IgG) in the serum of pregnant women who were previously seronegative) or on detection of specific immunoglobulin M (IgM) and IgG antibodies in association with low IgG avidity. Prenatal diagnosis of fetal CMV is imperfect and based on amniocentesis performed at least 8 weeks after presumed maternal infection and after 17 weeks of gestation. Hygiene information and education of pregnant women is currently the most effective strategy for prevention of CMV infection. The role of vaccines, antiviral drugs and immunoglobulins remains unproven.

Counseling for Fetal Central Nervous System Defects

AbstractFetal central nervous system defects are one of the commonest antenatally detected abnormalities. They consist of a wide array of lesions with heterogeneous etiologies and outcomes. Counselling of the family in such cases forms an integral part of management. However, this can be challenging due to diagnostic and prognostic uncertainties for many defects. Some lesions like anencephaly, holoprosencephaly, and lissencephaly, have an invariably poor outcome, and decision regarding pregnancy termination is straightforward. On the other hand, lesions like mild ventriculomegaly, isolated corpus callosum agenesis and posterior fossa lesions have a highly variable outcome, ranging from normal to severe handicaps, hence counseling for these is difficult. Detailed sonography by an expert sonologist and fetal MRI can help in detection of additional cerebral or extracerebral abnormalities, which being associated with a poor prognosis, can help in accurate counseling. An often-neglected aspect of counseling is the possibility of recurrence in subsequent pregnancies, due to an underlying genetic etiology in many of these defects. This can be assessed by pedigree information, suitable genetic testing and postmortem examination in case of pregnancy termination. Diagnosis of the genetic abnormality helps in accurate recurrence-risk prediction as well as early and timely prenatal diagnosis in at-risk pregnancies.

Perinatal and long-term outcomes in fetuses diagnosed with isolated unilateral ventriculomegaly: systematic review and meta-analysis.

The majority of studies on fetal ventriculomegaly have focused on the perinatal and long-term outcomes in fetuses with an antenatal diagnosis of bilateral ventriculomegaly. The aim of this study was to undertake a systematic review and meta-analysis to quantify the perinatal and long-term outcomes in fetuses diagnosed in the second or third trimester of pregnancy with isolated unilateral ventriculomegaly. MEDLINE, EMBASE and The Cochrane Library were searched electronically. Outcomes investigated included incidence of aneuploidy, congenital infection, progression of ventriculomegaly, associated brain and extracerebral abnormalities in the apparently isolated cases and neurodevelopmental delay in both apparently and truly isolated cases. Sensitivity analysis was performed according to whether the ventriculomegaly was mild/moderate (atrial width < 15 mm) or severe (atrial width ≥ 15 mm). Reference lists within relevant articles and reviews were hand-searched for additional reports. Cohort and case-control studies were included. Meta-analysis of proportions was used, and between-study heterogeneity was assessed using the I2 test. The search yielded 2053 citations. The full text was retrieved for 202, and 11 studies were included in the systematic review. In fetuses with apparently isolated unilateral ventriculomegaly, no chromosomal abnormalities were identified and the pooled prevalence of congenital infection was 8.2% (95% CI, 3.6-14.5%). The pooled prevalence of additional brain abnormalities detected prenatally and postnatally by magnetic resonance imaging was 5.1% (95% CI, 0.2-16.1%) and 6.4% (95% CI, 0.3-19.4%), respectively. The pooled prevalence of abnormal neurodevelopment was 5.9% (95% CI, 2.2-11.2%) in apparently isolated cases with an atrial width of < 15 mm, and it was 7.0% (95% CI, 3.2-12.2%) in fetuses with truly isolated unilateral ventriculomegaly. Most cases with apparently isolated ventriculomegaly were classified as mild/moderate (93.5%) and therefore the outcomes in this group were similar to those in the whole cohort of apparently isolated ventriculomegaly. The prevalence of aneuploidy, congenital infection and neurodevelopmental delay in fetuses with a prenatal diagnosis of isolated unilateral ventriculomegaly is likely to be low. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Prenatal features of isolated subependymal pseudocysts associated with adverse pregnancy outcome.

To identify at prenatal ultrasound (US) the features of apparently isolated subependymal pseudocysts (SEPC) that may indicate underlying pathology and should lead to further investigations. This was a retrospective study of cases with SEPC detected on prenatal US and/or magnetic resonance imaging (MRI). Those with apparently isolated SEPC at US were classified into two groups as follows: Group 1 (n = 29): normal prenatal US and MRI (except for SEPC) and normal outcome; Group 2 (n = 12): normal prenatal cerebral US (except for SEPC) and abnormal prenatal cerebral MRI with or without abnormal outcome. A third group (n = 9) included cases with abnormal prenatal US and MRI. The latter cases with obvious cerebral abnormalities at US were excluded from the statistical analysis as they do not represent a diagnostic dilemma for clinicians. Groups 1 and 2 were analyzed, comparing them with respect to their SEPC characteristics (size, number, location in relation to the caudothalamic notch and the ventricular horns and morphology) and extracerebral abnormalities. The mean ± SD SEPC great axis was longer in Group 2 (11.67 ± 5.82 mm) than it was in Group 1 (8.00 ± 5.64 mm) (P = 0.021), suggesting an optimal cut-off for size of SEPC of ≥ 9 mm (sensitivity = 75%, specificity = 62%) to maximize sensitivity for predicting pathological outcome. SEPC adjacent to the temporal horns and SEPC located posterior to the caudothalamic notch were observed more frequently in Group 2, indicating their association with poor outcome (P = 0.003 and P = 0.003, respectively). Atypical morphology and extracerebral abnormalities were observed more frequently in Group 2 (P = 0.013 and P = 0.044, respectively). There was no statistically significant difference between groups for either number or location of cysts along the inferior wall or adjacent to the lateral wall of the frontal horns (P = 0.591 and P = 0.156, respectively). When apparently isolated SEPC are observed at prenatal US, further investigations should be performed under the following circumstances: (1) SEPC great axis ≥ 9 mm; (2) SEPC adjacent to the occipital and temporal horns; (3) SEPC located posterior to the caudothalamic notch; (4) SEPC with atypical morphology.

A Surgical Case of Frontal Lobe Epilepsy Due to Focal Cortical Dysplasia Accompanied by Olfactory Nerve Enlargement: Case Report

A 45-year-old man came to our clinic due to refractory general tonic seizure and an attack of unintended yelling. Magnetic resonance imaging (MRI) demonstrated mild cortical hyperintensity on fluid attenuated inversion recovery (FLAIR) image in the left basal frontal area. Enlargement of the left olfactory nerve was also detected below the affected gyrus. Subtotal resection of the MRI-visible epileptogenic lesion was performed without any neurological deficit. The final pathological diagnosis was focal cortical dysplasia (FCD) type IIa. Seizures and yelling attacks subsided after surgery. Extracerebral abnormalities, including cranial nerve enlargement, are common in patients with hemimegalencephaly. However, such abnormalities are rare with FCD.

OC08.04: Modulation of total vascular resistance in early mild gestational hypertension decreases the rate of complications

In the first group (n=22) there were 2 symptomatic children with unilateral hearing loss. In 4 neonates, brain imaging revealed cerebral abnormalities, but long-term clinical follow-up was normal. The second group (n=10) included abnormal cerebral findings in 5 cases. TOP was performed twice. Six children were born asymptomatically, 2 children suffered from hearing loss. In group 3 (n=4), cerebral abnormalities were present in 3 cases. There was 1 symptomatic child with bilateral hearing loss, showing periventricular signal alterations in the white tissue on prenatal MRI. In group 4 (n=6), 4 fetuses had multiple cerebral and extracerebral abnormalities. Pathological examination confirmed fetal infection in 3 cases after TOP. One neonate received antiviral treatment with normal clinical findings on follow-up. In the other remaining cases there were only solitary minor abnormalities resulting in a normal neonatal outcome. Conclusions: Most often, MRI confirms the US findings. Occasionally MRI adds important prognostic information. In case US and MRI reveal multiple infection related abnormalities, fetal outcome is poor. Both fetal imaging modalities lack sensitivity to predict hearing loss.

Clinical and imaging characteristics of localized megalencephaly: a retrospective comparison of diffuse hemimegalencephaly and multilobar cortical dysplasia

Hemimegalencephaly is a well-known congenital malformation. However, localized megalencephaly, which may be one of the subtypes of hemimegalencephaly, has not been separately investigated. In the present study, we attempted to characterize the clinical and magnetic resonance (MR) imaging features of localized megalencephaly in comparison with ordinary diffuse hemimegalencephaly and multilobar cortical dysplasia. MR findings for 43 patients with hemimegalencephaly and ten with multilobar cortical dysplasia, which is the differential diagnosis of localized megalencephaly, were retrospectively reviewed. Clinical findings such as the onset and severity of seizures and imaging findings including the affected area of the brain, structures outside of the hemisphere, and interval morphological changes were examined. Of the 43 patients, 11 showed signs of localized megalencephaly (25.6%). Localized megalencephaly was predominantly seen on the left side (72.7%) and had a tendency toward severe-grade seizures compared to multilobar cortical dysplasia. The frequencies of the extracerebral abnormalities in the diffuse hemimegalencephaly, localized megalencephaly, and multilobar cortical dysplasia groups were 84.4%, 36.4%, and 0.0%, respectively. There were three localized megalencephaly patients whose affected areas shrank and whose images were similar to those of multilobar cortical dysplasia. Localized megalencephaly accounts for one quarter of all hemimegalencephaly cases in this study. The incidence of extracerebral abnormalities in patients with localized hemimegalencephaly was almost half that of patients with diffuse hemimegalencephaly. Extracerebral abnormalities were absent in patients with multilobar cortical dysplasia. Associated extracerebral abnormalities may be a clue to differentiating localized megalencephaly from multilobar cortical dysplasia.

MRI findings in the young infant with brainstem disconnection and extracerebral features. Report of one case and review of the literature

We present the young infant with the extremely rare brain abnormality–brainstem disconnection. Additionally, several extracerebral abnormalities were diagnosed: bilateral anotia, micrognatia, hypertelorism, scoliosis, ribs and vertebral anomalies. MR brain examination precisely demonstrated absence of the pons, with disruption between midbrain and hypoplastic medulla oblongata. The thin strands connecting the medulla with the midbrain and medulla with both cerebellar hemispheres were revealed. The large hamartoma of the tuber cinereum was found. In this study we review case reports published previously.

Comparison between magnetic resonance imaging and fetopathology in the evaluation of fetal posterior fossa non‐cystic abnormalities

To compare magnetic resonance imaging (MRI) and fetopathological findings in the evaluation of non-cystic fetal posterior fossa anomalies and to describe associated abnormalities. This was a prospective study from 2000 to 2005 of fetuses identified on ultrasound as having sonographic suspicion of posterior fossa malformation. All underwent a thorough MRI examination of the fetal brain, after which we classified each fetus as presenting one of the following pathologies: vermian hypoplasia or agenesis, cerebellar and/or brain stem hypoplasia, destructive or dysplastic lesions. All of the pregnancies were then terminated, after which the whole fetus underwent fetopathological examination. We compared the findings from MRI and fetopathological examinations and recorded the associated cerebral and extracerebral abnormalities. Twenty-five fetuses were included. MRI was performed at a mean gestational age of 31 weeks, and fetopathological examination at 33 weeks. In 12 cases we observed vermian hypoplasia, six had partial vermian agenesis, 11 had cerebellar hemisphere hypoplasia, seven had brain stem hypoplasia, four had destructive lesions and six had dysplastic lesions. The two techniques were similar in their performance with respect to the detection of vermian agenesis, brain stem hypoplasia and destructive lesions. There were four false-positive results of MRI for vermian hypoplasia and a poor agreement regarding cerebellar hemisphere hypoplasia. No dysplastic lesions were diagnosed by MRI. None of the posterior fossa malformations was isolated and many cerebral and extracerebral abnormalities were found. A systematic analysis of the posterior fossa in fetal MRI makes it possible to diagnose accurately most posterior fossa malformations. These malformations never occurred in isolation in our study.

Extracerebellar ectopic brain tissue in the posterior fossa

Intracranial extracerebral ectopic brain tissue (also called glioneuronal heterotopia) is encountered in rare developmental disorders. These lesions are mainly located at the base of the brain in the supratentorial region and are frequently associated with craniofacial anomalies. We report the prenatal sonographic and magnetic resonance imaging (MRI) findings of isolated extracerebellar ectopic brain tissue in the fetal posterior fossa, which was confirmed by postnatal MRI examination in a healthy infant. A 27-year-old woman at 28 weeks’ gestation was referred to our department with the diagnosis of a round mass in the fetal posterior fossa located in the cisterna magna, which had been identified on a routine ultrasound scan. Ultrasound examination (Antares, Siemens, Munich, Germany) confirmed the presence of a round echogenic non-vascularized mass of 12 mm in diameter located in the midline of the cisterna magna posterior to a normal vermis (Figure 1). The cerebellum was anatomically normal with a normal transverse cerebellar diameter for gestational age (32 mm). The size of the cisterna magna was also within normal ranges. No other structural cerebral or extracerebral abnormalities could be seen. Biometric parameters were normal for gestational age. Fetal cerebral MRI showed a round and apparently solid mass, posterior to the vermis, with a signal similar to that of normal brain tissue on T2-weighted imaging (Figure 2) and with no hemorrhagic changes on T1weighted imaging. Vermian and hemispheric cerebellar anatomy were normal. Although this lesion has not been described previously in this location, imaging findings were suggestive of ectopic/heterotopic cerebral tissue. On the basis of normal cerebellar anatomy with a complete vermis and otherwise normal cerebral and extracerebral anatomy and, following prenatal counseling with neuropediatricians, the couple decided to continue with the pregnancy. Follow-up at 33 weeks’ gestation found the MR signal, size and echogenicity of the lesion to be unchanged. Since the patient was lost to follow-up for

P02.03: Cerebral ventriculomegaly: prenatal aspects and early post‐natal evolution

The aim of this retrospective study is to analyse fetuses with cerebral ventriculomegaly, to look for associated anomalies, to precise the prenatal investigations and the early post-natal evolution. Between January 1998 and December 2004, all fetuses with cerebral ventriculomegaly diagnosed in our department of prenatal ultrasonography were reviewed. The associated fetal anomalies, the type of investigations and the pregnancy evolution were studied. 72 fetuses were identified, 60 (83%) with bilateral cerebral ventriculomegaly and 12 (17%) with unilateral ventriculomegaly. The ventriculomegaly was defined as mild (10–15 mm) in 35 cases (48%), moderate (16–20 mm) in 22 (31%) and severe (> 21 mm) in 15 (21%). The mean gestational age at the diagnosis was 27 weeks of pregnancy (14–36). The ventriculomegaly remained stable throughout pregnancy in 48% of cases, modified in 52% (reduced for 24% and worsened in 28%). Associated anomalies were detected with sonography in 55 fetuses 14 were extra-cerebral abnormalities and 36 intra-cerebral. Other prenatal investigations were performed: 34 karyotypes (abnormal 7), 13 fetal magnetic resonance imaging (abnormal 8), 9 maternal serologic studies (positive 4). The evolution was: 32 terminations of pregnancy, 5 intrauterine demises, 34 living births with 6 deaths in the early postnatal period. Cerebral ventriculomegaly represents a frequent prenatal anomaly. The prognosis is related with the size of lateral ventricle and the presence of associated anomalies, our rate of termination of pregnancy is high for severe cases.

Fetal MRI—does it make a difference?

Ultrasound is the primary method used for prenatal diagnosis of fetal structural abnormality. However, fetal magnetic resonance imaging (MRI) is increasingly available. This study compares fetal MRI findings with prenatal sonographic images and assesses the benefit of such additional imaging. This was a retrospective survey of cases in a London teaching hospital, where fetal MRI was performed. Sonographic and MRI findings were compared, and any additional value from MRI assessed. Twenty-one MRIs were performed between 21 and 34 weeks’ gestation, 12 for suspected cerebral abnormalities. Other indications included cranial and cervical masses, hemivertebrae, cystic adenomatoid malformation, abdominal masses, cloacal exstrophy and sacro-coccygeal teratoma. In nine of the 12 cases with cerebral abnormality, the MRI appearances agreed with sonographic findings. One pregnancy was continued after MRI excluded the likelihood of lissencephaly. Two pregnancies where a Dandy-Walker malformation was excluded underwent termination for other abnormalities. All but one of the extra-cerebral abnormalities were confirmed on MRI, the exception being an abdominal cyst which resolved spontaneously (confirmed on ultrasound). In one case, MRI gave additional information thus influencing pregnancy management.

The neurologic basis of Cheyne-Stokes respiration

1. 1. Clinical and physiologic studies were performed in twenty-eight patients with Cheyne-Stokes respiration (CSR). Five of the twenty-eight were examined postmortem. Control studies were performed in the following groups showing regular respiration: normal subjects, patients with congestive heart failure, and patients with unilateral and bilateral cerebral vascular disease. 2. 2. Neurologically, every subject with CSR exhibited signs of bilateral descending motor system dysfunction at supramedullary levels. Cardiac abnormalities and circulatory congestion, although frequent, were undetectable in five cases. 3. 3. Every subject with CSR had hyperventilation and respiratory alkalosis. Peak ventilation coincided with maximal PaCO 2, and apnea coincided with PaCO 2 levels considerably below the ventilatory threshold. 4. 4. Every subject with CSR had an increased respiratory sensitivity to CO 2, the mean ventilatory CO 2 response being approximately three times the normal. This increased sensitivity, which resulted from bilateral supramedullary brain dysfunction, was the principal cause of hyperpnea. Ventilation in CSR was also augmented by reduced oxygen tensions, resulting from moderate arterial oxygen desaturation. As a result, during late respiratory decrescendo, anoxemia continued to drive ventilation despite PaCO 2 levels considerably below the respiratory-stimulating threshold. 5. 5. Periodic breathing is a pattern of neurogenic hyperpnea in which intense hyperventilation alternates with posthyperventilation apnea. Extracerebral abnormalities, although they may augment ventilatory periodicity, are not the primary cause of Cheyne-Stokes respiration.