Neurocognitive monitoring in congenital central hypoventilation syndrome with the NIH Toolbox®.

Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy, caused by mutations in the paired-like homeobox gene PHOX2B, which alters control of breathing and autonomic nervous system regulation, necessitating artificial ventilation as life-support. A broad range of neurocognitive performance has been reported in CCHS, including an array of cognitive deficits. We administered the NIH Toolbox® Cognition Battery (NTCB), a novel technology comprised of seven tasks presented via an interactive computer tablet application, to a CCHS cohort and studied its convergent and divergent validity relative to traditional clinical neurocognitive measures. The NTCB was administered to 51 CCHS participants, including a subcohort of 24 who also received traditional clinical neurocognitive testing (Wechsler Intelligence Scales). Age-corrected NTCB scores from the overall sample and subcohort were compared to population norms. Associations between NTCB indices and Wechsler Intelligence scores were studied to determine the convergent and divergent validity of the NTCB. NTCB test results indicated reduced Fluid Cognition, which measures new learning and speeded information processing (p < 0.001), but intact Crystallized Cognition, which measures past learning, in CCHS relative to population norms. Moderate to strong associations (r > 0.60) were found between age-corrected NTCB Fluid and Crystallized indices and comparable Wechsler indices, supporting the convergent and discriminant validity of the NTCB. Results reveal deficits of Fluid Cognition in individuals with CCHS and indicate that the NTCB is a valid and sensitive measure of cognitive outcomes in this population. Our findings suggest that the NTCB may play a useful role in tracking neurocognition in CCHS.

Behavioral profile in a Dctn1G71A knock-in mouse model of Perry disease.

Perry disease (Perry syndrome) is a rare, rapidly progressive, autosomal dominant neurodegenerative disease characterized by parkinsonism, depression/apathy, weight loss, and respiratory symptoms including central hypoventilation. It is caused by missense mutations (e.g. p.G71A) in the DCTN1 gene. We previously generated transgenic mice that expressed human DCTN1G71A mutant protein under the control of Thy1 promoter. These mice exhibited apathy-like behavior and parkinsonism. However, it is possible that this phenotype was due to a gene-dosage imbalance or transgene insertion position. To circumvent these potential caveats, we have generated a knock-in mouse model carrying a p.G71A mutation in Dctn1. Heterozygous Dctn1G71A and wild-type littermates were subjected to a battery of behavioral analyses. Furthermore, immunohistochemistry for tyrosine hydroxylase (TH) was performed on brain sections of these mice, and TH signal intensity in substantia nigral neurons was quantified. Dctn1G71A mice were immobile for longer than wild-type mice of the same age and sex in the tail-suspension test, revealing depressive characteristics. In addition, the beam-walking test and pole test detected motor deficits in Dctn1G71A female mice. Finally, immunostaining revealed a decrease in TH immunoreactivity in neurons of the substantia nigra in the Dctn1G71A mice. Collectively, heterozygous Dctn1G71A mice showed depression-like behavior, motor deficits, and a functional reduction in substantia nigral neurons, as judged by TH immunostaining, thereby exhibiting multiple features of Perry disease. Hence, this mouse model will be useful in elucidating pathological mechanisms of Perry disease and for developing novel therapeutic strategies against it.

[Clinical and neuropsychological characteristics in congenital central hypoventilation syndrome]. / Aspectos clinicos y neuropsicologicos del sindrome de hipoventilacion central congenita.

INTRODUCTION: Congenital central hypoventilation syndrome (CCHS) syndrome is a rare disease caused by mutations in the PHOX2B gene. Patients show a reduced response to hypercapnia and hypoxia accompanied by diffuse disturbances of the autonomic nervous system and occasionaly also disturbances in neuroimaging. A specific neuropsychological profile has not been described in children and adolescents with CCHS. CASE REPORTS: We describe three cases (aged between 4 and 19 years) with different profiles of affectation in cognitive and functionality. These profiles are compared with the features described in the literature about neuropsychology in CCHS. CONCLUSIONS: The profile of functional impairment in the CCHS is variable: in case 1, a severe global developmental delay with autistic features and marked functional involvement is described. In case 2, bilateral atrophy of the hippocampus is associated with involvement in social cognition and in executive functions with moderate functional repercussion. Case 3 shows difficulties in some cognitive executive functions (planning and non-verbal fluency), but without functional repercussion. Neuropsychological assessment can help in the clinical management of these patients by determining and guiding the need for rehabilitation treatments.

TITLE: Aspectos clinicos y neuropsicologicos del sindrome de hipoventilacion central congenita.Introduccion. El sindrome de hipoventilacion central congenita (SHCC) es una enfermedad rara producida por mutaciones en el gen PHOX2B. Los pacientes muestran una reducida respuesta a la hipercapnia e hipoxia acompañada de alteraciones difusas del sistema nervioso autonomo y ocasionalmente alteraciones en neuroimagen. No se ha descrito un perfil neuropsicologico especifico en los niños y adolescentes con SHCC. Casos clinicos. Se presentan tres casos (de edades comprendidas entre 4 y 19 años) con diferente perfil de afectacion cognitiva y funcional. Se comparan los perfiles de los tres casos con los hallazgos descritos en la bibliografia sobre neuropsicologia en el SHCC. Conclusiones. El perfil de afectacion funcional en el SHCC es variable: en el caso 1 se describe un grave retraso global en el desarrollo con rasgos autistas y acusadas implicaciones funcionales. En el caso 2, la atrofia bilateral del hipocampo se asocia a deficit en cognicion social y alteraciones en funciones ejecutivas con moderada repercusion funcional. El caso 3 muestra dificultades en algunas funciones ejecutivas cognitivas (planificacion y fluidez no verbal), pero sin repercusion funcional. La evaluacion neuropsicologica puede ayudar en el manejo clinico de estos pacientes determinando y orientando la necesidad de tratamientos rehabilitadores.

Congenital central hypoventilation syndrome: Broader cognitive deficits revealed by parent controls.

OBJECTIVE: To investigate neurocognitive deficits in children with Congenital Central Hypoventilation Syndrome (CCHS) by comparing them to their parents, since parents comprise a particularly suitable control group matched on disease-extrinsic factors that can influence neurocognitive functioning. We compared CCHS patients to their parents and to population norms, hypothesizing that they would obtain lower intelligence test scores than both groups. We also compared patient-parent differences against patient-normative differences, to determine whether the two analytic approaches would yield different results. METHODS: We administered an intelligence screening, the Shipley-2, to 21 school-aged patients (age 14.2 ± 5.5 years) with PHOX2B mutation-confirmed CCHS and their parents. Patients also received detailed clinical intellectual assessments using the Wechsler scales. RESULTS: CCHS patients scored significantly below parents on Shipley-2 indices of intelligence, vocabulary, and abstraction, with a trend for perceptual reasoning. The CCHS patients scored significantly below population norms on indices of abstraction and perceptual reasoning. Patient-parent differences were significantly larger than patient-normative differences for vocabulary scores. CCHS patients scored significantly below population norms on Wechsler indices of intelligence, perceptual reasoning, working memory, and processing speed. CONCLUSIONS: CCHS may affect a broader range of cognitive abilities than previous research based on comparisons to population norms has indicated. Comparisons of CCHS children to their parents reveal deficits of vocabulary and abstract reasoning which have not been previously identified. A full understanding of the neurocognitive impact of CCHS requires comparisons between patients and other individuals such as friends, parents, or siblings who closely resemble them on disease-extrinsic characteristics.

Neuropsychological profile and social cognition in congenital central hypoventilation syndrome (CCHS): Correlation with neuroimaging in a clinical case.

INTRODUCTION: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder due to paired-like homeobox gene (PHOX2B) mutations. CCHS patients suffer from dysregulation of the autonomic nervous system characterized by the absence of or extremely reduced response to hypercapnia and hypoxia, with neuropsychological deficits. The aim of this exploratory study is to describe the longitudinal neuropsychological profile and its correlations with magnetic resonance imaging (MRI) of a child with CCHS with a PHOX2B mutation. METHOD: A comprehensive neuropsychological evaluation was conducted serially at age 7 years 4 months and 10 years 3 months, including assessment of intellectual functioning (IQ), motor functioning, perception, attention, executive functions, language, memory, social cognition, academic skills, and psychopathology. Reliable change index (RCI) scores were used to assess changes between assessments. We collected spin lattice relaxation time (T1)-weighted, fluid-attenuated inversion recovery (FLAIR), and spin spin lattice relaxation time (T2)-weighted images from the child at age 10 years 3 months using a 1.5-tesla MRI scanner. RESULTS: IQ, processing speed index (PSI), social cognition (theory of mind and facial emotion recognition), selective attention, naming, academic skills (reading/comprehension), and manual speed with right hand declined in the second evaluation relative to the initial evaluation, while visuoconstructional praxis, receptive vocabulary, working memory, and arithmetic skill improved. The patient showed a remarkable global deterioration in executive functions (planning, task flexibility, behavioral regulation, and metacognition) as revealed by parental report and clinical evaluation. MRI revealed gliosis from the head to tail of the hippocampus and thinning of parahippocampal gyri. CONCLUSIONS: In a clinical case of CCHS, serial evaluation revealed deterioration of executive functions and social cognition over a 3-year interval. These changes corresponded to hippocampal damage as revealed in MRI, which may have affected social cognition through its role in the default mode network. Serial neuropsychological assessment is clinically useful in managing the needs of these patients.

Improved Behavior and Neuropsychological Function in Children With ROHHAD After High-Dose Cyclophosphamide.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare, generally progressive, and potentially fatal syndrome of unclear etiology. The syndrome is characterized by normal development followed by a sudden, rapid hyperphagic weight gain beginning during the preschool period, hypothalamic dysfunction, and central hypoventilation, and is often accompanied by personality changes and developmental regression, leading to substantial morbidity and mortality. We describe 2 children who had symptomatic and neuropsychological improvement after high-dose cyclophosphamide treatment. Our experience supports an autoimmune pathogenesis and provides the first neuropsychological profile of patients with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation.

Congenital Central Hypoventilation Syndrome: Neurocognition Already Reduced in Preschool-Aged Children.

BACKGROUND: Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by severe hypoventilation and autonomic dysregulation, with typical presentation in the neonatal period, and deficient cognitive skills in school-aged patients. We hypothesized that younger (preschool) children with CCHS would also show neurocognitive delay and that CCHS-related physiologic factors would impact neurocognitive test results. METHODS: We studied developmental (Bayley) test results collected during routine clinical care in 31 children (mean age 25.0 ± 8.5 months; range, 6-40 months) with PHOX2B mutation-confirmed CCHS by comparing them with the normative reference mean from the Bayley standardization sample; we also examined associations between Bayley scores and CCHS disease-related factors. RESULTS: Preschool patients with CCHS fell significantly below the normative mean of 100 on Bayley indices of mental (mean, 83.35 ± 24.75) and motor (mean, 73.33 ± 20.48) development (P < .001 for both). Significantly lower Bayley mental and motor scores were associated with severe breath-holding spells, prolonged sinus pauses, and need for 24 h/d artificial ventilation. Lower Bayley motor scores were also associated with seizures. Bayley scores differed among children with the three most common polyalanine repeat expansion mutation genotypes (mental, P = .001; motor, P = .006), being essentially normal in children with the 20/25 genotype but significantly lower in the other genotype groups (P < .05). CONCLUSIONS: These results confirm neurodevelopmental impairment of CCHS preschoolers, with severity related to physiologic compromise and PHOX2B genotype. These findings suggest that adverse effects begin early in the disease process, supporting the need for neurodevelopmental monitoring and intervention from early infancy.

[Relation between psychological development and respiratory management in patients with congenital central hypoventilation syndrome in Japan].

OBJECTIVE: To evaluate the psychological development of patients with congenital central hypoventilation syndrome (CCHS). METHODS: We performed a questionnaire-based survey of 17 patients with CCHS aged over 7 years and assessed their clinical course, respiratory management, and psychological development. RESULTS: CCHS was present at birth in 15 patients, of which eight presented with respiratory failure with a low Apgar score. Twelve patients required mechanical ventilation with intubation, and five received mask ventilation. All patients with intubation underwent tracheostomy between 1 and 12 months of age (median 5.5 months), and most of them had associated conditions such as Hirschsprung disease. Four of 12 patients with intubation were eventually switched to mask ventilation and one to diaphragm pacing and mask ventilation. The patients undergoing mask ventilation had relatively milder disease severity and had fewer complications than did the patients with intubation. The psychological development of patients who received tracheostomy ranged from normal to severe retardation. Retardation was more likely to be severe in patients who received tracheostomy in late infancy. All patients who received mask ventilation experienced borderline to moderate psychological retardation. This effect could be attributed to poor compliance with mask fitting. CONCLUSION: Our findings suggest that the psychological development of CCHS patients was influenced by hypoxia; tracheostomy and strict respiratory management since the neonatal period were needed for neurological protection.

Health-related quality of life in young adults with congenital central hypoventilation syndrome due to PHOX2B mutations: a cross-sectional study.

BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disease due to PHOX2B mutations. CCHS patients suffer from many autonomic disorders, dominated clinically by defective ventilatory automatisms. From birth, the life of CCHS patients depends on ventilatory support during sleep, involving a high burden of care. Whether or not this impairs the quality of life of these patients during adulthood remains unknown. METHODS: We applied the medical outcome study short form-36 (SF-36) to 12 CCHS patients aged 15-33 (9 women) at the time of their passage from pediatric to adult care. Scores for the SF-36 dimensions were compared to the age- and gender-matched French reference population after transformation into standardized Z-scores. The SF-36 physical component summary score (PCS) and mental component summary score (MCS) were compared to American reference values. RESULTS: Median Z-scores were significantly different from zero for PF (physical functioning, p = 0.020) and GH (general health perception, p = 0.0342) and for PCS (p = 0.020). The other physical dimensions (RP, role limitation due to physical function; BP, bodily pain) and the mental dimensions (VT, vitality; SF, social functioning; RE, role limitation due to emotional function; MH, mental health) and MCS were not altered. CONCLUSIONS: We conclude that, despite the physical constraints imposed by CCHS and its anxiogenic nature, this disease is associated with an impairment of health-related quality of life in young adults that remains moderate. Whatever the underlying explanations, these results convey hope to parents with a child diagnosed with CCHS and for patients themselves.

Sleeping problems in mothers and fathers of patients suffering from congenital central hypoventilation syndrome.

PURPOSE: Advanced medical technology has resulted in an increased survival rate of children suffering from congenital central hypoventilation syndrome. After hospitalization, these technology-dependent patients require special home care for assuring ventilator support and the monitoring of vital parameters mainly during sleep. The daily challenges associated with caring for these children can place primary caregivers under significant stress, especially at night. Our study aimed at investigating how this condition affects mothers and fathers by producing poor sleep quality, high-level diurnal sleepiness, anxiety, and depression. METHODS: The study included parents of 23 subjects with congenital central hypoventilation syndrome and 23 healthy subjects. All parents filled out the Pittsburgh Sleep Quality Index (PSQI) questionnaire, Epworth Sleepiness Scale (ESS), Beck Depression Inventory (BDI-II), and Beck Anxiety Inventory (BAI). RESULTS: A comparison between the two groups showed that parents of patients had poorer sleep quality, greater sleepiness, and higher BDI-II scores compared to that of parents of healthy subjects (respectively, PSQI score 6.5 vs 3.8, ESS score 6.2 vs 4.3, BDI-II score 8.4 vs 5.7). Specifically, mothers of patients showed poorer sleep quality and higher BDI-II scores compared to that of mothers of controls (respectively, PSQI score 7.5 vs 3.8, BDI-II score 9.3 vs 5.9), whereas fathers of patients showed greater levels of sleepiness with respect to fathers of healthy children (respectively, ESS score 6.8 vs 4.0). These differences emerged in parents of younger children. CONCLUSIONS: Congenital central hypoventilation syndrome impacts the family with different consequences for mothers and fathers. Indeed, while the patients' sleep is safeguarded, sleeping problems may occur in primary caregivers often associated with other psychological disorders. Specifically, this disease affects sleep quality and mood in the mothers and sleepiness levels in the fathers.

Progressive paranoid psychosis in a 20-year-old with central congenital hypoventilation syndrome.

A 20-year-old man with a history of congenital central hypoventilation syndrome presented with recent-onset psychosis, catatonia, and a diagnosis of schizophrenia. Psychiatric symptoms were resistant to conventional treatment. A fluorodeoxyglucose positron emission tomography scan of the brain obtained during the hospitalization revealed a hypometabolism distribution more consistent with hypoperfusion than with primary central nervous system disease. Increased mechanical ventilation was successfully used to treat the psychiatric symptoms.

Effects of breathing training on voluntary hypo- and hyperventilation in patients with panic disorder and episodic anxiety.

Anxiety disorders are associated with respiratory abnormalities. Breathing training (BT) aimed at reversing these abnormalities may also alter the anxiogenic effects of biological challenges. Forty-five Panic Disorder (PD) patients, 39 Episodic Anxiety patients, and 20 non-anxious controls underwent voluntary hypoventilation and hyperventilation tests twice while psychophysiological measures were recorded. Patients were randomized to one of two BT therapies (Lowering vs. Raising pCO(2)) or to a waitlist. Before treatment panic patients had higher respiration rates and more tidal volume instability and sighing at rest than did non-anxious controls. After the Lowering therapy, patients had lower pCO(2) during testing. However, neither reactivity nor recovery to either test differed between patients and controls, or were affected by treatment. Although the two treatments had their intended opposite effects on baseline pCO(2), other physiological measures were not affected. We conclude that baseline respiratory abnormalities are somewhat specific to PD, but that previously reported greater reactivity and slower recovery to respiratory challenges may be absent.

End-tidal versus transcutaneous measurement of PCO2 during voluntary hypo- and hyperventilation.

Recent studies have shown that end-tidal PCO(2) is lower during anxiety and stress, and that changing PCO(2) by altering breathing is therapeutic in panic disorder. However, end-tidal estimation of arterial PCO(2) has drawbacks that might be avoided by the transcutaneous measurement method. Here we compare transcutaneous and end-tidal PCO(2) under different breathing conditions in order to evaluate these methods in terms of their comparability and usability. Healthy volunteers performed two hypoventilation (slow vs. paused breathing) and two hyperventilation tests (25 mm Hg at 18 vs. 30 breaths per minute). Three measurements of PCO(2) (two end-tidal and one transcutaneous device), tidal volume, and respiration rate were recorded. Before and after each test, subjects filled out a symptom questionnaire. The results show that PCO(2) estimated by the two methods was comparable except that for transcutaneous measurement registration of changes in PCO(2) was delayed and absolute levels were much higher. Both methods documented that paused breathing was effective for raising PCO(2), a presumed antidote for anxious hyperventilation. We conclude that since the two methods give comparable results choosing between them for specific applications is principally a matter of whether the time lag of the transcutaneous method is acceptable.

Neuropsychological, behavioral, and adaptive functioning of Swiss children with congenital central hypoventilation syndrome.

This study collected data about developmental problems in a cohort of children with congenital central hypoventilation syndrome. In 2003, in Switzerland, 11 children with this disease were registered. Nine of them gave their informed consent to participate in the study and were examined. Clinical assessments were conducted, including examinations of neuropsychological, behavioral, and adaptive functions using Kaufman-Assessment Battery for Children, Child Behavior Checklist, and Vineland Adaptive Behavior Scales. The mean age (+/- standard deviation) was 7.5 +/- 2.5 years. The cognitive tests showed problems in working memory functions with a near-to-normal full-range intelligence quotient (87.4 +/- 23.3). The children showed normal values (t-values < 67) on problem scales of behavior, although 5 of the 9 children showed elevated values on the attention and on the social interaction problem scales. Adaptive function problems were identified in communication and daily living skills.

Randomised trial of inpatient versus outpatient initiation of home mechanical ventilation in patients with nocturnal hypoventilation.

BACKGROUND: Long-term home mechanical ventilation (HMV) is usually initiated in hospital. Admission to hospital has resource implications and may not be reimbursable in some healthcare systems. METHODS: Twenty-eight stable neuromuscular and chest wall disease patients with nocturnal hypoventilation (transcutaneous carbon dioxide (TcCO(2) >6.5 kPa), were randomised to start HMV either as an outpatient (n=14, age range 12-62 years) or inpatient (n=14, age range 14-73 years). We compared effects of HMV on nocturnal and diurnal arterial blood gas tensions, ventilator compliance, healthcare professional (HCP) contact time, and time in hospital. RESULTS: Improvements in nocturnal arterial oxygen saturation (SaO(2)) and daytime PaO(2) were equivalent in both groups. Peak nocturnal TcCO(2), improved in both groups; % time TcCO(2) >6.5 kPa fell in the inpatient group and daytime PaCO(2) decreased significantly (p<0.05) in the outpatient group. The mean (SD) inpatient stay was 3.8 (1.0) days, and the outpatient attendance sessions 1.2 (0.4). HCP contact time including telephone calls was: inpatient 177 (99) min; outpatient 188 (60) min (p=not significant); 2 month ventilator compliance was: inpatient 4.32 (7); outpatient 3.92 (8) (p=not significant) hours per night. CONCLUSION: Outpatient initiation of HMV is feasible with equivalent outcome in the outpatient and the inpatient groups.

Effect of mental activity on breathing in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) is associated with hypoventilation during sleep, but breathing can be adequate during wakefulness. It has been assumed that in awake CCHS patients breathing is activated by the forebrain, even voluntarily (i.e. Ondine's Curse). We tested whether or not an abnormal breathing pattern can be provoked by intense mental concentration in CCHS patients as this would be expected to disturb any voluntary control over breathing if present. Breathing (inductance plethysmography), end-tidal PCO2) (PETCO2), arterial oxygen saturation (SaO2) and EEG were measured in 5 children with CCHS (aged 8-17 years) and 5 controls during 5 min periods while resting; reading; performing mental arithmetic and playing a hand-held "Nintendo" game. There were no significant differences between controls and CCHS (unpaired t-tests, P > 0.05) in mean breath duration, tidal volume, ventilation, SaO2 or PETCO2 during REST or the conditions of mental stimulation. Both groups increased ventilation during mental stimulation. Respiratory variability was not greater in CCHS in any condition. These data provide indirect evidence that CCHS patients do not require voluntary activation of every breath (they do not have Ondine's Curse) and suggest that mental concentration might stimulate the respiratory complex as part of a generalised CNS arousal.