Computer-aided diagnostic screen for Congenital Central Hypoventilation Syndrome with facial phenotype.

BACKGROUND: Congenital Central Hypoventilation Syndrome (CCHS) has devastating consequences if not diagnosed promptly. Despite identification of the disease-defining gene PHOX2B and a facial phenotype, CCHS remains underdiagnosed. This study aimed to incorporate automated techniques on facial photos to screen for CCHS in a diverse pediatric cohort to improve early case identification and assess a facial phenotype-PHOX2B genotype relationship. METHODS: Facial photos of children and young adults with CCHS were control-matched by age, sex, race/ethnicity. After validating landmarks, principal component analysis (PCA) was applied with logistic regression (LR) for feature attribution and machine learning models for subject classification and assessment by PHOX2B pathovariant. RESULTS: Gradient-based feature attribution confirmed a subtle facial phenotype and models were successful in classifying CCHS: neural network performed best (median sensitivity 90% (IQR 84%, 95%)) on 179 clinical photos (versus LR and XGBoost, both 85% (IQR 75-76%, 90%)). Outcomes were comparable stratified by PHOX2B genotype and with the addition of publicly available CCHS photos (n = 104) using PCA and LR (sensitivity 83-89% (IQR 67-76%, 92-100%). CONCLUSIONS: Utilizing facial features, findings suggest an automated, accessible classifier may be used to screen for CCHS in children with the phenotype and support providers to seek PHOX2B testing to improve the diagnostics. IMPACT: Facial landmarking and principal component analysis on a diverse pediatric and young adult cohort with PHOX2B pathovariants delineated a distinct, subtle CCHS facial phenotype. Automated, low-cost machine learning models can detect a CCHS facial phenotype with a high sensitivity in screening to ultimately refer for disease-defining PHOX2B testing, potentially addressing gaps in disease underdiagnosis and allow for critical, timely intervention.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): a collaborative review of the current understanding.

PURPOSE: To provide an overview of the discovery, presentation, and management of Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD). To discuss a search for causative etiology spanning multiple disciplines and continents. METHODS: The literature (1965-2022) on the diagnosis, management, pathophysiology, and potential etiology of ROHHAD was methodically reviewed. The experience of several academic centers with expertise in ROHHAD is presented, along with a detailed discussion of scientific discovery in the search for a cause. RESULTS: ROHHAD is an ultra-rare syndrome with fewer than 200 known cases. Although variations occur, the acronym ROHHAD is intended to alert physicians to the usual sequence or unfolding of the phenotypic presentation, including the full phenotype. Nearly 60 years after its first description, more is known about the pathophysiology of ROHHAD, but the etiology remains enigmatic. The search for a genetic mutation common to patients with ROHHAD has not, to date, demonstrated a disease-defining gene. Similarly, a search for the autoimmune basis of ROHHAD has not resulted in a definitive answer. This review summarizes current knowledge and potential future directions. CONCLUSION: ROHHAD is a poorly understood, complex, and potentially devastating disorder. The search for its cause intertwines with the search for causes of obesity and autonomic dysregulation. The care for the patient with ROHHAD necessitates collaborative international efforts to advance our knowledge and, thereby, treatment, to decrease the disease burden and eventually to stop, and/or reverse the unfolding of the phenotype.

Ventilatory and Orthostatic Challenges Reveal Biomarkers for Neurocognition in Children and Young Adults With Congenital Central Hypoventilation Syndrome.

BACKGROUND: Children and young adults with congenital central hypoventilation syndrome (CCHS) are at risk of cognitive deficits. They experience autonomic dysfunction and chemoreceptor insensitivity measured during ventilatory and orthostatic challenges, but relationships between these features are undefined. RESEARCH QUESTION: Can a biomarker be identified from physiologic responses to ventilatory and orthostatic challenges that is related to neurocognitive outcomes in CCHS? STUDY DESIGN AND METHODS: This retrospective study included 25 children and young adults with CCHS tested over an inpatient stay. Relationships between physiologic measurements during hypercarbic and hypoxic ventilatory challenges, hypoxic ventilatory challenges, and orthostatic challenges and neurocognitive outcomes (by Wechsler intelligence indexes) were examined. Independent variable inclusion was determined by significant associations in Pearson's analyses. Multivariate linear regressions were used to assess relationships between measured physiologic responses to challenges and neurocognitive scores. RESULTS: Significant relationships were identified between areas of fluid intelligence and measures of oxygen saturation (SpO2) and heart rate (HR) during challenges. Specifically, perceptual reasoning was related to HR (adjusted regression [ß] coefficient, -0.68; 95% CI, 1.24 to -0.12; P = .02) during orthostasis. Working memory was related to change in HR (ß, -1.33; 95% CI, -2.61 to -0.05; P = .042) during the hypoxic ventilatory challenge. Processing speed was related to HR (ß, -1.19; 95% CI, -1.93 to -0.46; P = .003) during orthostasis, to baseline SpO2 (hypercarbic and hypoxic ß, 8.57 [95% CI, 1.63-15.51]; hypoxic ß, 8.37 [95% CI, 3.65-13.11]; P = .002 for both) during the ventilatory challenges, and to intrachallenge SpO2 (ß, 5.89; 95% CI, 0.71-11.07; P = .028) during the hypoxic ventilatory challenge. INTERPRETATION: In children and young adults with CCHS, SpO2 and HR-or change in HR-at rest and as a response to hypoxia and orthostasis are related to cognitive outcomes in domains of known risk, particularly fluid reasoning. These findings can guide additional research on the usefulness of these as biomarkers in understanding the impact of daily physical stressors on neurodevelopment in this high-risk group.

Transitional care and clinical management of adolescents, young adults, and suspected new adult patients with congenital central hypoventilation syndrome.

PURPOSE: With contemporaneous advances in congenital central hypoventilation syndrome (CCHS), recognition, confirmatory diagnostics with PHOX2B genetic testing, and conservative management to reduce the risk of early morbidity and mortality, the prevalence of identified adolescents and young adults with CCHS and later-onset (LO-) CCHS has increased. Accordingly, there is heightened awareness and need for transitional care of these patients from pediatric medicine into a multidisciplinary adult medical team. Hence, this review summarizes key clinical and management considerations for patients with CCHS and LO-CCHS and emphasizes topics of particular importance for this demographic. METHODS: We performed a systematic review of literature on diagnostics, pathophysiology, and clinical management in CCHS and LO-CCHS, and supplemented the review with anecdotal but extensive experiences from large academic pediatric centers with expertise in CCHS. RESULTS: We summarized our findings topically for an overview of the medical care in CCHS and LO-CCHS specifically applicable to adolescents and adults. Care topics include genetic and embryologic basis of the disease, clinical presentation, management, variability in autonomic nervous system dysfunction, and clarity regarding transitional care with unique considerations such as living independently, family planning, exposure to anesthesia, and alcohol and drug use. CONCLUSIONS: While a lack of experience and evidence exists in the care of adults with CCHS and LO-CCHS, a review of the relevant literature and expert consensus provides guidance for transitional care areas.

Neurocognition as a biomarker in the rare autonomic disorders of CCHS and ROHHAD.

PURPOSE: Congenital central hypoventilation syndrome (CCHS) and rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) are rare disorders of autonomic regulation with risk for disrupted neurocognitive development. Our aim is to summarize research on neurocognitive outcomes in these conditions, advance understanding of how to best support these individuals throughout development, and facilitate future research. METHODS: We conducted a narrative review of literature on neurocognitive outcomes in CCHS and ROHHAD, supplemented with previously unpublished data from patients with CCHS and ROHHAD at our Center for Autonomic Medicine in Pediatrics (CAMP). RESULTS: Individuals with CCHS and ROHHAD experience a wide range of neurocognitive functioning ranging from above average to below average, but are at particular risk for difficulties with working memory, processing speed, perceptual reasoning, and visuographic skills. An assessment framework emphasizing fluid cognition seems especially appropriate for these conditions. Owing to small cohorts and varied methods of data collection, it has been difficult to identify associations between disease factors (including CCHS PHOX2B genotypes) and cognitive outcomes. However, results suggest that early childhood is a period of particular vulnerability, perhaps due to the disruptive impact of recurrent intermittent hypoxic episodes on brain and cognitive development. CONCLUSION: Neurocognitive monitoring is recommended as a component of routine clinical care in CCHS and ROHHAD as a marker of disease status and to ensure that educational support and disability accommodations are provided as early as possible. Collaborative efforts will be essential to obtain samples needed to enhance our understanding of neurocognitive outcomes in CCHS and ROHHAD.

Evolution of physiologic and autonomic phenotype in rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation over a decade from age at diagnosis.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare cause of syndromic obesity with risk of cardiorespiratory arrest and neural crest tumor. No ROHHAD-specific genetic test exists at present. Rapid weight gain of 20-30 pounds, typically between ages 2-7 years in an otherwise healthy child, followed by multiple endocrine abnormalities herald the ROHHAD phenotype. Vigilant monitoring for asleep hypoventilation (and later awake) is mandatory as hypoventilation and altered control of breathing can emerge rapidly, necessitating artificial ventilation as life support. Recurrent hypoxemia may lead to cor pulmonale and/or right ventricular hypertrophy. Autonomic dysregulation is variably manifest. Here we describe the disease onset with "unfolding" of the phenotype in a child with ROHHAD, demonstrating the presentation complexity, need for a well-synchronized team approach, and optimized management that led to notable improvement ("refolding") in many aspects of the child's ROHHAD phenotype over 10 years of care. CITATION: Khaytin I, Stewart TM, Zelko FA, et al. Evolution of physiologic and autonomic phenotype in rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation over a decade from age at diagnosis. J Clin Sleep Med. 2022;18(3):937-944.

Auto-titrating CPAP for the treatment of obstructive sleep apnea in children.

STUDY OBJECTIVES: In-laboratory titration polysomnography (PSG) is standard to determine optimal therapeutic continuous positive airway pressure (CPAP) in children with obstructive sleep apnea (OSA). The use of auto-titrating CPAP devices (autoCPAP) as an alternative to CPAP titration has not been well studied in children. We hypothesized that autoCPAP-derived pressures (PMEAN, PPEAKMEAN, P90) would be similar to titration PSG pressure (PPSG). METHODS: This is a retrospective study of children with OSAS initiated on autoCPAP between 2007 and 2017, who used autoCPAP for at least 2 h/night and who had adequate titration PSG were included in the analysis. AutoCPAP-derived pressures were obtained from use downloads and compared with PPSG. PPSG predictive factors were analyzed by median regression. Nonparametric methods were used for analysis. RESULTS: Of 110 children initiated on autoCPAP, 44 satisfied the inclusion criteria. Age (median (interquartile range)) was 13.01 (9.98-16.72) years, and 63.6% were obese. PPSG median (interquartile range) was 8 (7-11) cmH2O, mean autoCPAP-derived pressure (PMEAN) was 6.2 (5.6-7.6) cmH2O, peak mean pressure (PPEAKMEAN) was 9.4 (7.7-11.1) cmH2O, and average device pressure ≤ 90% of the time (P90) was 8.1 (7.2-9.7) cmH2O. AutoCPAP-derived pressures correlated with PPSG (P < .05). PMEAN was lower than the other 3 pressures (P < .0002). Median regression analysis demonstrated that after adjusting for patient characteristics such as age, sex, and obesity status, autoCPAP-derived pressures remained significant predictors of PPSG (P < .05). There were no significant interactions between these patient characteristics and autoCPAP-derived pressures. CONCLUSIONS: This study demonstrates that autoCPAP-derived pressures correlate with the titration PSG-derived pressures. These results indicate that autoCPAP can be used in the pediatric population and can determine pressures that are close to the titration pressures.

Potassium channel modulation by a toxin domain in matrix metalloprotease 23.

Peptide toxins found in a wide array of venoms block K(+) channels, causing profound physiological and pathological effects. Here we describe the first functional K(+) channel-blocking toxin domain in a mammalian protein. MMP23 (matrix metalloprotease 23) contains a domain (MMP23(TxD)) that is evolutionarily related to peptide toxins from sea anemones. MMP23(TxD) shows close structural similarity to the sea anemone toxins BgK and ShK. Moreover, this domain blocks K(+) channels in the nanomolar to low micromolar range (Kv1.6 > Kv1.3 > Kv1.1 = Kv3.2 > Kv1.4, in decreasing order of potency) while sparing other K(+) channels (Kv1.2, Kv1.5, Kv1.7, and KCa3.1). Full-length MMP23 suppresses K(+) channels by co-localizing with and trapping MMP23(TxD)-sensitive channels in the ER. Our results provide clues to the structure and function of the vast family of proteins that contain domains related to sea anemone toxins. Evolutionary pressure to maintain a channel-modulatory function may contribute to the conservation of this domain throughout the plant and animal kingdoms.

Quantification of optical images of cortical responses for inferring functional maps.

Optical imaging of cortical signals enables the mapping of functional organization across large patches of cortex with good spatial resolution. But techniques for the quantitative analysis and interpretation of these images are limited. Frequently the functional architecture of the cortex is inferred from the visible topography of cortical reflectance images averaged or differenced across stimulus conditions and scaled or color-coded for presentation. Such qualitative assessments have sometimes led to divergent conclusions particularly about the organization of spatial and temporal frequency preferences in the primary visual cortex. We applied quantitative methods derived from signal detection theory to objectively interpret optical images. The differential response to any two arbitrary stimuli was represented at each pixel as the probability of discriminating between the two stimuli given the reflectance values at that pixel. These probability maps reduced false alarms and provided better signal-to-noise ratio in fewer trials than difference maps. We applied these methods to optical images of primate primary visual area (V1) obtained in response to sinusoidal gratings of different orientations and spatiotemporal frequencies. Clustering by orientation preference was stronger than that for spatial frequency, whereas clustering by temporal frequency preference was the weakest, largely in agreement with a previous electrophysiological study that quantified the degree of clustering of neurons for various response properties using uniform, quantitative criterion. We suggest that probability maps can extend the applicability of optical imaging to investigations of finer aspects of cortical functional organization through better signal-to-noise ratio and uniform, quantitative criteria for interpretation.

Relationship between spontaneous and evoked spike-time correlations in primate visual cortex.

Coincident spikes have been implicated in vision-related processes such as feature binding, gain modulation, and long-distance communication. The source of these spike-time correlations is unknown. Although several studies have proposed that cortical spikes are correlated based on stimulus structure, others have suggested that spike-time correlations reflect ongoing cortical activity present even in the absence of a coherent visual stimulus. To examine this issue, we collected single-unit recordings from primary visual cortex (V1) of the anesthetized and paralyzed prosimian bush baby using a 100-electrode array. Spike-time correlations for pairs of cells were compared under three conditions: a moving grating at the cells' preferred orientation, an equiluminant blank screen, and a dark condition with eyes covered. The amplitudes, lags, and widths of cross-correlation histograms (CCHs) were strongly correlated between these conditions although for the blank stimulus and dark condition, the CCHs were broader with peaks lower in amplitude. In both preferred stimulus and blank conditions, the CCH amplitudes were greater when the cells within the pair had overlapping receptive fields and preferred similar orientations rather than nonoverlapping receptive fields and different orientations. These data suggest that spike-time correlations present in evoked activity are generated by mechanisms common to those operating in spontaneous conditions.

Functional organization of temporal frequency selectivity in primate visual cortex.

Several studies have shown that neurons with similar response properties are arranged together in domains across primary visual cortex (V1). An orderly pattern of domains has been described for preferences to ocular dominance, orientation, and spatial frequency. Temporal frequency preference, another important attribute of the visual scene, also might be expected to map into different domains. Using optical imaging and a variety of quantitative methods, we examined how temporal frequency selectivity is mapped in V1 of the prosimian primate, bush baby (Otolemur garnetti). We found that unlike other attribute maps, selectivity for different temporal frequencies is arranged uniformly across V1 with no evidence of local clustering. Global tuning for temporal frequency, based on magnitude of response, showed a good match to previous tuning curves for single neurons. A peak response was found around 2.0 Hz, with smaller attenuation at lower temporal frequencies than at higher frequencies. We also examined whether the peak temporal frequency response differed between anatomical compartments defined by cytochrome oxidase (CO). No significant differences in the preference for temporal frequency were found between these CO compartments. Our findings show that key sensory attributes that are linked in perception can be organized in quite distinct ways in V1 of primates.

The D-diastereomer of ShK toxin selectively blocks voltage-gated K+ channels and inhibits T lymphocyte proliferation.

The polypeptide toxin ShK is a potent blocker of Kv1.3 potassium channels, which are crucial in the activation of human effector memory T cells (T(EM)); selective blockers constitute valuable therapeutic leads for the treatment of autoimmune diseases mediated by T(EM) cells, such as multiple sclerosis, rheumatoid arthritis, and type-1 diabetes. The critical motif on the toxin for potassium channel blockade consists of neighboring lysine and tyrosine residues. Because this motif is sufficient for activity, an ShK analogue was designed based on D-amino acids. D-allo-ShK has a structure essentially identical with that of ShK and is resistant to proteolysis. It blocked Kv1.3 with K(d) 36 nm (2,800-fold lower affinity than ShK), was 2-fold selective for Kv1.3 over Kv1.1, and was inactive against other K(+) channels tested. D-allo-ShK inhibited human T(EM) cell proliferation at 100-fold higher concentration than ShK. Its circulating half-life was only slightly longer than that of ShK, implying that renal clearance is the major determinant of its plasma levels. D-allo-ShK did not bind to the closed state of the channel, unlike ShK. Models of D-allo-ShK bound to Kv1.3 show that it can block the pore as effectively as ShK but makes different interactions with the vestibule, some of which are less favorable than for native ShK. The finding that an all-D analogue of a polypeptide toxin retains biological activity and selectivity is highly unusual. Being resistant to proteolysis and nonantigenic, this analogue should be useful in K(+) channel studies; all-d analogues with improved Kv1.3 potency and specificity may have therapeutic advantages.

Unequal representation of cardinal vs. oblique orientations in the middle temporal visual area.

A possible neurobiological basis for the "oblique effect" is linked to the finding that more neural machinery is devoted to processing cardinal vs. oblique orientations in primary visual cortex (V1). We used optical imaging to determine whether more territory is devoted to processing horizontal and vertical orientations than oblique orientations in owl monkey middle temporal visual area (MT), a visual area highly sensitive to moving stimuli. We found that more of MT was devoted to representing cardinal than oblique orientations, and that the anisotropy was more prominent in parts of MT representing central vision (< or =10 degrees). Neural responses to orientations of 0 degrees and 90 degrees were also greater than those to 45 degrees and 135 degrees . In comparison, an overrepresentation of cardinal orientations in the representation of central vision in owl monkey V1 was relatively small and inconsistent. Our data could explain the greater sensitivity to motion discrimination when stimuli are moved along cardinal meridians and suggest that the neural machinery necessary to explain the motion oblique effect either originates in MT or is enhanced at this level.

Optical imaging of visually evoked responses in the middle temporal area after deactivation of primary visual cortex in adult primates.

The middle temporal area (MT) is a visual area in primates with direct and indirect inputs from the primary visual cortex (V1), a role in visual motion perception, and a suggested role in "blindsight." When V1 is deactivated, some studies report continued activation of MT neurons, which has been attributed to an indirect pathway to MT from the superior colliculus. Here we used muscimol to deactivate V1 while optically imaging visually evoked activity in MT in two primates, owl monkeys and galagos, where MT is exposed on the brain surface. The partial loss of V1 inputs abolished all or nearly all evoked activity in the retinotopically matched part of MT. Low levels of activation that persisted in portions of MT that were unstimulated or retinotopically congruent with the blocked portion of V1 appeared to reflect the spread of activity from stimulated to unstimulated parts of MT. Thus, a significant pathway based on the superior colliculus was not demonstrated.

Targeting effector memory T cells with a selective peptide inhibitor of Kv1.3 channels for therapy of autoimmune diseases.

The voltage-gated Kv1.3 K(+) channel is a novel target for immunomodulation of autoreactive effector memory T (T(EM)) cells that play a major role in the pathogenesis of autoimmune diseases. We describe the characterization of the novel peptide ShK(L5) that contains l-phosphotyrosine linked via a nine-atom hydrophilic linker to the N terminus of the ShK peptide from the sea anemone Stichodactyla helianthus. ShK(L5) is a highly specific Kv1.3 blocker that exhibits 100-fold selectivity for Kv1.3 (K(d) = 69 pM) over Kv1.1 and greater than 250-fold selectivity over all other channels tested. ShK(L5) suppresses the proliferation of human and rat T(EM) cells and inhibits interleukin-2 production at picomolar concentrations. Naive and central memory human T cells are initially 60-fold less sensitive than T(EM) cells to ShK(L5) and then become resistant to the peptide during activation by up-regulating the calcium-activated K(Ca)3.1 channel. ShK(L5) does not exhibit in vitro cytotoxicity on mammalian cell lines and is negative in the Ames test. It is stable in plasma and when administered once daily by subcutaneous injection (10 mug/kg) attains "steady state" blood levels of approximately 300 pM. This regimen does not cause cardiac toxicity assessed by continuous EKG monitoring and does not alter clinical chemistry and hematological parameters after 2-week therapy. ShK(L5) prevents and treats experimental autoimmune encephalomyelitis and suppresses delayed type hypersensitivity in rats. ShK(L5) might prove useful for therapy of autoimmune disorders.

Optical imaging of visually evoked responses in prosimian primates reveals conserved features of the middle temporal visual area.

Optical imaging of intrinsic cortical responses to visual stimuli was used to characterize the organization of the middle temporal visual area (MT) of a prosimian primate, the bush baby (Otolemur garnetti). Stimulation with moving gratings revealed a patchwork of oval-like domains in MT. These orientation domains could, in turn, be subdivided into zones selective to directional movements that were mainly orthogonal to the preferred orientation. Similar, but not identical, zones were activated by movements of random dots in the preferred direction. Orientation domains shifted in preference systematically either around a center to form pinwheels or as gradual linear shifts. Stimuli presented in different portions of the visual field demonstrated a global representation of visual space in MT. As optical imaging has revealed similar features in MT of New World monkeys, MT appears to have retained these basic features of organization for at least the 60 million years since the divergence of prosimian and simian primates.