Meta-iodobenzylguanidine myocardial scintigraphy in Perry disease.

INTRODUCTION: Perry disease (Perry syndrome), a hereditary TAR DNA-binding protein 43 (TDP-43) proteinopathy, is caused by dynactin subunit 1 (DCNT1) mutations and is characterized by rapidly progressive parkinsonism accompanied by depression, apathy, unexpected weight loss, and respiratory symptoms including central hypoventilation and central sleep apnea. Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is considered a diagnostic biomarker for Lewy body disease (LBD), as denervation of cardiac sympathetic nerves is a pathological feature in LBD. However, our previous studies have reported a decreased cardiac uptake of MIBG in patients with Perry disease. In this study, we aimed to correlate the MIBG myocardial scintigraphy findings with clinical features in Perry disease. METHODS: We evaluated data obtained from a multicenter survey of patients of Japanese origin with suspected Perry disease, who visited neurology departments in Japan from January 2010 to December 2018. We screened each patient's DNA for the DCTN1 mutation using Sanger sequencing and obtained the clinical details of all patients including findings from their MIBG myocardial scintigraphy. RESULTS: We identified two novel mutations, p.G71V and p.K68E, in DCTN1 in patients from two different families. The majority of patients (7/8, 87.5%) showed a decrease in cardiac uptake (heart to mediastinum ratio) in MIBG myocardial scintigraphy. These patients commonly presented with symptoms related to autonomic dysfunction: constipation, fecal incontinence, urinary disturbance, and orthostatic hypotension. CONCLUSIONS: MIBG myocardial scintigraphy may be a useful biomarker of autonomic dysfunction in Perry disease.

Adult-onset congenital central hypoventilation syndrome due to PHOX2B mutation.

Central hypoventilation in adult patients is a rare life-threatening condition characterised by the loss of automatic breathing, more pronounced during sleep. In most cases, it is secondary to a brainstem lesion or to a primary pulmonary, cardiac or neuromuscular disease. More rarely, it can be a manifestation of congenital central hypoventilation syndrome (CCHS). We here describe a 25-year-old woman with severe central hypoventilation triggered by analgesics. Genetic analysis confirmed the diagnosis of adult-onset CCHS caused by a heterozygous de novo poly-alanine repeat expansion of the PHOX2B gene. She was treated with nocturnal non-invasive ventilation. We reviewed the literature and found 21 genetically confirmed adult-onset CCHS cases. Because of the risk of deleterious respiratory complications, adult-onset CCHS is an important differential diagnosis in patients with central hypoventilation.

Sleep-disordered breathing and nocturnal hypoventilation in children with the MECP2 duplication syndrome: A case series and review of the literature.

There is limited knowledge on the occurrence of respiratory manifestations and sleep-disordered breathing in particular in children with the MECP2 duplication syndrome. Although sleep-disordered breathing and nocturnal hypoventilation are currently not cited as an important symptom in these children, we present three cases who all had an abnormal breathing during sleep. In view of the consequences associated with sleep apnea and hypoventilation, we advise to perform a polysomnography in children with MECP2 duplication. Different treatment modalities (ENT surgery, CPAP, and non-invasive ventilation) can be applied to successfully treat these conditions.

DCTN1-related Parkinson-plus disorder (Perry syndrome).

Dynactin-1 (DCTN1)-related Parkinson-plus disorder (Perry syndrome) is an autosomal dominant neurodegenerative disorder characterised by levodopa-resistant parkinsonism, weight loss, mood change and central hypoventilation. Ventilatory insufficiency is the predominant cause of death. It has been previously described in 87 people from 20 families with a worldwide distribution. It is now recognised as a distinct TDP-43 proteinopathy caused by a pathological mutation in DCTN1. Its rarity and clinical overlap with other neurodegenerative diseases increase the risk of delayed or incorrect diagnosis. Ventilatory support can improve life expectancy but this depends upon its recognition; overall its prognosis remains poor. We report a patient with DCTN1-related Parkinson-plus disorder, in whom genetic confirmation came only after death.

Network Localization of Central Hypoventilation Syndrome in Lateral Medullary Infarction.

BACKGROUND AND PURPOSE: The brainstem plays a key role in the control of respiration. Strokes involving the lateral medulla can rarely produce a central hypoventilation syndrome (CHS) characterized by loss of automatic respiration called Ondine's curse. In this study, we investigated the neuroanatomical correlates of CHS in patients with lateral medullary infarction (LMI). METHODS: Cases of CHS following LMI were identified from searching our medical records and literature. Voxel-based lesion-symptom mapping and lesion network-symptom-mapping (LNSM) analysis was performed to identify the regions connected to the lesion sites based on normative functional connectome data. RESULTS: Sixteen patients with CHS and 32 controls were included. The ventro-lateral region of the rostral medulla showed a significant association with CHS. LNSM analysis showed connections of this region to the rostral ventro-lateral medulla and caudal pons. CONCLUSIONS: In patients with LMI, disruption of the respiratory control network, at the level of ventro-lateral region of the rostral medulla, could result in CHS.

Portable multi-parameter electrical impedance tomography for sleep apnea and hypoventilation monitoring: feasibility study.

OBJECTIVE: Quantitative ventilation monitoring and respiratory event detection are needed for the diagnosis of sleep apnea and hypoventilation. We developed a portable device with a chest belt, nasal cannula and finger sensor to continuously acquire multi-channel signals including tidal volume, nasal pressure, respiratory effort, body position, snoring sound, ECG and SpO2. The unique feature of the device is the continuous tidal volume signal obtained from real-time lung ventilation images produced by the electrical impedance tomography (EIT) technique. APPROACH: The chest belt includes 16 electrodes for real-time time-difference EIT imaging and ECG data acquisitions. It also includes a microphone, accelerometer, gyroscope, magnetometer and pressure sensor to acquire, respectively, snoring sound, respiratory effort, body position and nasal pressure signals. A separate finger sensor is used to measure SpO2. The minute ventilation signal is derived from the tidal volume signal and respiration rate. MAIN RESULTS: The experimental results from a conductivity phantom, four swine subjects and one human volunteer show that the developed multi-parameter EIT device could supplement existing polysomnography (PSG) and home sleep test (HST) devices to improve the accuracy of sleep apnea diagnosis. The portable device could be also used as a new tool for continuous hypoventilation monitoring of non-intubated patients with respiratory depression. SIGNIFICANCE: Following the feasibility study in this paper, future validation studies in comparison with in-lab PSG, HST and end-tidal CO2 devices are suggested to find its clinical efficacy as a sleep apnea diagnosis and hypoventilation monitoring tool.

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.

Effects of Progressive Hypoventilation on Left Ventricular Appearance: An Alternative Etiology of Acute Sonographic Short-Axis D-Shaping.

OBJECTIVES: The purpose of this study was to evaluate the effects of progressive hypoventilation on echocardiographic measures of the left ventricular (LV) appearance in a porcine model. METHODS: Ten piglets were included in the experimental group, and 5 served as controls. The experimental group underwent 3 interventions of progressive hypoventilation (baseline: tidal volume, 240 mL; respiratory frequency, 16 minutes-1 ; first intervention: tidal volume, 240 mL; respiratory frequency, 8 minutes-1; second intervention: tidal volume, 240 mL; respiratory frequency, 4 minutes-1 ; and third intervention: tidal volume, 120 mL; respiratory frequency, 4 minutes-1 ). Respiratory resuscitation was initiated if the MAP decreased to 50% of the baseline level or at the end of the third intervention. Transthoracic sonography and invasive measurements were obtained throughout. The primary end point was the LV end-diastolic eccentricity index, a measure of LV D-shaping. RESULTS: The median LV end-diastolic eccentricity index increased from 1.1 (interquartile range, 1.0-1.1) at baseline to 1.4 (1.3-1.4) 3 minutes after the third intervention (P < .001) and returned to baseline after resuscitation (P = .093). The MAP declined from 87 mm Hg (81-92 mm Hg) to 50 mmHg (33-66 mm Hg) after initiation of the third intervention (P < .001). The mean pulmonary arterial pressure increased from 20 mm Hg (15-21 mm Hg) to 39 mm Hg (38-40 mm Hg) during the second intervention (P < .001). CONCLUSIONS: Progressive hypoventilation led to a marked D-configuration of the LV and a sharp decrease in systemic blood pressure. After respiratory resuscitation, sonographic measures normalized. These findings were explainable by the pressure changes observed within the left and right ventricles.

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.

In vivo dopaminergic and serotonergic dysfunction in DCTN1 gene mutation carriers.

INTRODUCTION: We used positron emission tomography (PET) to assess dopaminergic and serotonergic terminal density in three subjects carrying a mutation in the DCT1 gene, two clinically affected with Perry syndrome. METHODS: All subjects had brain imaging using 18F-6-fluoro-l-dopa (FDOPA, dopamine synthesis and storage), (+)-11C-dihydrotetrabenazine (DTBZ, vesicular monoamine transporter type 2), and 11C-raclopride (RAC, dopamine D2/D3 receptors). One subject also underwent PET with 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB, serotonin transporter). RESULTS: FDOPA-PET and DTBZ-PET in the affected individuals showed a reduction of striatal tracer uptake. Also, RAC-PET showed higher uptake in these area. DASB-PET showed significant uptake changes in left orbitofrontal cortex, bilateral anterior insula, left dorsolateral prefrontal cortex, left orbitofrontal cortex, left posterior cingulate cortex, left caudate, and left ventral striatum. CONCLUSIONS: Our data showed evidence of both striatal dopaminergic and widespread cortical/subcortical serotonergic dysfunctions in individuals carrying a mutation in the DCTN1 gene.

Evaluation of lung ventilation and alveolar permeability in cirrhosis.

UNLABELLED: This study sought to evaluate lung ventilation and alveolar permeability (AP) in patients with cirrhosis of the liver. METHODS: Pulmonary function in 29 patients with cirrhosis was measured by 99mTc-DTPA aerosol inhalation lung scintigraphy, using commercial lung radio-aerosol delivery units. Equilibrium lung ventilation images were visually interpreted according to the presence or absence of inhomogeneous distribution, inverted base-to-apex gradient and segmental defects. Degree of AP damage to the upper, middle, lower and total right lung was expressed as the slopes of the time-activity curves from dynamic lung images. The patients were classified into three groups, according to cirrhotic severity, using the modified Child's classification (A = good; B = fair; C = poor). Twelve healthy nonsmokers (2 women, 10 men; 42-75 yr old) formed the control group, and all had normal chest radiographic and pulmonary function test results. RESULTS: None of the 29 patients had significantly abnormal lung ventilation findings, but 13 had reduced lung ventilation in the basilar lung zone. The incidence of lung ventilation abnormalities was 20% (3 of 15), 50% (3 of 6) and 88% (7 of 8) in patients with nil, slight-to-moderate and moderate-to-severe ascites, respectively (p < 0.05 for nil versus moderate-to-severe ascites). The AP studies showed higher time-activity curve slopes for patients with cirrhosis than for normal control subjects. The slopes for the right total lung showed no significant differences among the three groups; however, those for right upper and right lower lung showed significant differences between some subgroups. In addition, albumin and bilirubin levels showed no significant correlation with slope values in cirrhotic patients. CONCLUSION: Although lung ventilation is normal in most patients with cirrhosis of the liver (16 [55%] of 29 in the present study), the disease can predispose patients to AP damage; however, the degree of damage is not related to cirrhotic severity.

[The effect of different ventilation under anaesthesia upon intracerebral x-ray findings (author's transl)]. / Der Einfluss unterschiedlicher Ventilationsgrössen unter Narkosebedingungen auf die Cerebralgefässe im Carotisangiogramm

In 35 patients carotid angiography was performed under general anaesthesia (Halothane or NLA) under hyper- and hypoventilation conditions. Hyperventilation led to arterial vasoconstriction. The changes in vessel diameter correlated with the difference from hyper- to hypoventilation. Under hypoventilation the veins were filled earlier and better. In case of tumour and in case of insult with angiographically verified blush the pathological vessels were better stained with hyperventilation. Anaesthetics did not influence the X-Ray findings. Patients should be hyperventilated during carotid angiography. Only in certain cases an angiogram under hypoventilation allows a clearer X-Ray interpretation.