Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
Central alveolar hypoventilation, a disorder of impaired ventilatory response to hypercapnia and hypoxemia, may be congenital, acquired, or idiopathic. Congenital central hypoventilation syndrome (CCHS) is most often caused by mutation of the gene PHOX2B and generally presents during the first year of life as respiratory failure in a neonate necessitating mechanical ventilation. These patients exhibit hypoventilation, which is generally worsened in sleep, and they may also suffer from varying degrees of dysautonomia. Rarely, these mutations are associated with neurocristopathies including Hirschsprung disease and malignancies of neural crest origin. Evidence is emerging linking PHOX2B mutations to structural changes within the central nervous system in patients affected by congenital central hypoventilation syndrome. The idiopathic form is characterized by decreased alveolar ventilation that leads to nocturnal hypercapnia in individuals who have no lung disease, obesity, skeletal malformation, or neuromuscular disorder to account for the hypoventilation. Central hypoventilation may also arise as an acquired disease in the context of brainstem injury or structural disorder.
• Central alveolar hypoventilation may be congenital (genetic), acquired, or idiopathic.
• The underlying neurologic disorder involves an absent or reduced response to carbon dioxide resulting in hypercapnia and hypoxemia.
• A thorough evaluation should be performed in all cases to rule out other identifiable neuromuscular, cardiopulmonary, and skeletal etiologies.
• Genetic testing and neurologic imaging are indicated in all suspected cases.
• Early diagnosis and initiation of nocturnal noninvasive positive pressure ventilation is a key therapeutic strategy.
Congenital central alveolar hypoventilation syndrome was first described in 1970, and the genetic etiology was finally elucidated in 2003 (63; 04). A full description may be found in the 2014 International Classification of Sleep Disorders—Third Edition (ICSD-3) under the name congenital central alveolar hypoventilation syndrome (01).
The term Ondine’s curse, which was first applied to the condition of central alveolar hypoventilation in a 1962 case series of 3 adult patients with high cervical and brainstem lesions following surgery, is derived both from an 1811 novella, Undine, by the German writer Friedrich de la Motte Fouqué and from a subsequent reimagining of the story in the 1938 play “Ondine” by Jean Giradoux (85; 31). In this play, Ondine, a water nymph, falls in love with a knight named Hans. However, their love is ill-fated, and when Ondine is jilted by Hans, her uncle, the King of the Sea, curses Hans. Hans loses all automaticity: “I don’t see unless I tell my eyes to see… A moment of inattention and I forget to hear, to breathe…” When he finally falls asleep, Hans stops breathing and dies. Ondine’s curse, therefore, properly refers only to the condition where hypoventilation is restricted to the sleeping state.
The idiopathically acquired form of central alveolar hypoventilation is also described in the ICSD-3 under Sleep-Related Nonobstructive Alveolar Hypoventilation, Idiopathic. It is characterized by blunted chemoresponsiveness in the absence of identifiable abnormalities (pulmonary, cardiac, neurologic, or muscular). When hypoventilation occurs during the day (in addition to nocturnal sleep), the condition is referred to as idiopathic (primary) alveolar hypoventilation.
• Congenital central alveolar hypoventilation syndrome usually presents in the first year of life as respiratory distress, shallow breathing, and cyanosis that are most evident during sleep.
• The phenotype can be incompletely penetrant, with some affected individuals being relatively asymptomatic and only incidentally diagnosed later in life.
• Congenital and acquired forms of the disorder can cooccur with a variety of conditions, usually dysautonomia in the former case and lesions in the brainstem, spine, or respiratory neurons in the latter case.
• In the case of congenital central alveolar hypoventilation, prognosis is usually good, with the benefit of earlier recognition and treatment with nocturnal ventilation.
Congenital central alveolar hypoventilation syndrome is a rare genetic condition, which generally presents in the first year of life, although later presentations are reported (52; 15). Typically, the newborn presents with respiratory distress, shallow breathing, and cyanosis and requires mechanical ventilation and transfer to an intensive care unit. Abnormal blood gases with hypercapnia are a hallmark for this condition. Elimination of other causes of abnormal breathing, such as sepsis, cardiac malformation, seizure disorder, and neuromuscular disease is important. Congenital central hypoventilation syndrome is a dysfunction of the autonomic control of breathing, and the diagnosis may be confirmed by abnormal responses to hypercapnic challenge during sleep as noted in polysomnography, and the syndrome is definitively identified by genetic testing for PHOX2B mutation (28).
The spectrum of clinical presentation of congenital central alveolar hypoventilation syndrome is broad. Mild hypoventilation and shallow breathing during quiet sleep accompanying normal ventilation during wakefulness may be seen. In more severe cases, children demonstrate severe apneas and hypoventilation during sleep and various degrees of hypoventilation during wakefulness, with the development of serious respiratory acidosis due to a partially or completely absent response to hypercapnia and hypoxemia. Autonomic and brainstem dysfunction are often found. Rarely, infants may present with a syndrome of Hirschsprung disease and/or neuroblastoma before the subsequent development of respiratory issues (11).
The previous clinical criteria for diagnosing congenital central hypoventilation syndrome included (1) persistent hypoventilation during quiet (non-REM) sleep with PaCO2 greater than 60 mmHg; (2) symptoms during the first year of life; and (3) an absence of lung, cardiac, or neuromuscular disease (02). The 2010 revised recommendations now also require PHOX2B gene mutation to confirm the diagnosis of congenital central alveolar hypoventilation syndrome (03). Additionally, genetic testing of parents with affected children is also recommended.
Congenital central alveolar hypoventilation may occur in association with the following disorders:
• Autonomic nervous system dysfunction: elevated heart rate levels and reduced heart rate variability (109; 99), abnormal circadian blood pressure pattern (100), and bradyarrhythmias from hypercapnic acidosis (88). Familial dysautonomia has also been reported.
• Derivatives of neural crest malformation: Hirschsprung disease is a congenital aganglionosis of the intestines and occurs in 13% to 50% of patients with congenital central alveolar hypoventilation. Haddad syndrome is the combination of congenital central alveolar hypoventilation and Hirschsprung disease. Both entities belong to a family of disorders called neurocristopathies, referring to an early disturbance in neural crest cell development (103).
• Derivatives of neural crest tumors: neuroblastoma and ganglioneuroma.
• Ophthalmological abnormalities: cranial nerve palsies, Leber hereditary optic neuropathy (83) and convergence insufficiency, strabismus, and pupillary abnormalities (30).
• Esophageal dysmotility: lower esophageal motility dysfunction (23).
• Central nervous system malformation: Chiari II malformation and Leigh disease (39).
A variant of central hypoventilation, known as late-onset central hypoventilation syndrome, presents in previously healthy children and has features similar to congenital central alveolar hypoventilation. Additional features include rapid-onset obesity, hypothalamic dysfunction (45), hypoventilation, and autonomic dysregulation (ROHHAD). Respiratory failure is usually precipitated following a respiratory tract infection, administration of an anesthetic or a hypnotic, or by adenotonsillar hypertrophy.
Idiopathic central alveolar hypoventilation occurs as a result of reduced ventilation, which leads to nocturnal hypercapnia and hypoxemia. Unlike congenital central hypoventilation syndrome patients, who, when properly ventilated at night, do not have sleep abnormalities, patients with idiopathic central alveolar hypoventilation typically exhibit sleep fragmentation (insomnia with frequent arousals and wake episodes) and lighter stages of sleep (05). Daytime symptoms include hypersomnolence, morning headaches, peripheral edema, polycythemia, and cor pulmonale, with abnormal pulmonary function tests.
Comparatively, the acquired form of central alveolar hypoventilation is typically caused by a structural lesion, which leads to the loss of control of automatic respiration. It occurs in all ages and may result from asphyxia, central nervous system infection, trauma, tumor, cerebral infarction, or intracranial hemorrhage. Following recovery from coma, hypercapnia is noted, sometimes along with brainstem lesions identifiable on MRI. The acquired form may be most evident in obese, middle-aged subjects, with an estimated prevalence of 0.3% in the general population (67).
Patients have an attenuated sense of breathlessness following exercise, particularly underwater swimming. The condition often becomes apparent after acute respiratory failure requiring intubation followed by carbon dioxide retention or difficulty weaning from the ventilator and can be unmasked in the setting of standard administration of sedatives.
Numerous case reports of association with other disorders or other acquired forms are described:
• Acute respiratory failure in obese males induced by infection, trauma, or high altitude (62).
• Bilateral cervical cordotomy, more commonly performed in the 1960s (50).
• Neurosarcoidosis with diaphragmatic paresis secondary to sarcoid lesion (48).
• Cervical anterior spinal artery syndrome presumably secondary to a reticulospinal pathway lesion, which normally activates ventilatory muscles during sleep (60).
• Resolution of Ondine curse in a 72-year-old woman after suboccipital decompression (34).
• Eventration of the diaphragm as a result of birth injury, cardiothoracic operation, or part of a congenital condition affecting phrenic nerve (26).
• Medullary thyroid cancer (78).
• Cerebral venous thrombosis (09).
• Vascular bilateral posterolateral medullary infarcts, visible on MRI (19), Leigh syndrome, or other metabolic disorders (18).
• Bilateral medullary plaques caused by multiple sclerosis (06).
• Alternative ptosis of both the right and left eyes and esotropia (64).
• Following Haemophilus influenzae type b meningitis and extensive herpes simplex infection with subsequent brainstem and cervical cord injury (96).
• Bilateral medullary myeloma lesions with clinical response to chemotherapy but persistent hypoventilation and central sleep apnea (79).
• Central apneas and hypoventilation in sleep secondary to interictal epileptiform discharges (57).
• Central hypoventilation, drowsiness, hypoxia, falls, and upper extremity weakness and numbness in the setting of os odontoideum (12).
• Central alveolar hypoventilation caused by aneurysmal megadolichobasilar artery (36).
• Development of central alveolar hypoventilation approximately 4 years after the onset of progressive supranuclear palsy (38).
• Central alveolar hypoventilation secondary to a lateral medullary infarction after endovascular patent artery occlusion for vertebral artery dissecting aneurysm (94).
• Ondine’s curse co-occuring with temporal lobe seizures related to para-neoplastic antibodies (anti-Hu and Zic4) in the context of small cell lung cancer (46).
In the case of congenital central hypoventilation syndrome, morbidity and mortality are related to timely diagnosis and referral to an experienced pediatric center. Serious complications include cardiac arrhythmias, lethargy, respiratory arrest, and, most seriously, death during sleep. The prognosis is generally worse in patients with Hirschsprung disease, ganglioneuroma, or neuroblastoma. Prolonged survival and an overall good quality of life are possible today, and with earlier recognition of the syndrome, serious complications can be avoided.
Children and adolescents with congenital central hypoventilation syndrome may also have developmental and cognitive problems that require special attention. One study demonstrated problems in working memory functions, interpersonal communication, and daily living skills in this population; however, it suggested near-normal intelligence quotients (82). In a study comparing congenital central hypoventilation syndrome patients to their parents, the children scored significantly below their parents in indices of intelligence, vocabulary, and abstraction, as well as below population normative data for IQ, reasoning, processing speed, and working memory (111). Measures of neurocognitive function may already be reduced in preschool-age children (13).
A full-term infant born by cesarean section to non-consanguineous parents underwent further evaluation when he did not pass meconium in the first 24 hours of life. Work-up revealed signs of intestinal obstruction and prompted colonic biopsy that showed findings consistent with Hirschsprung disease. The patient was intubated and sedated for an ileostomy and successfully discharged home afterwards.
However, at 4 weeks of life, he was noted to develop unusual pauses in breathing while sleeping, which prompted readmission to the hospital. Further work-up revealed that the patient was having oxygen desaturations associated with these pauses in breathing. Arterial blood gas analysis revealed a compensated respiratory acidosis. He was intubated and ventilated. A diagnosis of congenital central hypoventilation syndrome was suspected and prompted PHOX2B mutation analysis. This revealed a heterozygous non-polyalanine repeat (NPARM) mutation. After discussion with family regarding the diagnosis of congenital central hypoventilation syndrome, the family agreed to placement of a tracheostomy.
Further review of family history revealed that the patient’s maternal uncle had also had Hirschsprung disease and died of a neuroblastoma at 4 years of age. The patient’s mother denied any history of sleep disturbance. She underwent genetic testing for PHOX2B mutation and was found to have the same NPARM mutation. Empiric evaluation of the patient’s mother’s sleep revealed mild central sleep apnea. The patient’s grandparents also underwent genetic testing, and the grandfather was found to also be heterozygous for the same mutation carried by his daughter and grandson.
This case is a modified version of a case reported by Low and colleagues in Pediatric Pulmonology (56). As discussed in this article, NPARM mutations account for roughly 10% of PHOX2B mutations and usually result in more severe, syndromic manifestations of the disease, as in this patient’s case—presenting with Haddad syndrome. However, this case also speaks to the variable penetrance of this mutation given a lack of symptoms in both the grandfather and the patient’s mother.
• The main genetic mutation associated with congenital central hypoventilation is PHOX2B, which is believed to be involved in early neural crest cell migration with a central role in the generation of normal respiratory patterning and autonomic function.
• Disruption of the upstream and downstream components of the Phox2b pathway in the ventral medullary chemostatic centers likely explains the impaired ventilatory response, which is most evident in sleep due to the lack of volitional respiratory control.
Genetics. Congenital central hypoventilation syndrome is most often due to heterozygous mutations of the gene encoding paired-like homeobox 2b, PHOX2B, a transcription factor that maps to chromosome 4p12. PHOX2B is expressed in both the central and the peripheral autonomic nervous system during human embryonic development. It is believed to be involved in early neural crest cell migration with a central role in the generation of normal respiratory patterning and autonomic function. It is also the predisposing gene for occurrence of neuroblastoma in different mutational patterns, ganglioglioma, and Hirschsprung disease.
Function. Phox2b expression in the brainstem respiratory network is preferentially associated with neurons involved in chemosensory integration, specifically by a chain of neurons involved in the integration of peripheral and central chemoreception. Studies in Phox2b transgenic mice suggest that hypercapnic ventilatory response impairment in congenital central hypoventilation syndrome may be related to Phox2B-expressing neuronal loss or maldevelopment in the nucleus tractus solitarius and retrotrapezoid nucleus, which are important centers of respiratory chemoreception and control (35; 27).
PHOX2B mutations disrupt breathing automaticity during sleep without causing major impairment of respiration during waking (91).
Genotype-phenotype correlations. Heterozygous mutations in PHOX2B were found in individuals with congenital central hypoventilation syndrome, with at least 90% of PHOX2B gene mutations consisting of abnormal alanine expansions within a 20-repeat polyalanine expansion tract in exon 3 resulting from (GCN)n triplet repeat expansions (Parodi et al 2007; 43). In a Japanese cohort of 92 subjects, 86 had polyalanine repeat mutations (PARMs) and 6 had nonpolyalanine repeat mutations (NPARMs). Of the subjects with PARMs, it was noted that all subjects with 26 or more repeats presented with hypoventilation at birth. Those with 25 or fewer repeats had hypoventilation at variable timepoints or not at all (87). As such, the association of increased number of repeats with more severe respiratory presentation has been suggested, though rare cases of delayed/adult presentations in individuals with over 6 additional repeats suggest incomplete penetrance through a multitude of gene-gene interactions (44). Comparatively, NPARMs comprise less than 10% of PHOX2B mutations and are known to produce more severe disruption of PHOX2B function, usually presenting as a syndrome associated with Hirschsprung aganglionosis and/or neurocristopathies (43).
Other associated genes. Increased prevalence of ventilatory dependence, Hirschsprung disease, and neural crest tumors were seen more frequently in the NPARM group as compared to those with polyalanine repeat mutations (Berry-Kravis et al 2006; 11). Other mutations have been described in association with the congenital central hypoventilation syndrome phenotype, including genes involved in migration of neural crest origin, as well as genes upstream and downstream of Phox2b in biological pathways such as RET, GDNF, EDNRB, EDN3, LBX1, and MYO1H (25; 37). The involvement of multiple genes suggests that the genetic involvement has a complex pattern of inheritance.
Pathophysiology. The primary factors controlling breathing are arterial carbon dioxide via brain tissue pH. Alveolar ventilation is principally a function of carbon dioxide, as oxygen tension is normally maintained at levels higher than those that induce stimulation of the breathing system. Ventilatory responses to hypercapnia and to hypoxia help to maintain normal arterial blood gas tension (93). Peripheral chemoreceptors mediate responses to hypoxia, whereas central chemoreceptors mediate responses to carbon dioxide (via hydrogen ion concentrations). The central chemoreceptors are thought to be located near the surface of the fourth ventricle on the ventral side of the medulla oblongata, rostral and medial to the hypoglossal roots. Normally, progressive hypercapnia induces a linear increase in minute ventilation, whereas progressive hypoxia induces a hyperbolic increase. If a defect impairs the sensory system for monitoring carbon dioxide levels, ventilation is affected, particularly when sleep results in the loss of "wake stimuli" and volitional breath control, which facilitate control of ventilation during wake (24).
In patients with congenital central alveolar hypoventilation syndrome, exposure to 100% oxygen results in further hypoventilation compared to baseline, suggesting that the peripheral chemoreceptors are functional. The extent of hypoventilation is also state dependent, being maximal during deep NREM sleep with relatively normal gas exchange during REM (86). During wakefulness, children with congenital central alveolar hypoventilation have absent rebreathing ventilatory responses to hypoxia and hypercapnia. During exercise, children with congenital central alveolar hypoventilation may become hypoxic and hypercapnic; they increase their minute ventilation primarily by an increase in respiratory rate rather than by tidal volume. Further, minute ventilation does not match carbon dioxide production.
Neuroimaging and structural correlates. Structural and functional imaging with MRI indicates abnormalities in both the forebrain and the brainstem (76). Whether these changes contribute to the pathogenesis or are a result of tissue hypoxia is unclear. Postmortem analysis of neonatal lethal cases has shown loss of neurons in the locus coeruleus. This is mirrored in abnormal development of the locus coeruleus in a transgenic mouse model of the same PHOX2B mutation (70). Although radiological evaluations of the brain have failed to identify a lesion to account for the clinical and physiological features, a functional MRI compared activity at baseline and at 2 minutes of hypoxic challenge (15% oxygen, 85% nitrogen) in congenital central hypoventilation syndrome patients compared to controls. Results showed significant differences in the magnitude and timing of responses between the 2 groups indicative of deficient neurovascular activation in response to hypoxia (late or none) in congenital central hypoventilation syndrome patients, specifically in the posterior thalamic, cerebellar, midbrain, and limbic structures (58). These findings partially explain the absent perception of air hunger and lack of discomfort in patients with congenital central hypoventilation syndrome.
Association of congenital central hypoventilation syndrome with the occurrence of Hirschsprung disease, congenital neuroblastoma, ganglioneuroblastoma, and benign ganglioneuroma suggests that the primary defect relates to neural crest cell migration and function. Vagal hyperresponsiveness, sinus pauses, bradyarrhythmia, and an attenuated response to endogenous sympathetic stimulation suggest a diffuse alteration in autonomic nervous system function (71). In line with this hypothesis is the finding that autonomic nervous system dysfunction was more common in relatives of the patients with the syndrome compared to control subjects (108).
Comparatively, idiopathic alveolar hypoventilation syndrome is not associated with structural lesions and does not appear to have an identifiable etiology.
• Incidence is estimated to be anywhere from 1 per 150,000 to 1 per 200,000 live births.
Congenital, idiopathic, and acquired forms of central alveolar hypoventilation are rare. According to the French Congenital Central Hypoventilation Syndrome Registry, in 2005 the incidence was estimated to be 1 per 200,000 live births in France with an overall mortality rate of 38%, and a median age of death of 3 months (98). The median age of diagnosis was 3.5 months prior to 1995, but it has improved to less than 2 weeks in recent years. In a 2005 analysis of 43 patients in the French Congenital Central Hypoventilation Syndrome Registry, individuals had a mean age of 9 years (range 2 months to 27 years), 16% had Hirschsprung disease, and 31 (91%) of the 34 genetically tested individuals were heterozygous for PHOX2B mutations (98). An estimate of the minimum incidence of congenital central hypoventilation syndrome in Japan was calculated to be an average 1 per 148,000 births for years 2008 to 2013 (87), possibly due to increased awareness of the condition.
• There are no known preventive strategies other than early detection and appropriate counseling of parents who are known to be carriers of the mutation.
• Central nervous system depressants (including alcohol) should be avoided, whenever possible, due to the concomitant respiratory depression.
• Due to the likelihood of dysautonomia, cardiology consultation is important for evaluation and determination as to whether a pacemaker is needed.
No means of prevention are known for congenital or idiopathic central alveolar hypoventilation. However, early recognition of the disease and associated risk factors can expedite interventions and possibly preserve neurocognitive function. Case reports of mother-daughter transmission, siblings, and twins with congenital central hypoventilation syndrome suggest that genetic counseling of parents and siblings is appropriate after identification of individuals with congenital central hypoventilation syndrome. This is particularly relevant given the association noted between sudden infant death syndrome (SIDS) and PHOX2B polyalanine length variants in certain populations (53). There are cases reported of severe adverse events, including coma and death, related to alcohol use in adolescents and young adults with congenital central hypoventilation. Patients should be advised to abstain from alcohol or other substances that are known to cause respiratory suppression (14). One of the more serious yet preventable complications of central hypoventilation syndrome is cardiac autonomic dysregulation, which can lead to sudden death (33). Early cardiac workup and prediction for the need of a pacemaker is crucial. When genetic testing reveals PHOX2B mutations in asymptomatic adult family members, these patients should be followed longitudinally for the development of respiratory and cardiac disturbances (43).
The infant presenting with apnea or respiratory failure must have other more common etiologies rigorously excluded, including sepsis, pulmonary infections, cardiopulmonary and neurologic malformations, intoxication, trauma, and neuromuscular disease.
In the adult with unexplained respiratory failure and inability to wean from mechanical ventilation, the differential diagnosis includes obstructive and restrictive lung disease, severe ventilation-perfusion mismatch associated with pulmonary emboli or other causes, respiratory muscle weakness or fatigue, neuromuscular disease, and toxins affecting neuromuscular or central nervous system function. Adults with nocturnal hypoxemia or hypercapnia should also be considered for other disorders, such as obstructive sleep apnea syndrome, central sleep apnea syndrome, and obesity hypoventilation syndrome.
Rarely, the congenital form of central alveolar hypoventilation is associated with neurocristopathies including Hirschsprung disease and malignancies of crest cell origin, including congenital neuroblastoma, ganglioneuroblastoma, and benign ganglioneuroma. As a result of involvement of neural crest cells, dysautonomia – vagal hyperresponsiveness, sinus pauses, bradyarrhythmia, and/or an attenuated response to endogenous sympathetic stimulation – is frequently present, even in individuals who may not have significant respiratory symptoms (71; 51).
Lesions anywhere along the pathway from the chemoreceptive centers in the medulla, through the high cervical spine, to the phrenic nerves can result in an acquired form of central alveolar hypoventilation. As such, various disorders have been associated with the acquired form: vascular (medullary infarct, cervical anterior spinal artery syndrome, cerebral venous thrombosis), inflammatory/immunologic (neurosarcoidosis, multiple sclerosis, anti-Hu and Zic4 paraneoplastic antibodies), infectious (meningitis), traumatic (cordotomy, anatomic brainstem compression), oncologic (metastatic), and neurodegenerative (progressive supranuclear palsy).
• The 2010 American Thoracic Society policy statement indicated that genetic testing for the PHOX2B gene mutation is key to the diagnosis of congenital central alveolar hypoventilation.
• Attended polysomnography is recommended at the time of initial investigation (in order to demonstrate sleep-related hypoventilation) and repeated every 3 to 4 months until age 5 or 6 and yearly thereafter.
• Other diagnostic evaluations are used in order to rule out confounding conditions that may underlie the acquired form or can masquerade as the congenital form including primary pulmonary investigation with chest x-ray or computed tomography (CT) scan, neurologic evaluation including MRI and consideration of neuromuscular diagnostics, and structural and physiologic cardiac investigations.
According to consensus of the American Thoracic Society published in 1999, the diagnosis of congenital central alveolar hypoventilation syndrome required monitoring during sleep without mechanical ventilation. The 2010 American Thoracic Society policy statement concluded that suspected congenital central alveolar hypoventilation syndrome diagnosis is confirmed by demonstrating a PHOX2B gene mutation by sequential testing starting with a screening test that, if negative, should be followed by the sequel PHOX2B sequencing test in cases of high clinical suspicion (107). This statement also specifies other testing and diagnostic thresholds of such testing. These include tests to rule out other etiologies of hypoventilation: chest x-ray or computed tomography (CT) scan, neurologic evaluation including MRI and consideration of muscle biopsy, and echocardiogram. These tests are described further below.
Cardiopulmonary evaluation. Electrocardiogram, echocardiogram, Holter monitoring, and chest x-ray or CT may be indicated to rule out autonomic dysfunction, right heart failure, pulmonary hypertension, and primary lung disease. In 1 retrospective study, congenital heart disease was found in 30% of patients with molecularly confirmed congenital central hypoventilation syndrome, primarily manifesting as anomalies of the proximal aortic arch and proximal coronary arteries (55). Furthermore, in a retrospective chart review of 72 congenital central alveolar hypoventilation patients, 22% (16) had evidence of potential life-threatening cardiac arrhythmias, most of which had significant sinus pauses on ambulatory monitoring without necessarily manifesting symptoms of syncope, dizziness, chest pain, tingling in the left arm, or palpitations (51).
Imaging studies. MRI of the brain should be performed to evaluate for intracranial lesions. The acquired forms are associated with intracranial hemorrhage, ischemic stroke, or tonsillar herniation. If Hirschsprung disease is suspected, MRI of the spine is indicated as well to evaluate the patient for ganglioneuromas.
Neurologic evaluation searching for hypotonia and neuromuscular disorders. Testing involves nerve conduction studies and electromyography. Muscle biopsy to look for myopathic disorders and pupillometry to assess for autonomic dysfunction may have a role as well (77). If diaphragmatic paresis is suspected, physicians should perform diaphragmatic fluoroscopy and ultrasound. If Hirschsprung disease is present, barium enema will show bowel distention, and colon biopsy will demonstrate an aganglionic colon.
Metabolic and mitochondrial disease screening. Late-onset congenital central hypoventilation syndrome in children may present with nonspecific signs, including cardiopulmonary compromise, autonomic dysregulation, and hypotonia, and it can masquerade as a metabolic syndrome (eg, Leigh disease, pyruvate dehydrogenase deficiency, and carnitine deficiency) (81). In the early stages of evaluation, consultation with a medical geneticist may be helpful.
Genetic workup. Clinical diagnostic testing for congenital central hypoventilation syndrome involves targeted mutation analysis or sequence analysis. Polyacrylamide gel electrophoresis PHOX2B screening testing is an appropriate first-line investigation. If negative in the setting of suspected congenital central alveolar hypoventilation syndrome, the sequel PHOX2B sequencing test should be performed (41). More information can be accessed at the following site:www.genetests.org.
It is recommended that a sleep study be performed at the time of initial work-up (07), followed by every 3 to 4 months until 5 to 6 years of age. Annual evaluation after 6 years of age is adequate, provided the patient is stable (32), as the patients require assisted ventilation throughout their lifetime.
Evaluation of patients with suspected idiopathic central hypoventilation. For adults presenting with unexplained (idiopathic) hypoventilation or hypoxemia infectious, cardiac, pulmonary, and neuromuscular causes must be excluded. Patients with idiopathic alveolar hypoventilation syndrome show evidence of abnormal pulmonary function with formal testing, as well as polycythemia, chronic hypoxemia, and hypercapnia, and it has been suggested that an elevated serum bicarbonate level may be of diagnostic value (61). If a mutation of PHOX2B is identified in a child, gene mutations should be systematically examined in any biological adult relative with unexplained central hypoventilation, and all, even apparently healthy, biological parents in order to determine if they harbor a somatic mosaic (101). One report indicates the possibility of germline mosaicism for PHOX2B mutations in parents, emphasizing the importance of screening subsequent pregnancies in families with a child that has congenital central hypoventilation syndrome (80). Adults who present with reduced cardiac baroreflex and blunted sympathetic mediated response should be suspected of having the adult-onset type of central alveolar hypoventilation (20). Polysomnography often demonstrates periods with reduced tidal volumes lasting several minutes along with sustained hypoxemia, which tends to worsen during REM sleep. Hypercapnia occurs during episodes of hypoventilation, due to a decreased minute ventilation. Polysomnography with the monitoring of blood gases by arterial catheter will typically demonstrate central apneas with hypercapnia that is greatest in NREM sleep, less pronounced in REM sleep, and least apparent during wakefulness. Apnea duration may increase at the end of the night, reflecting further blunting by sleep fragmentation of already abnormal arousal responses.
• The goal of treatment is to ensure adequate ventilation, particularly during sleep.
• Ventilation during sleep must be assessed regularly and an apnea-heart rate alarm should be used.
• Tracheostomy is required in a number of cases but due to risks of infection and impairments of speech and swallowing, transitioning to noninvasive positive pressure ventilation should be a therapeutic goal when safe and tolerable.
• If ventilation is inadequate during both wakefulness and sleep, diaphragmatic pacing is a practical alternative once the patient is ambulating.
The goal of treatment is to ensure adequate ventilation, particularly during sleep, as these metabolic perturbations, especially in congenital central alveolar hypoventilation syndrome, have neurocognitive sequelae (110). Initial management often requires intubation and mechanical ventilation.
Available options for long-term mechanical ventilation include noninvasive positive airway pressure (PAP) ventilation with bilevel positive airway pressure in the spontaneous/timed mode (S/T) or intelligent volume-assured pressured support (iVAPS), phrenic nerve/diaphragmatic pacing, negative pressure ventilation by body chamber, and tracheostomy (16; 47). Chronic mechanical ventilation dependence is the norm.
If central alveolar hypoventilation is a problem only during sleep, nasal ventilation is suitable. In infants with this disorder, early use of noninvasive positive pressure (nasal bilevel positive airway pressure) decreases complications caused by prolonged artificial ventilation or tracheostomy (65). However, in 2 infants, bilevel positive airway pressure (with spontaneous/timed mode) failed to provide suitable ventilation and tracheostomy was performed; therefore, application of bilevel positive airway pressure for patients younger than 5 years might not be the general norm of treatment (17). Newer modes of invasive or noninvasive support, such as average volume-assured pressure support, may be tried for comfort or changing needs of individual children as they age (102). Ventilation during sleep must be assessed regularly, and an apnea-heart rate alarm should be used.
Preparation should be made for a trial of a negative pressure chamber to avoid potential complications of pseudoprognathism or midface hypoplasia, which are commonly associated with prolonged use of nasal masks for noninvasive positive pressure ventilation in children (NPPV). Negative pressure ventilators of the cuirass or poncho type may be used additively with bilevel positive airway pressure to prevent upper airway closure due to negative pressure suction initiated by the ventilator and the lack of coordination between ventilator and upper airway muscle contractions. One study found that homecare support is beneficial for children needing mechanical ventilation, and it represents a valid alternative to long hospitalization for children with stable chronic respiratory failure (73).
Tracheostomy for children carries risks of morbidity and mortality and is associated with complications such as speech and swallowing impairments and infections of the upper airway. Eventual transition from this invasive form of ventilation to NPPV is possible during childhood with a proposed stepwise approach being put forward on how to make the transition (75). If tolerated, tracheostomies should be capped during the day and attached to a ventilator with humidified air at night. Despite the complications associated with tracheostomy, 1 study of the neurocognitive function of 88 children with congenital central alveolar hypoventilation syndrome over the age of 6 suggested that early (< 3 months of age) tracheostomy was associated with higher cognitive function than delayed (> 3 months of age) tracheostomy or NPPV (72).
If ventilation is inadequate during both wakefulness and sleep, diaphragmatic pacing is a practical alternative once the patient is ambulating. There is a potential for obstructive apnea to occur if pacing results in decannulation of tracheostomy; however, this can be mitigated by optimizing stimulator amplitude in response to polysomnographic findings (68; 106). Evaluation of enlarged tonsils and adenoids is essential to determine if removal is required in the context of obstructive sleep apnea. Occasionally, bilateral pacing is usually required, especially in infants and young children with congenital central hypoventilation syndrome, and it may be successfully implemented in children as young as 9 months of age (21). An alarm and regular assessment of the integrity of the system are required to prevent unexpected respiratory failure (10). Complications include destruction of the phrenic nerve, inability to pace the nerve at the time of surgery, infection and dehiscence of the surgical site, and breakage of the electrode wire. Malfunction of any part of the equipment may also occur, with failure of the receiver expected about 4 years to 5 years after placement. Although technical problems are substantial, a survey of 150 subjects using diaphragmatic pacing found that 64% lived at home, 23% were in a hospital, 13% were in rehabilitation, and less than 5% were in nursing homes (29).
Consideration should be given to social surroundings, family support, bed partner, age, life expectancy, and financial situation. The initiation and follow up of nocturnal noninvasive positive airway pressure support for stable alveolar hypoventilation syndromes have previously been reviewed (08). Although the condition is serious, it can be controlled with prospects for optimal daytime performance, employment, and social life. Patients can be transitioned from one device to another in order to obtain optimal management (for example, from bilevel positive airway pressure to negative chamber ventilation or phrenic nerve pacing), but transition may be challenging if the child is younger than 7 years of age (95).
Although congenital central hypoventilation syndrome is classically a chronic and permanent condition, cases have been reported in which clinical improvement or remission was possible. Clinical improvement with medroxyprogesterone in a patient with a right-sided pontomedullary stroke has been described (89). Two children with congenital central alveolar hypoventilation syndrome were successfully weaned off of mechanical ventilation with exogenous medroxyprogesterone (66). Another case report describes recovery of chemosensitivity to carbon dioxide in a woman with congenital central alveolar hypoventilation syndrome associated with desogestrel, a potent oral contraceptive (92). This relationship was further investigated in a mouse model, which suggested that desogestrel may improve resting ventilation in congenital central hypoventilation syndrome patients by stimulating baseline respiratory frequency, a known physiologic effect of progesterones (42). In addition to restoring a degree CO2 chemoresponsiveness, gonane progestins appear to increase the basal respiratory drive (54). That being said, pharmacologic management is unlikely to be sufficient for most patients who ultimately require ventilatory assistance, at least during sleep. It has also been noted that the antiepileptic medication carbamazepine improved daytime apneic episodes in a single patient but had no overt effect on sleep-related hypoventilation (84).
Despite varying courses and severities between patients, life-long follow-up is recommended. Cardiac monitoring should be performed to surveil for the emergence of abnormalities, particularly sinus pauses (100). One patient, who already utilized a diaphragmatic pacer, was successfully treated by the implantation of a dual chamber pacemaker for arrhythmias (49). No device-device interaction was noted in another patient with cardiac and diaphragmatic pacemakers for congenital central hypoventilation (68). Routine pulse oximetry, end-tidal carbon dioxide levels, and frequent checks of the ventilatory system chosen are essential to ensure continued efficacy.
Finally, children with congenital central hypoventilation syndrome may experience progressive worsening of social cognition and executive function, and therefore, close monitoring of developmental milestones and serial neurocognitive evaluation, paired with early intervention, should be considered (22).
Over the last few decades this disorder has evolved from one of high neonatal mortality to a less severe or diverse array of phenotypes that are being recognized later in life in both primary, genetic cases as well as in association with precipitating CNS pathology. Despite some pharmacologic agents bearing benefits for ventilation (eg, carbamazepine and desogestrel), there is currently no cure for the condition. The mainstays of treatment are lifetime assisted ventilation and multidisciplinary care. However, with carefully coordinated care and safety precautions most individuals are able to live reasonably normal lives, given that the main focus of treatment is resolution of sleep-predominant inadequate sleep drive through invasive and noninvasive ventilatory support or neurostimulation.
Among individuals with the mutation-based, congenital form of the disease, neurocognitive outcomes are often related to the nature and timing of ventilation (97). Nonetheless, most individuals generally demonstrate low-average intelligence (97). Moreover, awareness of other associated conditions – from clinically significant dysautonomia (most importantly lethal asystole) to gastrointestinal dysmotility to neural-crest-cell-derived tumors – has led to a multidisciplinary approach that can effectively assess and manage all dimensions of care resulting in only a modest adverse impact of the condition on patient quality of life (104).
Patients with congenital central alveolar hypoventilation syndrome often have children of their own. The theoretical hazard of reduced central ventilatory drive in congenital central alveolar hypoventilation syndrome, combined with the mechanical load of the enlarging uterus, mandates frequent respiratory monitoring with mechanical ventilation in sleep and during spontaneous breathing while awake (03). As such, in apparently healthy individuals late-onset CHS might be unmasked by an otherwise uncomplicated pregnancy (90). In individuals with a known congenital central hypoventilation syndrome phenotype, prenatal PHOX2B gene testing of the fetus is also recommended to plan care of the newborn.
Anesthesiologists should be made aware of the disorder in order to plan for appropriate postoperative airway and ventilatory management. One case reports successful anesthetic management and recovery from a dental procedure in a child with congenital central hypoventilation syndrome and Hirschsprung disease (40). Another case involved a child who presented with unanticipated postoperative respiratory complications after anesthesia for elective tonsillectomy; the child eventually required a tracheostomy and long-term ventilatory support (59). One report highlights the following considerations regarding administration of anesthesia to central alveolar hypoventilation patients (69):
• Regional anesthesia (eg, lumbar epidural) is preferred.
• Spinal anesthesia should be avoided as it may precipitate hemodynamic instability.
• Short-acting anesthetic agents are preferred.
• Due to hypotonia, avoidance of neuromuscular blocker agents during intubation is advised (69).
On occasion, central hypoventilation due to brainstem lesions or compression may be unmasked with the use of anesthesia (105).
Chronic respiratory disease in childhood can be a major stressor for families. The parents of children with congenital central hypoventilation syndrome have poor sleep quality, increased daytime sleepiness, and higher scores on a depression index than the parents of healthy subjects (74). In such cases, is important to counsel parents on the importance of their own wellness as well as establish cautious but hopeful expectations regarding the efficacy of therapies.
Logan Schneider MD
Dr. Schneider of Stanford University School of Medicine received a stock grant from Knit Health as an advisor, a stock option from Hatch Baby as an advisor, consulting fees from Harmony Biosciences and Jazz Pharmaceuticals for speakers bureau, and a consulting fee from Alphabet.See Profile
Michael J Howell MD
Dr. Howell of the University of Minnesota has no relevant financial relationships to disclose.See Profile
Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Jan. 18, 2022
Sleep disturbances are common after traumatic brain injury, affecting 30% to 84% of individuals, with varying degree of head injury. Not only can they
Dec. 04, 2021
Delayed sleep-wake phase disorder is a circadian rhythm sleep disorder characterized by late bedtime and wake times and an inherent delay of biological rhythms compared to the natural daylight, usually beginning in adolescence. Patients have otherwise normal sleep in quality and quantity. Treatment typically includes melatonin and bright light, augmented with behavior and lifestyle modifications.
Nov. 06, 2021
African sleeping sickness is a devastating epidemic that affects tens of thousands of sub-Saharan Africans. The causative agent usually belongs to 1 of 3 species of the Trypanosoma genus and is transmitted to humans through a vector, the tsetse fly. Neurologic manifestations, including headache, altered EEG, and mood changes, may occur during the initial febrile period before trypanosomes can be detected in the cerebrospinal fluid and are associated with meningeal inflammation.
Oct. 09, 2021
Neuropharmacology & Neurotherapeutics
Modafinil is indicated for the management of excessive daytime sleepiness associated with narcolepsy. The FDA has approved its use to improve wakefulness in patients with excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome and shift-work sleep disorder. Although modafinil improves measures of sleepiness, it does not normalize them because it does not correct the basic underlying cause. Therefore, treatment may be required for an indefinite period.
Oct. 06, 2021
Confusional arousals are a type of parasomnia categorized under disorders of arousal, which generally emerge from stage N3 sleep (delta sleep) or relate to arousals occurring during non-REM stage N1 or N2 sleep. Common behaviors include confusion, disorientation, loss of memory and conversing, relative unresponsiveness to environmental stimuli, and display of more or less complex automatic behavior.
Oct. 05, 2021
Oct. 04, 2021
Insomnia appears in several forms: (1) difficulty initiating sleep, (2) repeated or lengthy awakenings, (3) early awakenings, (4) inadequate total sleep time, or (5) poor quality of sleep as reflected by its consequences, including daytime sleepiness. The ICSD-3 defines 3 different classification systems for insomnia: chronic insomnia disorder, short-term insomnia disorder, and other insomnia disorder. Complications of insomnia include impaired responses to infections, increase in inflammation, higher levels of the stress hormone cortisol, and other biomarkers related to fatigue and poor health.
Sep. 28, 2021