Atypical presentations of leigh syndrome: a case series and review

Patients with Leigh syndrome classically present in early childhood with developmental regression, ataxia, and hypotonia with subsequent respiratory and brainstem dysfunction. However, the clinical presentation can be highly variable. This report presents five cases of Leigh syndrome with atypical presentations. The first patient is a 17-month-old female who presented with progressive limb weakness diagnosed as Guillain-Barre syndrome. Postmortem examination demonstrated Leigh syndrome confined to the spinal cord. The case series then describes two sisters one of whom presented at 11 years of age with central respiratory failure and encephalopathy. Her 15-year-old sister presented with a progressive diplegia. The fourth patient presented with bronchiolitis and apnea at 3 months of age due to bilateral brainstem lesions. Her second cousin presented at 6 months of age with hypotonia, blindness, and tonic seizures. All patients had laboratory and radiologic findings consistent with Leigh syndrome. Evidence of spinal cord involvement was observed on magnetic resonance imaging in four of the five patients. Leigh syndrome can involve any level of the neuroaxis, resulting in a wide variety of presentations. Many atypical variants are observed, of which clinicians should be aware. Evidence of brainstem or spinal cord involvement should also be sought in patients with Leigh syndrome.     

Variability of localization and intensity of damage of the white matter of the brain and cerebellum in genetically conditioned diseases

The investigations were based on 3 cases with Leigh, 5 cases with Krabbe's, 4 cases of Alpers, 2 cases with Sandhoff, 1 case with Alexander's disease and 1 case with metachromatic leukodystrophy. In 1 case included into the study we have diagnosed nonketotic hyperglycinemia II. All the diseases under examination are recognized as genetically conditioned or are supposed to be of genetic origin. Damage of the white matter in a more delineated form in certain regions was found in Leigh disease. The changes demonstrated a variable degree of intensity from demyelination to necrosis. More extensive lesions of white matter in gyri and semivoal centrum were found in diseases with simultaneously damaged gray matter e.g. in Alpers and Sandhoff disease. The most extensive changes of diffuse demyelination were found in Krabbe's and Alexander's disease. In these diseases demyelination was accompanied with specific morphological structures e.g. globoidal cells (Krabbe's disease) and Rosenthal fibers (Alexander's disease). The peculiar type of demyelination was characteristic for nonketotic hyperglycinemia of type II. It was expressed by demyelination with vacuolization.     

Respiratory disturbances in rett syndrome: don't forget to evaluate upper airway obstruction

Rett syndrome is characterized by loss of motor and social functions, development of stereotypic hand movements, seizures, and breathing disturbances. This study evaluates the presence of overnight respiratory disturbances. Polysomnography in combination with a questionnaire (the Sleep Disturbance Scale for Children) was performed in 12 Dutch patients with Rett. Respiratory disturbances were present in all, clinically relevant in 10 (apnea hypopnea per hour 1.0-14.5). In 8 children, central apneas were present during the day often with obstructive apneas at night. In 6, obstructive sleep apnea syndrome was diagnosed, in 3 severe, with frequent oxygen desaturations. Significant respiratory complaints were present in 3 patients, all had obstructive sleep apnea syndrome. Of the 12 patients with Rett, 8 (67%) snored, and in 5 obstructive sleep apnea syndrome was present. In children, hypertrophied tonsils and adenoids are a common cause of obstructive sleep apnea syndrome, which may benefit from therapeutic intervention. We recommend performing polysomnography in patients with Rett syndrome and respiratory complaints.     

Diurnal sleep apnea in myotonic dystrophy]

We investigated diurnal sleep apnea in myotonic dystrophy with respiratory inductive plethysmography. Five of eight patients met criteria for sleep apnea syndrome and had central apnea mainly. In a case showing periodic breathing with apnea like Cheyne-Stokes type breathing, the duration of apnea and breath was even and the tidal volume went waxing and waning regularly. In the other four cases, central apneas were observed in sequence, but the duration of apnea and the tidal volume changed variously. Large breaths between apneas elevated arterial oxygen saturation rather than stable breaths without apnea. We suspected that hypoxemia, which exacerbated by involvement of respiratory muscles, supine position and sleep, initiated the hyperventilation between apneas. And then the saturation of oxygen raised by hyperventilation would cause central sleep apnea.     

EEG findings in children and adolescents with mitochondrial encephalomyopathies: a study of 25 cases

EEG was studied in 25 children and adolescents with mitochondrial encephalomyopathies, defined on the basis of clinical, biochemical and morphological criteria. Twenty cases conformed to well-known mitochondrial syndromes: Alpers syndrome [6], Leigh syndrome [2], MERRF (myoclonus epilepsy and ragged red fibers) syndrome [3], MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) syndrome [5] and Kearns-Sayre syndrome [4]. Many patients were followed for several years with repeated EEG. In all, 112 EEG records were included in the study. A common feature of all the mitochondrial encephalomyopathic syndromes was slowing of the alpha rhythm. Epileptic discharges were seen in most syndromes. In spite of the small number of cases in each group, in Alpers, MERRF and MELAS syndromes we found sequential EEG patterns which seemed to be typical of the respective syndromes. In contrast, in Kearns-Sayre syndrome, a slow background rhythm was the only consistent finding. We conclude that EEG, especially repeated recordings, may be of help in the diagnostic evaluation of mitochondrial encephalomyopathies.     

Sleep apnea as a feature of bulbar stroke

Medullary disorders can be associated with a sleep apnea syndrome. The present patient developed a sleep apnea syndrome with approximately 25 episodes of apnea or hypopnea during each hour of sleep following a lateral medullary infarction. The presence of predisposing factors and involvement of respiratory centers in the area of the medullary lesion may determine the appearance of sleep apnea with brainstem infarction. Investigation of breathing during sleep may be helpful in such cases.     

Neuropsychological deficits and sleep in myotonic dystrophy

Eight patients with myotonic dystrophy underwent comprehensive neuropsychological testing and overnight polysomnography to assess whether the waking cognitive impairment might be attributable to sleep structure abnormalities or to sleep-related respiratory problems. Patients showed substantial neuropsychological deficits, fragmented nocturnal sleep and, in half the patients, sleep apnea and/or hypopnea both mainly of central type. There was no statistically significant correlation between the degree of daytime cognitive deficit and the degree of sleep fragmentation or of respiratory problems at night. It was concluded that the neuropsychological deficit in mytonic dystrophy cannot be attributed to a secondary effect of nocturnal sleep apnea or sleep disruption but probably represents a direct effect of CNS lesions.     

Frequent breathing-related electroencephalogram arousals in four patients with mild obstructive sleep apneas

We report cases of four patients with mild obstructive sleep apnea syndrome (OSAS) with frequent breathing-related electroencephalogram (EEG) arousals which led to excessive daytime sleepiness. In spite of a relatively low apnea hypopnea index (AHI), sleep was disrupted by frequent EEG arousals associated with respiratory effort as observed in upper airway resistance syndrome. The effects of sleep stage and sleep position on EEG arousals were also investigated. We consider that AHI alone is not a sufficient index to assess severity of OSAS, and it is very important to examine microarousals by the alteration of esophageal pressure in addition to the effect of sleep position.     

Leigh and Leigh-like syndrome in children and adults

Leigh syndrome (also termed subacute, necrotizing encephalopathy) is a devastating neurodegenerative disorder, characterized by almost identical brain changes, e.g., focal, bilaterally symmetric lesions, particularly in the basal ganglia, thalamus, and brainstem, but with considerable clinical and genetic heterogeneity. Clinically, Leigh syndrome is characterized by a wide variety of abnormalities, from severe neurologic problems to a near absence of abnormalities. Most frequently the central nervous system is affected, with psychomotor retardation, seizures, nystagmus, ophthalmoparesis, optic atrophy, ataxia, dystonia, or respiratory failure. Some patients also present with peripheral nervous system involvement, including polyneuropathy or myopathy, or non-neurologic abnormalities, e.g., diabetes, short stature, hypertrichosis, cardiomyopathy, anemia, renal failure, vomiting, or diarrhea (Leigh-like syndrome). In the majority of cases, onset is in early childhood, but in a small number of cases, adults are affected. In the majority of cases, dysfunction of the respiratory chain (particularly complexes I, II, IV, or V), of coenzyme Q, or of the pyruvate dehydrogenase complex are responsible for the disease. Associated mutations affect genes of the mitochondrial or nuclear genome. Leigh syndrome and Leigh-like syndrome are the mitochondrial disorders with the largest genetic heterogeneity.     

Sleep apnea in well-controlled myasthenia gravis

Polygraphic monitoring of the respiratory status during sleep provides a definitive test for the presence of the sleep apnea syndrome. This syndrome has been recognized in various kinds of neurological disorders. However, as far as we know, there have been no reports of describing the sleep apnea syndrome in myasthenia gravis (MG). We conducted overnight polygraphic sleep studies of 10 patients of clinically well-controlled MG. Patients: We examined 10 patients of MG (4 men and 6 women). The subtypes of MG were IIA(1), IIB(8) and V(1) according to Osserman's criteria. Results: Six patients, with an average age of 47.8 and the average duration of 6.2 years, had polysomnographically obstructive and central types of sleep apnea, appearing longer than 10 seconds and more than 30 times in one night. Their mean Apnea Index (AI) was 14.6. The duration of mean apnea was 23.4 seconds and 99.0 times the average frequency. On the other hand, in four patients of MG, averaged age at 30.8 and for a 0.9-year duration, the sleep apnea syndrome was never seen. Therefore, the longest duration of MG tended to have the sleep apnea syndrome. Discussion: Six out of the 10 patients of MG had obstructive and central types of the sleep apnea syndrome. Since their respiratory functions examined in a daytime were normal and the physical findings concerned with MG were well controlled by medications, our findings of nocturnal sleep apnea might be indicative of a central cholinergic system disturbance in MG during sleep.     

Leigh syndrome with spinal cord involvement due to a hemizygous NDUFA1 mutation

Leigh syndrome, which is a common phenotype of pediatric mitochondrial disease, is a progressive neurodegenerative disease. The typical neuroimaging findings of Leigh syndrome include bilateral symmetric lesions in the basal ganglia and/or the brainstem. However, there are a few reports on spinal cord involvement in patients with Leigh syndrome. In the present case, magnetic resonance imaging (MRI) obtained during infancy revealed symmetric lesions in the substantia nigra of a patient with Leigh syndrome with an NDUFA1 mutation; lesions of the bilateral putamen and brainstem were subsequently observed. Additionally, our patient presented large and extended spinal cord lesions. Therefore, this case is suggesting that we should consider the occurrence of spinal cord lesions as an atypical finding in Leigh syndrome.     

Clinical efficacy and indication of acetazolamide treatment on sleep apnea syndrome

The efficacy and indication of acetazolamide treatment on patients with sleep apnea syndrome (SAS) were discussed from assessing the changes of polysomnographic findings with the treatment in 75 SAS patients. For the patients as a whole, respiratory disorder variables improved significantly during the treatment. However, the number of acetazolamide treatment responders who showed a decrease of apnea hypopnea index (AHI) to 50% or less of the pretreatment value numbered only 34 (45.3%). The lower values of body mass index and AHI in the responder group indicated that monotherapy with acetazolamide is the treatment choice only for mild SAS cases without obesity. However, combined treatment with acetazolamide and uvulopalatopharyngoplasty was thought to be beneficial for severe cases.     

Central sleep apnea and partial obstruction of the upper airway

Seven men with central sleep apnea underwent polygraphic monitoring during sleep for at least 3 nights, in combination with other tests. Five patients had complaints of disturbed sleep; the other 2 were selected because they had central sleep apnea caused by bilateral brainstem lesions. The first 5 had a small upper airway, documented by cephalometric roentgenograms. Nasal continuous positive airway pressure, administered to improve the suspected respiratory load during sleep, eliminated the central sleep apnea in the first 5 patients but had, as expected, no positive effect on the central apnea of the 2 patients with brainstem lesions.     

The Koga Hospital Center for studies on sleep: status report

Between September 1996 and January 1999 we used polysomnography (PSG) to examine 473 patients (involving a total of 662 records). The diagnosis was a sleep-related breathing disorder in 256 patients, including sleep apnea syndrome (SAS) in 194 patients, sleep hypoxicemia in 18 and insomnia in the other four. The SAS consisted of three subtypes: central apnea (CA) in 56 patients, obstructive apnea (OA) in 124 and mixed apnea (MA) in eight. The ratio of central apnea was relatively higher than the national average. Among the 473 patients, the most common complication was heart disease (133 patients) while other complications included hypertension, and respiratory and cerebrovascular diseases. Concerning the therapy for these patients, continuous positive airway pressure therapy was the most commonly applied and was effective in each type of SAS (CA, OA, MA). Other therapies included prosthetic mandibular advancement, bilevel positive airway pressure, medication and ENT operations. In Koga Hospital, there are many patients with heart disease and/or respiratory disease. We examined those patients who presented with snoring and/or apnea using PSG. Among these patients, SAS was the most common sleep disorder. The relative ratio of CA was high and the average age was higher than those with OA.     

Polysomnographic and urodynamic changes in a case of obstructive sleep apnea syndrome with enuresis

A 53-year-old female patient with obstructive sleep apnea syndrome was reported. She had complained of enuresis as well as a 15-year history of snoring, but she had no complaint of sleep and awake disturbance. Polysomnographic study showed repeated obstructive apnea and hypopnea with an apnea/hypopnea index of 52.6, and severe oxygen desaturation during sleep. On cystometography during sleep, the changing amplitude of the spike wave corresponds to the changes of respiratory efforts against a closed upper airway. The patient was treated successfully with imipramine and acetazolamide for the obstructive sleep apnea and enuresis. Apnea/hypopnea index, nocturnal oxygen desaturation, and sleep architecture were improved, and enuresis completely disappeared. Cystometrography during sleep showed that the average amplitude of the spike wave tended to be low. Percentage urinary volume during sleep compared with 24 h volume was significantly reduced. We considered that the enuresis was mainly related to increased intra-abdominal pressure produced by respiratory efforts and enhanced nocturnal urine production.     

Sleep apnea in patients with postpolio syndrome

We studied sleep architecture and sleep apnea pattern in patients with postpolio syndrome (PPS). Ten patients with clinical signs of PPS underwent polysomnographic recording for two consecutive nights. Although sleep efficiency and proportions of sleep stages were within the normal range, sleep architecture was disrupted owing to sleep apnea. Patients with bulbar involvement had more frequent sleep apnea (mean sleep apnea index, 11.09) than patients without (apnea index, 5.88). The former also had significantly more central apnea, which occurred more commonly during non-rapid-eye-movement (NREM) than rapid-eye-movement (REM) sleep, than those without bulbar signs. This finding suggests reduction in forebrain control of compromised bulbar respiratory centers during NREM sleep in PPS.     

Treatment of sleep apnea syndrome in a Down syndrome patient with behavioral problems by noninvasive positive pressure ventilation: a successful case report

The use of noninvasive positive pressure ventilation (NPPV) is increasingly accepted as a treatment of respiratory problems in patients with neuromuscular disease. However, its use in mentally retarded and un-cooperative patients has not been reported. We report here the evaluation and treatment of sleep apnea in a Down syndrome patient. After recovering from a life threatening respiratory failure the patient had persistent sleep apnea syndrome. Limited examinations disclosed that he had two types of apnea; obstructive and central type apnea. Our treatment was a diet with intake restricted up to 1,000 kcal per day for the obstructive apnea, and NPPV with low dosage of oxygen for the obstructive and central apnea. With these treatments in one year's hospitalization, his quality of life was significantly improved. He has continued the treatment in the outpatient department and enjoys a better quality of life both at home and in the community. The successful treatment of this case may become an example of the more extensive use of NPPV for such respiratory problems in handicapped children and adults with behavioral problems.     

Respiratory dysfunction in sleep apnea associated with quetiapine

Quetiapine is an atypical antipsychotic with good tolerability, but has recently been associated with respiratory dysfunction. The aim of this work is to report on moderate to severe respiratory dysfunction after normal oral doses of quetiapine in two obese patients with sleep apnea syndrome (SAS). In the first case, acute respiratory failure and coma occurred after a single normal oral dose of quetiapine in combination with lorazepam (although even higher doses of lorazepam alone were tolerated) in a patient with previously unknown SAS. Intensive care treatment and mechanical ventilation led to full recovery. The second case was a patient with an operated obstructive SAS in which quetiapine was associated with nocturnal respiratory dysfunction and confusion. Respiratory function should be monitored when using quetiapine in patients with possible sleep apnea, particularly in obese patients and when given in combination with benzodiazepines.     

Complex insomnia: insomnia and sleep-disordered breathing in a consecutive series of crime victims with nightmares and PTSD.

BACKGROUND: Sleep disturbance in posttraumatic stress disorder is very common. However, no previous posttraumatic stress disorder studies systematically examined sleep breathing disturbances, which might influence nightmares, insomnia, and posttraumatic stress disorder symptoms. METHODS: Forty-four consecutive crime victims with nightmares and insomnia underwent standard polysomnography coupled with a nasal pressure transducer to measure airflow limitation diagnostic of obstructive sleep apnea and upper airway resistance syndrome. RESULTS: Forty of 44 participants tested positive on objective sleep studies based on conservative respiratory disturbance indices of more than 15 events per hour; 22 patients suffered from obstructive sleep apnea and 18 suffered from upper airway resistance syndrome. CONCLUSIONS: In an uncontrolled study, insomnia and sleep-disordered breathing were extremely prevalent in this small and select sample of crime victims. Research is needed to study 1) prevalence of sleep-disordered breathing in other posttraumatic stress disorder populations using appropriate controls and nasal pressure transducers and 2) effects of sleep treatment on posttraumatic stress symptoms in trauma survivors with comorbid obstructive sleep apnea or upper airway resistance syndrome. In the interim, some posttraumatic stress disorder patients may benefit from sleep medicine evaluations.     

Relationship between abnormal respiratory control and perinatal brainstem and cerebellar infarctions

Clinical and neuropathologic studies were performed in 5 infants who had brainstem or cerebellar infarction and respiratory control abnormalities during early infancy. The anatomic distribution of brainstem infarction was closely related to the failure of neural respiratory control as was unilateral cerebral hemorrhagic infarction to sudden death. Brainstem and cerebellar lesions may be important in the pathogenetic mechanism of sleep apnea and sudden infant death syndrome due to brainstem tegmental gliosis and cerebellar respiratory control disturbance.