Antibodies Against ZSCAN1 in Pediatric and Adult Patients With Non-Paraneoplastic ROHHAD Syndrome.

OBJECTIVES: To report the association of zinc finger and SCAN domain containing 1 antibodies (ZSCAN1-abs) with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome in patients without tumor. METHODS: Patients with symptoms compatible with ROHHAD syndrome but without an associated tumor were selected from our database. Serum and CSF samples were examined for the presence of ZSCAN1-abs by an in-house cell-based assay. In addition, samples from 149 patients with several inflammatory and noninflammatory disorders and 50 healthy participants served as controls. RESULTS: Thirteen patients with ROHHAD syndrome were identified. Of these, we had paired serum/CSF samples from 6 patients and only serum from the other 7. Five of 6 patients (83.3%) with paired serum/CSF (4 children, 1 adult) had ZSCAN-abs only in CSF and 1 had antibodies in serum and CSF. ZSCAN1-abs were not detected in the remaining 7 patients with ROHHAD with only serum available or in any of the 199 control samples. DISCUSSION: Patients with ROHHAD syndrome should be investigated for the presence of ZSCAN1-abs in CSF. The antibodies do not necessarily predict the presence of a tumor. The detection of ZSCAN1-abs in an adult patient suggests that this condition also occurs beyond the pediatric age.

Anti-N-Methyl-D-Aspartate Receptor-Mediated Encephalitis: Recent Advances in Diagnosis and Treatment in Children.

Anti-N-methyl-d-aspartate receptor-mediated encephalitis (anti-NMDAR encephalitis) is increasingly recognized in children and adolescents. There is a recognizable pattern of clinical symptoms, similar between children and adults. There are some differences in children including the frequency of presenting symptoms, the presence of hypoventilation, and the identification of an associated tumor. Early tumor removal and treatment with immunotherapy is important for rapid recovery. The prognosis can be surprisingly good but some children have lasting neurocognitive deficits.

Pseudo-piano playing motions and nocturnal hypoventilation in anti-NMDA receptor encephalitis: response to prompt tumor removal and immunotherapy.

Tumor resection is recommended in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, however it is often difficult during an early stage of the disease. We report here the efficacy of early tumor removal in a patient with anti-NMDAR encephalitis. This 21-year-old woman was admitted to another hospital with rapidly progressive psychiatric symptoms, a decreased level of consciousness, and seizures. Abdominal CT showed a pelvic mass. On day 1 of admission to our center, she developed hypoventilation requiring mechanical support. She had orofacial dyskinesias with well-coordinated, pseudo-piano playing involuntary finger movements. Based on these clinical features, she was immediately scheduled for tumor resection on day 3. While awaiting surgery, she began to receive high-dose intravenous methylprednisolone. After tumor removal, she received plasma exchange, followed by intravenous immunoglobulin and additional high-dose methylprednisolone. Two weeks after tumor removal, she started following simple commands and progressive improvement, although she remained on mechanical ventilation for 10 weeks due to nocturnal central hypoventilation. Anti-NMDAR antibodies in serum/CSF were detected. Pathological examination showed immature teratoma with foci of infiltrates of B- and T-cells. Early tumor resection with immunotherapy facilitates recovery from this disease, but central hypoventilation may require long mechanical support. Non-jerky elaborate finger movements suggest antibody-mediated disinhibition of the cortico-striatal systems.

[Update on anti-NMDA receptor encephalitis].

A new category of treatment-responsive encephalitis has been proposed in association with antibodies to neuronal cell membrane antigens, including voltage-gated potassium channel (VGKC), N-methyl-D-aspartic acid receptor (NMDAR), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), gamma-aminobutyric acid (GABA) B receptor and other antigens that have not yet been characterized. Among the forms of encephalitis under this category, anti-NMDAR encephalitis is a distinct disorder characterized by the predictable sequential development of symptoms; prodromal symptoms are initially noted, followed by prominent psychiatric symptoms, seizures, an unresponsive/catatonic state, hypoventilation, and involuntary orofacial-limb movements. This disorder usually affects young women with ovarian teratoma but may also affect women of any age or even men. A recent study revealed that the main epitope targeted by anti-NMDAR antibodies lies in the extracellular N-terminal domain of the NR1 subunit (25-380 amino-acid residues); the NR2B subunit is not necessarily involved. The antibodies are shown to produce selectively and reversibly reduce postsynaptic NMDARs clusters without complement activation. Considering the symptomatology of anti-NMDAR encephalitis and the results of cell culture analysis, we speculate that the overall antibody-mediated inhibition of NMDARs expressed on GABAergic interneurons, glutamatergic neurons and dopaminergic neurons may cause neuropsychiatric symptoms and dyskinesias via dopamine and glutamate dysregulation. We also hypothesize that these antibodies affect not only trafficking/localization/clustering of postsynaptic NMDARs, but also the expression of other receptors including AMPAR and dopamine receptors, by including a chronic state of exposure to excessive or decreased neurotransmitters release. The establishment of an animal model is awaited to resolve these issues. Anecdotal reports have revealed that recovery may be spontaneous without tumor resection but early tumor resection along with aggressive immunotherapy facilitates early functional recovery. In a recent case, a microscopic teratoma was detected on autopsy; therefore exploratory laparotomy may be considered in severe refractory cases.

Alteration of serotonergic receptors in the brain stems of human patients with respiratory disorders.

We compared the developmental changes of 5-hydroxytryptamine (5-HT) 1 A and 5-HT2 A receptor immunoreactivity in the nuclei in relation to the cardiorespiratory or autonomic function in the human brain stem in sudden infant death syndrome (SIDS) and congenital central hypoventilation syndrome (CCHS) patients and age-matched controls by means of immunohistochemical methods. There were significant decreases in 5-HT1 A and 5-HT2 A receptor immunoreactivity in the dorsal nucleus of the vagus, solitary nucleus and ventrolateral medulla in the medulla oblongata, and significant increases in the periaqueductal gray matter (PAG) of the midbrain in SIDS victims, but there were no significant differences between those in CCHS patients and controls. The decreased immunoreactivity of the receptors in the medulla oblongata was accompanied by brain stem gliosis. Therefore, the decreases in the receptors may be secondary to chronic hypoxia or repeated ischemia, but may be causally related to some impairment of the developing cardiorespiratory neuronal system. As 5-HT1 A and 5-HT2 A receptors were the most abundant in the fetal period and then decreased with subsequent development, the increases in 5-HT1 A and 5-HT2 A receptor immunoreactivity in PAG may reflect delayed neuronal maturation, but may also reflect compensatory changes in response to hypofunctioning serotonergic neurons in the medulla oblongata in SIDS. There was no abnormal expression of 5-HT1 A and 5-HT2 A receptors in CCHS brain stems, and so the pathophysiology seems to be different between SIDS and CCHS patients.

[The pathogenesis of hypoventilation in the operated lung]. / K voprosu o patogeneze gipoventiliatsii operirovannogo legkogo.

The content of immunocompetent cells, activity of lipid peroxidation processes, function of the surfactant system, and levels of prostacyclin and thromboxane were studied in 9 patients with resected lungs in the perioperative period separately for the intact and operated on lung. The function of immunocompetent cells deteriorated in both lungs after surgery. The levels of albumin and thromboxane were increased in the bronchoalveolar washings from the lung operated on reliably more than in those from intact lung, and the surface active characteristics deteriorated. Eight patients developed hypoventilation of the operated on lung in the postoperative period.