Genetic, electrophysiological, and pathological studies on patients with SCN9A-related pain disorders.

BACKGROUND AND AIMS: Voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, has been linked to diverse painful peripheral neuropathies, represented by the inherited erythromelalgia (EM) and paroxysmal extreme pain disorder (PEPD). The aim of this study was to determine the genetic etiology of patients experiencing neuropathic pain, and shed light on the underlying pathogenesis. METHODS: We enrolled eight patients presenting with early-onset painful peripheral neuropathies, consisting of six cases exhibiting EM/EM-like disorders and two cases clinically diagnosed with PEPD. We conducted a gene-panel sequencing targeting 18 genes associated with hereditary sensory and/or autonomic neuropathy. We introduced novel SCN9A mutation (F1624S) into a GFP-2A-Nav1.7rNS plasmid, and the constructs were then transiently transfected into HEK293 cells. We characterized both wild-type and F1624S Nav1.7 channels using an automated high-throughput patch-clamp system. RESULTS: From two patients displaying EM-like/EM phenotypes, we identified two SCN9A mutations, I136V and P1308L. Among two patients diagnosed with PEPD, we found two additional mutations in SCN9A, F1624S (novel) and A1632E. Patch-clamp analysis of Nav1.7-F1624S revealed depolarizing shifts in both steady-state fast inactivation (17.4 mV, p < .001) and slow inactivation (5.5 mV, p < .001), but no effect on channel activation was observed. INTERPRETATION: Clinical features observed in our patients broaden the phenotypic spectrum of SCN9A-related pain disorders, and the electrophysiological analysis enriches the understanding of genotype-phenotype association caused by Nav1.7 gain-of-function mutations.

Differentiating early clinical features of Panayiotopoulos syndrome from acute encephalopathy.

BACKGROUND: Panayiotopoulos syndrome (PS) is a common benign epilepsy in childhood, characterized by predominantly autonomic symptoms such as emesis, pallor, and seizures, which are often prolonged. In an emergency room (ER), particularly when unconsciousness is prolonged, differentiating PS from acute encephalopathy is challenging. In this study, we aimed to elucidate the differences in clinical features of patients with PS and acute encephalopathy who visited our ER. METHODS: We retrospectively reviewed 18 patients who were transferred to our ER because of status epilepticus later diagnosed as PS, and 30 patients with acute encephalopathy, between July 2012 and July 2017. We compared patient demographics, clinical characteristics, and treatment. RESULTS: Most patients (90%) with acute encephalopathy had convulsive seizures of greater than or equal to 15 min, whereas only three patients (17%) with PS had convulsive seizures of greater than or equal to 15 min (P < 0.001). In addition, seizures were treatable in all patients with PS with a small dose of midazolam (0.1 mg/kg), but all patients with acute encephalopathy required midazolam at 0.3 mg/kg or more (P < 0.001). More patients with PS had autonomic symptoms compared to those with acute encephalopathy (e.g., vomiting [78% vs. 3%, P < 0.001]). Non-convulsive status epilepticus was observed in 22% of PS patients, but not in any acute encephalopathy patients. In contrast, fever was observed in all patients with acute encephalopathy (100%), but less frequently in those with PS (11%, P < 0.001). CONCLUSION: PS was characterized by 1) convulsive seizures shorter than 15 min, 2) seizures treatable with small doses of midazolam, and 3) autonomic symptoms. PS could be differentiated from acute encephalopathy in the early stages of the syndrome.

Isolated cranial neuritis of the oculomotor nerve: Expanding the MOG phenotype?

Autoantibody against myelin oligodendrocyte glycoprotein (MOG) has been reported in a range of demyelinating neurological entities. Recent studies demonstrate a wider spectrum of MOG-IgG-associated disorders with the discovery of MOG-IgG-positive brainstem encephalitis, cortical encephalitis, and cranial nerve involvement with concurrent central nervous system involvement. We present a MOG-IgG-positive pediatric patient diagnosed with isolated oculomotor neuritis without concurrent central nervous system neuroimaging lesions, in the absence of a demyelinating event. Brain MRI shows swelling and gadolinium enhancement of the left oculomotor nerve at the cisternal segment. This is the first report to demonstrate MOG-IgG seropositivity in isolated cranial nerve lesions. This case may expand the clinical phenotype of MOG-IgG-associated diseases, and clinicians should not hesitate to test for MOG-IgG in cases with neuroimaging features of cranial neuritis alone.

Indocyanine green fluorescence videoangiography for reliable variations of supraclavicular artery flaps.

BACKGROUND: Pedicled flaps are useful for reconstructive surgery. Previously, we often used vascularized supraclavicular flaps, especially for head and neck reconstruction, but then shifted to using thoracic branch of the supraclavicular artery (TBSA) flaps. However, limited research exists on the anatomy of TBSA flaps and on the use of indocyanine green (ICG) fluorescence videoangiography for supraclavicular artery flaps. We utilized ICG fluorescence videoangiography to harvest reliable flaps in reconstructive operations, and describe the results herein. METHODS: Data were retrospectively reviewed from six patients (five men and one woman: average age, 54 years; range, 48-60 years) for whom ICG videoangiography was performed to observe the skin perfusion of a supraclavicular flap after it was raised. Areas where the flap showed good enhancement were considered to be favorable for flap survival. The observation of ICG dye indicated good skin perfusion, which is predictive of flap survival; therefore, we trimmed any areas without dye filling and used the remaining viable part of the flap. RESULTS: The flaps ranged in size from 13×5.5 cm to 17×6.5 cm. One patient received a conventional supraclavicular flap, four patients received a TBSA flap, and one patient received a flap that was considered to be intermediate between a supraclavicular flap and a TBSA flap. The flaps completely survived in all cases, and no flap necrosis was observed. CONCLUSIONS: The TBSA flap is very useful in reconstructive surgery, and reliable flaps could be obtained by using ICG fluorescence videoangiography intraoperatively.

Differences between nurses' and care workers' estimations of pain prevalence among older residents.

A high prevalence of pain and difficulties with pain assessment has been widely reported among residents of long-term-care facilities. We explored nurses' and care workers' estimations of residents' pain (both general and chronic) and the number of residents with unknown pain status. We also examined the relationship between the prevalence of pain and assessment strategies undertaken by nurses and care workers. A cross-sectional design was used. Nurses and care workers across 750 long-term care facilities in four Japanese prefectures were asked to participate. Questionnaires were administered to one nurse and care worker at each facility. The questionnaires assessed the estimated numbers of residents who had pain in general, chronic pain, or unknown pain status on the day of data collection, and pain assessment strategies use by the health care professionals. In all, 263 (17.5%) questionnaires were returned from 147 nurses (55.9%) and 116 care workers (44.1%). The nurses' and care workers' median estimations of pain and chronic pain prevalence among residents were 11.6 and 9.4 and 29.4 and 15.5, respectively (p < .001). Estimations of pain prevalence were significantly higher among nurses who had observed signs of pain among residents in the previous month (p = .04) and who applied a multidisciplinary approach to pain assessment and management (p = .007) than among nurses who did not do either. Nurses and care workers had relatively low estimations of the prevalence of pain among their residents. Staff should undertake appropriate and sufficient pain assessments in order to improve their understanding of residents' pain.

Intravenous immunoglobulin-induced neutrophil apoptosis in the lung during murine endotoxemia.

BACKGROUND: The pathophysiologic features of acute respiratory distress syndrome (ARDS) are attributed to neutrophil accumulation and over-activation. Low blood immunoglobulin G concentrations in septic shock patients are associated with higher risk of developing ARDS. This study showed the effects of intravenous immunoglobulin (IVIg) on neutrophil apoptosis and accumulation in the lung during murine endotoxemia. METHODS: Male C57BL/6J mice were injected with saline or 7 mg/kg of lipopolysaccharide (LPS), and 3 h later also were injected with saline, IVIg 300 mg/kg, or IVIg 1000 mg/kg intraperitoneally. At 12 h after LPS injection, mice were sacrificed and peripheral blood and lungs were collected. The lung messenger ribonucleic acid expression (tumor necrosis factor-α [TNF-α], inducible nitric oxide synthase [iNOS], and intercellular adhesion molecule-1 [ICAM-1]) was determined using quantitative realtime reverse transcriptase-polymerase chain reaction. Lungs were immersed in 4% paraformaldehyde and then embedded in paraffin. Tissue slices were prepared and stained with naphthol AS-D chloroacetate esterase to detect neutrophils. The numbers of neutrophils (characterized by the segment number of their nuclei) were counted. Peripheral neutrophil apoptosis was detected by annexin V using flow cytometry and lung neutrophil apoptosis was detected by cleaved caspase-3 using immunohistochemistry. RESULTS: The survival rates of the saline group, LPS group, and IVIg group were all 100%. Apoptosis of peripheral blood neutrophils was inhibited by LPS. Neutrophil accumulation in the lung was decreased by both IVIg 300 mg/kg and 1000 mg/kg. Segmented neutrophils were reduced by IVIg during endotoxemia. However, IVIg 300 mg/kg and 1000 mg/kg had no influence on the lung messenger ribonucleic acid expression of TNF-α, iNOS, or ICAM-1. Cleaved-caspase-3-positive neutrophils were increased in the IVIg 300 mg/kg group during endotoxemia. The 1000 mg/kg IVIG dose reduced the number of segmented neutrophils, but did not induce cleaved-caspase 3-positive neutrophils. CONCLUSION: A therapeutic IVIg dose can attenuate neutrophil accumulation and regulate neutrophil apoptosis in the lung during endotoxemia. It is possible that the pathways by which IVIG induces neutrophil apoptosis may differ depending on the IVIg concentration.