Mepolizumab in CRSwNP/ECRS and NP: the phase III randomised MERIT trial in Japan, China, and Russia.

BACKGROUND: This randomised, double-blind, placebo-controlled, parallel-group, 52-week Phase III study (MERIT; NCT04607005) assessed mepolizumab efficacy and safety in patients with chronic rhinosinusitis with nasal polyps (CRSwNP)/eosinophilic CRS (ECRS) in Japan, Russia, and China, for which data are limited. METHODOLOGY: Eligible patients (enrolled at 60 centres) had blood eosinophil count >2%, endoscopic bilateral NP score ≥5, nasal obstruction visual analogue scale (VAS) score >5, ≥2 sinonasal symptoms, and either previous sinus surgery or systemic corticosteroid use/intolerance. Patients were randomised (1:1) to receive mepolizumab 100 mg subcutaneously or placebo every 4 weeks, plus standard of care. Co-primary endpoints: change from baseline in total endoscopic NP score (ENPS) (Week 52) and nasal obstruction VAS score (Weeks 49-52). Post hoc analyses conducted in a modified intent-to-treat (mITT) population excluded patients from two study sites, related to Good Clinical Practice violations by the Site Management Organisation overseeing these sites. These were considered the primary efficacy analyses. RESULTS: In the mITT population, mepolizumab (n=80) versus placebo (n=83) significantly improved nasal obstruction VAS score from baseline to Week 49-52 and was associated with a trend of total ENPS improvements at Week 52. Mepolizumab/placebo on-treatment adverse events (AEs) occurred in 68/84 and 65/85 patients in the safety population (treatment-related AEs: 2/84 and 5/85, respectively), and on-treatment serious AEs in 0/84 and 4/85 patients, respectively (no fatalities reported). CONCLUSIONS: Mepolizumab was effective and well-tolerated in patients with CRSwNP/ECRS from Japan, Russia, and China.

Olfactory and taste dysfunctions caused by COVID-19: a nationwide study.

BACKGROUND: Olfactory dysfunctions (OD) and taste dysfunctions (TD) are widely recognized as characteristic symptoms of COVID-19; however, the frequency and mode of occurrence has varied depending on the viral mutation. The prevalence and characteristics of OD/TD in Japan have not been definitively investigated. The purpose of this study is to assess the prevalence of OD/TD in Japan during the Alpha variant epidemic, and measure symptom prolongation at 6 months and 1 year later following initial infection. METHODS: Patients treated for COVID-19 between February to May 2021 were evaluated for OD/TD symptoms and provided with a QOL questionnaire. Olfactory tests and taste tests were performed using Open Essence and Taste Strips, respectively. RESULTS: Among the 251 COVID-19 patients who participated, 119 underwent both olfactory and taste tests. Prevalence of subjective OD and TD at the time of survey was 57.8% and 40.2%, respectively. After 12 months, the prevalence fell to 5.8% for OD and 3.5% for TD. Among the OD/TD patients, 36.6% experienced parosmia, and 55.4% experienced parageusia. Prevalence of parosmia and parageusia was higher at 6 and 12 months than at the time of survey. Patients with long-lasting disease reported qualitative dysfunctions and scored significantly higher in food-related QOL problems. Most patients who were aware of their hyposmia had low scores on the olfactory test (83.1%). In contrast, only 26.7% of patients who were aware of their hypogeusia had low scores on the taste test. CONCLUSIONS: The prevalence of COVID-19-related OD and TD at the time of survey was 57.8% and 40.2%, respectively. Subjective symptoms of OD and TD persisted for one year in 5.8% and 3.5% of patients, respectively. More than half of the patients with OD or TD complained of qualitative dysfunction and a decrease in their QOL related to eating and drinking. Most patients with TD did not have true TD, but rather developed flavour disorders associated with OD. This conclusion is supported by the finding that patients with subjective OD had low scores on the olfactory test, whereas most patients with subjective TD had normal scores on the taste test.

Nerve growth factor levels in cerebrospinal fluid from patients neurologic disorders.

Nerve growth factor levels were measured in the cerebrospinal fluid from 73 patients with neurologic disorders and non-neurologic acute illnesses by a two-site enzyme immunoassay. Elevated nerve growth factor levels in cerebrospinal fluid were demonstrated in 2 of 7 patients with bacterial meningitis, 7 of 14 patients with viral meningitis or encephalitis, and 1 with multiple sclerosis. Follow-up examinations of the 3 patients (1 with bacterial meningitis, 1 with viral meningitis, and 1 with multiple sclerosis) at convalescent stage showed diminished nerve growth factor levels in cerebrospinal fluid. None of the other patients showed elevation of nerve growth factor levels in cerebrospinal fluid. Nerve growth factor levels in cerebrospinal fluid were not correlated with cell numbers in patients with meningitis or encephalitis. No relationship was observed between nerve growth factor levels and outcome in patients with viral meningitis or encephalitis and bacterial meningitis. Nerve growth factor in cerebrospinal fluid may play a role in neuronal recovery or function as an immunomodulator in children with inflammatory and immune-mediated neurologic disorders.

Sensorineural deafness in siblings with adenosine deaminase deficiency.

Two siblings with adenosine deaminase deficiency were successfully treated with allogeneic bone marrow transplantation without conditioning. Although the patients were free from infections after immunologic reconstitution, both showed sensorineural deafness at 1 year of age. Because there were no structural abnormalities in the inner and middle ears, no evidence of prenatal infections of rubella, cytomegalovirus or toxoplasma, and no postnatal infection of mumps in the siblings, sensorineural deafness might be one of the neurologic problems associated with adenosine deaminase deficiency.

Communicating hydrocephalus in a patient with Gaucher's disease type 3.

The case of a 3-year-old male with type 3 Gaucher's disease, whose genotype for the beta-glucosidase gene was D409H/unknown mutation, is presented. After the onset of visceral and neurologic signs during infancy, a radiologic investigation at 3 years of age revealed communicating hydrocephalus, an unusual complication of Gaucher's disease. A ventriculoperitoneal shunt operation led to clinical and radiologic improvement. The possibility of this complication should be considered in the treatment of patients with Gaucher's disease.

Biphasic clinical course and early white matter abnormalities may be indicators of neurological sequelae after status epilepticus in children.

Clinical course and serial neuroimaging findings are not fully described in children who have had neurological sequelae following status epilepticus. We found four patients who had neurological sequelae out of 42 children with status epilepticus in 2004. MRI studies were reviewed with specific attention to diffusion-weighted images (DWI) and the apparent diffusion coefficient (ADC). Proinflammatory cytokines, including tumor necrosis factor-alpha and interleukin-6, were measured in the cerebrospinal fluid (CSF) (3 patients). The clinical course showed biphasic; initial status epilepticus and neurological exacerbation along with seizure recurrence four to five days after onset. Within three days after initial status epilepticus, CT (all patients) and MRI (2 patients) did not show any abnormalities. From four to ten days after onset, MRI demonstrated diffuse hyperintensity in the cerebral white matter on DWI and hypointensity on ADC maps in all patients. Diffuse brain atrophy progressed thereafter. Tumor necrosis factor-alpha or interleukin-6 was elevated in all patients. A biphasic clinical course may be a specific feature for neurological sequelae. The preferential white matter involvement on MRI and elevated CSF cytokines indicate that glial dysfunction may play an important role in the pathophysiology of status epilepticus-associated cerebral damage.

An early-onset case of multiple sclerosis with thalamic lesions on MRI.

We present here an early-onset case of multiple sclerosis (MS) with thalamic lesions. The patient first experienced an episode of ataxic gait at 2 years 3 months of age, with spontaneous remission within 1 month. At 5 years 4 months, she was admitted because of cerebellar ataxia, oculomotor restriction and feeding difficulty. Magnetic resonance imaging (MRI) showed multiple well-defined lesions in the white matter of the cerebellum, mid-brain, periventricle and right frontal lobe. Cerebrospinal fluid (CSF) showed a mild elevation of both immunoglobulin G (IgG) and myelin basic protein (MBP). Serum anti-myelin antibody was also positive, although leukocytosis and elevation of C-reactive protein were not found. Methylprednisolone pulse therapy relieved symptoms within 2 weeks and the abnormal MRI and CSF findings gradually improved. At 6 years 6 months of age, she incurred a third episode of cerebellar ataxia and disturbance of consciousness. Magnetic resonance imaging revealed recurrence and extension of the previous lesions as well as new lesions in the thalamus and internal capsule. CSF IgG and MBP level showed a higher elevation than in the second episode. The combination of the cerebellar, brain-stem, cerebral and thalamic lesions with remission and exacerbation, supported by MRI and CSF findings, allowed the diagnosis of clinically definite MS to be made. This is one of the youngest cases of MS yet described, with the first attack occurring at 27 months of age. In addition, this case is unique for the involvement of the gray matter in the thalamus.

Elevated nerve growth factor levels in cerebrospinal fluid associated with progressive cortical atrophy.

Using a two-site enzyme-linked immunosorbent assay, we measured nerve growth factor (NGF) levels in cerebrospinal fluid (CSF) from 40 patients with or without brain atrophy due to various neurologic disorders. White matter and cortical atrophies were assessed by frontal horn index (FHI) and subarachnoid space area/inner skull space area (SSA/ISSA) ratio, respectively. CT findings of 40 patients were classified into 4 grades: normal (< mean + 2SD), grade I (mean + 2SD < or = or < mean + 4SD), grade II (mean + 4SD < or = < mean + 8SD), and grade III (mean + 8SD < or =). NGF levels in CSF were significantly elevated in 3 of 6 patients with grade III cortical atrophy and normal in 2 with grade II atrophy, 4 with grade I atrophy and 28 without atrophy. Cortical atrophy was progressive in the 3 with NGF elevation in CSF. With respect to white matter atrophy, NGF elevation was observed in none of 3 with grade III white matter atrophy, two of 4 with grade II atrophy, none of 3 with grade I atrophy and one of 30 without atrophy. The symptoms of the two of three with NGF elevation were progressive at the time of obtaining the CSF samples, while those of other patients without NGF elevation were non-progressive. The present study suggests that NGF elevation in CSF may reflect extensive cortical degenerative change.