Current state of hypnotic use disorders: Results of a survey using the Japanese version of Benzodiazepine Dependence Self-Report Questionnaire.

AIMS: Benzodiazepine receptor agonists (BZ-RAs) are frequently prescribed to treat insomnia; however, their long-term use is not recommended. To introduce an appropriate pharmaco-therapy, the current state and background factors of BZ-RAs' dependence must be elucidated. In this study, we developed a Japanese version of the Benzodiazepine Dependence Self-Report Questionnaire (Bendep-SRQ-J) and conducted a study of BZ-RAs' use disorder. METHODS: The Bendep-SRQ-J was created with permission from the original developer. Subjects were inpatients and outpatients receiving BZ-RAs between 2012 and 2013. Clinical data collected were Bendep-SRQ-J scores, sleep disorders for which BZ-RAs were prescribed, physical comorbidities, psychotropic drugs, and lifestyle factors. Logistic analysis was performed to extract factors associated with severe symptoms. RESULTS: Of the 707 patients prescribed BZ-RAs, 324 had voluntarily tapered or discontinued their drugs. Logistic analysis showed that the total number of drugs administered in the last 6 months correlated with both worsening of symptoms or conditions. This was more notable among younger patients, and the proportion of patients with severe symptoms or conditions increased with the increasing number of drugs. CONCLUSION: Using the Bendep-SRQ-J, we elucidated the current state of BZ-RA dependence. Nearly half of the patients were non-compliant. The proportion of patients with severe symptoms or disease conditions increased with the increase in the number of drugs administered. These findings highlight the need for clinicians to be aware of the likelihood of benzodiazepine dependence, especially in young patients and patients prescribed multiple hypnotics.

Sudden onset of sleep caused by hypothalamic infarction: a case report.

BACKGROUND: Hypothalamic lesions, such as tumors and demyelinating diseases, reportedly cause abnormal sleepiness. However, stroke involving the hypothalamus has rarely been described. Here, we report a patient with infarction restricted to the hypothalamus who presented with sudden onset of sleep. CASE PRESENTATION: A 42-year-old woman with a history of migraine without aura presented with irresistible sleepiness and developed several episodes of sudden onset of sleep. Neurological examinations were unremarkable except for partial left Horner syndrome. Brain magnetic resonance imaging (MRI) revealed a high-intensity lesion restricted to the left hypothalamus on diffusion-weighted and fluid-attenuated inversion recovery MRI images. Cerebrospinal fluid (CSF) orexin-A levels obtained on hospital day 3 after her sleepiness had resolved were normal (337 pg/mL; normal > 200 pg/mL). Serum anti-nuclear and anti-aquaporin 4 (AQP4) antibodies and CSF myelin basic protein and oligoclonal band were negative. A small hypothalamic infarction was suspected, and the patient was treated with intravenous edaravone and argatroban, as well as oral clopidogrel. Three months later, there had been no clinical relapse, and the hypothalamic lesion had almost disappeared on follow-up MRI. No new lesion suggestive of demyelinating disease or tumor was observed. CONCLUSION: Hypothalamic stroke should be considered a cause of sudden onset of sleep.

Could istradefylline be a treatment option for postural abnormalities in mid-stage Parkinson's disease?

BASEGROUND: Postural abnormalities are refractory complications observed in mid- to late-stage Parkinson's disease (PD). METHODS: We analyzed the effects of istradefylline, a selective adenosine A2A receptor antagonist, on posture in 21 levodopa-treated PD patients from the subanalysis of a three-month open-label study. RESULTS: The subitem score of posture (3.13) on the Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III significantly improved following istradefylline treatment (baseline, 1.3±1.0 points vs 3months, 0.9±0.9 points; p<0.05). Among 18 patients who had postural abnormalities at baseline, defined as 1 point or greater on MDS-UPDRS part III subitem 3.13, posture improved in 9 (50%) and was unchanged in 9 (50%) patients after istradefylline treatment. Improved and unchanged groups did not show differences in baseline characteristics, except for tendency for a higher rate of Hoehn and Yahr stage IV and V (Off state) observed in the improved group. Changes in scores of posture (3.13) did not correlate with those of other MDS-UPDRS part III items, PD Questionnaire-8, PD Sleep Scale-2 and Epworth Sleepiness Scale. CONCLUSION: Based on our preliminary findings, istradefylline could be an effective treatment option for postural abnormalities in mid-stage PD patients.

Istradefylline improves daytime sleepiness in patients with Parkinson's disease: An open-label, 3-month study.

BACKGROUND: Istradefylline, a selective adenosine A2A receptor antagonist, has been reported to improve daily "off time" and motor symptoms in patients with Parkinson's disease (PD). However, the effect of istradefylline on sleep problems has not been thoroughly investigated. METHODS: We evaluated the effect of istradefylline on daytime sleepiness, sleep disturbances, and motor symptoms in 22 PD patients who were affected by the wearing off phenomenon in an open-label, 3-month study. Participants received 20-40mg/day istradefylline once daily (morning) over a 3-month period. The Epworth Sleepiness Scale (ESS), PD sleep scale (PDSS)-2 and PD Questionnaire (PDQ-8) were administered at baseline, 2weeks, 1month, 2months and 3months. At baseline and 3months, patients were evaluated on the Movement Disorder Society Revision of the Unified PD Rating Scale (MDS-UPDRS) parts III and IV. RESULTS: Twenty-one patients (95.5%) completed the study. At 3months, MDS-UPDRS part III (-5.3, p=0.0002) and part IV (-2.5, p=0.001) scores improved and off time decreased significantly (-50.1min, p=0.0004). PDQ-8 scores were unchanged at 3months. ESS scores decreased significantly at 2months and 3months (-2.4 and -3.3, respectively, p<0.0001), but the total PDSS-2 scores did not change. CONCLUSION: Istradefylline improved daytime sleepiness in PD patients, possibly through its effect on enhancing alertness. In addition, the lack of significant changes in the total PDSS-2 scores over the study period suggests istradefylline had no negative impact on sleep.

Insulinoma Masquerading as Rapid Eye Movement Sleep Behavior Disorder: Case Series and Literature Review.

Insulinoma is a rare endocrine tumor that can cause a wide variety of symptoms, including abnormal nocturnal behavior. We report on 3 patients with insulinoma who presented with abnormal nocturnal behavior and injury during sleep, which simulated rapid eye movement (REM) sleep behavior disorder (RBD). In case 1, the fasting glucose level was 15  mg/dL, and insulin levels were elevated (15  µU/mL). In case 3, when the patient was transferred to the hospital because of a disturbance of consciousness, hypoglycemia (29  mg/dL) was detected. In contrast, in case 2, fasting glucose sampling did not indicate hypoglycemia, but continuous glucose monitoring revealed nocturnal hypoglycemia. The time from initial symptoms to a diagnosis of insulinoma ranged from 7 months to 2 years. All 3 patients had previously received anticonvulsant drugs for suspected epilepsy, but the medications were ineffective. Polysomnography showed no evidence of REM sleep without atonia in any of the 3 patients. No patient remembered any events that occurred during sleep. When a patient manifests abnormal behavior during the night and early morning, glucose monitoring should be performed, especially during the night and early morning. Clinicians should be aware that although insulinomas are rare, they can mimic parasomnias, such as RBD.

Risk factors for neurodegeneration in idiopathic rapid eye movement sleep behavior disorder: a multicenter study.

OBJECTIVE: To assess whether risk factors for Parkinson disease and dementia with Lewy bodies increase rate of defined neurodegenerative disease in idiopathic rapid eye movement (REM) sleep behavior disorder (RBD). METHODS: Twelve centers administered a detailed questionnaire assessing risk factors for neurodegenerative synucleinopathy to patients with idiopathic RBD. Variables included demographics, lifestyle factors, pesticide exposures, occupation, comorbid conditions, medication use, family history, and autonomic/motor symptoms. After 4 years of follow-up, patients were assessed for dementia or parkinsonism. Disease risk was assessed with Kaplan-Meier analysis, and epidemiologic variables were compared between convertors and those still idiopathic using logistic regression. RESULTS: Of 305 patients, follow-up information was available for 279, of whom 93 (33.3%) developed defined neurodegenerative disease. Disease risk was 25% at 3 years and 41% after 5 years. Patients who converted were older (difference = 4.5 years, p < 0.001), with similar sex distribution. Neither caffeine, smoking, nor alcohol exposure predicted conversion. Although occupation was similar between groups, those who converted had a lower likelihood of pesticide exposure (occupational insecticide = 2.3% vs 9.0%). Convertors were more likely to report family history of dementia (odds ratio [OR] = 2.09), without significant differences in Parkinson disease or sleep disorders. Medication exposures and medical history were similar between groups. Autonomic and motor symptoms were more common among those who converted. Risk factors for primary dementia and parkinsonism were generally similar, except for a notably higher clonazepam use in dementia convertors (OR = 2.6). INTERPRETATION: Patients with idiopathic RBD are at very high risk of neurodegenerative synucleinopathy. Risk factor profiles between convertors and nonconvertors have both important commonalities and differences.

Comorbidity and medication in REM sleep behavior disorder: a multicenter case-control study.

OBJECTIVE: This controlled study investigated associations between comorbidity and medication in patients with polysomnographically confirmed idiopathic REM sleep behavior disorder (iRBD), using a large multicenter clinic-based cohort. METHODS: Data of a self-administered questionnaire on comorbidity and medication use of 318 patients with iRBD and 318 matched controls were analyzed. Comparisons between cases and controls were made using logistic regression analysis. RESULTS: Patients with iRBD were more likely to report depression (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.3-2.9) and concomitant antidepressant use (OR 2.2, 95% CI 1.4-3.6). Subanalysis of antidepressant agents revealed that the increased use of antidepressants in iRBD was due to selective serotoninergic reuptake inhibitors (OR 3.6, 95% CI 1.8-7.0) and not due to other antidepressant classes. Patients with iRBD reported more lifetime antidepressant use than comorbid depression (antidepressant use: OR 1.9, 95% CI 1.1-3.3; depression: OR 1.6, 95% CI 1.0-2.5). Patients with iRBD reported more ischemic heart disease (OR 1.9, 95% CI 1.1-3.1). This association did not change substantially when adjusting for cardiovascular risk factors (OR 2.3, 95% CI 1.3-3.9). The use of inhaled glucocorticoids was higher in patients with iRBD compared to controls (OR 5.3, 95% CI 1.8-15.8), likely reflecting the higher smoking rate in iRBD (smoking: OR 15.3, 95% CI 2.0-118.8; nonsmoking: OR 2.4, 95% CI 0.4-13.2) and consequent pulmonary disease. CONCLUSIONS: This large study confirms the association between comorbid depression and antidepressant use in iRBD. In addition, there was an unexpected association of iRBD with ischemic heart disease that was not explained by cardiovascular risk factors.

Dream-enacting behaviour is associated with impaired sleep and severe headache-related disability in migraine patients.

BACKGROUND: Sleep disorders, nightmares and visual hallucinations have been reported in migraine patients, which may suggest the involvement of rapid eye movement (REM) sleep regulation in migraine. However, the relationship between migraine and REM sleep behaviour disorder (RBD) remains unclear. METHODS: To investigate the clinical correlates of dream-enacting behaviours (DEB) in migraine patients, we assessed episodic migraine patients ( N = 161, mean age 33.1 years) and headache-free control subjects ( N = 140, mean age 33.1 years) under 50 years of age in a cross-sectional, case-control study. The Japanese version of the RBD screening questionnaire was used, and subjects scoring 5 or higher were defined as having DEB. RESULTS: A significantly increased frequency of DEB was observed in migraine patients compared to controls (24.2% vs. 14.3%). Migraine patients with DEB presented higher scores on the Migraine Disability Assessment and Pittsburgh Sleep Quality Index and an increased rate of smoking compared to those without DEB. Duration of migraine and headache frequency and intensity were not different between migraine patients with or without DEB. CONCLUSION: DEB was associated with impaired sleep and severe headache-related disability in migraine patients and may reflect brainstem dysfunction and increased brain excitability in migraine patients.

A single-question screen for rapid eye movement sleep behavior disorder: a multicenter validation study.

BACKGROUND: Idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia that is an important risk factor for Parkinson's disease (PD) and Lewy body dementia. Its prevalence is unknown. One barrier to determining prevalence is that current screening tools are too long for large-scale epidemiologic surveys. Therefore, we designed the REM Sleep Behavior Disorder Single-Question Screen (RBD1Q), a screening question for dream enactment with a simple yes/no response. METHODS: Four hundred and eighty-four sleep-clinic-based participants (242 idiopathic RBD patients and 242 controls) completed the screen during a multicenter case-control study. All participants underwent a polysomnogram to define gold-standard diagnosis according to standard criteria. RESULTS: We found a sensitivity of 93.8% and a specificity of 87.2%. Sensitivity and specificity were similar in healthy volunteers, compared to controls or patients with other sleep diagnoses. CONCLUSIONS: A single-question screen for RBD may reliably detect disease, with psychometric properties favorably comparable to those reported for longer questionnaires.

Evaluation of contributing factors to restless legs syndrome in migraine patients.

Recent studies have provided evidence for a positive association between migraine and restless legs syndrome (RLS), although the exact mechanisms and contributing factors remain unclear. A cross-sectional, case-control study was conducted, including patients with migraine (n = 262) and headache-free control subjects (n = 163). Migraine was diagnosed according to International Classification of Headache Disorders II criteria. RLS diagnosis was made based on four essential criteria as described by the International Restless Legs Syndrome Study Group. All patients completed the Migraine Disability Assessment (MIDAS) questionnaire, Beck Depression Inventory (BDI)-II scores, Pittsburgh Sleep Quality Index (PSQI), and Epworth Sleepiness Scale (ESS). A total of 210 blood samples were collected to correlate various parameters with RLS. RLS frequency was significantly greater in patients with migraine than in controls (13.7 vs. 1.8%). Migraine patients with RLS had high scores for MIDAS, BDI-II, PSQI, and ESS compared with those without RLS. In addition, migraine patients with RLS had a high rate of smoking and RLS family history, as well as increased levels of serum phosphorus and urea nitrogen compared with those without RLS. However, there was no difference in serum iron and ferritin levels between the groups. In migraine patients, logistic regression analysis revealed that positive RLS family history, BDI-II, ESS, and serum phosphorus levels were significant RLS predictors. Our study confirmed a positive association between RLS and migraine. RLS comorbidity in migraine patients was associated with insomnia, daytime sleepiness, depressive symptoms, headache-related disability, and increased serum phosphorus levels. These findings may provide a better understanding of RLS pathogenesis in migraine.

Aggressive undifferentiated colon carcinoma producing granulocyte-colony stimulating factor: report of a case.

We report a rare case of granulocyte-colony stimulating factor (G-CSF)-producing undifferentiated carcinoma of the ascending colon. A 52-year-old Japanese man presented with a rapidly growing, aggressive abdominal tumor, and severe leukocytosis (63 000/mm(3)). The serum level of G-CSF was remarkably elevated to 640 pg/ml (normal, <18.1 pg/ml). The patient underwent palliative cytoreductive surgery for ascending colon carcinoma with lymph node and liver metastases. Histological examination revealed an undifferentiated carcinoma of the ascending colon. The tumor cells were positive for G-CSF on immunohistochemical staining. The leukocyte counts and G-CSF level decreased after surgery. Thus, we diagnosed G-CSF-producing colon carcinoma. His general condition deteriorated rapidly and he died of residual tumor growth on postoperative day 24.

Laparoscopic treatment for torsion of the gallbladder in a 7-year-old female.

A 7-year-old girl was diagnosed with viral enteritis and was admitted to our hospital. Sudden right upper quadrant tenderness appeared 2 days after admission. Ultrasonography revealed a large thick-walled cystic gallbladder and an inflammation-induced hyperechoic cystic duct. The long axis of the gallbladder was in a horizontal rather than a vertical alignment. Computed tomography demonstrated a markedly enlarged gallbladder with a slightly thickened wall and an enhanced twisted cystic pedicle. The diagnosis of gallbladder torsion led to laparoscopic detorsion and cholecystectomy. The gallbladder was gangrenous and was rotated counterclockwise with the attachment of the mesentery to the inferior surface of the liver. Although it occurs more rarely in children than in adults, torsion of the gallbladder must be considered in the differential diagnosis of an acute abdomen. Early diagnosis and immediate laparoscopic intervention can help to achieve an excellent patient outcome.

[A case of the oldest old patient with advanced esophageal cancer responding completely to the combination chemotherapy of docetaxel/5-fluorouracil/nedaplatin with radiation].

An 86-year-old man was admitted with dysphagia. Endoscopic examination revealed an advanced esophageal cancer located in the lower thoracic esophagus. Histological analysis revealed moderately differentiated squamous cell carcinoma. The clinical stage was diagnosed as T2N0M0, stage II. He received radiation therapy in combination with chemotherapy using docetaxel, 5-fluorouracil and nedaplatin. After chemoradiotherapy (CRT), the carcinoma could not be detected by CT or endoscopy, and endoscopic biopsy revealed no cancer cells in categorization as resulting complete response. Adverse event consisted of grade 2 in leukopenia. We could not detect relapse, metastases or late side effect of CRT at present, 24 months after CRT.

The REM sleep behavior disorder screening questionnaire: validation study of a Japanese version.

BACKGROUND: REM sleep behavior disorder (RBD) is a parasomnia characterized by intermittent loss of normal skeletal muscle atonia during REM sleep and elaborate motor activity associated with dream mentation. Idiopathic RBD (iRBD) has a known association with neurodegenerative diseases such as synucleinopathies. Recently, a specific screening scale for assessment of REM sleep behavior disorder (RBDSQ) was validated. Detection of RBD using a Japanese version of the RBDSQ would be useful in the stepwise diagnostic process. We investigated the validity and reliability of a Japanese version of this instrument, the RBDSQ-J. METHODS: Subjects were 52 patients with iRBD diagnosed according to criteria in the International Classification of sleep disorders, second edition, 55 obstructive sleep apnea syndrome (OSAS) patients who responded well to CPAP therapy after a diagnosis of RBD was ruled out by history and polysomnography (PSG) and 65 healthy subjects. RESULTS: An RBDSQ-J score cut-off of 5.0 was considered useful for differentiating the iRBD group from the healthy subjects or the OSAS group. Cronbach's alpha for the entire RBDSQ-J was 0.866. CONCLUSION: The RBDSQ-J had high sensitivity, specificity, and reliability and would be applicable as a screening method for iRBD in the elderly Japanese population.

[Pathophysiology of restless legs syndrome].

Restless legs syndrome (RLS) is a sensorimotor disorder that is frequently associated with periodic leg movements (PLMS). RLS is generally considered to be a central nervous system (CNS)-related disorder although no specific lesion has been found to be associated with the syndrome. Reduced intracortical inhibition has been demonstrated in RLS by transcranial magnetic stimulation. Some MRI studies have revealed the presence of morphologic changes in the somatosensory cortex, motor cortex and thalamic gray matter. The results of SPECT and PET studies showed that the limbic and opioid systems also play important roles in the pathophysiology of RLS. A functional MRI study revealed abnormal bilateral cerebellar and thalamic activation during the manifestation of sensory symptoms, with additional red nucleus and reticular formation activity during PLMS. PLMS is likely to occur in patients with spinal cord lesions, and some patients with sensory polyneuropathy may exhibit RLS symptoms. RLS symptoms seem to depend on abnormal spinal sensorimotor integration at the spinal cord level and abnormal central somatosensory processing. PLMS appears to depend on increased excitability of the spinal cord and a decreased supraspinal inhibitory mechanism from the All diencephalic dopaminergic system. RLS symptoms respond very dramatically to dopaminergic therapy. The results of analysis by PET and SPECT studies of striatal D2 receptor binding in humans are inconclusive. However, studies in animal models suggest that the participation of the All dopaminergic system and the D3 receptor in RLS symptoms. The symptoms of RLS are aggravated in those with iron deficiency, and iron treatment ameliorates the symptoms in some patients. Neuroimaging studies, analysis of the cerebrospinal fluid, and studies on postmortem tissue and use of animal models have indicated that low brain iron concentrations and dysfunction of iron metabolism and intracellular iron may play key roles in the pathogenesis of RLS. The "iron-dopamine model" explains that iron deficiency in the brain causes an abnormality in the dopaminergic system leading to manifestation of RLS. Genetic factors are also important in the development of RLS. A positive family history for RLS has been reported by 40% to 60% of RLS patients. Five loci (RLS 1: 12q, RLS 2: 14q, RLS 3: 9p, RLS 4: 2q, RLS 5: 20p) have been described. Genome-wide association studies have identified variants within the intronic or intergenetic regions of MEIS1 (2p), LBXCOR1/MAP2K5 (15q), BTBD9 (6p), neuronal nitric oxide synthase (NOS1) (12q) and protein tyrosine phosphatase receptor type delta (9p) genes. In conclusion, disturbances in the central dopaminergic system, disturbances in iron metabolism, and genetics seem to be the primary factors in the pathophysiology of RLS.

[A case of double advanced cancer with esophageal and hypopharyngeal carcinoma responding completely to combination chemotherapy of docetaxel/5-fluorouracil and nedaplatin with radiation].

A 69-year-old male was admitted to our hospital because of dysphagia. The diagnosis was double cancer with hypopharyngeal and esophageal carcinoma from upper gastrointestinal endoscopic examination. Pathological examinations of the double cancer revealed moderately-differentiated squamous cell carcinoma. Computed tomography(CT)of the neck and abdomen showed metastases of the right neck and cardiac lymph nodes. Clinical stagings of the double cancer were Stage III (T1, N1, M0)in hypopharyngeal carcinoma and Stage III (T3, N1, M0)in esophageal carcinoma, respectively. He received radiation therapy in combination with chemotherapy using docetaxel(DOC), 5-fluorouracil (5-FU)and nedaplatin(CDGP). After this combination chemoradiation therapy(CRT), the adverse event was grade 2 in leucopenia and grade 2 in gastrointestinal toxicity. Repeated macroscopic and histological examinations after CRT revealed disappearance of the hypopharyngeal and advanced esophageal carcinoma with lymph node metastasis, leading to a complete response(CR). He had maintained CR for the 20 months since undergoing CRT. This combination chemotherapy of DOC, 5-FU and CDGP with radiation may well be effective and tolerable for patients with double cancer of hypopharyngeal and esophageal carcinoma.

[A case of ascending colon cancer with local recurrence responding completely to alternating modified-FOLFOX6 and FOLFIRI regimens(modified-FIREFOX regimen)].

A 58-year-old woman underwent right hemicolectomy with lymph node dissection(D2)for advanced ascending colon cancer which pathological examinations revealed to be moderately-differentiated adenocarcinoma. CEA and CA19-9 levels increased 6 months after the operation. She started adjuvant chemotherapy with oral administration of UFT-E(400 mg/day), but CEA and CA19-9 levels continued to elevate. However, a recurrent tumor was not detected by computed tomography(CT)and endoscopic examinations. A local recurrence in the right lateral abdominal wall was confirmed by PET-CT examination. We then conducted modified-FOLFOX6/FOLFIRI alternating regimen(modified- FIREFOX regimen). After this therapy, repeated PET-CT showed that the abnormal FDG-uptake concentration had disappeared, leading to a complete response(CR). The adverse event was grade 3 in leucopenia and grade 2 in gastrointestinal toxicity. She had maintained CR for the 12 months since undergoing chemotherapy. CEA and CA19-9 levels reduced to the normal range. We report this case with some review of the literature.

[A case of hepatic portal venous gas caused by chemo-radiation therapy for an advanced esophageal cancer].

Hepatic portal venous gas(HPVG)is a rare condition with a poor prognosis. A 40-year-old man underwent esophagectomy for stage IV esophageal cancer followed by chemotherapy. Four months later, he admitted to our hospital because of the increases of residual tumors and started chemoradiotherapy(CRT)with 5-FU, CDDP and radiation. Computed tomography(CT)scan revealed PR, and blood examination showed decreases in WBC and platelet counts. Fourty days after CRT, he suddenly complained severe pain in the left chest and abdomen, and vomiting. CT scan showed HPVG in the left lobe of the liver and pneumatosis cystoides intestinalis in the wall of the gastric tube. He died of multiple organ failure. To our knowledge, this is a first case of HPVG associated with CRT for esophageal cancer.