Subacute Myelo-optico-neuropathy Research Articles

Founder genetic variants of ABCC4 and ABCC11 in the Japanese population are not associated with the development of subacute myelo-optico-neuropathy (SMON).

BackgroundSubacute myelo‐optico‐neuropathy (SMON) is a severe neurological disorder associated with clioquinol administration, which frequently occurred in Japan during the 1950s and 1960s. The unique genetic background of the Japanese population is considered to be strongly involved in the development of this neurological disease. Recently, genetic variants of ABCC4 (OMIM: 605250) and ABCC11 (OMIM: 607040), which are particularly common in the Japanese population, were suggested as possible genetic susceptibility factors for the development of SMON.MethodsWe analyzed 125 Japanese SMON patients who provided consent for this study. Patient DNA was collected from peripheral blood, and genetic analysis was performed for ABCC4 rs3765534 (c.2268G>A, p.Glu857Lys) and ABCC11 rs17822931 (c.538G>A, p.Gly180Arg) polymorphisms using the Sanger sequencing method and/or TaqMan PCR method. The frequency distribution of each polymorphism was compared with that in healthy Japanese people recorded in two genomic databases (Human Genomic Variation Database and Integrative Japanese Genome Variation Database), and each genotype was compared with the clinical features of patients.ResultsThe frequencies of ABCC4 rs3765334 and ABCC11 rs17822931 polymorphisms in SMON patients and healthy Japanese people were not significantly different in the multifaceted analysis.ConclusionWe conclude that the ABCC4 rs3765334 and ABCC11 rs17822931 polymorphisms are not associated with the development of SMON.

Fifity years after the identification of the cause of SMON

SMON (subacute myelo-optico-neuropathy) is toxic neurological disease which had a profound impact on the population in Japan in 1960's. The clinical characteristics of SMON includes an ascending sensory disturbance, spasticity, and visual impairment typically following abdominal symptoms. Infection was first suspected as an underlying cause of this epidemic. The disorder was ultimately attributed to the overuse of clioquinol, based on the analysis of green urine from affected patients and confirmed by the epidemiological surveys and experimental animal studies. The factors that contributed to the prevalence of SMON which remains the worst example of drug-associated toxicity in Japan to date include the conversion of clioquinol from a purely topical agent to an orally-administered drug, dogma associated with drug safety, relatively limited regulation of drug use, an increase in the number of prescriptions due to the availability of universal insurance, as well as the complexity of the associated abdominal symptoms. Periodical examination of the patients diagnosed with SMON continues to this day. As such, it is important to have a better understanding of clioquinol-induced neurotoxicity together with the mechanisms underlying drug susceptibility; we should not permit the memory of this severe and prominent drug-associated toxicity fade from view.

Clioquinol kills astrocyte-derived KT-5 cells by the impairment of the autophagy-lysosome pathway.

Clioquinol has been implicated as a causative agent for subacute myelo-optico-neuropathy (SMON) in humans, although the mechanism remains to be elucidated. In this study, we utilized astrocyte-derived cell line, KT-5 cells to explore its potential cytotoxicity on glial cells. KT-5 cells were exposed in vitro to a maximum of 50μM clioquinol for up to 24h. 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenylte trazolium bromide (MTT) assay of the cells revealed that clioquinol induced significant cell damage and death. We also found that clioquinol caused accumulation of microtubule-associated protein light chain-3 (LC3)-II and sequestosome-1 (p62) in a dose- and time-dependent manner, suggesting the abnormality of autophagy-lysosome pathway. Consistent with these findings, an exposure of 20μM clioquinol induced the accumulation of cellular autophagic vacuoles. Moreover, an exposure of 20μM clioquinol provoked a statistically significant reduction of intracellular lysosomal acid hydrolases activities but no change in lysosomal pH. It also resulted in a significant decline of intracellular ATP levels, enhanced cellular levels of reactive oxygen species, and eventually cell death. This cell death at least did not appear to occur via apoptosis. 10μM Chloroquine, lysosomal inhibitor, blocked the autophagic degradation and augmented clioquinol-cytotoxicity, whereas rapamycin, an inducer of autophagy, rescued clioquinol-induced cytotoxicity. Thus, our present results strongly suggest clioquinol acts as a potentially cytotoxic agent to glial cells. For future clinical application of clioquinol on the treatment of neurological and cancer disorders, we should take account of this type of cell death mechanism.

Sleep problems in subacute myelo-optico neuropathy (SMON)

Subacute myelo-optico neuropathy (SMON) patients typically suffer from sequelae that cause sleep disturbances. We sought to examine the prevalence of sleep problems among SMON patients. We conducted a questionnaire-based survey concerning sleep problems among 106 SMON patients, and 110 age- and gender-matched control participants. The prevalence of subjective insomnia (6 ≤ Athens Insomnia Scale score) was 89.6% among SMON patients, which was significantly higher than among control participants 54.4%. Sleep quality measured with the Pittsburgh Sleep Quality Index (PSQI) revealed that the prevalence of poor sleepers (6 ≤ PSQI score) was higher among SMON patients than control participants (75.6% vs 39.6%, respectively). Subscale analyses of rapid eye movement sleep behavior disorder screening questionnaire revealed that scores on two items (“dreams match nocturnal behavior” and “limb movements”) were significantly higher among SMON patients than control participants. In addition, daytime sleepiness scores were significantly higher among SMON patients than control participants (4 ≤ Epworth Sleepiness Scale scores: 54.0% vs 29.0%, respectively). The current study revealed that most SMON patients suffer from insomnia with dissatisfactory sleep quality, likely due to their long-term physical sequelae. Moreover, SMON patients showed higher rates of daytime sleepiness and sleep medication intake, which could be related to reduced activity during the day, as well as insomnia.

The usefulness of [123I]‐metaiodobenzylguanidine myocardial scintigraphy in patients with subacute myelo‐optico‐neuropathy

AbstractBackgroundPatients with subacute myelo‐optico‐neuropathy (SMON), caused by clioquinol intoxication more than 40 years ago, had been suffered from various kinds of autonomic disorders, such as diarrhea, constipation, and incontinence. [123I]‐metaiodobenzylguanidine (MIBG) myocardial scintigraphy is a sensitive test for diagnosis of Parkinson's disease (PD).AimWe tried to clarify the usefulness of MIBG myocardial scintigraphy in SMON patients for diagnosing PD.MethodsThe MIBG myocardial scintigraphy was investigated in fifteen SMON patients who were suffered from various kinds of autonomic symptoms. In these SMON patients, four patients (mean age ± SD; 73.3 ± 6.8) showed early stage of PD, whose Hoehn–Yahr (H–Y) stage was stage I or stage II, but the other eleven patients (mean age ± SD; 78.0 ± 7.6) had not any signs or symptoms of Parkinsonism.ResultsFour patients with early stages of PD showed significantly reduced MIBG uptake. Eleven patients except one without Parkinsonism showed normal MIBG uptake. No apparent relation between the degree of the autonomic symptoms and the MIBG uptake was observed. One patient without Parkinsonism showed significantly reduced MIBG uptake and was suggested to be suffered from a preclinical state of PD, since the [123I]‐ioflupane single‐photon emission computed tomography scintigraphy showed decreased uptake of isotopes in the bilateral striate regions 8 years after the MIBG myocardial scintigraphy.ConclusionThe MIBG myocardial scintigraphy in SMON patients with various kinds of autonomic symptoms is useful as a highly sensitive and specific tool for diagnosing PD.

Physical Disabilities Related to the Depressive Mental States of Japanese Patients with Subacute Myelo-optico-neuropathy.

Objective The aim of this study was to clarify the clinical conditions related to the depressive mental states in Japanese patients with subacute myelo-optico-neuropathy (SMON), caused by clioquinol intoxication more than 40 years previously. Methods The changes in the mental states with aging were investigated in 25 Japanese SMON patients (mean age: 77.2 years old, range: 53-90) using a Japanese version of the Zung Self-rating Depression Scale (J-SDS) questionnaires with supportive interviews by the clinical psychotherapist and medical checkup records. These mental and medical examinations were repeated more than twice within 2 to 11 years' interval. The J-SDS questionnaires were also examined in 25 age-matched non-SMON elderly people. Results The total J-SDS scores of most of the SMON patients decreased with age without significant changes in the mean Barthel index scores during this study period. The mean J-SDS scores at the first and latest studies were significantly higher than in the age-matched healthy elderly people. The total J-SDS scores of the latest study were significantly correlated with the degree of physical disability, such as the inverse total Barthel index scores, severity of SMON or gait disturbance, but not with the age. Conclusion The total J-SDS scores of most of the SMON patients tended to decrease with age. Repeating mental supportive interviews and medical examinations by experts helped to improve the depressive mental state and revealed close relationship between the mental state and the physical disabilities of the SMON patients.

Tongue strength in patients with subacute myelo-optico-neuropathy

Subacute myelo-optico-neuropathy (SMON) is a neurodegenerative disease that may be caused by overdose or prolonged oral administration of clioquinol. Recently, dysphagia has attracted attention as a complication of SMON. To investigate lingual control in SMON, we examined patients with SMON using assessments of maximum tongue pressure, compared with dysphagia-related diseases, such as sporadic inclusion body myositis (sIBM) and amyotrophic lateral sclerosis (ALS), and healthy volunteer. The mean maximum tongue pressure (Pmax) in patients with SMON was 14.7 ± 5.8 kPa, while it was 33.6 ± 4.4 kPa in the controls. In contrast, the mean Pmax for patients with ALS with or without bulbar involvement was 7.8 ± 2.7 kPa and 34.4 ± 5.7 kPa, respectively, while it was 29.4 ± 8.2 kPa in patients with sIBM. Pmax values correlated with lower limb weakness in SMON patients. Decreases in Pmax may be involved in the development of dysphagia in patients with SMON.

P.5.d.002 - The statistical analysis of the changes of the depressive mental states of Japanese patients with subacute myelo-optico neuropathy

P.5.d.002 - The statistical analysis of the changes of the depressive mental states of Japanese patients with subacute myelo-optico neuropathy

Change over time in the treatment condition for patients with subacute myelo-optico-neuropathy in Japan

Background: Subacute myelo-optico-neuropathy (SMON) is a severe neuro-degenerative disorder caused by poisoning due to oral administration of clioquinol. It is characterized by impaired vision, optic atrophy, subacute myelopathy, spasticity, and dysesthesia of lower limbs and trunk. In Japan, over 12,000 cases developed from 1950s to1970, so many patients are still suffering although we have no new patients. Annual medical examination for SMON patients has been carried out as a permanent state measure.

Importance of Strength Training of the Triceps Surae Muscles for Improvement of Walking Speed in Patients with Subacute Myelo-Optico-Neuropathy

Two patients with subacute myelo-optico-neuropathy (SMON) were evaluated by using the functional reach test (FRT) in the standing position, and by measuring the gait speed for 10m before and after strength training of the triceps surae muscles through calf-raise training in the standing position. The reach distance in FRT and the walking speed after strength training of the triceps surae muscles through calf raising were improved compared with those before the calf-raise training in both patients. The results of this study suggested that strength training of the triceps surae muscles improves not only the walking ability but also the balance function in patients with SMON.

The Aggravation of Depression with Aging in Japanese Patients with Subacute Myelo-optico-neuropathy (SMON).

Objective We attempted to clarify the factors related to the aggravation of depression in patients with subacute myelo-optico-neuropathy (SMON) caused by clioquinol intoxication more than 35 years previously. Methods We investigated changes in the depressive mental states that occurred with aging in 19 Japanese SMON patients (mean age, 78.3 years; range, 66-89 years) according to their scores on the Japanese version of the Zung Self-rating Depression Scale (SDS), which were obtained 3-10 years previously and their current scores. The depressive state was further evaluated using simultaneous semi-structured interviews. Results The depressive mental states of 6 patients, whose current total SDS scores had increased by ≥10% in comparison to the previous score, were considered to have been aggravated with aging. The mean current total SDS score of these six patients was significantly higher than the mean score of the 13 patients whose conditions were not aggravated. Among the 20 SDS questionnaires, the patients whose conditions were aggravated showed significantly higher scores in diurnal variation, sleep disturbance and weight loss. The semi-structured interviews revealed that physical disabilities due to the sequelae of SMON, a lack of acceptance of SMON, and a decline in social activities were important factors in the aggravation of their depressive mental states with aging. Conclusion The maintenance of social activities with public support was important for coping among Japanese SMON patients with a depressive mental state, especially those who could not walk independently or who could not go outside freely without assistance.

The prevalence of dementia in subacute myelo-optico-neuropathy (SMON) patients who underwent medical checkups.

Subacute myelo-optico-neuropathy (SMON) is a known adverse effect of clioquinol use; however, clioquinol dissolves beta-amyloid aggregation in Alzheimer's disease (AD). Therefore, we investigated the prevalence of dementia in SMON patients and whether past clioquinol use affected the current incidence of AD. We included 647 SMON patients (195 men, 452 women; mean age 77.9 years) who had undergone medical checkups including the mini-mental state examination (MMSE) in 2012. Of them, 105 patients scored ≤23 on the MMSE assessment. The presence/absence of dementia and disease backgrounds were obtained by a questionnaire. Then, using the medical checkup database, the correlation between the degree of severity when signs of SMON were at their worst and the concurrent presence or absence of AD at present was analyzed. In patients ≥65 years of age, the estimated prevalence of dementia was approximately 10.9% (95% confidence interval: 7.9%-13.8%). The concurrent presence of AD at present was not correlated with the past degree of SMON severity when the SMON signs were at their worst. The 10.9% prevalence of dementia in SMON patients was lower than a previously reported 15% prevalence found in the general population. According to these results, we cannot draw a definitive conclusion regarding the preventive effect of clioquinol on AD. Additionally, the lack of association between the onset of AD and past severity of SMON precludes definitive conclusions on the relationship between concurrent presence of AD and past clioquinol use.

Cognitive and affective functions of aged subacute myelo-optico neuropathy patients in Japan

Background Subacute myelo-optico neuropathy was the first epidemic drug intoxication that affected many people in Japan in the 1970s. Aim More than 40 years later, we assessed the real conditions of subacute myelo-optico neuropathy patients. Methods The present study examined current cognitive and affective functions, activities of daily living, and vascular endothelial function in aged subacute myelo-optico neuropathy patients (n = 28) compared with age-, sex-, body mass index- and years of schooling-matched normal controls (n = 141). Results Mini-Mental State Examination, Hasegawa Dementia Scale-Revised, Montreal Cognitive Assessment and Frontal Assessment Battery scores were not significantly lower in subacute myelo-optico neuropathy patients, but the Geriatric Depression Scale was significantly higher without apathy. Computerized touch-panel tests showed poor performance in the flipping cards game, arranging pictures game and beating devils game, whereas activities of daily living and vascular endothelial function were within normal limits. Conclusion The present study shows that subacute myelo-optico neuropathy patients showed essentially normal cognitive function using standard cognitive assessments, although the touch-panel tests detected some decline in subacute myelo-optico neuropathy patients. Subacute myelo-optico neuropathy patients presented a higher depression score without evident apathy, activities of daily living decline or vascular endothelial dysfunction.

Histone deacetylase inhibitor attenuates neurotoxicity of clioquinol in PC12 cells.

Clioquinol is considered to be a causative agent of subacute myelo-optico neuropathy (SMON), although the pathogenesis of SMON is yet to be elucidated. We have previously shown that clioquinol inhibits nerve growth factor (NGF)-induced Trk autophosphorylation in PC12 cells transformed with human Trk cDNA. To explore the further mechanism of neuronal damage by clioquinol, we evaluated the acetylation status of histones in PC12 cells. Clioquinol reduced the level of histone acetylation, and the histone deacetylase (HDAC) inhibitor Trichostatin A upregulated acetylated histones and prevented the neuronal cell damage caused by clioquinol. In addition, treatment with HDAC inhibitor decreased neurite retraction and restored the inhibition of NGF-induced Trk autophosphorylation by clioquinol. Thus, clioquinol induced neuronal cell death via deacetylation of histones, and HDAC inhibitor alleviates the neurotoxicity of clioquinol. Clioquinol is now used as a potential medicine for malignancies and neurodegenerative diseases. Therefore, HDAC inhibitors can be used as a candidate medicine for the prevention of its side effects on neuronal cells.

SMON: toxicity of clioquinol and the status quo

Subacute myelo-optico-neuropathy (SMON) is a disease characterized by subacute onset of sensory and motor disorders in the lower half of the body and visual impairment preceded by abdominal symptoms. A large number of SMON were observed throughout Japan, and the total number of cases reached nearly 10,000 by 1970. Despite clinical features mimicking infection or multiple sclerosis, SMON was confirmed as being caused by ingestion of clioquinol, an intestinal antibacterial drug, based on extensive epidemiological studies. After the governmental ban on the use of clioquinol in September 1970, there was a dramatic disappearance of new case of SMON. In the 1970s, patients with SMON initiated legal actions against the Government and pharmaceutical companies, and the court ruled that the settlements would be made as health management allowances and lasting medical check-ups. The physical condition of patients with SMON remains severe owing to SMON as well as gerontological complications. The pathological findings in patients with SMON included symmetrical demyelination in the lateral and posterior funiculi of the spinal cord and severe demyelination of the optic nerve in patients with blindness. Although clioquinol may show activity against Alzheimer's disease or malignancy, its toxic effects cause severe irreversible neurological sequelae. Thus, caution must be exercised in the clinical use of clioquinol.

P.4.b.007 Changes of the depressive mental states with aging in Japanese patients with subacute myelo-optico-neuropathy (SMON)

P.4.b.007 Changes of the depressive mental states with aging in Japanese patients with subacute myelo-optico-neuropathy (SMON)

Superoxide dismutase as a target of clioquinol-induced neurotoxicity

Subacute myelo-optico-neuropathy (SMON) is a progressive neurological disorder affecting the spinal cord, peripheral nerves and optic nerves. Although it has been assumed that SMON was caused by intoxication of clioquinol, the mechanism underlying clioquinol-induced neurotoxicity is not fully understood. This study aimed to clarify the relevance of oxidative stress to clioquinol-induced neurotoxicity and the cause of the enhanced oxidative stress. Clioquinol induced cell death in human-derived neuroblastoma cell line, SH-SY5Y, in a dose-dependent manner. This process was accompanied by activation of caspase-3 and enhanced production of reactive oxygen species (ROS). We examined whether clioquinol inhibited the activity of superoxide dismutase-1 (SOD1), based on its metal chelating properties. Clioquinol inhibited activities of purified SOD1 in a dose-dependent manner. Cytosolic SOD activities were also inhibited in SH-SY5Y cells treated with clioquinol. Finally, addition of exogenous SOD1 to the culture significantly reduced enhanced ROS production and cell death induced by clioquinol in SH-SY5Y cells. These findings suggested that enhanced oxidative stress caused by inhibition of SOD1 undelay clioquinol-induced neurotoxicity and was relevant to the pathogenesis of SMON.

P.2.b.022 Worsening conditions for the depressive mental states with aging in Japanese patients with subacute myelo-optico-neuropathy (SMON)

P.2.b.022 Worsening conditions for the depressive mental states with aging in Japanese patients with subacute myelo-optico-neuropathy (SMON)

T-3. MONのウイルス学的研究

T-3. MONのウイルス学的研究

P.2.a.001 A five year comparative study of the depressive states in eight Japanese female patients with subacute myelo-optico-neuropathy (SMON)

P.2.a.001 A five year comparative study of the depressive states in eight Japanese female patients with subacute myelo-optico-neuropathy (SMON)