Subacute Myelo-optico-neuropathy Patients 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.

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.

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.

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.

Current Perception Threshold in Subacute Myelo-Optico-Neuropathy

ABSTRACTWe report the first current perception threshold (CPT) examination of sensory disturbance in subacute myelo-optico-neuropathy (SMON). SMON patients experience serious neurological symptoms, including dysesthesia, sensory loss, motor weakness, and visual impairment. During CPT examination, 5 Hz, 250 Hz, and 2,000 Hz stimulations were used to stimulate C fibers, A-δ fibers, and A-β fibers, respectively. Ten SMON patients (mean age, 73.8 ± 8.4 years) and ten age-matched controls (72.3 ± 6.3 years) were studied using CPT measured at the index finger and near the external malleolus. The CPTs to 250 Hz and 2,000 Hz stimulations near the external malleolus were significantly higher and the CPT to 5 Hz stimulation was significantly lower in the SMON group than in the control group. Although peripheral nerve impairment is mild in SMON, pathological examination shows a decrease of large fibers. This is thought to increase the CPTs to 250 Hz and 2,000 Hz stimulations. The center of the gate control of pain exists in the posterior horn receiving information from the dorsal root ganglion. The dorsal root ganglion at the lumber cord is strongly impaired in SMON; therefore, the gate control may not work effectively, and decreases CPT to 5 Hz stimulation.

Change in Activities of Daily Living, Functional Capacity, and Life Satisfaction in Japanese Patients with Subacute Myelo-Optico-Neuropathy

BackgroundThere have been few reports on longitudinal change in activities of daily living (ADL), functional capacity, and life satisfaction in patients with subacute myelo-optico-neuropathy (SMON).MethodsA total of 1309 SMON patients 40 to 79 years of age underwent a medical examination conducted by the SMON Research Committee during the period from 1993 through 1995 (baseline) in Japan; 666 (51%) were followed-up after 12 years and were thus eligible for analysis. We calculated scores for ADL, functional capacity, and life satisfaction at baseline, and at 3, 6, 9, and 12 years after baseline, using data from medical examinations conducted in 1993 through 2007. The Barthel Index, the Tokyo Metropolitan Institute of Gerontology Index of Competence, and the patient’s response to the question “Are you satisfied with life?” were used to assess ADL, functional capacity, and life satisfaction, respectively.ResultsAs compared with baseline, the mean scores for ADL, functional capacity, and life satisfaction were all significantly lower after 12 years in men and women, with the exception of life satisfaction in women. The change in scores for functional capacity from baseline to year 12 was significantly associated with change in life satisfaction; however, the changes in ADL and age at baseline were not.ConclusionsWe observed decreases in ADL, functional capacity, and life satisfaction among SMON patients. Our results suggest that a decrease in life satisfaction can be prevented by maintaining or improving functional capacity.

Activities of Daily Living, Functional Capacity, and Life Satisfaction of Subacute Myelo-Optico-Neuropathy Patients in Japan

BackgroundPatients with subacute myelo-optico-neuropathy (SMON) suffer from a number of serious neurological symptoms that adversely affect their activities of daily living (ADL). However, the effects of these neurological symptoms on functional capacity and life satisfaction have not been reported.MethodsWe analyzed data from 1,300 SMON patients aged 55–94 years that was obtained at medical check-ups carried out by the SMON Research Committee in 2004–2006 in Japan. The neurological symptoms investigated were visual impairment, dysbasia, symptoms of the lower extremities, and sensory symptoms. Neurological symptoms were classified by severity. The Barthel Index, the Tokyo Metropolitan Institute of Gerontology Index of Competence, and the participant’s response to the question “Are you satisfied with life?” were used to evaluate ADL, functional capacity, and life satisfaction, respectively. Data were analyzed using a proportional odds model with the scores for these items as ordinal dependent variables.ResultsFor most neurological symptoms, scores for ADL, functional capacity, and life satisfaction were significantly lower in participants with severe or moderate neurological symptoms than in those with nearly normal results upon examination. The odds ratio for life satisfaction due to superior functional capacity was significant after adjustment for sex, age, and ADL score.ConclusionThe presence of neurological symptoms in SMON patients was associated with low functional capacity, life satisfaction, and ADL. Our results suggest that the life satisfaction of SMON patients can be increased by improving their functional capacity.

Depression in Patients with Subacute Myelo-Optico- Neuropathy (SMON)

We investigated the psychiatric disorders in subacute myelo-optico-neuropathy (SMON) patients by structured interview. The prevalence of major depressive disorder in SMON patients was estimated by structured interview and using Beck's depression inventory (BDI) questionnaires. Psychiatric conditions were evaluated in 26 SMON patients (9 males, 17 females, mean age 70.7 years) living in Kyoto prefecture through a structured interview given by psychiatrists. BDI questionnaires and clinical symptoms of SMON were investigated in 106 patients, ranging from 51 to 91 years in age (mean, 73.5) with SMON patients living in Kinki area. BDI questionnaires were obtained from 92 age-matched aged healthy people, ranging from 57 to 91 years in age (mean, 75.8), living in Kyoto city. Among the psychiatric disorders in SMON patients, the prevalence of major depressive disorder and suicidal ideation significantly increased during the period of clioquinol intake and four patients (15.4%) out of 26 SMON patients still suffer from major depressive disorder. The prevalence of major depressive disorder in SMON patients was estimated at 15.1% (16/106) and this percentage was about seven times as frequent as in the age-matched aged healthy people (2.2%; 2/92). In female SMON patients, the degree of the depressive states was significantly correlated with the severe degree of dysesthesia of the lower extremities, and it was inversely correlated with the duration of SMON disease and the total scores of the Barthel index. This is the first report that shows the prevalence of major depressive disorder in SMON patients at present, which was seven times more frequent than age-matched aged healthy persons.

Disability and Lifestyle of Subacute Myelo-Optico-Neuropathy and Stroke Patients and Elderly Persons Living at Home : A Comparison of the Barthel Index Score and the Frenchay Activities Index Score

To evaluate subacute myelo-optico-neuropathy (SMON) and stroke patients and elderly persons by using the Barthel Index (BI) and Frenchay Activities Index (FAI) and to reveal the disability and lifestyle of SMON patients, cross sectional comparison study was performed. Forty SMON patients, 92 age-matched stroke patients with the same level of BI score and 92 age-matched elderly persons living at home were subjected in this study. The SMON patients responded to a self-administered BI and FAI at their yearly health counseling, and the score of the BI and FAI of stroke outpatients and elderly persons were sampled from the databases. The differences in age distribution and sex ratio between the three groups were analyzed by the chi2 test and one-way analysis of variance, respectively, and the differences in BI and FAI between the three groups were analyzed by the Kruskal-Wallis test, followed by the Mann-Whitney test. The BI total score of the SMON patients was the same as that of the stroke patients and lower than that of the elderly persons. The 4 items of self-care index and 2 items of mobility index in the SMON patients were rated significantly higher and lower than the stroke patients respectively, and all items except eating and toileting in the SMON patients were rated lower than elderly persons (Mann-Whitney test, P < 0.05). The FAI scores in the SMON patients were lower than the elderly persons and higher than the stroke patients. These results suggest that the scores of the BI and FAI differentiated the features of disability and lifestyle of the SMON patients from those of stroke patients and elderly persons.

Diminished skin vasodilator response to local heating in patients with long-standingsubacute myelo-optico-neuropathy

Background Local heating of non-glabrous skin increases skin blood flow (SkBF) in two phases: the initial peak (P1) is mediated by sensory axon reflex, and the plateau phase (P2) is thought to be mediated by local production of substances including nitric oxide. We evaluated P1 and P2 responses in subacute myelo-optico-neuropathy (SMON). Methods SkBF response to local heating from 32 °C (5 min of baseline) to 42 °C (at least for 30 min) of the dorsal surface of the hand skin were measured in 7 SMON patients (67.6 ± 10.0 years) and 7 normal control volunteers (65.0 ± 7.4 years) participated. Results Mean values of SkBF at P1 (SkBFP1) and SkBF during P2 (SkBFP2) were significantly lower in SMON patients than in controls ( p < 0.05, p < 0.05). Mean SkBFP1/SkBF at baseline (SkBFbase) and SkBFP2/SkBFbase ratios were significantly lower in SMON patients than in controls ( p < 0.01 and p < 0.05, respectively). Conclusions The SkBF response to local heating was diminished in SMON patients. This may reflect the involvement of the spinal cord, peripheral sensory nerves, and sympathetic post-ganglionic nerves in SMON.

Investigation of visual disorders of subacute myelo‐optico‐neuropathy (SMON) patients 32 years after onset: Questionnaire‐based survey and ophthalmological examination

An investigation of subacute myelo‐optico‐neuropathy (SMON) patients (20 male and 132 female, aged 31–93 years) was conducted in December 1998 using a self‐administered questionnaire. Following this survey, ophthalmological examinations were performed on 33 patients between 1998 and 2000. The questionnaire‐based survey revealed that the prevalence of patients with cataracts was 52.0%, and those with glaucoma was 9.4%. By dividing the patients into two groups, according to the levels of visual disturbances at the time of onset of SMON, we found that the prevalence of glaucoma was higher in the group with visual disturbances than in the group with normal vision. However, the prevalence of cataracts, optico‐neuritis and fundus hemorrhage was not considerably different between the two groups. Ophthalmological examinations (e.g. intraocular pressure test, visual field test, slit lamp microscopy test, funduscopic examination) revealed that 63.6% of patients had cataracts, and 12.1% had glaucoma (9.1% for normal tension glaucoma). The ophthalmological examination revealed that the prevalence of normal tension glaucoma in the SMON patients tended to be higher than in other surveys in the general population of Japan. SMON patients need follow‐up ophthalmological examinations, especially for glaucoma, on a nationwide scale.

Characteristics of fingertip photoplethysmography in patients with sub-acute myelo-optico-neuropathy

Fingertip photoplethysmography is a useful technology for evaluating arterial distensibility, which is thought to reflect the extent of arteriosclerosis or vascular tone mediated by vasomotor nerves. We recorded fingertip photoplethysmograms in 15 patients with sub-acute myelo-optico-neuropathy (SMON) and 27 normal control subjects. The SMON patients were classified into a SMON(+) group of 9 patients with risk factor(s) for arteriosclerosis and a SMON(−) group of 6 patients without risk factor(s).

Subacute myelo-optico-neuropathy: clioquinol intoxication in humans and animals.

It remains a tragic event that some 10,000 individuals in Japan developed a unique neurologic disease, subacute myelo-optico-neuropathy (SMON). Many of the affected patients still suffer serious sequelae, such as dysesthesia and muscle weakness in the lower extremities, and loss or deficits in visual acuity. Neuropathologic studies on SMON patients and experimental reproduction of the disease in animals which had been administered clioquinol helped resolve the etiology of this disease. Common pathologic features seen in SMON patients and in dogs and cats chronically intoxicated with clioquinol were distal dominant axonopathy, mainly in the spinal long tracts and optic tracts. Particular abdominal symptoms present in patients after clioquinol ingestion could also be reproduced experimentally in dogs. SMON research in Japan may be worth reviewing for determining the etiology and preventing similar neurotoxic diseases in the future.

Evaluation of Cardiopulmonary Function in SMON Patients at the Mass Examination in Japan.

The purpose of this study was to investigate autonomic disorder of the cardiopulmonary system of patients who were diagnosed as hypoventilation according to coefficient of variation of R-R (CVR-R) in electrocardiograms of SMON (subacute myelo-optico-neuropathy) patients at mass examinations in many regions of Aichi Prefecture in Japan. One hundred twenty two patients, diagnosed as SMON ranging in age from fifty one to eighty eight (mean 72.1) participated. As investigation items, ventilation capability (%VC, %FVC, FEVl%, %MMF, V50 and V25) and CVR-R (during deep breathing load) were measured. The following results were obtained: 1) Ventilation functions among patients: those who had %VC of equal or less than 80%, or those who had FEVl% of equal or less than 70% were 44 cases (36.1%). 2) CVR-R during deep breathing: SMON patients were divided into two groups of ventilation capability normal group and depression group. During deep breathing, significantly higher values than at the resting time were shown in ages equal and below seventy of ventilation capability depression group. Based on the above results, among ventilation capability depression group, disturbance of activities of parasympathetic nerve system was estimated to exist, because CVR-R showed lower values then those of normal group at the resting, while it showed a significant increase at the time of deep breathing load.

PS-45-8 Effects of abstinence of smoking on event-related potentials and midlatency responses

To study the cognitive function in 13 patients with sequelae of subacute myelo-optico-neuropathy (SMON), event-related potentials (ERPs) were elicited with tones, clicks, and colored visual stimuli in different tasks. P300 latency was delayed, and P300 amplitude reduced or absent in 5 patients (38%), although neuropsychological assessment for dementia did not differ between patients and 21 age-matched normal controls. P300 and N200 latencies with the tone/tone auditory stimuli and N200 latency with the visual stimuli were significantly delayed, but the latencies of early components (N100 and P200) were not delayed. These findings suggest that SMON patients may have cognitive dysfunction to a slight degree.