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.

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.

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.

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.

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.

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.

We report a patient with subacute myelo-optico-neuropathy (SMON) in whom spinal anesthesia was employed to treat fracture of the femur neck. An 87-year-old woman was diagnosed as having SMON at the age of 45. The patient was admitted to our hospital with fracture of the femur neck. Aspiration pneumonia was also suspected with shadow in the right lung on the chest X-P The percutaneous oxygen saturation (Spo2) with room air was 77%. Spinal anesthesia with 5 mg of 0.5% hyperbaric bupivacaine and 20 mcg of fentanyl was performed at L3-4. The level of anesthesia was T4. During surgery, no severe pain in the lower limbs was observed. Three hours after the end of surgery, the level of anesthesia was T9. On the day after surgery, the extent of dysesthesia and reflex were similar to those before surgery. General anesthesia has been chosen in SMON patients, because there was a report of severe pain of the lower limbs after spinal anesthesia with dibucaine. In our patient, general anesthesia was considered inappropriate due to hypoxemia. We used a mixture of bupivacaine and fentanyl for spinal anesthesia, because the neurotoxicity of bupivacaine is weaker than that of dibucaine.

Throughout my research life, I experienced to discover the causes of some neurological diseases in Japan. 1) SMON (subacute myelo-optico-neuropathy). Since the early 1960s, a peculiar neurological disease became prevalent throughout Japan. Through the chemical analysis of the green urine, characteristic of this disease, it was found that this disease was caused by intoxication of the administered clioquinol, an anti-diarrheal drug. This discovery is a big topic in the history of Japanese medicine. 2) In early 1970s, I experienced many young patients with oedema and polyneuropathy in Kagoshima. Finally it was found that the disease was the long-forgotten beriberi, which had disappeared several decades ago. We must always be aware of beriberi even now, as far as we eat well-polished rice. 3) In 1972, we noticed a group of sporadic paraparesis in Kagoshima, which was 20 years later confirmed to be induced by human T lymphotropic virus type-I (HTLV-I). We named this disease as "HTLV-I associated myelopathy" (HAM). It gave a strong impact that the causative virus of adult T cell leukemia (ATL) can induce entirely different diseases, in terms of both the clinical course and the pathological features. It was also proven that HAM was identical with tropical spastic paraparesis, (TSP), which had been prevalent in many areas of tropical zones. These experiences are good examples of our slogan "to keep in mind to send message of scientific progress from the local area to the international stage.

Japanese Society of Neurology (JSN) was established in 1960 with 643 members, and in 2009 it has grown up to a big society having more than 8,000 members including 3,600 neurology board specialists. JSN has greatly contributed in elucidating and resolving many socio-medical problems. I will take three topics including SMON (subacute myelo-optico-neuropathy), infectious Creutzfeldt-Jakob disease (CJD) and Minamata disease. SMON was a new epidemic disease characterized by subacute optic neuritis and myeloneuropathy associated with diarrhea and abdominal symptoms. The research committee clarified that it was a neurological complication of chinoform, a drug for gastroenteritis. CJD surveillance started in 1996 for variant CJD, and uncovered many patients who developed CJD after human dura draft. The government prohibited to use non-inactivated human dura. Minamata disease is an organic mercury poisoning of people who took fish contaminated by mercury in Minamata bay in Kumamoto or in Aganogawa river in Niigata. The factories discharged water contaminated with mercury which was accumulated in fish and shellfish. Still many victims claim for compensation to the companies and government. Neurologists in Kumamoto and Niigata greatly contributed to diagnose and treat the victims and to clarify the cause of the disease.

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.

Acquired copper deficiency has recently been recognized as a cause of myeloneuropathy mimicking subacute combined degeneration due to vitamin B-12 deficiency. A remote history of gastric surgery is frequently associated with this syndrome. However, the very limited prevalence of severe copper deficiency in patients with a history of gastric surgery suggests that additional contributing factors are likely to be involved. We describe a patient with copper deficiency and a previous Billroth II partial gastrectomy for gastric carcinoma, presenting with severe myelo-optico-neuropathy, demyelinating lesions of the brain, and subjective hyposmia. An abnormal glucose breath test also revealed small bowel bacterial overgrowth syndrome. Copper replacement therapy associated with antibiotic therapy was effective in preventing further neurological damage and in obtaining mild improvement. We propose that copper status should be evaluated in all patients presenting with unexplained noninflammatory myeloneuropathy. Small bowel bacterial overgrowth syndrome should be investigated as a cause of generalized malabsorption and a possible contributing factor to copper deficiency after gastric surgery, as should occult zinc ingestion.

The subacute myelo-optico-neuropathy (SMON) was hazard caused by clioquinol, an antiseptic, prescribed for the treatment of diarrhea and other bowel symptoms. Its overdosing and long-term taking led to the occurrence of SMON, for which physicians should be responsible. Clioquinol, originally a disinfectant powder for external use, was diverted later to a drug for internal use to sterilize the bowel where no intestinal absorption or action after absorption was expected. An annotation on the 6th Revision of the Japan Pharmacopoeia (1954) allowed irregular increase in its dosage depending on the severity of illness. An annotation on the 7th Revision (1961) ignoring the 6 papers published in the 1930's, 1940's or 1950's claimed that its metabolism was poorly known, yet neglected significant side effect and substantial absorption from the intestine. Its characterization as a superficial disinfectant helped the annotators be less interested in its absorption and its internal actions and side effects. Attention paid by clinicians to a polyneuropathy-like syndrome that complicated an uncontrollable hemorrhagic diarrhea (1958) and an encephalomyelitis or a paralysis of the lower half of the body associated with diarrhea or other bowel symptoms (1960, 1961) started the recognition of a new disease. During the dispute induced by the mass occurrence of the disease in several instances postmortem examination with neuropathologic expertise, especially of T. Tsubaki, Y. Toyokura and H. Tsukagoshi (1964), characterized SMON as a non-inflammatory new disease of the spinal cord, optic nerve and peripheral nerve with a pseudo-systemic degeneration of posterior and lateral columns and, therefore played a decisive role in establishing the truth of SMON. The discovery of the green hairy tongue (the tongue coated with green hairs) of SMON by T. Takasu, A. Igata and Y. Toyokura (January 1970) aroused researchers' interest in the green color of SMON and thereby began solving the cause of SMON. The discovery of the green urine in SMON patients by A. Igata, M. Hasebe and T. Tsuji (May 1970) especially facilitated the identification of the green substance in SMON that was achieved by M. Yoshioka and Z. Tamura (June 1970). The green color was derived from a chelate compound of clioquinol with ferric iron. The early epidemiological analysis related clioquinol taking to the occurrence of SMON well enough for the Japanese Government to take an administrative measure for the temporary suspension of selling clioquinol containing drugs and the postponing of their use (September 1970). Extensive and intensive multidisciplinary investigations conducted for the subsequent 20 months led to the conclusion by the SMON Investigation and Research Committee (Head: R. Kono) that the neurological disorders of patients who were diagnosed as SMON for the most part were caused by taking clioquinol (March 1972). Close clinical observation of patients opened a way to recognize a new disease and elucidate its cause. Expert specialized technical knowledge and skills established the firm knowledge of the new disease. The study of SMON began as a personal research and after its achievement was exposed to the public a great many investigators in different fields concerted efforts to solve problems. Both steps were indispensable for completing the study.

One thousand and thirty-one longstanding patients with subacute myelo-optico-neuropathy (SMON; 275 males, 756 females; mean age +/- S.D., 72.9 +/- 9.6 years; age at onset 37.6 +/- 9.8 years; duration of illness 35.3 +/- 4.0 years) were examined in 2002, 32 years after banning of clioquinol. At onset, 66.7% of patients were unable to walk, and 4.7% complete blindness. At present time, about 41% of patients were still difficult to walk independently, including 15.8% of completely loss of locomotion. One point six percent of patients were in complete blindness and 5.8% had severe visual impairment. The majority (95.6 - 97.7%) of patients exhibited sensory disturbances including superficial and vibratory sensations and dysesthesia. Dysautonomia was observed as leg hypothermia in 79.8%, urinary incontinence in 60.7%, and bowel disturbance in 95.3%. As complication, high incidence was revealed with cataract (56.2%), hypertension (40.2%), vertebral disease (35.5%), and limb articular disease (31.5%). These results indicate the serious sequelae of clioquinol intoxication, SMON.

Patients of subacute myelo-optico-neuropathy (SMON) suffer from neurological disorders for a long time. The authors report anesthetic management of two patients with SMON. One patient was a 82-year-old woman suffering from SMON for 49 years. Sensory examination revealed numbness and hypesthesia in the both lower extremities. She underwent open reduction for femoral neck fracture. The other patient was a 91-year-old man suffered from SMON for 31 years. Sensory examination revealed weakness of leg muscles. He underwent transurethral resection of prostate. We chose general anesthesia for both patients instead of spinal anesthesia because of reported complications related to spinal anesthesia in patients with the disease. Intraoperative courses were uneventful and there were no neurological deteriorations postoperatively in both patients. One of the chief symptoms of patients with SMON is numbness of the lower extremity. Therefore patients of SMON may feel uncomfortable to the numbness by spinal or epidural anesthesia. This is the main reason we recommend general anesthesia for patients with SMON.

The present case, 78-years-old female, had been troubled with SMON during 28 years, and was suddenly died from cerebral hemorrhage. The neuropathology characteristic for SMON could not be revealed in the spinal cord on routine histological preparations. There were decreasing number of immunopositive granules in the nucleus gracilis of medulla oblongata for synaptophysin, and in the marginal zone of the lumbar dorsal horn for substance P. These findings showed the presence of tractus gracilis degeneration and the disappearance of nociceptive fibers from the dorsal roots, respectively. To elucidate the histopathological changes of the spinal cord in long standing cases with SMON, the 11 cases reported were reviewed. The mean duration from the onset to death was 22.8 years(16 to 33 years). The mean age was 76.3 years old(54 to 92), and the 10 cases were female. All cases showed sensory impairment of the lower extremities, while deep tendon reflex exaggerated was seen in 7 cases. There were nine cases involving dorsal funiculi degeneration of the spinal cord, in contrast the lateral funiculi alternation were noticed in only two cases. It was considered that the corticospinal tract alteration becomes undiscernible during the long course, although the dorsal funiculi degeneration remained.

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.

A 79-year-old woman with subacute myelo-optico-neuropathy (SMON) underwent a bilateral mastectomy for breast cancer. She has been suffering from SMON for 32 years. Her preoperative neurological examination revealed cryesthesia and dyskinesia in the lower extremity, and numbness in the crues. Physical examination revealed respiratory dysfunction. A combination of general anesthesia and epidural block was employed to minimize the dose of anesthetics which may affect the neuronal symptoms. Intraoperative course was uneventful and continuous epidural block was effective for postoperative pain control. There was no neurological deterioration postoperatively.

SMON (subacute myelo-optico-neuropathy) may result from clioquinol neurotoxicity. An 81-year-old woman underwent internal fixation for left intertrochanteric fracture. She had been diagnosed as having SMON twenty years previously. Sensory examination revealed paresthesia and decreased deep sensation in the lower extremity. A recent neuropathological report shows that in long-term SMON of about fifteen years, degeneration is located from the medulla oblongata to T5-6. We performed spinal anesthesia of which the level of analgesia was below T5-6 in the present case. The level of anesthesia was determined by the pinprick test, and was recognized as below T10. Postoperatively, both the sensory level of analgesia and vital signs remained stable. There was no worsening of neurological findings after spinal anesthesia, including the postoperative period. In conclusion, spinal anesthesia which was limited to below the level of degeneration could be applied in a case of long-term SMON.

To investigate the relationship between CYP2D6 genotypes (reported to be associated with the susceptibilities to Parkinson's disease and multisystem atrophy) and the possible susceptibility to neuroleptic malignant syndrome (NMS) and subacute myelo-optico-neuropathy (SMON), we analyzed the CYP2D6 gene by polymerase chain reaction and restriction fragment length polymorphism in Japanese schizophrenia patients with a history of NMS. There was no significant difference in the frequency of the poor metabolizer genotype of CYP2D6 between the cases with a history of NMS and controls (p > 0.05). The frequency of the mutation located at the HhaI site in exon 6 of CYP2D6 in the cases was higher, but not significantly (p > 0.05; the mutated allele frequency was 0.25), than that in the controls, schizophrenia patients without NMS (0.11) and healthy controls (0.09). The frequency (0.10) of the HhaI mutation type in patients with a diagnosis of SMON was also not significantly higher than in healthy controls. These results suggest that the poor metabolizer and HhaI polymorphism of CYP2D6 may not be a useful molecular marker for predicting the onset of NMS and SMON.

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.

Several kinds of immunological abnormalities have been found more frequently in patients with subacute myelo-optico-neuropathy (SMON). To investigate whether the B-cell immune system is implicated in aging in patients with SMON, we examined serum levels of immunoglobulin including IgG, IgM, and IgA, and the number of CD20+ cells (B lymphocytes) and CD20+ CD23+ cells (activated B lymphocytes) using flow cytometry, and compared them with those in age-matched controls. We also investigated whether the number of HLA-DR+ cells was correlated with those of CD20+ cells, CD20+ CD23+ cells, or HLA-DR+CD3+ cells (activated T lymphocytes) in patients with SMON. Serum levels of IgG, IgM and IgA were decreased with aging both in the patients with SMON and in the controls, and no significant difference was found between the two groups. Although the patients with SMON tended to show higher levels of CD20+ and CD20+ CD23+ cells than the age-matched controls, there were no significant differences between the two groups. The number of HLA-DR+ cells was correlated not with that of CD20+ cells or CD20+ CD23+ cells, but with that of HLA-DR+CD3+ cells. In patients with SMON, it is likely that the B-cell immune system is mainly implicated in the effect of aging, but it is unlikely that other factors than aging are associated with the B-cell immune system. The increase in the number of HLA-DR+ cells associated with aging in patients with SMON reflects the increase in the number of activated T lymphocytes, and is not correlated with the changes of B lymphocytes.

It has been reported that some kinds of immunological abnormalities are more frequently seen in patients with subacute myelo-optico-neuropathy (SMON), as compared with normal subjects. In order to examine whether ageing and clioquinol intoxication in the past may be implicated in the immunological disorders of the patients, we investigated soluble interleukin-2 receptors (sIL-2R) and an appearance of HLA-DR positive T cells using two color flow cytometry analysis in the peripheral blood of 29 patients with SMON, who lived in Nagano Prefecture. The mean level of HLA-DR positive T cells in the total of SMON patients was significantly high as compared with that of normal subjects (p < 0.001). The mean levels of HLA-DR positive T cells were also significantly high in SMON patients in their fifties and younger, sixties, and seventies and older, respectively, as compared with those of normal subjects (p < 0.05, respectively). The mean level of sIL-2R in the total of SMON patients was significantly high as compared with that of normal subjects (p < 0.01). The mean levels of sIL-2R were also high in SMON patients in their fifties and younger, sixties, and seventies and older. An especially significant increase was seen in SMON patients in their sixties (p < 0.01). SMON patients with higher levels of HLA-DR positive T cells tended to have higher levels of sIL-2R, and statistical analysis showed a significant correlation between them (r = 0.696, p < 0.001). An increase in HLA-DR positive T cells and sIL-2R indicates an increase in activated T cells.(ABSTRACT TRUNCATED AT 250 WORDS)