[Clinical characteristics of seizure-predominant autoimmune encephalitis and utility of anti-neuronal antibody scores for early treatment].

We analyzed 20 patients diagnosed with autoimmune neurological diseases with seizure predominance. In these patients, we examined the usefulness of Antibody Prevalence in Epilepsy and Encephalopathy (APE2) score and Antibodies Contributing to Focal Epilepsy Signs and Symptoms (ACES) score in autoimmune encephalitis (AE) for facilitating early treatment. APE2 score was positive in 19 of 20 patients. ACES score was positive in 15 of 20 patients, and 4 of 5 of the patients with negative ACES score did not have AE. Comprehensive assessment including the use of the above scores is desirable in the early stage of AE.

Hashimoto Encephalopathy Presenting with Acute Psychosis and Inappropriate Secretion of Antidiuretic Hormone: A Rare Case Responding to Steroid Therapy.

BACKGROUND Hashimoto's encephalopathy (HE) is an autoimmune encephalopathy that can involve various symptoms including psychosis. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) may be a complication in some neurological diseases. However, the simultaneous occurrence of subacute psychosis and SIADH as the manifestation of HE, observed in the present case, has rarely been reported. CASE REPORT A 72-year-old man was hospitalized with a 4-month history of abnormal behaviors, including talkativeness, stopping consumption of coffee and cigarettes, hoarding garbage, and sleep disorders. On physical examination, increased and incoherent speech with flight of idea and delusion were observed. The Mini-Mental State Examination score was 28/30. Laboratory findings included hyponatremia due to SIADH and a positive result for anti-thyroid and anti-NH2 terminal of alpha-enolase antibodies. Cerebrospinal fluid examination revealed only elevation of IL-6. Brain magnetic resonance imaging was unremarkable; however, (I-123)-iodoamphetamine single-photon emission computed tomography showed extensive hyperperfusion involving the brainstem and bilateral frontal and medial temporal lobes. Electroencephalography showed generalized slow waves, but there were no epileptiform discharges. After 2 courses of high-dose intravenous methylprednisolone followed by oral prednisolone, his symptoms improved. Based on the findings of clinical features and steroid responsiveness, he was diagnosed with HE. Oral prednisolone and antipsychotic drugs were decreased without a relapse and he was discharged to his home. CONCLUSIONS Although psychosis complicating SIADH is rare, HE should be considered in the differential diagnosis because of its treatment efficacy.

Possible Chronic Graft-versus-host Disease in the Central Nervous System Manifesting as Cerebellar Ataxia after Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia.

A 44-year-old woman was admitted to our hospital with a fever, dizziness, and gait disturbance after undergoing allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia followed by graft-versus-host disease. She presented with cerebellar ataxia, nystagmus, and numbness of the lower extremities. Brain magnetic resonance imaging and perfusion scintigraphy showed progressive cerebellar involvement. Cerebrospinal fluid tests showed mildly elevated protein and IgG levels without pleocytosis. Anti-ganglioside antibodies were detected, but their levels did not follow the patient's clinical course. The patient did not respond sufficiently to steroids or other immunotherapies. We herein report the clinical characteristics of this case and a literature review.

Spinocerebellar Ataxia Type 31 Exacerbated by Anti-amino Terminal of Alpha-enolase Autoantibodies.

We herein report a 61-year-old woman who was genetically diagnosed with spinocerebellar ataxia type 31 whose symptoms were modified by anti-amino terminal of alpha-enolase (NAE) antibodies, known as a biomarker of Hashimoto's encephalopathy (HE), and ultimately responded to immunotherapy. The relative titers of anti-NAE antibodies increased when her cerebellar ataxia showed acute deterioration and decreased after immunotherapy. This is the first report of cerebellar ataxia associated with genetic spinocerebellar ataxia with concomitant cerebellar type HE. Physicians should be mindful of measuring anti-NAE antibodies to prevent overlooking patients with genetic spinocerebellar ataxia with treatable simultaneous ataxic diseases.

Cerebral Oxidative Stress in Early Alzheimer's Disease Evaluated by 64Cu-ATSM PET/MRI: A Preliminary Study.

Oxidative stress imaging using diacetyl-bis (N4-methylthiosemicarbazone) (Cu-ATSM) was applied to the evaluation of patients with early Alzheimer's disease (eAD). Ten eAD patients (72 ± 9 years) and 10 age-matched healthy controls (HCs) (73 ± 9 years) participated in this study. They underwent dynamic PET/MRI using 11C-PiB and 64Cu-ATSM with multiple MRI sequences. To evaluate cerebral oxidative stress, three parameters of 64Cu-ATSM PET were compared: standardized uptake value (SUV), tracer influx rate (Kin), and a rate constant k3. The input functions were estimated by the image-derived input function method. The relative differences were analyzed by statistical parametric mapping (SPM) using SUV and Kin images. All eAD patients had positive and HC subjects had negative PiB accumulation, and MMSE scores were significantly different between them. The 64Cu-ATSM accumulation tended to be higher in eAD than in HCs for both SUV and Kin. When comparing absolute values, eAD patients had a greater Kin in the posterior cingulate cortex and a greater k3 in the hippocampus compared with lobar cortical values of HCs. In SPM analysis, eAD had an increased left operculum and decreased bilateral hippocampus and anterior cingulate cortex compared to HCs. 64Cu-ATSM PET/MRI and tracer kinetic analysis elucidated cerebral oxidative stress in the eAD patients, particularly in the cingulate cortex and hippocampus.

Case Report: Paraneoplastic Hashimoto's Encephalopathy Associated With Lymphomatosis Cerebri With Periodic Synchronous Discharges Resembling Creutzfeldt-Jakob Disease.

Hashimoto's encephalopathy (HE) is an autoimmune encephalopathy that presents with various clinical symptoms, including cognitive deterioration, convulsive seizures, and personality changes. HE is associated with thyroid autoimmunity; however, few cases have been reported to develop as paraneoplastic syndrome. Herein, we report the case of a 73-year-old woman with onset of rapidly progressive dementia. Brain magnetic resonance imaging showed diffuse T2 hyperintensity areas involving the bilateral cerebral white matter, right midbrain tegmental area, left cerebral peduncle, and right middle cerebellar peduncle without clear diffusion hyperintensities and gadolinium enhancement. Her neurological symptoms worsened rapidly, and she presented with the apallic syndrome. Electroencephalogram showed periodic synchronous discharge, suggestive of Creutzfeldt-Jakob disease. However, a brain biopsy revealed infiltration of atypical lymphoid cells expressing CD20, and the anti-NH2 terminal of the α-enolase antibody was detected, diagnosing the complication with lymphomatosis cerebri and HE. High-dose intravenous methylprednisolone therapy and oral prednisolone with whole cranial irradiation enabled her to have simple conversations and consume food orally; however, severe cognitive impairment persisted. Although HE is a rare complication of malignant lymphoma, clinicians should be aware that it could be strongly suspected if the clinical symptoms worsen in the absence of imaging changes.

[Hashimoto Encephalopathy].

Hashimoto encephalopathy (HE) has been recognized as a new clinical disease based on an autoimmune mechanism associated with Hashimoto's thyroiditis. HE is successfully treated with steroids. In 2005, we discovered serum autoantibodies against the NH2-terminal of α-enolase (NAE) as a highly specific diagnostic biomarker for HE. We analyzed the serum anti-NAE autoantibodies and clinical features in many cases of HE from institutions in Japan and other countries. Approximately half of the patients with HE had anti-NAE antibodies. In our study, HE was widely distributed in patients aged 50-60 years. Most patients with HE were in euthyroid states, and all patients had anti-thyroid antibodies. The common neuropsychiatric features of these patients were consciousness disturbance and psychosis, followed by cognitive dysfunction, involuntary movements, seizures, and ataxia. Abnormalities in EEG and decreased cerebral blood flow on the brain SPECT were common findings. In contrast, abnormalities on the brain MRI were rare except for diffuse subcortical lesions and limbic lesions. Patients with HE had varied clinical phenotypes, including acute encephalopathy, chronic psychiatric form, and other particular clinical presentations, such as limbic encephalitis, progressive cerebellar ataxia, and Creutzfeldt-Jakob disease (CJD)-mimic form. The cerebellar ataxic form of HE clinically mimics spinocerebellar degeneration (SCD) and is characterized by the absence of nystagmus, absent or mild cerebellar atrophy, and lazy background activities on electroencephalography (EEG). Taken together, these features should indicate the possibility of encephalopathy associated with thyroid disorders.

High prevalence of serum anti-NH2-terminal of α-enolase antibodies in patients with multiple system atrophy and corticobasal syndrome.

BACKGROUND: Hashimoto's encephalopathy with serum anti-NH2-terminal of α-enolase (NAE) antibodies occasionally displays clinical symptoms such as cerebellar ataxia and parkinsonism. We studied the frequency of anti-NAE antibodies in patients with Parkinson-plus syndrome. METHODS: We examined the positive rates of anti-NAE antibodies in 47 patients with multiple system atrophy (MSA), 29 patients with Parkinson's disease (PD), eight patients with corticobasal syndrome (CBS), and 18 patients with progressive supranuclear palsy (PSP) using conventional immunoblot analysis. RESULTS: Positive anti-NAE antibody rates of 31.9%, 10.3%, 50.0%, and 11.1% were reported in the MSA, PD, CBS, and PSP patients, respectively. The duration from onset to a wheelchair-bound state in seropositive MSA patients tended to be shorter than that in seronegative MSA patients. CONCLUSIONS: Anti-NAE antibodies are detected in some patients clinically diagnosed with MSA and CBS. Although its pathophysiological significance remains uncertain, serum anti-NAE antibodies might represent a prognostic marker in the clinical course of MSA.

Molecular imaging for mitochondrial metabolism and oxidative stress in mitochondrial diseases and neurodegenerative disorders.

BACKGROUND: Increasing evidence from pathological and biochemical investigations suggests that mitochondrial metabolic impairment and oxidative stress play a crucial role in the pathogenesis of mitochondrial diseases, such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, and various neurodegenerative disorders. Recent advances in molecular imaging technology with positron emission tomography (PET) and functional magnetic resonance imaging (MRI) have accomplished a direct and non-invasive evaluation of the pathophysiological changes in living patients. SCOPE OF REVIEW: In this review, we focus on the latest achievements of molecular imaging for mitochondrial metabolism and oxidative stress in mitochondrial diseases and neurodegenerative disorders. MAJOR CONCLUSIONS: Molecular imaging with PET and MRI exhibited mitochondrial metabolic changes, such as enhanced glucose utilization with lactic acid fermentation, suppressed fatty acid metabolism, decreased TCA-cycle metabolism, impaired respiratory chain activity, and increased oxidative stress, in patients with MELAS syndrome. In addition, PET imaging clearly demonstrated enhanced cerebral oxidative stress in patients with Parkinson's disease or amyotrophic lateral sclerosis. The magnitude of oxidative stress correlated well with clinical severity in patients, indicating that oxidative stress based on mitochondrial dysfunction is associated with the neurodegenerative changes in these diseases. GENERAL SIGNIFICANCE: Molecular imaging is a promising tool to improve our knowledge regarding the pathogenesis of diseases associated with mitochondrial dysfunction and oxidative stress, and this would facilitate the development of potential antioxidants and mitochondrial therapies.

Gerstmann's Syndrome in a Patient Double-positive for Antibodies against the N-methyl-D-aspartate Receptor and NH2-terminal of α-enolase.

We herein report a case of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis concurrent with NH2-terminal of α-enolase (NAE) antibodies. A 36-year-old Japanese woman presented with Gerstmann's syndrome followed by jerky involuntary movements, seizure, autonomic instability, and consciousness disturbance. NAE antibodies were detected in the serum; however, NMDAR antibodies were identified in the cerebrospinal fluid with a cell-based assay, confirming the diagnosis of anti-NMDAR encephalitis. This case highlights the fact that Gerstmann's syndrome can be a manifestation of anti-NMDAR encephalitis and that NAE may be identified concurrently with NMDAR antibodies, suggesting that the diagnosis of Hashimoto encephalopathy requires the reasonable exclusion of alternative diagnoses, including anti-NMDAR encephalitis.

PET Imaging for Oxidative Stress in Neurodegenerative Disorders Associated with Mitochondrial Dysfunction.

Oxidative stress based on mitochondrial dysfunction is assumed to be the principal molecular mechanism for the pathogenesis of many neurodegenerative disorders. However, the effects of oxidative stress on the neurodegeneration process in living patients remain to be elucidated. Molecular imaging with positron emission tomography (PET) can directly evaluate subtle biological changes, including the redox status. The present review focuses on recent advances in PET imaging for oxidative stress, in particular the use of the Cu-ATSM radioligand, in neurodegenerative disorders associated with mitochondrial dysfunction. Since reactive oxygen species are mostly generated by leakage of excess electrons from an over-reductive state due to mitochondrial respiratory chain impairment, PET with 62Cu-ATSM, the accumulation of which depends on an over-reductive state, is able to image oxidative stress. 62Cu-ATSM PET studies demonstrated enhanced oxidative stress in the disease-related brain regions of patients with mitochondrial disease, Parkinson's disease, and amyotrophic lateral sclerosis. Furthermore, the magnitude of oxidative stress increased with disease severity, indicating that oxidative stress based on mitochondrial dysfunction contributes to promoting neurodegeneration in these diseases. Oxidative stress imaging has improved our insights into the pathological mechanisms of neurodegenerative disorders, and is a promising tool for monitoring further antioxidant therapies.

Serial brain MRI changes related to autoimmune pathophysiology in Hashimoto encephalopathy with anti-NAE antibodies: A case-series study.

PURPOSE: Hashimoto encephalopathy (HE) is an autoimmune-mediated encephalopathy associated with anti-thyroid antibodies. We previously discovered serum autoantibodies against the NH2-terminal of α-enolase (NAE), which serve as a specific diagnostic biomarker for HE and may be involved in the autoimmune pathophysiology of HE, including vasculitis. Although the common findings of brain magnetic resonance imaging (MRI) in HE have been recognized as normal or non-specific white matter lesions, serial MRI changes have been less well studied. The aim of this study was to clarify detailed and longitudinal MRI changes in HE associated with anti-NAE antibodies. METHODS: We investigated serial brain MR images in 12 Japanese patients with HE who had serum anti-NAE antibodies. RESULTS: Brain MRI showed diffuse white matter abnormalities and/or multiple small subcortical lesions in 10 patients. These lesions were apparently non-specific; however, in 7 of these patients we observed expanding and diminishing white matter lesions, emerging subcortical high-intensity spots on diffusion-weighted images, or reversible limbic lesions, which worsened at relapse and improved after recovery following immunotherapies. CONCLUSION: MRI lesions that fluctuate according to the disease condition were frequently observed in HE patients with anti-NAE antibodies, which suggests that these fluctuation may be associated with the autoimmune pathophysiology of HE.

Biology of the vernix caseosa: A review.

The vernix caseosa is a complex membranous structure comprising 80% water, 10% protein, and 10% lipids including barrier lipids such as ceramides, free fatty acids, phospholipids and cholesterol, synthesized partly by fetal sebaceous glands during the last trimester of pregnancy in an antero-posterior and dorsoventral manner. Because of its lipid content, vernix is hydrophobic and protects the skin from excessive water exposure during the development of the stratum corneum. The vernix caseosa has various functions during fetal transition from an intrauterine to an extrauterine environment, including lubrication of the birth canal during parturition, barrier function to prevent water loss, temperature regulation, for innate immunity and for intestinal development. This review discusses the evidence supporting the prenatal and postnatal functions of vernix caseosa, along with its structure, composition, and physical and biological characteristics. Understanding the biology of the vernix may facilitate improved care of preterm infants immediately post-partum.

Neurogenic bladder associated with xeroderma pigmentosum type A: A case report and literature review.

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease caused by a defect in deoxyribonucleic acid repair. Along with cutaneous symptoms, neurological symptoms are important clinical features of XP. However, information on neurogenic bladder occurrence among XP cases is rare. Herein, we describe a case of neurogenic bladder in a patient with XP type A (XPA). In this case, low bladder compliance, impaired bladder emptying, and urethral sphincter discoordination were significant cystometric findings, and frequent febrile urinary tract infection was a clinical problem. XPA patients often cannot express their symptoms because of cognitive dysfunction. Close follow-up and assessments are necessary.

Hashimoto's Encephalopathy Presenting with Smoldering Limbic Encephalitis.

Hashimoto's encephalopathy (HE) is a steroid-responsive autoimmune encephalopathy associated with Hashimoto thyroiditis. We herein report a case of HE manifesting "smoldering" limbic encephalitis with persisting symptoms and abnormalities on examinations. Although our patient experienced partial clinical remission after treatment, hippocampal hypermetabolism on [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) and subclinical seizures on video electroencephalography persisted. Hypermetabolism on FDG-PET was improved by additional prednisolone therapy. Thus, as with other autoimmune limbic encephalitis cases, HE can take a course of "smoldering" encephalitis. FDG-PET and electroencephalogram findings can reflect the disease activity degree in such patients, although with certain neurophysiological and biochemical distinctions.

[Positron Emission Tomography Imaging for Oxidative Stress in Mitochondrial and Neurodegenerative Diseases].

Oxidative stress and mitochondrial dysfunction are assumed to be the pathogenic molecular mechanisms underlying various neurodegenerative diseases. We applied positron emission tomography (PET) with [62Cu] diacetyl-bis (N4-methylthiosemicarbazone) (62Cu-ATSM) to image cerebral oxidative stress based on mitochondrial dysfunction in living patients. In our previous study, we observed an increased retention of Cu-ATSM in in vitro cell lines with mitochondrial respiratory failure, suggesting that 62Cu-ATSM uptake can be a promising biomarker for evaluating oxidative stress in patients with mitochondrial or neurodegenerative diseases. PET imaging with 62Cu-ATSM successfully demonstrated the increased uptake in brain lesions of a patient with mitochondrial disease (MELAS), in the striatum of patients with Parkinson's disease, and in the motor cortex and motor-related cortices of patients with amyotrophic lateral sclerosis. The uptake for these disease-related brain regions strongly correlated with disease severity, indicating that oxidative stress based on mitochondrial dysfunction is associated with the neurodegenerative process in these diseases. 62Cu-ATSM PET imaging for oxidative stress has improved our insights into the pathological mechanisms of neurodegenerative diseases and may be a promising tool for monitoring further antioxidant and mitochondrial therapies.

Therapeutic regimen of L-arginine for MELAS: 9-year, prospective, multicenter, clinical research.

OBJECTIVE: To examine the efficacy and safety of the therapeutic regimen using oral and intravenous L-arginine for pediatric and adult patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). METHODS: In the presence and absence of an ictus of stroke-like episodes within 6 h prior to efficacy assessment, we correspondingly conducted the systematic administration of oral and intravenous L-arginine to 15 and 10 patients with MELAS in two, 2-year, prospective, multicenter clinical trials at 10 medical institutions in Japan. Subsequently, patients were followed up for 7 years. The primary endpoint in the clinical trial of oral L-arginine was the MELAS scale, while that for intravenous L-arginine was the improvement rates of headache and nausea/vomiting at 2 h after completion of the initial intravenous administration. The relationships between the ictuses of stroke-like episodes and plasma arginine concentrations were examined. RESULTS: Oral L-arginine extended the interictal phase (p = 0.0625) and decreased the incidence and severity of ictuses. Intravenous L-arginine improved the rates of four major symptoms-headache, nausea/vomiting, impaired consciousness, and visual disturbance. The maximal plasma arginine concentration was 167 µmol/L when an ictus developed. Neither death nor bedriddenness occurred during the 2-year clinical trials, and the latter did not develop during the 7-year follow-up despite the progressively neurodegenerative and eventually life-threatening nature of MELAS. No treatment-related adverse events occurred, and the formulations of L-arginine were well tolerated. CONCLUSIONS: The systematic administration of oral and intravenous L-arginine may be therapeutically beneficial and clinically useful for patients with MELAS.

Arterial spin labeling MR imaging for the clinical detection of cerebellar hypoperfusion in patients with spinocerebellar degeneration.

PURPOSE: The aim of this study was to evaluate the clinical utility of arterial spin labeling (ASL) magnetic resonance imaging (MRI) for the detection of cerebellar hypoperfusion in patients with spinocerebellar degeneration (SCD). METHODS: Regional cerebral blood flow (CBF) were obtained from ASL and 123I-IMP single-photon emission computed tomography (SPECT) images by volume-of-interest analysis in patients with SCD (n = 16). Regional CBF were also measured by ASL in age-matched controls (n = 19) and by SPECT in separate controls (n = 17). The cerebellar CBF values were normalized to the CBF values for the whole gray matter (nCBF) in ASL and SPECT. RESULTS: The mean cerebellar nCBF measured by ASL was lower in patients with SCD (0.70 ±â€¯0.09) than in the controls (0.91 ±â€¯0.05) (p < 0.001), which was consistent with the comparison using SPECT (0.82 ±â€¯0.05 vs. 0.98 ±â€¯0.05, p < 0.001). The cerebellar nCBF measured by ASL significantly correlated with that determined by SPECT in patients (r = 0.56, p < 0.001). CONCLUSIONS: ASL imaging showed decreased cerebellar blood flow, which correlated with that measured by SPECT, in patients with SCD. These findings suggest the clinical utility of noninvasive MRI with ASL for detecting cerebellar hypoperfusion in addition to atrophy, which would aid the diagnosis of SCD.

Hashimoto's encephalopathy mimicking a brain tumor and its pathological findings: A case report.

Hashimoto's encephalopathy is characterized by the presence of anti-thyroid antibodies with no alternative cause. Patients with Hashimoto's encephalopathy present with various clinical symptoms and magnetic resonance imaging (MRI) findings. To our knowledge, this is the first documented report of Hashimoto's encephalopathy with MRI findings mimicking a brain tumor. The patient was a 41-year-old woman with a history of Hashimoto's disease. She experienced gradually worsening Parkinsonism and an MRI revealed a brain tumor-like lesion at the left caudate nucleus. She underwent a brain biopsy that revealed diffuse gliosis and perivascular lymphocyte infiltration with CD3+ T-cell predominance. No pathological signs of a brain tumor were found. Hashimoto's encephalopathy was suspected based on the patient's history and the presence of anti-thyroid antibodies. Her symptoms and the MRI findings improved with glucocorticoid treatment. Although there exist only a few studies on the pathology of Hashimoto's encephalopathy, our findings were consistent with those of previous reports. Our findings suggest cerebral vasculitis as an underlying etiology of Hashimoto's encephalopathy. We also emphasize the importance of considering Hashimoto's encephalopathy as a differential diagnosis of brain tumors.

[Hashimoto's Encephalopathy and Autoantibodies].

Encephalopathy occasionally occurs in association with thyroid disorders, most of which are treatable. These encephalopathies include a neuropsychiatric disorder associated with hypothyroidism named myxedema encephalopathy. Moreover, Hashimoto's encephalopathy (HE) has been recognized as a new clinical disease based on an autoimmune mechanism associated with Hashimoto's thyroiditis, and can be successfully treated using steroids. Recently, we discovered that the serum autoantibodies against the NH2-terminal of α-enolase (NAE) were a highly specific diagnostic biomarker for HE. We analyzed the serum anti-NAE autoantibodies and the clinical features in many cases of HE from institutions across Japan and other countries. About half the patients with HE had anti-NAE antibodies. Patient age was widely distributed with two peaks (around 20-30 years old and 60-80 years old). Most patients with HE were in euthyroid states and all patients had anti-thyroid antibodies. The common neuropsychiatric features include disturbance of consciousness, psychosis, cognitive dysfunction, involuntary movements, seizures, and ataxia. Electroencephalograph (EEG) abnormalities and decreased cerebral blood flow on brain single positron emission computed tomography are common findings, whereas abnormalities on brain magnetic resonance imaging are rare. Patients with HE present with various clinical phenotypes such as an acute encephalopathy form and chronic psychiatric form. Other clinical forms include limbic encephalitis, progressive cerebellar ataxia, and Creutzfeldt-Jakob disease (CJD)-mimic forms. The cerebellar ataxia form of HE clinically mimics spinocerebellar degeneration (SCD) and is characterized by the absence of nystagmus, absent or mild cerebellar atrophy, and lazy background activity on EEG. Taken together, clinicians should pay attention to the possibility of encephalopathy associated with thyroid disorders.