Objectives: To evaluate neuromuscular signs and symptoms in patients with newly diagnosed hypothyroidism and hyperthyroidism.

Methods: A prospective cohort study was performed in adult patients with newly diagnosed thyroid dysfunction. Patients were evaluated clinically with hand held dynamometry and with electrodiagnosis. The clinical features of weakness and sensory signs and the biochemical data were evaluated during treatment.

Results: In hypothyroid patients 79% had neuromuscular complaints, 38% had clinical weakness (manual muscle strength testing) in one or more muscle groups, 42% had signs of sensorimotor axonal neuropathy, and 29% had carpal tunnel syndrome. Serum creatine kinase did not correlate with weakness. After 1 year of treatment 13% of the patients still had weakness. In hyperthyroid patients 67% had neuromuscular symptoms, 62% had clinical weakness in at least one muscle group that correlated with FT4 concentrations, but not with serum CK. Nineteen per cent of the patients had sensory-motor axonal neuropathy and 0% had carpal tunnel syndrome. The neuromuscular signs developed rapidly, early in the course of the disorder and were severe, but resolved rapidly and completely during treatment (average time 3.6 months).

Conclusions: Neuromuscular symptoms and signs were present in most patients. About 40% of the hypothyroid patients and 20% of the hyperthyroid patients had predominantly sensory signs of a sensorimotor axonal neuropathy early in the course of thyroid disease. Weakness in hyperthyroidism evolved rapidly at an early stage of the disorder and resolved completely during treatment, suggesting a functional muscle disorder. Hand held dynamometry is sensitive for the detection of weakness and for the clinical evaluation of treatment effects. Weakness in hypothyroidism is more difficult to treat, suggesting myopathy.

Background: Thyroid hormones exert critical roles throughout the body and play an important and permissive role in neuroendocrine, neurological, and neuromuscular function.

Methods: We performed a PubMed search through June 2014 with search terms including "hypothyroidism," "hyperthyroidism," "neurological complications," "neuropathy," "myopathy," "congenital hypothyroidism," and "encephalopathy." Relevant publications reviewed included case series, individual case reports, systematic reviews, retrospective analyses, and randomized controlled trials. The neurological outcomes of congenital hypothyroidism were reviewed, along with the clinical features of associated neuromuscular syndromes of both hypothyroidism and hyperthyroidism, including other autoimmune conditions. Evidence for, and pathophysiological controversies surrounding, Hashimoto encephalopathy was also reviewed.

Results: The establishment of widespread newborn screening programs has been highly successful in attenuating or preventing early and irreversible neurological harm resulting from congenital thyroid hormone deficiency, but some children continue to display neuromuscular, sensory, and cognitive defects in later life. Acquired disorders of thyroid function such as Hashimoto thyroiditis and Graves' disease are associated with a spectrum of central nervous system and/or neuromuscular dysfunction. However, considerable variation in clinical phenotype is described, and much of our knowledge of the role of thyroid disease in childhood neurological disorders is derived from adult case series.

Conclusions: Early and aggressive normalization of thyroxine levels in newborn infants with congenital hypothyroidism is important in minimizing neurological sequelae, but maternal thyroid hormone sources are also critically important to the early developing brain. A spectrum of neurological disorders has been reported in older children with acquired thyroid disease, but the frequency with which these occur remains poorly defined in the literature, and much must be extrapolated from adult data. A high index of suspicion for acquired thyroid disease is paramount in the investigation of many neurological disorders of youth, as many reported sequelae of hypothyroidism and hyperthyroidism are reversible with appropriate endocrine management.

Neurological and psycholocial assessment was carried out on 30 patients aged 2.7 to 21 years (mean 9.4) who were being treated for hypothyroidism starting before the age of 2 years. Their IQ scores lay in the normal range (71--122; mean 92.4) but 77% showed at least one sign of impaired brain function. Clumsiness was found in 33%, behaviour disorders in 23%, speech disorders in 20%, learning disorders in 26%, squint in 53%, nystagmus in 10%, and minor motor disorders in 50%. Many showed several of these features and hypothyroidism in early life appears to lead to widespeard impairment of brain function. These neurological findings were equally common in patients in whom treatment started between 4 and 10 weeks of age and patients treated after 10 weeks, suggesting that early detection of hypothyroidism by neonatal screening may be of limited benefit. Children who have been hypothyroid in early infancy require careful assessment to prevent further visual, emotional, scholastic, or vocational difficulties.

Hypothyroidism, a commonly encountered thyroid disorder, usually manifests with readily recognizable typical features. However, an unusual presentation of a classic thyroid disorder may hinder accurate diagnosis in certain instances. One such rare initial presentation of hypothyroidism is recurrent hypokalemic paralysis, and existing reports in the literature are sparse. It has been more commonly reported in thyrotoxicosis. We report the case details and clinical outcomes of two middle-aged individuals (a 34-year-old male and a 37-year-old female) with recurrent episodes of hypokalemic paralysis. Their clinical examination revealed pure motor hyporeflexia quadriparesis with hypotonia and diminished deep tendon reflexes without any autonomic dysfunction. They had no significant previous medical history. Biochemical findings revealed hypokalemia in both cases (1.4 and 1.9 mEq/L, respectively) with elevated levels of thyroid‑stimulating hormone and thyroid‑related antibodies in both individuals, thus, confirming the diagnosis of autoimmune hypothyroidism. Immediate treatment with intravenous and oral potassium correction helped in the recovery. Thyroxine supplementation was considered a follow-up treatment, and for a one-year follow-up period there were no complaints of limb weakness reported in both individual.

Hashimoto's thyroiditis (HT) is the most frequent cause of hypothyroidism in areas with sufficient iodine intake. While the impact of thyroid function on mood and cognition is well known, only in the recent years, an increasing number of studies report on the association of HT with cognitive and affective disturbances also in the euthyroid state. Recent imaging studies have shown that these impairments are accompanied by altered brain perfusion, in particular, in the frontal lobe and a reduced gray matter density in the left inferior gyrus frontalis. Brain function abnormalities in euthyroid patients with HT may be subtle and only detected by specific testing or even severe as it is the case in the rare neuropsychiatric disorder Hashimoto's encephalopathy (HE). The good response to glucocorticoids in patients with HE indicates an autoimmune origin. In line with this, the cognitive deficits and the high psycho-social burden in euthyroid HT patients without apparent signs of encephalopathy appear to be associated with anti-thyroid peroxidase auto-antibody (TPO Abs) levels. Though in vitro studies showing binding of TPO Abs to human cerebellar astrocytes point to a potential direct role of TPO Abs in the pathogenesis of brain abnormalities in HT patients, TPO Abs may function only as a marker of an autoimmune disorder of the central nervous system. In line with this, anti-central nervous system auto-antibodies (CNS Abs) which are markedly increased in patients with HT disturb myelinogenesis in vitro and, therefore, may impair myelin sheath integrity. In addition, in HT patients, production of monocyte- and T-lymphocyte-derived cytokines is also markedly increased which may negatively affect multiple neurotransmitters and, consequently, diverse brain neurocircuits.

Signs and symptoms of hypothyroidism
The well-known signs and symptoms of hypothyroidism tend to be more subtle than those of hyperthyroidism. Dry skin, cold sensitivity, fatigue, muscle cramps, voice changes, and constipation are among the most common. Less commonly appreciated and typically associated with severe hypothyroidism are carpal tunnel syndrome, sleep apnea, pituitary hyperplasia that can occur with or without hyperprolactinemia and galactorrhea, and hyponatremia that can occur within several weeks of the onset of profound hypothyroidism. Although, for example, in the case of some symptoms such as voice changes subjective (12,56) and objective (57) measures differ. Several rating scales (56,58,59) have been used to assess the presence and, in some cases, the severity of hypothyroidism, but have low sensitivity and specificity. While the exercise of calculating clinical scores has been largely superseded by sensitive thyroid function tests, it is useful to have objective clinical measures to gauge the severity of hypothyroidism. Early as well as recent studies strongly correlate the degree of hypothyroidism with ankle reflex relaxation time, a measure rarely used in current clinical practice today (60).
Normalization of a variety of clinical and metabolic end points including resting heart rate, serum cholesterol, anxiety level, sleep pattern, and menstrual cycle abnormalities including menometrorrhagia are further confirmatory findings that patients have been restored to a euthyroid state (61–65). Normalization of elevated serum creatine kinase or other muscle (66) or hepatic enzymes following treatment of hypothyroidism (67) are additional, less well-appreciated and also nonspecific therapeutic endpoints.

Untreated adult hypothyroidism may be associated with cognitive and emotional impairment, but the precise underlying neuropathological mechanism is unknown. We investigated the brain morphological and functional abnormalities associated with cognition and emotion in hypothyroidism. This is a cross-sectional observational study. Forty-four newly diagnosed adult hypothyroid patients and 54 well-matched healthy controls (HCs) were enrolled. All participants underwent three-dimensional T1-weighted imaging and resting-state functional magnetic resonance imaging (MRI). Morphological and seed-based functional connectivity (FC) analyses were performed to compare the intergroup differences. Neuropsychological tests, including the Montreal Cognitive Assessment (MoCA) Scale, 24-item Hamilton Depression Rating Scale (HAMD-24), and Hamilton Anxiety Rating Scale (HAMA) were administered. Thyroid function test and blood lipid levels were measured. Correlations were computed between neuropsychological and biochemical measures with neuroimaging indices. Sensitive morphological or functional neuroimaging indicators were identified using receiver operating characteristic (ROC) analysis. Compared with HCs, hypothyroid patients demonstrated lower total and subdomain scores on the MoCA and higher HAMD-24 and HAMA scores. Morphological analysis revealed the hypothyroid patients had significantly reduced gray matter (GM) volumes in the right superior frontal gyrus, superior temporal gyrus, left dorsolateral superior frontal gyrus, middle frontal gyrus, and supplementary motor area as well as significantly increased GM volumes in the bilateral cerebellar Crus I and left precentral gyrus. Furthermore, seed-based FC analysis of hypothyroid patients showed increased FC between the right cerebellar Crus I and left precentral gyrus, triangular part of the inferior frontal gyrus, and angular gyrus of the inferior parietal lobe. The language scores of the MoCA were positively correlated with Jacobian values of the left supplementary motor area ( = 0.391,  = 0.046) and precentral gyrus ( = 0.401,  = 0.039). ROC analysis revealed FC value between cerebellar Crus I and angular gyrus could differentiate groups with relatively high accuracy (sensitivity: 75%, specificity: 77.8%, area under the curve: 0.794 [CI 0.701-0.888],  < 0.001). Untreated adult-onset hypothyroidism may be associated with impaired cognition and anxiety or depression. GM morphological alterations and FC of the cerebellum with subregions of the frontal and parietal lobes may represent key neuropathological mechanisms underlying the cognitive deterioration and mood dysregulation observed in hypothyroid adults. Clinical Trial Registration Number: chiCTR2000028966.

Context: Declarative memory largely depends upon normal functioning temporal lobes (hippocampal complex) and prefrontal cortex. Animal studies suggest abnormal hippocampal function in hypothyroidism.

Objective: The aim of the study was to assess declarative memory in overt and subclinical (SCH) hypothyroid patients before and after l-T(4) (LT4) replacement and in matched normal subjects.

Design And Setting: A prospective, open-labeled interventional study was conducted at a teaching hospital.

Participants And Intervention: Hypothyroid (n = 21) and SCH (n = 17) patients underwent neuropsychological tests at baseline and 3 and 6 months after LT4 replacement. Normal subjects were studied at the same time-points.

Main Outcome: Tests of spatial, verbal, associative, and working memory; attention; and response inhibition and the Hospital Anxiety and Depression Scale were administered.

Results: Baseline deficits in spatial, associative, and verbal memory, which rely upon the integrity of the hippocampal and frontal areas, were identified in patients with overt hypothyroidism. Spatial and verbal memory were impaired in SCH patients (P < 0.05). TSH levels correlated negatively (P < 0.05) with these deficits. After LT4 replacement, verbal memory normalized. Spatial memory normalized in the SCH group but remained impaired in the hypothyroid group. Associative memory deficits persisted in the overt hypothyroid group. Hospital Anxiety and Depression Scale scores did not correlate with cognitive function. Measures of attention and response inhibition did not differ from control subjects.

Conclusion: Cognitive impairment occurs in SCH and more markedly in overt hypothyroidism. These impairments appear predominantly mnemonic in nature, suggesting that the etiology is not indicative of general cognitive slowing. We propose that these deficits may reflect an underlying disruption of normal hippocampal function and/or connectivity.

Hashimoto's thyroiditis (HT) is the most frequent cause of hypothyroidism in areas with sufficient iodine intake. While the impact of thyroid function on mood and cognition is well known, only in the recent years, an increasing number of studies report on the association of HT with cognitive and affective disturbances also in the euthyroid state. Recent imaging studies have shown that these impairments are accompanied by altered brain perfusion, in particular, in the frontal lobe and a reduced gray matter density in the left inferior gyrus frontalis. Brain function abnormalities in euthyroid patients with HT may be subtle and only detected by specific testing or even severe as it is the case in the rare neuropsychiatric disorder Hashimoto's encephalopathy (HE). The good response to glucocorticoids in patients with HE indicates an autoimmune origin. In line with this, the cognitive deficits and the high psycho-social burden in euthyroid HT patients without apparent signs of encephalopathy appear to be associated with anti-thyroid peroxidase auto-antibody (TPO Abs) levels. Though in vitro studies showing binding of TPO Abs to human cerebellar astrocytes point to a potential direct role of TPO Abs in the pathogenesis of brain abnormalities in HT patients, TPO Abs may function only as a marker of an autoimmune disorder of the central nervous system. In line with this, anti-central nervous system auto-antibodies (CNS Abs) which are markedly increased in patients with HT disturb myelinogenesis in vitro and, therefore, may impair myelin sheath integrity. In addition, in HT patients, production of monocyte- and T-lymphocyte-derived cytokines is also markedly increased which may negatively affect multiple neurotransmitters and, consequently, diverse brain neurocircuits.

Background: Increasing evidence has linked the thyroid dysfunction to the pathogenesis of dementia. Evidence from clinical studies has demonstrated that hypothyroidism is related to an increased risk of dementia. But the association of hyperthyroidism with dementia is largely unknown.

Methods: We used the adenovirus containing thyrotropin receptor (TSHR) amino acid residues 1-289 (Ad-TSHR289)-induced Graves' disease (GD) phenotype in Alzheimer's disease (AD) model mice (APP/PS1 mice) to evaluate the effect of hyperthyroidism on the cognitive function and β-amyloid (Aβ) accumulation.

Results: GD mice exhibited a stable long-term hyperthyroidism and cognitive deficits. Single Cell RNA-sequencing analysis indicated that microglia function played a critical role in the pathophysiological processes in GD mice. Neuroinflammation and polarization of microglia (M1/M2 phenotype) and activated receptor-interacting serine/threonine protein kinase 3 (RIPK3)/mixed lineage kinase domain-like pseudo-kinase (MLKL)-mediated necroptosis contributed to the pathological process, including Aβ deposition and neuronal loss. RIPK3 inhibitor could inhibit GD-mediated Aβ accumulation and neuronal loss.

Conclusions: Our findings reveal that GD hyperthyroidism aggravates cognitive deficits in AD mice and induces Aβ deposition and neuronal loss by inducing neuroinflammation and RIPK3/MLKL-mediated necroptosis.

Importance: In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings. Objective: To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia. Design, Setting, and Participants: This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021. Exposures: Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values. Main Outcomes and Measures: The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated. Results: Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia. Conclusions and Relevance: In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.

Accumulated evidence showed that thyroid diseases induced cognitive decline. However, the relationship between thyroid hormones (THs) and cognition in older euthyroid people is still unclear. Our study aimed to estimate the association between THs within the euthyroid range and cognition in community-dwelling older adults in China. Data were extracted from a cohort study on the health status of rural older adults from the Guizhou province in China (HSRO). Serum thyroid-stimulating hormone (TSH), free thyroxine (FT), and free triiodothyronine (FT) were measured using the electrochemiluminescence immunoassay. Cognitive function was evaluated by the Mini-Mental State Examination (MMSE). Linear regression and a binary logistic regression model were used to explore the relationship between THs and cognition in euthyroidism (TSH level of 0.27 ~ 4.20mIU/L). A total of 957 euthyroidism individuals were included in this study, with a mean (SD) age of 71.34 (6.35) years. In individuals with euthyroidism, serum TSH and FT levels were positively associated with cognition (TSH:β = 0.06, 95% CI  0.01 ~ 0.11, P = 0.03; FT:β = 0.07, 95% CI  0.01 ~ 0.12, P = 0.01); and serum FT and TSH levels were significantly associated with cognitive domains (P < 0.05). Further, euthyroid individuals in the lowest serum FT(OR = 1.96; 95% CI 1.27 ~ 3.03) quartile had a twofold increased risk of cognitive impairment compared to those in the highest quartile after adjusting for potential confounding factors. These findings suggested that low levels of FT could be an independent risk factor for cognitive impairment in older euthyroid adults. Additionally, a positive linear association exists between serum FT levels and cognitive domains (such as immediate memory, language, and attention). Further studies are needed to determine the underlying mechanisms and the community significance of these findings.