Hypothyroidism and hyperthyroidism are common medical disorders that are often accompanied by diverse types of neurologic and neuromuscular dysfunction. Although some of these associated disorders are well known to physicians, others are not. All of these neurologic manifestations are important because they can severe as important clues to the diagnosis of a thyroid disorder. Furthermore, they are often related to the patients' presenting complaints. In addition, much like other manifestations of thyroid dysfunction, they are often reversible with return of the patient to the euthyroid state.

[A2] Clinical consequences of thyrotoxicosis
The cellular actions of thyroid hormone are mediated by T3, the active form of thyroid hormone. T3 binds to two specific nuclear receptors (thyroid hormone receptor α and β) that regulate the expression of many genes. Nongenomic actions of thyroid hormone include regulation of numerous important physiologic functions.
Thyroid hormone influences almost every tissue and organ system. It increases tissue thermogenesis and basal metabolic rate and reduces serum cholesterol levels and systemic vascular resistance. Some of the most profound effects of increased thyroid hormone levels occur within the cardiovascular system (25). Untreated or partially treated thyrotoxicosis is associated with weight loss, osteoporosis, atrial fibrillation, embolic events, muscle weakness, tremor, neuropsychiatric symptoms, and rarely cardiovascular collapse and death (26,27). Only moderate correlation exists between the degree of thyroid hormone elevation and clinical signs and symptoms. Symptoms and signs that result from increased adrenergic stimulation include tachycardia and anxiety and may be more pronounced in younger patients and those with larger goiters (28). The signs and symptoms of mild, or subclinical, thyrotoxicosis are similar to those of overt thyrotoxicosis but differ in magnitude. Measurable changes in basal metabolic rate, cardiovascular hemodynamics, and psychiatric and neuropsychological function can be present in mild thyrotoxicosis (29).

Thyroid hormone influences almost every tissue and organ system. It increases tissue thermogenesis and basal metabolic rate and reduces serum cholesterol levels and systemic vascular resistance. Some of the most profound effects of increased thyroid hormone levels occur within the cardiovascular system (25). Untreated or partially treated thyrotoxicosis is associated with weight loss, osteoporosis, atrial fibrillation, embolic events, muscle weakness, tremor, neuropsychiatric symptoms, and rarely cardiovascular collapse and death (26,27). Only moderate correlation exists between the degree of thyroid hormone elevation and clinical signs and symptoms. Symptoms and signs that result from increased adrenergic stimulation include tachycardia and anxiety and may be more pronounced in younger patients and those with larger goiters (28). The signs and symptoms of mild, or subclinical, thyrotoxicosis are similar to those of overt thyrotoxicosis but differ in magnitude. Measurable changes in basal metabolic rate, cardiovascular hemodynamics, and psychiatric and neuropsychological function can be present in mild thyrotoxicosis (29).
[B] How should clinically or incidentally discovered thyrotoxicosis be evaluated and initially managed?
[B1] Assessment of disease severity
Assessment of thyrotoxic manifestations, and especially potential cardiovascular and neuromuscular complications, is essential in formulating an appropriate treatment plan. Although it might be anticipated that the severity of thyrotoxic symptoms is proportional to the elevation in the serum levels of free T4 and T3, in one small study of 25 patients with GD, the Hyperthyroid Symptom Scale did not strongly correlate with free T4 or T3 and was inversely correlated with age (28). The importance of age as a determinant of the prevalence and severity of hyperthyroid symptoms has recently been confirmed (30). Cardiac evaluation may be necessary, especially in the older patient, and may require an echocardiogram, electrocardiogram, Holter monitor, or myocardial perfusion studies (31). The need for evaluation should not postpone therapy of the thyrotoxicosis. In addition to the administration of β-blockers (31), treatment may be needed for concomitant myocardial ischemia, congestive heart failure, or atrial arrhythmias (25). Anticoagulation may be necessary in patients in atrial fibrillation (32). Goiter size, obstructive symptoms, and the severity of Graves' orbitopathy (GO), the inflammatory disease that develops in the orbit in association with autoimmune thyroid disorders, can be discordant with the degree of hyperthyroidism or hyperthyroid symptoms.

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.

The versatile clinical manifestations of the Hashimoto's chronic autoimmune thyroiditis often include psycho-neurological disorders. Although hypothyroidism disturbs significantly the ontogenesis and functions of central nervous system, causing in severe cases of myxedema profound impairment of cognitive abilities and even psychosis, the behavioral, motor and other psychoneurological disorders accompany euthyroid and slightly hypothyroid cases and periods of Hashimoto's disease as well, thus constituting the picture of so called "Hashimoto's encephalopathy". The entity, although discussed and explored for more than 50 years since its initial descriptions, remains an enigma of thyroidology and psychiatry, because its etiology and pathogenesis are obscure. The paper describes the development of current views on the role of thyroid in ontogeny and functions of brain, as well as classical and newest ideas on the etiology and pathogenesis of Hashimot's encephalopathy. The synopsis of the world case reports and research literature on this disorder is added with authors' own results obtained by study of 17 cases of Hashimoto's thyroiditis with schizophrenia-like clinical manifestations. The relation of the disease to adjuvant-like etiological factors is discussed. Three major mechanistic concepts of Hashimoto's encephalopathy are detailed, namely cerebral vasculitis theory, hormone dysregulation theory and concept, explaining the disease via direct action of the autoantibodies against various thyroid (thyroperoxidase, thyroglobulin, and TSH-receptor) and several extrathyroid antigens (alpha-enolase and other enzymes, gangliosides and MOG-protein, onconeuronal antigens) - all of them expressed in the brain. The article demonstrates that all above mentioned concepts intermingle and prone to unification, suggesting the unified scheme of pathogenesis for the Hashimoto's encephalopathy. The clinical manifestations, criteria, forms, course, treatment and prognosis of Hashimoto's encephalopathy and its comorbidity to other diseases - are also discussed in brief. The relation between Hashimoto's encephalopathy and non-vasculitis autoimmune encephalomyelitides of paraneoplastic and non-paraneoplastic origin is emphasized [1 figure, bibliography - 200 references].

Thyroid disorders are common in the general population and in hospitalized patients. Thyroid disease may present first with neurological complications or else may occur concurrently in patients suffering other neurological disorders, particularly those with an autoimmune etiology. For this reason neurologists will commonly encounter patients with thyroid disease. This chapter provides an overview of the neurological complications and associations of disorders of the thyroid gland. Particular emphasis is placed on conditions such as thyrotoxic periodic paralysis and myxedema coma in which the underlying thyroid disorder may be occult leading to a first, often emergency, presentation to a neurologist. Information about clinical features, diagnosis, pathogenesis, therapy, and prognosis is provided. Emphasis is placed on those aspects most likely to be relevant to the practicing neurologist and the interested reader is directed to references to good, recent review articles for further information.

Normal thyroid metabolism is essential for human development, including the formation and functioning of the central and peripheral nervous system. Disorders of thyroid metabolism are increasingly recognized within the spectrum of paediatric neurological disorders. Both hypothyroid and hyperthyroid disease states (resulting from genetic and acquired aetiologies) can lead to characteristic neurological syndromes, with cognitive delay, extrapyramidal movement disorders, neuropsychiatric symptoms, and neuromuscular manifestations. In this review, the neurological manifestations of genetic disorders of thyroid metabolism are outlined, with particular focus on Allan-Herndon-Dudley syndrome and benign hereditary chorea. We report in detail the clinical features, major neurological and neuropsychiatric manifestations, molecular genetic findings, disease mechanisms, and therapeutic strategies for these emerging genetic 'brain-thyroid' disorders.

[A2] Clinical consequences of thyrotoxicosis
The cellular actions of thyroid hormone are mediated by T3, the active form of thyroid hormone. T3 binds to two specific nuclear receptors (thyroid hormone receptor α and β) that regulate the expression of many genes. Nongenomic actions of thyroid hormone include regulation of numerous important physiologic functions.
Thyroid hormone influences almost every tissue and organ system. It increases tissue thermogenesis and basal metabolic rate and reduces serum cholesterol levels and systemic vascular resistance. Some of the most profound effects of increased thyroid hormone levels occur within the cardiovascular system (25). Untreated or partially treated thyrotoxicosis is associated with weight loss, osteoporosis, atrial fibrillation, embolic events, muscle weakness, tremor, neuropsychiatric symptoms, and rarely cardiovascular collapse and death (26,27). Only moderate correlation exists between the degree of thyroid hormone elevation and clinical signs and symptoms. Symptoms and signs that result from increased adrenergic stimulation include tachycardia and anxiety and may be more pronounced in younger patients and those with larger goiters (28). The signs and symptoms of mild, or subclinical, thyrotoxicosis are similar to those of overt thyrotoxicosis but differ in magnitude. Measurable changes in basal metabolic rate, cardiovascular hemodynamics, and psychiatric and neuropsychological function can be present in mild thyrotoxicosis (29).

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.

The versatile clinical manifestations of the Hashimoto's chronic autoimmune thyroiditis often include psycho-neurological disorders. Although hypothyroidism disturbs significantly the ontogenesis and functions of central nervous system, causing in severe cases of myxedema profound impairment of cognitive abilities and even psychosis, the behavioral, motor and other psychoneurological disorders accompany euthyroid and slightly hypothyroid cases and periods of Hashimoto's disease as well, thus constituting the picture of so called "Hashimoto's encephalopathy". The entity, although discussed and explored for more than 50 years since its initial descriptions, remains an enigma of thyroidology and psychiatry, because its etiology and pathogenesis are obscure. The paper describes the development of current views on the role of thyroid in ontogeny and functions of brain, as well as classical and newest ideas on the etiology and pathogenesis of Hashimot's encephalopathy. The synopsis of the world case reports and research literature on this disorder is added with authors' own results obtained by study of 17 cases of Hashimoto's thyroiditis with schizophrenia-like clinical manifestations. The relation of the disease to adjuvant-like etiological factors is discussed. Three major mechanistic concepts of Hashimoto's encephalopathy are detailed, namely cerebral vasculitis theory, hormone dysregulation theory and concept, explaining the disease via direct action of the autoantibodies against various thyroid (thyroperoxidase, thyroglobulin, and TSH-receptor) and several extrathyroid antigens (alpha-enolase and other enzymes, gangliosides and MOG-protein, onconeuronal antigens) - all of them expressed in the brain. The article demonstrates that all above mentioned concepts intermingle and prone to unification, suggesting the unified scheme of pathogenesis for the Hashimoto's encephalopathy. The clinical manifestations, criteria, forms, course, treatment and prognosis of Hashimoto's encephalopathy and its comorbidity to other diseases - are also discussed in brief. The relation between Hashimoto's encephalopathy and non-vasculitis autoimmune encephalomyelitides of paraneoplastic and non-paraneoplastic origin is emphasized [1 figure, bibliography - 200 references].

The consequences of hypothyroidism on cognition are long known since the description of dementia associated with hypothyroidism. Additional data from experimental studies support the impact of thyroid hormones on the central nervous system and cognition. Cognitive impairment in relation with hypothyroidism (even sub clinical hypothyroidism) in elderly subjects involves memory, attention, and executive functions. Hypothyroidism may be associated with somatic, neurologic, psychiatric, social and environmental data. Cross-sectional and longitudinal studies are frequently heterogeneous but suggest a complex relationship between hypothyroidism and cognition.

Some levothyroxine (LT4)-treated hypothyroid patients report a constellation of persistent and distressing cognitive symptoms that has been termed brain fog. This narrative review focuses on attempts to define and measure hypothyroid-associated brain fog, summarize possible etiologies and contributing factors, present treatment options, and propose avenues for future research. Published literature was reviewed to summarize available information on patient-reported symptoms associated with brain fog in hypothyroidism, as well as objective evidence of impairment based on neurocognitive testing and functional imaging studies. Given the limited information specific for hypothyroid-associated brain fog, relevant data from other medical conditions associated with brain fog were also reviewed and incorporated into recommendations for clinical care and future research areas. Hypothyroid-associated brain fog has not been well defined or quantitated, and the underlying pathophysiology is unclear. Symptoms vary among patients but commonly include fatigue, depressed mood, and cognitive difficulties in the areas of memory and executive function. Symptoms often predate the diagnosis of hypothyroidism, and the magnitude of cognitive impairment can range from mild to severe. Regardless of severity, these symptoms are associated with impaired quality of life and cause dissatisfaction with treatment, so often lead to requests for alternate therapies. Disease-specific and psychological factors impact the experience of brain fog in complex ways, including potential limitations in LT4 monotherapy, self-knowledge of a disease state, and expectations for therapeutic effects. Brain fog is a variable symptom complex in people with hypothyroidism, causing significant distress and diminished quality of life. In the absence of proven therapies, individualized treatment plans are recommended, which incorporate thyroid-specific, general medical, and psychosocial approaches. In particular, cognitive rehabilitation is an underutilized technique that is beneficial in other medical conditions associated with brain fog and could improve symptoms in hypothyroid people. The limitations in our current knowledge and questions presented throughout this review highlight a major need for clinical research in this understudied area. Future research should include attention to standardization of survey instruments to quantitate brain fog in hypothyroid people, as well as rigorously designed intervention studies.

The association of thyroid dysfunction with alterations in mood and cognition has been recognised since some of the earliest descriptions of thyroid disease. Over the years, researchers have aimed to further define these effects throughout the spectrum of thyroid disorders, to better understand the underlying condition and refine indications for treatment. More recently, attention has turned towards examining the impact of differences in thyroid hormones within the normal reference range, particularly in older adults, providing new insights into the association of thyroid hormone with cognitive decline. This review summarises the evidence assessing the influence of thyroid hormone on mood and cognition in overt and subclinical hypothyroidism, within the reference range, and in subclinical and overt hyperthyroidism. Treatment of overt thyroid dysfunction largely resolves associated disturbances in mood and cognitive dysfunction, however in the setting of overt hypothyroidism subtle detrimental effects on cognition may not be fully reversed. Subclinical hyperthyroidism and higher free thyroxine (FT4) within the normal range have been associated with poorer cognitive outcomes. Future research including randomised controlled trials are required to confirm causality and guide the assessment of benefits vs risks of intervention in the increasing population of older adults with subclinical thyroid disease.

[A2] Clinical consequences of thyrotoxicosis
The cellular actions of thyroid hormone are mediated by T3, the active form of thyroid hormone. T3 binds to two specific nuclear receptors (thyroid hormone receptor α and β) that regulate the expression of many genes. Nongenomic actions of thyroid hormone include regulation of numerous important physiologic functions.
Thyroid hormone influences almost every tissue and organ system. It increases tissue thermogenesis and basal metabolic rate and reduces serum cholesterol levels and systemic vascular resistance. Some of the most profound effects of increased thyroid hormone levels occur within the cardiovascular system (25). Untreated or partially treated thyrotoxicosis is associated with weight loss, osteoporosis, atrial fibrillation, embolic events, muscle weakness, tremor, neuropsychiatric symptoms, and rarely cardiovascular collapse and death (26,27). Only moderate correlation exists between the degree of thyroid hormone elevation and clinical signs and symptoms. Symptoms and signs that result from increased adrenergic stimulation include tachycardia and anxiety and may be more pronounced in younger patients and those with larger goiters (28). The signs and symptoms of mild, or subclinical, thyrotoxicosis are similar to those of overt thyrotoxicosis but differ in magnitude. Measurable changes in basal metabolic rate, cardiovascular hemodynamics, and psychiatric and neuropsychological function can be present in mild thyrotoxicosis (29).

Some levothyroxine (LT4)-treated hypothyroid patients report a constellation of persistent and distressing cognitive symptoms that has been termed brain fog. This narrative review focuses on attempts to define and measure hypothyroid-associated brain fog, summarize possible etiologies and contributing factors, present treatment options, and propose avenues for future research. Published literature was reviewed to summarize available information on patient-reported symptoms associated with brain fog in hypothyroidism, as well as objective evidence of impairment based on neurocognitive testing and functional imaging studies. Given the limited information specific for hypothyroid-associated brain fog, relevant data from other medical conditions associated with brain fog were also reviewed and incorporated into recommendations for clinical care and future research areas. Hypothyroid-associated brain fog has not been well defined or quantitated, and the underlying pathophysiology is unclear. Symptoms vary among patients but commonly include fatigue, depressed mood, and cognitive difficulties in the areas of memory and executive function. Symptoms often predate the diagnosis of hypothyroidism, and the magnitude of cognitive impairment can range from mild to severe. Regardless of severity, these symptoms are associated with impaired quality of life and cause dissatisfaction with treatment, so often lead to requests for alternate therapies. Disease-specific and psychological factors impact the experience of brain fog in complex ways, including potential limitations in LT4 monotherapy, self-knowledge of a disease state, and expectations for therapeutic effects. Brain fog is a variable symptom complex in people with hypothyroidism, causing significant distress and diminished quality of life. In the absence of proven therapies, individualized treatment plans are recommended, which incorporate thyroid-specific, general medical, and psychosocial approaches. In particular, cognitive rehabilitation is an underutilized technique that is beneficial in other medical conditions associated with brain fog and could improve symptoms in hypothyroid people. The limitations in our current knowledge and questions presented throughout this review highlight a major need for clinical research in this understudied area. Future research should include attention to standardization of survey instruments to quantitate brain fog in hypothyroid people, as well as rigorously designed intervention studies.

The consequences of hypothyroidism on cognition are long known since the description of dementia associated with hypothyroidism. Additional data from experimental studies support the impact of thyroid hormones on the central nervous system and cognition. Cognitive impairment in relation with hypothyroidism (even sub clinical hypothyroidism) in elderly subjects involves memory, attention, and executive functions. Hypothyroidism may be associated with somatic, neurologic, psychiatric, social and environmental data. Cross-sectional and longitudinal studies are frequently heterogeneous but suggest a complex relationship between hypothyroidism and cognition.

Hypothyroidism and hyperthyroidism are common medical disorders that are often accompanied by diverse types of neurologic and neuromuscular dysfunction. Although some of these associated disorders are well known to physicians, others are not. All of these neurologic manifestations are important because they can severe as important clues to the diagnosis of a thyroid disorder. Furthermore, they are often related to the patients' presenting complaints. In addition, much like other manifestations of thyroid dysfunction, they are often reversible with return of the patient to the euthyroid state.

The association of thyroid dysfunction with alterations in mood and cognition has been recognised since some of the earliest descriptions of thyroid disease. Over the years, researchers have aimed to further define these effects throughout the spectrum of thyroid disorders, to better understand the underlying condition and refine indications for treatment. More recently, attention has turned towards examining the impact of differences in thyroid hormones within the normal reference range, particularly in older adults, providing new insights into the association of thyroid hormone with cognitive decline. This review summarises the evidence assessing the influence of thyroid hormone on mood and cognition in overt and subclinical hypothyroidism, within the reference range, and in subclinical and overt hyperthyroidism. Treatment of overt thyroid dysfunction largely resolves associated disturbances in mood and cognitive dysfunction, however in the setting of overt hypothyroidism subtle detrimental effects on cognition may not be fully reversed. Subclinical hyperthyroidism and higher free thyroxine (FT4) within the normal range have been associated with poorer cognitive outcomes. Future research including randomised controlled trials are required to confirm causality and guide the assessment of benefits vs risks of intervention in the increasing population of older adults with subclinical thyroid disease.