Introduction
Background
The thyroid gland plays an important role in tissue metabolism and development. It secretes thyroxine (3,5,3'5'-tetraiodothyronine), which is abbreviated as T4, and small amounts of 3,5,3'-triiodothyronine, abbreviated T3. Both have systemic effects. Abnormal thyroid hormone levels lead to hypothyroid and hyperthyroid states. Inadequate thyroid hormone during development leads to congenital hypothyroidism (also known as cretinism) with associated irreversible brain damage.
Pathophysiology
Thyroid hormones regulate protein synthesis by affecting gene transcription and mRNA stabilization.
Hyperthyroidism
In hyperthyroidism (ie, thyrotoxicosis) increased thyroid function leads to increased cardiac output at rest and after exercise but to decreased muscle bulk and function.
Muscle activity shows altered electrical responses, altered energy metabolism, and increased sensitivity to beta-adrenergic stimuli. In a clinical study of experimental thyrotoxicosis, the activity of oxidative and glycolytic enzymes in skeletal muscle decreased by 21-37%. Lean body mass decreases and rate of whole body protein breakdown is enhanced. Thyroid hormones have profound effects on mitochondrial oxidative activity, synthesis and degradation of proteins, sensitivity of tissues to catecholamines, differentiation of muscle fibers, capillary growth, and levels of antioxidant enzymes and compounds. Muscles show contraction weakness and lack of normal contraction potentiation. Patients have lower levels of carnitine.
The central effects of hyperthyroidism are most pronounced in development. Cerebral circulation and oxygen consumption elevate. Studies on rat brain mitochondria show minimal effects. Measurements from rats suggest well-preserved brain iodothyronine homeostasis despite high thyroid hormone levels. Brain T4 and T3 concentrations and brain T3 production and turnover rates do not change significantly. Levels of glutamate dehydrogenase and pyruvate dehydrogenase activity in the brain are reduced. Beta-adrenergic binding sites in the cerebral cortex are increased and gamma-aminobutyric acid (GABA) binding sites are decreased. Brain levels of serotonin, 5-hydroxyindoleacetic acid, and substance P are altered. Native pain sensitivity and number of opiate receptors are increased. Thyroid hormones affect myelination, therefore increased levels lead to oxidative damage to the myelin membrane and/or the oligodendroglial cells.
Hypothyroidism
In hypothyroidism, muscle contraction and relaxation are slowed while duration is prolonged.
The amount of myosin ATPase decreases. Slowing of release and reaccumulation of calcium in the endoplasmic reticulum may decrease relaxation. In peripheral nerves, segmental demyelination has been observed with decreased nerve conduction velocities. Patients develop polyneuropathy with loss of reflexes and weakness. Decreases in vibration, joint-position, and touch-pressure sensations also are seen.
Frequency
United States
Thyroid disease is common in adults.
- One survey found the prevalence of hypothyroidism to be 1.4% in adult females and 0.1% in adult males. The prevalence of Graves disease, a hyperthyroid condition, is 1.9% in females and about 0.19% in males. Peak age incidence is in the range of 30-50 years.
- Congenital disease occurs in 1 per 4000 neonates in North America and Western Europe. This is seen more frequently in areas of iodine deficiency.
International
About 1 billion people are at risk for iodine deficiency disorders.
- Endemic goiter is most the common manifestation and has a varying prevalence.
- In communities with severe iodine deficiency, prevalence is 5-15% but can reach 100%. This situation occurs in developing countries.
Mortality/Morbidity
- Neurologic complications are seldom fatal.
- Congenital complications of iodine deficiency lead to cretinism and neonatal myxedema.
- Untreated myxedema may lead to myxedema coma and eventually to death in children and adults.
- Severity of symptoms of thyroid disease varies with the degree and duration of the deficiency.
- Some degree of myopathy is found in about 50% of thyrotoxic patients.
- Thyroid storm is an emergency requiring rapid therapy to prevent death.
- Although now uncommon, postoperative thyroid disease can be seen.
Race
No race predilection is known.
Sex
Thyroid disease is more common in women, but men also are affected.
Age
Thyroid disease is most common in adults aged 30-50 years, but all age groups are affected. Cretinism and neonatal myxedema manifest in the intrauterine/perinatal period.
Clinical
History
Presenting symptoms depend on whether thyroid hormone levels are increased or decreased. Symptoms are generalized initially. Neurologic signs appear after months to years. The brain, peripheral nerves, and muscular systems can be affected.
- Hypothyroidism
- Hypothyroidism occurs when T4 and T3 levels fall below physiologically required levels.
- Severe hypothyroidism results in myxedema, which results from accumulation of hydrophilic mucopolysaccharides in subcutaneous tissues.
- The term myxedema can be synonymous with hypothyroidism. However some reserve myxedema for severe hypothyroidism only.
- Common symptoms include the following:
- Weakness, fatigue, lethargy, and somnolence
- Cold intolerance, decreased sweating
- Dry, coarse skin
- Headache
- Swelling of the face and extremities
- Impaired memory and cognition, poor concentration
- Mild weight gain (with anorexia)
- Coarseness of voice and impaired hearing
- Paresthesias and arthralgias
- Muscle cramps
- Constipation
- Hyperthyroidism
- Hyperthyroidism results from excessive levels of T4 and T3.
- Symptoms include the following:
- Confusion
- Seizures
- Nervousness and tremor, emotional lability
- Muscle weakness
- Heat intolerance
- Weight loss (with increased appetite)
- Palpitations
Physical
- Hypothyroidism
- In infants this results in cretinism, which manifests as delayed physical and mental development. Affected infants have enlarged tongues, a coarse cry, thickened subcutaneous tissues, potbelly, umbilical hernia, hearing defects, and speech defects.
- Other findings are slowness and masking or disinhibition of facial expression.
- Strabismus may be noted.
- Some develop thalamic posturing, with severe motor deficits and a characteristic posture.
- When the patient is laid on one side, the undermost limb extends and the uppermost limb flexes.
- Other signs include microcephaly; inability to sit, stand, or walk; prominent primitive facial reflexes (especially the visual suck reflex); blepharospasm; and a prominent glabellar reflex.
- Patients appear autistic (ie, total disregard of surroundings and absence of purposeful activity).
- Other signs include the following:
- Hypotonia
- Cerebellar signs manifesting with ataxia, tremor, and dysmetria
- Polyneuropathy
- Cranial nerve deficits
- Entrapment neuropathy (eg, carpal tunnel syndrome)
- Slowing of voluntary movements
- Myopathic weakness, which can be subdivided into 4 subtypes: Kocher-Debre-Semelaigne syndrome, Hoffmann syndrome, atrophic form, and myasthenic form. Muscle hypertrophy is very rare in hypothyroid patients.
- Neuropsychiatric signs - Dementia, apathy, mental dullness, irritability, sleepiness.
- Hashimoto encephalopathy (HE), a rare, sometimes controversial classification of neurologic syndromes occurring in patients with steroid-responsive autoimmune thyroid disease. It was first described in 1966 and was associated with serum anti-thyroid antibodies. A single case report linked Hashimoto encephalopathy with painful legs and moving toes syndrome.1 Other case reports of miscarriages, focal seizures, and palatal tremor associated with Hashimoto encephalopathy have also been made.
- Hyperthyroidism
- Hyperthyroidism manifests systemically, affecting primarily muscle function and the central nervous system.
- It is associated with neuropsychiatric and neurologic syndromes and myopathy (eg, chronic thyrotoxic myopathy, exophthalmic ophthalmoplegia/infiltrative ophthalmopathy/Graves ophthalmopathy), thyrotoxic periodic paralysis, and myasthenia gravis.
- Neuropsychiatric syndromes include the following:
- Patients may manifest irritability, nervousness, tremulousness, apprehension, emotional lability, and agitation.
- Major depression, anxiety, hypomania or mania, schizophreniform disorder, and delirium also may occur. Milder deficits in memory, complex problem solving, and attention may be present.
- Psychosis (visual and auditory hallucinations) is infrequent.
- The clinical picture is seldom clear. The onset of symptoms is insidious, and often patients are referred to psychiatrists before the diagnosis is made.
- This is especially true for older patients, in whom dementia or depression is suspected.
- The presence of such symptoms may be related to the premorbid personality, but no definitive studies exist to support this theory.
- One of the difficulties in establishing the contribution of a premorbid personality is the inability of precisely determining the onset of thyroid dysfunction.
- Psychiatric symptoms have no direct relationship to the severity of the hyperthyroidism; once thyroid hormone levels are back to normal, the symptoms may resolve over months.
- Neurologic syndromes include chorea, ballism, embolic stroke secondary to tachycardia-induced atrial fibrillation, status epilepticus, and coma (which may occur in thyrotoxic crises). A case report describes a triad of acute ataxia, Graves disease, and stiff person syndrome.2
- Chronic thyrotoxic myopathy is a common complication.
- This myopathy is characterized by progressive weakness and wasting of skeletal musculature.
- Goiter of the nodular type is often present (and sometimes exophthalmos).
- More than 50% of thyrotoxic patients have some degree of myopathy.
- The myopathy is slowly progressive; the pelvic girdle and thigh muscles are affected preferentially.
- Exophthalmic ophthalmoplegia also is known as Graves ophthalmopathy and infiltrative ophthalmopathy.
- This refers to weakness of external ocular muscles and exophthalmos from Graves disease.
- Strabismus and diplopia may be present, as well as pain and lid retraction.
- The term infiltrative ophthalmopathy refers to ocular muscle histology that suggests an autoimmune process: prominent fibroblastic tissue, degenerated fibers, and infiltration of lymphocytes, mononuclear leukocytes, and lipocytes.
- Thyrotoxic periodic paralysis resembles familial periodic paralysis and manifests with attacks of mild to severe weakness, during which serum potassium levels are generally low.
- Thyrotoxic neuropathy was also reported. Both the clinical and electrophysiological abnormalities resolved with treatment of the thyrotoxicosis.
- Myasthenia gravis may be associated with hyperthyroidism.
- Hyperthyroidism is seen in 5% of patients with myasthenia gravis.
- Conversely, incidence of myasthenia gravis is 20-30 times higher in hyperthyroid patients than in the general population.
- Weakness and muscle atrophy from hyperthyroid myopathy can coexist with other abnormalities secondary to myasthenia gravis.
Causes
Clinicians must be able to identify characteristic neurologic deficits of thyroid disease so as to predict and possibly prevent neurologic complications. These include drug effects, which can suppress thyroid-stimulating hormone (TSH) secretion, inhibit thyroid hormone release or synthesis, decrease hormone-protein binding, or inhibit conversion of T4 to T3.
- Drugs affecting the thyroid
- Dopamine, L-dopa
- Glucocorticoid excess
- Iodide
- Lithium carbonate
- Sulfonylureas
- Phenylbutazone
- Phenytoin
- Salicylates
- Fenclofenac
- Furosemide
- Propylthiouracil
- Propranolol
- Amiodarone
- Iopanoic acid (Telepaque), iopodate (Oragrafin)
- Causes of hyperthyroidism
- Graves disease
- Toxic multinodular goiter
- Toxic adenoma
- Iodide-induced hyperthyroidism
- Subacute thyroiditis
- Factitious (exogenous) thyroiditis
- Neonatal thyrotoxicosis (eg, pregnant mother with Graves disease)
- TSH-secreting pituitary tumor
- Nontumorigenic pituitary-induced hyperthyroidism
- Choriocarcinoma (uterine or testicular origin) or hydatidiform mole
- Struma ovarii
- Hyperfunctioning thyroid carcinoma (usually metastatic)
- Causes of hypothyroidism: Hypothyroidism can be primary, secondary, or due to tissue resistance to thyroid hormone.
- Primary causes
- Destructive lesions such as Hashimoto thyroiditis
- Idiopathic myxedema
- Radioactive iodine therapy for hyperthyroidism
- Subtotal thyroidectomy (eg, surgery for Graves disease)
- Neck irradiation for other diseases
- Following acute thyroiditis (can be transient)
- Cystinosis
- Defects in enzymes that are necessary for thyroid hormone synthesis (congenital goiter)
- Endemic goiter (iodine deficiency)
- Iodine excess (>6 mg/d)
- Drug-induced thyroid agenesis
- Thyroid dysgenesis or ectopy
- Maternal iodide
- Antithyroid drugs
- Secondary causes
- Hypothalamic dysfunction due to neoplasm
- Eosinophilic granuloma or therapeutic irradiation
- Pituitary dysfunction due to neoplasm
- Pituitary surgery or irradiation
- Idiopathic hypopituitarism
- Sheehan syndrome (ie, postpartum pituitary necrosis)
- Dopamine infusion
- Severe illness
- Heatstroke
- Traumatic brain injury
- Primary causes
More on Thyroid Disease |
 Overview: Thyroid Disease |
| Differential Diagnoses & Workup: Thyroid Disease |
| Treatment & Medication: Thyroid Disease |
| Follow-up: Thyroid Disease |
| References |
| Next Page » |
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Further Reading
Keywords
thyroid neuropathy, thyroid myopathy, hyperthyroidism, hypothyroidism, Graves disease, myxedema, cretinism, thyrotoxicosis, Graves ophthalmopathy, thyroid eye disease, thyroid ophthalmopathy, thyroid orbitopathy, infiltrative ophthalmopathy, thyroid disease, T3, T4, thyroxine, thyroid hormones, regulation of thyroid hormones, myasthenia gravis, chronic thyrotoxic myopathy
