Neurological Manifestations of Thyroid Disease Clinical Presentation

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 - In children, subclinical hypothyroidism has been associated with exacerbation of migraine headaches ^[5]

• 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 - Prognosis is good if patients become euthyroid ^[6]

• Nervousness and tremor, emotional lability

• Muscle weakness

• Heat intolerance

• Weight loss (with increased appetite)

• Palpitations

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, ^[7] 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 ^{[8, 9]} : 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. ^[10] Other case reports of miscarriages, focal seizures, and palatal tremor associated with Hashimoto encephalopathy have also been made. Rare cases of primary demyelination and encephalopathy have also been reported. There have also been reports of the encephalopathy mimicking vascular occlusion of the middle cerebral artery. ^[11]

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.

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). ^[12] A case report describes a triad of acute ataxia, Graves disease, and stiff person syndrome. ^[13]

A single case of reversible and unilateral corticospinal tract disease was reported recently. It was thought to be secondary to autoimmune free T3-thyrotoxicosis, and improved significantly with carbimazole 10 mg daily. The patient had low TSH, high T3 , normal T4 and very high antithyroid peroxidase antibody. ^[14]

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.

Graves disease has been associated with intracranial arterial stenosis/occlusion (moyamoya syndrome). The exact mechanism is unknown; it is believed that thyroid hormones may augment vascular sensitivity to the sympathetic nervous system and induce pathological changes in the arterial walls. ^[15]

Subclinical hyperthyroidism has been linked to sudden unexpected death in epilepsy (SUDEP). The mechanism is hypothesized to be facilitation of cardiovascular abnormalities. Subclinical hyperthyroidism has been reported to increase heart rate, left ventricular mass, and cardiac contractility, which, in turn, could lead to diastolic dysfunction and impaired ventricular ejection fraction response to exercise and atrial arrhythmias. ^[16]

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 are as follows:

• 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 are as follows:

• 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)

Hypothyroidism can be primary, secondary, or due to tissue resistance to thyroid hormone.

Primary causes of hypothyroidism are as follows:

• 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 of hypothyroidism are as follows:

• 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 ^[17]

• Traumatic brain injury