Neurological Manifestations of Thyroid Disease Workup

Blood levels of thyroid hormone and serum thyrotropin (ie, TSH) are the most important diagnostic tests. levels of free T4 and free T3 in serum provide a better assessment of the thyroid status than total T4 and T3. The levels of T4 and T3 are decreased in hypothyroidism, and they are increased in hyperthyroidism.

Serum TSH levels range from 0.5 to 5.0 microunits per milliliter. TSH is increased in hypothyroidism, and as thyroid function becomes autonomous, it decreases. It is a useful marker for the efficacy of therapy. The TSH-immunometric assay (TSH-IMA) can discriminate directly between normal TSH and reduced levels without requiring the use of the thyrotropin-releasing hormone (TRH) infusion test. If TSH levels remain high in cases of treated hypothyroidism, the possibility of a TSH-secreting pituitary adenoma should be considered.

TRH infusion test can be performed by infusing TRH intravenously and measuring TSH in serum to determine the presence of TSH in the pituitary. TSH is reduced in hyperthyroidism in autonomous thyroid production and hypothalamic pituitary disease. This test has been superseded by the TSH-IMA.

Thyroid hormone-binding ratio (known previously as T4 and T3 uptake) and transthyretin levels are rarely useful for common clinical purposes.

Radioactive iodine (RAI) uptake can differentiate causes of hyperthyroidism: subacute thyroiditis (low uptake) versus Graves disease (high uptake).

Antithyroid antibodies, the most important being thyroid microsomal antibody (TMAb), are seen in 95% of patients with Hashimoto thyroiditis but in only 10% of adults with no disease. In Graves disease, 55% of patients have circulating TMAbs. Recently, in a small study, antithyroid antibodies were found to be the most common abnormality in a group of patients with autoimmune manifestations and atypical neurologic features.

Antithyroperoxidase antibodies from patients with Hashimoto encephalopathy were found to bind to cerebellar cells expressing glial fibrillary acid protein. ^[18]

Thyroglobulin antibodies (TGAbs) are present in the serum of 60% of patients with Hashimoto disease.

Interestingly, increased levels of thyroglobulin antibodies and/or antithyroid peroxidase antibodies have been found in patients with aquaporin-4 (AQP4) antibody–positive CNS autoimmunity and multiple sclerosis, both in pediatric and adult age groups. AQP4 antibody plays an important role in the pathophysiology of neuromyelitis optica (NMO) spectrum disorders, and such patients have a high frequency of autoimmune thyroid disease. ^[19]

Antibodies against thyroid TSH receptor (TRAbs) are seen in the serum of patients with Graves disease.

Serum thyroglobulin is most useful in follow-up of metastatic thyroid carcinoma after thyroidectomy.

Creatine kinase (CK) levels may be elevated.

Cerebrospinal fluid (CSF) protein may be increased.

Imaging studies such as MRI or CT scan are of limited use in thyroid disease. Pituitary or hypothalamic tumors can be seen, as can metastatic lesions of thyroid carcinoma, which are usually solitary. In cases of severe exophthalmic ophthalmoplegia, extraocular muscle swelling can be observed on both MRI and CT scans (sometimes impinging on the optic nerve). Brains of adults with congenital hypothyroidism may show atrophy, especially of the brain stem and perisylvian regions (with cerebellum sparing). Patients with antibodies against thyroid antigens may show nonspecific MRI changes, probably due to demyelination.

Thyroid scan (which involves either radioactive iodine 123 or iodine 131) correlates thyroid function and structure. It can diagnose the functional state of a thyroid nodule or search for thyroid tissue in neck masses.

Thyroid ultrasound can assess whether a thyroid mass is solid or cystic. It is used usually to help in diagnosing a single thyroid nodule; cystic lesions may be simple cysts or benign follicular tumors, which could be managed medically, sparing the patient the need for surgery. However, follicular carcinoma also can become cystic, in which case tissue biopsy would be required. Solid masses suggest a possible tumor, in which case the treating physician would be inclined to proceed to surgery.

Electroencephalography in hyperthyroidism

EEG may support the suspicion of CNS involvement. Alpha rhythm is accelerated, and rolandic mu rhythm may be augmented.

Some have reported paroxysmal bursts and clinical seizures (eg, grand mal). Patients with epilepsy and thyroid dysfunction may respond poorly to anticonvulsants until the underlying endocrine problem is treated. Thyroxine can produce epileptic activity. In thyrotoxic crises with encephalopathy, EEG abnormalities are characterized by marked slowing with superimposed fast activity. Triphasic waves are reported rarely.

Electroencephalography in hypothyroidism

EEG is characterized by an excess of low-voltage activity with a poor or absent alpha-blocking response. In myxedematous coma, slow, low-voltage activity predominates. Generalized periodic sharp wave discharges, mimicking Jakob-Creutzfeldt encephalopathy, have been reported in one case. EEG abnormalities tend to resolve as thyroid abnormalities are treated. In myxedematous infants, delay in EEG development (especially of sleep spindle) can occur. Generally, EEG shows excessive low-voltage slowing.

Electromyography

EMG generally provides limited information. Proximal muscles are more likely to show an abnormal pattern than distal muscles. In hyperthyroid patients, abnormalities include reduced duration of mean action potentials and increased mean percentage of polyphasic potentials. Large action potentials may be seen in thyrotoxic myopathy but are not associated histologically with neuropathic change and are not believed to indicate denervation. In hypothyroidism, EMG changes include polyphasic action potentials, hyperirritability, repetitive discharges after reflex motion, and low-voltage, short-duration motor unit potentials. Changes usually resolve as thyroid function normalizes.

Nerve conduction studies

Nerve conduction velocities (NCV) are decreased in hypothyroid patients with polyneuropathy. Patients show diffuse sensory neuropathy due to axonal degeneration and not, as previously thought, to segmental demyelination. Amplitude of sensory compound nerve action potentials (CNAP) is reduced and NCVs are slowed. In carpal tunnel syndrome, typical nerve conduction abnormalities are seen.

One case was reported of severe hyperthyroidism with motor-sensory neuropathy, moderately slow NCVs, absent sural CNAP, and low sural sensory NCV. Thyrotoxic neuropathy (also known as Basedow paraplegia) is very rare.

Evoked potential studies 

Generally these are not useful in thyroid disease. Visual evoked potentials show increased latencies in hyperthyroidism with no change after patients become euthyroid. ^{[20, 21, 22, 23]}

In hypothyroid patients, amplitudes are decreased and latencies are prolonged. Latencies and amplitudes improved inconsistently among some patients as thyroid function normalized. Brainstem evoked responses are marginally useful, with some studies showing abnormalities. Patients who had been hyperthyroid for longer than 6 months showed increased N19-P23 amplitudes in median somatosensory evoked potentials with the latency unaffected.

The following procedures may be needed:

• Thyroidectomy

• Fine-needle biopsy

• Muscle or peripheral nerve biopsy: This can confirm diagnosis or differentiate diagnoses. Both hyperthyroid and hypothyroid patients may have disturbed levels of carnitine but by separate mechanisms. ^[24]

Hypothyroidism

Sural nerve biopsies reveal axonal degeneration.

Electron microscopy reveals the following:

• Focal microfibrillar disorganization, sometimes with nemaline rods

• Mitochondrial accumulation

• Occasional basophilic degeneration: In cardiac and skeletal muscle, basophilic degeneration is due to deposits of polysaccharide material.

• No definite abnormalities in muscle from individuals with congenital hypothyroidism

Muscle histology reveals the following:

• Type I fiber excess

• Atrophy of type I and II fibers

• Altered oxidative enzyme activity, abnormal collection of glycogen, peripheral crescents, and distention of cytoplasmic reticulum

• Vacuolar myopathy

• Increased central nuclear counts

• Central cores with oxidative activity in type I fibers

• Impaired myelin formation

Hyperthyroidism

Sural nerve biopsies reveal the following:

• Excessive axonal branching

• Degenerative changes of preterminal axons

• Edematous protein infiltration of endoneurium and perineurium

• Segmental demyelination in teased fiber preparation

Electron microscopy reveals the following:

• Increased glycogen, acid mucopolysaccharides, and aggregates of glycogen and cytoplasmic laminar bodies in Schwann cells

• In brain, small neuronal cell bodies with increased cell packing density, decreased neurophil, decreased myelin, and gliosis (especially in the substantia nigra and globus pallidus)

Muscle histology reveals the following:

• Few pathologic changes in hyperthyroidism

• Mild atrophy, infiltration of fat cells, nonspecific focal myofibrillar degeneration, mitochondrial hypertrophy, and focal dilatation of transverse tubular system