Neurological Manifestations of Thyroid Disease Workup
- Author: Gabriel Bucurescu, MD, MS; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE more...
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 This test has been superseded by the TSH-IMA.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.
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.
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.
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 [15, 16, 17, 18]
Generally these are not useful in thyroid disease. Visual evoked potentials show increased latencies in hyperthyroidism with no change after patients become euthyroid.} 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:
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. 
Sural nerve biopsies reveal axonal degeneration.
Electron microscopy reveals the following:
Focal microfibrillar disorganization, sometimes with nemaline rods
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
Increased central nuclear counts
Central cores with oxidative activity in type I fibers
Impaired myelin formation
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
Cao L, Wang F, Yang QG, Jiang W, Wang C, Chen YP, et al. Reduced thyroid hormones with increased hippocampal SNAP-25 and Munc18-1 might involve cognitive impairment during aging. Behav Brain Res. 2012 Apr 1. 229(1):131-7. [Medline].
Fallah R, Mirouliaei M, Bashardoost N, Partovee M. Frequency of subclinical hypothyroidism in 5- to 15-year-old children with migraine headache. J Pediatr Endocrinol Metab. 2012. 25(9-10):859-62. [Medline].
Song TJ, Kim SJ, Kim GS, Choi YC, Kim WJ. The prevalence of thyrotoxicosis-related seizures. Thyroid. 2010 Sep. 20(9):955-8. [Medline].
Tuncel D, Cetinkaya A, Kaya B, Gokce M. Hoffmann's syndrome: a case report. Med Princ Pract. 2008. 17 (4):346-8. [Medline].
Li L, Zheng FP, Wang G, Li H. Recurrent hashimoto's encephalopathy, showing spontaneous remission: a case report. Intern Med. 2011. 50(12):1309-12. [Medline].
Santoro D, Colombo I, Ghione I, Peverelli L, Bresolin N, Sciacco M. Steroid-responsive Hashimoto encephalopathy mimicking Creutzfeldt-Jakob disease. Neurol Sci. 2011 Aug. 32(4):719-22. [Medline].
Guimaraes J, Santos L, Bugalho P. Painful legs and moving toes syndrome associated with Hashimoto's disease. Eur J Neurol. 2007 Mar. 14(3):343-5. [Medline].
Muthipeedika JM, Moosa A, Kumar A, Suchowersky O. Bilateral chorea--ballism associated with hyperthyroidism. Mov Disord. 2005 Apr. 20(4):512; author reply 512. [Medline].
Chia SY, Chua R, Lo YL, Wong MC, Chan LL, Tan EK. Acute ataxia, Graves' disease, and stiff person syndrome. Mov Disord. 2007 Oct 15. 22(13):1969-71. [Medline].
Ohba S, Nakagawa T, Murakami H. Concurrent Graves' disease and intracranial arterial stenosis/occlusion: special considerations regarding the state of thyroid function, etiology, and treatment. Neurosurg Rev. 2011 Jul. 34(3):297-304; discussion 304. [Medline].
Scorza FA, Arida RM, Cysneiros RM, Terra VC, de Albuquerque M, Machado HR. Subclinical hyperthyroidism and sudden unexpected death in epilepsy. Med Hypotheses. 2010 Apr. 74(4):692-4. [Medline].
Parker RJ, Davidson AC. Hypothyroidism--an unexpected diagnosis following emergency treatment for heatstroke. Int J Clin Pract Suppl. 2005 Apr. 31-3. [Medline].
Blanchin S, Coffin C, Viader F, Ruf J, Carayon P, Potier F, et al. Anti-thyroperoxidase antibodies from patients with Hashimoto's encephalopathy bind to cerebellar astrocytes. J Neuroimmunol. 2007 Dec. 192(1-2):13-20. [Medline].
Sellner J, Kalluri SR, Cepok S, Hemmer B, Berthele A. Thyroid antibodies in aquaporin-4 antibody positive central nervous system autoimmunity and multiple sclerosis. Clin Endocrinol (Oxf). 2011 Aug. 75(2):271-2. [Medline].
Avramides A, Papamargaritis K, Mavromatis I, et al. Visual evoked potentials in hypothyroid and hyperthyroid patients before and after achievement of euthyroidism. J Endocrinol Invest. 1992. 15:749-753. [Medline].
Ozata M, Ozkardes A, Corakci A, Gundogan MA. Subclinical hypothyroidism does not lead to alterations either in peripheral nerves or in brainstem auditory evoked potentials (BAEPs). Thyroid. 1995. 5(3):201-205. [Medline].
Ozkardes A, Ozata M, Beyhan Z, et al. Acute hypothyroidism leads to reversible alterations in central nervous system as revealed by somatosensory evoked potentials. Electroencephalography and clinical neurophysiology. 1996. 100:500-504. [Medline].
Tamburini G, Tacconi P, Ferrigno P, et al. Visual evoked potentials in hypothyroidism: a long-term evaluation. Electromyogr Clin Neurophysiol. 1998. 38:201-205. [Medline].
Sinclair C, Gilchrist JM, Hennessey JV, Kandula M. Muscle carnitine in hypo- and hyperthyroidism. Muscle Nerve. 2005 Sep. 32(3):357-9. [Medline].
Alevizaki M, Synetou M, Xynos K, Alevizaki CC, Vemmos KN. Hypothyroidism as a protective factor in acute stroke patients. Clin Endocrinol (Oxf). 2006 Sep. 65(3):369-72. [Medline].
Dai A, Wasay M, Dubey N, Giglio P, Bakshi R. Superior sagittal sinus thrombosis secondary to hyperthyroidism. J Stroke Cerebrovasc Dis. 2000 Mar-Apr. 9(2):89-90. [Medline].
Ni J, Gao S, Cui LY, Li SW. Intracranial arterial occlusive lesion in patients with Graves' disease. Chin Med Sci J. 2006 Sep. 21(3):140-4. [Medline].
Peralta AR, Canhão P. Hypothyroidism and cerebral vein thrombosis--a possible association. J Neurol. 2008 Jul. 255(7):962-6. [Medline].