Neurologic manifestations of hyperthyroidism and Graves' disease

Neurologic manifestations of hyperthyroidism and Graves' diseaseAuthorDevon I Rubin, MDSection EditorsMichael J Aminoff, MD, DScDouglas S Ross, MDDeputy EditorJanet L Wilterdink, MDDisclosuresAll topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Oct 2012. | This topic last updated: Feb 6, 2012.

INTRODUCTION — Hyperthyroidism is a common medical condition in the general population. The most common cause of hyperthyroidism is Graves' disease, but elevated thyroid hormone levels may occur due to thyroiditis, multinodular goiter, toxic thyroid nodule, or excess thyroid hormone supplementation.

Common systemic features of hyperthyroidism include palpitations, heat intolerance, and weight loss. A number of central and peripheral nervous system manifestations may also occur in patients with hyperthyroidism (table 1). In many cases, the neurologic manifestations occur in conjunction with the systemic features of the disease, but these may be the presenting symptom in some patients.

This topic reviews the neurologic manifestations of hyperthyroidism. Other clinical features of hyperthyroidism are discussed separately. (See "Overview of the clinical manifestations of hyperthyroidism in adults" and "Clinical manifestations and diagnosis of hyperthyroidism in children and adolescents".) The diagnosis of hyperthyroidism is also discussed separately. (See "Diagnosis of hyperthyroidism".)

COGNITIVE DYSFUNCTION AND SEIZURES — Cognitive impairment is common in hyperthyroidism and may present as one or more different syndromes. In one review of elderly patients with hyperthyroidism, dementia and confusion was found in 33 percent and 18 percent of patients, respectively [1]. Studies in younger individuals with newly-diagnosed or induced hyperthyroidism have found lower cognitive scores compared with controls [2-4].

There is also inconclusive evidence suggesting that mild hyperthyroidism may be a risk factor for dementia. Case control and population-based cohort studies have had conflicting results, with some finding a positive association between low thyrotropin (TSH) levels and others not [5-9]. Low TSH in this setting may represent subclinical hyperthyroidism, but may instead be associated with hypothyroidism if it is the result of decreased thyrotropin-releasing hormone production, itself a consequence of neurodegeneration. (See "Neurologic manifestations of hypothyroidism", section on 'Alzheimer disease'.)

Clinical features — Patients with thyrotoxicosis may experience behavioral and personality changes, such as psychosis, agitation, and depression. Less overt manifestations that are more common in less severe thyrotoxicosis include anxiety, restlessness, irritability, and emotional lability [10]. Insomnia is also common. Elderly patients may have a less activated presentation with depression and lethargy, so-called apathetic thyrotoxicosis [1]. These behavioral manifestations are accompanied by cognitive impairments, particularly impaired concentration, confusion, poor orientation and immediate recall, amnesia, and constructional difficulties.

Seizures may accompany the encephalopathy of acute thyrotoxicosis and occasionally are the presenting clinical feature [11]. They may be focal or generalized [11-14]. Tremor and hyperreflexia with other pyramidal tract signs are also common features of the neurologic examination in thyrotoxicosis [15]. (See 'Tremor' below and 'Motor neuron disease' below.)

The presentation of cognitive dysfunction in hyperthyroidism is usually subacute; however, a more protracted course similar to a degenerative dementia has also been described [16]. In severe thyrotoxicosis, a condition frequently referred to as thyroid storm, the neurologic presentation is more fulminant, progressing if untreated through an agitated delirium to somnolence and ultimately to coma [17]. In many of these cases there is an underlying stressor, such as sepsis, trauma, or a recent surgical procedure. Seizures are more prominent in this setting and may include status epilepticus [12,13,18]. Other clinical features of thyroid storm, such as tachycardia, fever, and gastrointestinal symptoms, are commonly present (table 2).

Laboratory features — There are no reports of abnormalities on magnetic resonance imaging (MRI) or computed tomography (CT) neuroimaging studies. However, in one patient, single photon emission CT (SPECT) demonstrated diffusely reduced cerebral uptake with an accentuation in the temporoparietal regions bilaterally, which improved following resolution of the hyperthyroid state [16].

Nonspecific electroencephalography (EEG) abnormalities have been reported in 43 percent of patients with hyperthyroid encephalopathy [19]. EEG may demonstrate diffuse slowing, bitemporal sharp waves, polyspike and slow wave discharges, or may be normal [11,14]. In addition, an unusually high voltage with prolonged photic response and triphasic waves have been described in individual patients [11,20].

Pathogenesis — The mechanism of cognitive and behavioral dysfunction in hyperthyroidism is not known. Improvement of some clinical features (attention and concentration) with beta-blocker therapy suggests a role for a hyperthyroid-induced hyperactive adrenergic system, possibly disrupting the adrenergic pathways between the locus ceruleus and frontal lobe that subserve attention and vigilance [16]. Others propose that hyperthyroidism may produce oxidative stress, producing neuronal injury and hastening a presentation of degenerative or vascular dementia [8].

The etiology of seizures in thyrotoxicosis is also not known. Animal studies have demonstrated that exogenous administration of thyroxine lowers the seizure threshold. Elevated thyroxine levels have also been associated with precipitating seizures in two patients with previously well-controlled juvenile myoclonic epilepsy [21].