Thyroid Disease and the Nervous System

Disorders of the thyroid gland are common and arefrequently accompanied by neurologic complications. Prevalence estimations have suggested that 1 to 2 percent of general medical, geriatric, and psychiatric inpatients have some form of thyroid disease. Neurologists should be aware of the common and the more unusual neurologic complications of thyroid disease, since they may be the presenting feature of the thyroid disorder and because they are usually readily corrected with appropriate treatment.

Neurologic Complications of Hypothyroidism

Hypothyroidism is a common disorder, with data from the National Health and Nutrition Examination Survey indicating that 1 in 300 persons in the United States has hypothyroidism. The commonest causes of hypothyroidism are autoimmune destruction, thyroidectomy, and radioiodine ablation of the gland. Fewer than 10 percent of cases of hypothyroidism are secondary to pituitary or hypothalamic disease.

Neurologic complications are common in patients with hypothyroidism, and all levels of the nervous system may be involved. The neurologic complications of hypothyroidism may be grouped into the following categories: (1) congenital hypothyroidism; (2) encephalopathy that may result in coma or a seizure disorder; (3) psychologic changes; (4) sleep disorders; (5) cerebellar ataxia; (6) cranial nerve lesions; (7) myopathy; (8) peripheral nerve disorders; and (9) miscellaneous conditions.

Neurologic Features of Congenital Hypothyroidism

Congenital hypothyroidism (CH), previously called cretinism, is the commonest treatable cause of neonatal encephalopathy, with data from neonatal screening programs revealing an incidence of 1:3,000 to 1:4,000. It occurs secondary to dysgenesis of the thyroid gland or to severe maternal deficiency of dietary iodine. Neurologic complications include developmental delay, pyramidal signs in a proximal distribution, and extrapyramidal signs. Many patients have a characteristic gait, reflecting dysfunction of both the pyramidal and the extrapyramidal motor systems, in combination with laxity and deformity of the joints. Other common clinical features include strabismus, deafness, ataxia, and primitive reflexes. Imaging of the brain shows basal ganglia calcification in one-third of patients. In addition, evidence suggests that CH leads to reduced hippocampal volume, even when treated, and psychometric testing reveals that patients score below age-matched controls in verbal memory. Similarly, reduced IQ scores have also been reported in children with CH. Learning impairment and changes in hippocampal CA1 pyramidal cell excitability have been reported in hypothyroid mice.

Adult patients with CH typically manifest physical signs of spasticity affecting the trunk and proximal limb-girdle musculature, with relative sparingof the distal extremities. Magnetic resonance imaging (MRI) of the brain has shown abnormalities in the globus pallidus and substantia nigra, with increased signal on T1-weighted images and hypointensity on T2-weighted images, and only a modest degree of cerebral atrophy. Overall however, neuroradiologic findings seem to be similar in children with CH when compared to healthy controls. It has been suggested that the main insult to the central nervous system (CNS) may involve processes such as dendritic arborization and synaptogenesis, which are not evident on MRI.

In the developing brain, thyroid hormone has important effects on the regulation of neurofilament gene expression and on several genes encoding mitochondrial proteins. Thyroid hormone also regulates the timing of appearance and regional distribution of laminin, an extracellular matrix protein that provides key guidance signals to migrating neurons within the CNS. Disruption in the expression of laminin may play a role in the derangement of neuronal migration observed in the brain of patients with CH.

A detailed consideration of the inborn errors of thyroid gland development and thyroid hormone synthesis responsible for permanent CH is beyond the scope of this chapter, but recent reviews on the topic provide additional details. Primary CH is due to abnormal development of the thyroid gland in 85 percent of instances. A group of patients with CH poorly responsive to treatment and featuring additional signs of choreoathetosis, muscular hypotonia, and pulmonary problems were found to have mutations to thyroid transcription factor 1. Mutations to genes coding proteins required for thyroid hormone synthesis cause 10 to 15 percent of permanent primary CH; thyroid peroxidase is the protein most commonly affected. Furthermore, mutations in a transmembrane thyroid hormone transporter, MCT-8, result in abnormal levels of circulating iodothyronines as well as global developmental delay, central hypotonia, spastic quadriplegia, dystonic movements, rotatory nystagmus, and impaired gaze and hearing in affected males. Heterozygous females have a milder thyroid phenotype and no neurologic abnormalities.

Encephalopathy, Coma, and Seizures

Slowness, impairment of attention and concentration, somnolence, and lethargy are common symptoms in hypothyroidism. Occasionally, a life-threatening encephalopathy termed “myxedema coma” develops in patients with chronic, untreated hypothyroidism. A high index of suspicion is required to diagnose myxedema coma, particularly in the elderly, in whom features of hypothyroidism may be difficult to distinguish from depression or dementia.

In the compensated hypothyroid state, physiologic adaptations include a shift of the vascular pool away from the periphery to the central core to sustain normal body temperature. In chronic hypothyroidism, these adaptations tend to produce a degree of diastolic hypertension as well as a decrease in blood volume of up to 20 percent. Many organ systems and metabolic pathways are profoundly altered by chronic deficiency of thyroid hormone. Alterations in myocardial biochemistry produce impairment of cardiac contractility; the ventilatory response to hypercapnia is abnormal; hyponatremia may result from a reduction in free water clearance; and suppression of bone marrow function may result in normochromic normocytic anemia and an impaired white blood cell response to infection. Reduction in insulin clearance and decreased gluconeogenesis may produce a tendency to hypoglycemia, and patients are predisposed to toxic drug effects owing to reduced plasma clearance of all drugs. The corticosteroid response to stress is also likely to be impaired, even when basal serum cortisol levels are normal.

The majority of patients who develop myxedema coma are elderly and have a history suggestive of gradual deterioration. Three key clinical features are universally present in myxedema coma: depression of consciousness, a precipitating illness or event, and defective temperature control. Common precipitating factors include infection, trauma, stroke, hypothermia, hypoglycemia, carbon dioxide narcosis, and administration of certain drugs that have a CNS depressant effect. The body temperature is subnormal in many cases, but relative hypothermia may also occur, with the patient having an inappropriately normal temperature in the presence of sepsis. Most patients have clinical signs in keeping with long-standing hypothyroidism. Seizures occur in approximately 20 percent of cases; focal neurologic signs are not usually observed unless there has been a concomitant cerebrovascular event.

The pathophysiology is not fully understood but centers on the effects of low intracellular triiodothyronine (T3), particularly on the heart, which leads to decreased inotropism and chronotropism. Laboratory investigations are often abnormal but seldom show diagnostic abnormalities. In critically ill patients, it may be difficult to distinguish between severe hypothyroidism and the sick euthyroid syndrome, and it may be necessary to measure levels of free circulating thyroid hormone. The electrocardiogram typically shows sinus bradycardia, with low voltage and prolongation of the QT interval. Chest radiography may reveal a pleural or pericardial effusion. Hyponatremia may be present, and the serum cholesterol level is sometimes elevated. Serum creatine kinase (CK) and lactate dehydrogenase levels are often raised. Lumbar puncture may reveal an elevated opening pressure, and the cerebrospinal fluid (CSF) protein concentration is often raised. The electroencephalogram (EEG) is commonly abnormal; in keeping with a metabolically induced encephalopathy, the frequency of the posterior dominant rhythm decreases, often into the theta range, and triphasic waves may be present.

The key to the successful treatment of myxedema coma is early recognition and the rapid institution of appropriate therapeutic measures, usually in the intensive care unit (ICU). Hypothyroid coma has a high mortality rate, and treatment should not be delayed for confirmatory laboratory data. Besides the use of intravenous thyroxine, it should include broad-spectrum antibiotics to cover any underlying infection and stress doses of glucocorticoids until specific laboratory results become available. Patients may not mount an appropriate leukocyte response or fever even in the presence of severe infection. The main principles of management also include correction of electrolyte and blood sugar abnormalities, passive rewarming, control of seizures, and respiratory and circulatory support. Different specific treatment regimens are advocated, with some authors preferring thyroxine (T4) monotherapy at a loading dose of 200 to 300 μg intravenously followed by 100 μg intravenously for maintenance. When stable, oral replacement at a dose of 1.6 μg/kg can be used with dose adjustment guided by thyroid-stimulating hormone (TSH) and free T4 levels.

Early recognition and improved ICU care have improved outcomes, but mortality remains at around 20 percent ; factors associated with poor outcome include hypotension and bradycardia at presentation, sepsis, reduced Glasgow Coma Scale score, the need for mechanical ventilation, and hypothermia unresponsive to treatment.

Neuropathologic studies of patients with myxedema coma have been few and usually have shown only the presence of cerebral edema with or without diffuse neuronal changes.

There is a relatively high incidence of seizures in hypothyroidism, occurring in up to 20 percent of untreated patients. Drop attacks (sudden repeated falls without warning symptoms and without loss of consciousness) also occur and resolve with therapy. Patients with severe hypothyroidism may present with convulsive or nonconvulsive status epilepticus. Clinicians should be alert to the possibility of underlying hypothyroidism when the recovery timeof the patient following a seizure is unusually prolonged.

Mental Changes

Hypothyroidism may be associated with mood disorders, in particular, depression. Treatment of thehypothyroidism usually resolves the affective problem, although the response of individuals to treatment may be modulated by common polymorphisms of thyroid hormone transporters and deiodinases. The colorful term myxedema madness has been used to describe the florid mental-state changes that may occur in hypothyroid patients, including irritability, paranoia, hallucinations, delirium, and psychosis. These symptoms are typically reversible but often take longer than physical symptoms to resolve; in some cases a degree of cognitive impairment may persist, particularly if treatment is delayed, perhaps due to irreversible damage secondary to chronic metabolic changes.

An increased incidence of hypothyroidism has been noted in patients with various major psychiatric illnesses. For example, there is an association between hypothyroidism and bipolar affective disorder, particularly in patients with a “rapid cycling” form of the illness, and up to 50 percent of these patients have positive antithyroid antibody titers. Clinical and subclinical hypothyroidism in depression and bipolar disorder may adversely affect or delay the response to treatment. Many patients with depression, even when viewed as chemically euthyroid, have alterations in their thyroid function, including slight elevation of the serum thyroxine, blunting of the TSH response to thyrotropin-releasing hormone stimulation, and detectable titers of antithyroid antibodies. These changes are generally reversed following alleviation of the depression. It has also been recognized that depressed patients with hypothyroidism may manifest different symptoms than patients with lowmood and no concurrent hypothyroidism. Generally speaking, hypothyroidism is a reversible cause of cognitive impairment, most commonly manifesting as psychomotor slowing, memory impairment, visuospatial problems, and reduced constructional dexterity.

More subtle neuropsychologic abnormalities have also been documented in hypothyroid patients and may include impairment of learning, word fluency, and some aspects of attention, visual scanning, and motor speed. Treatment of the hypothyroidism may result in some cognitive improvement. Mood and neuropsychologic function may improve more satisfactorily in hypothyroid patients treated with a combination of thyroxine plus triiodothyronine, rather than thyroxine alone.

Disorders of Sleep

Both obstructive and central sleep apnea may occur in patients with hypothyroidism. Obstructive sleep apnea (OSA) appears to be far more common, with estimates that the prevalence is over 50percent in patients with hypothyroidism, while the prevalence of hypothyroidism in all OSA patients is less than 3 percent. The combination ofhypothyroidism and OSA appears to increase the risk of cognitive impairment. Factors contributing to the development of OSA include narrowing of the upper airway due to deposition of mucopolysaccharides and extravasation of protein into the tissues of the tongue and nasopharynx, as wellas hypertrophy of the genioglossus. Centrally, there appears to be reduced chemosensitivity to hypercapnia.

Thyroid hormone replacement therapy usually results in improvement in ventilatory drive following normalization of TSH. Improvement in airway dimensions may require a longer period of euthyroidism (up to 12 months), and only at this stage will nocturnal snoring decrease. In some patients, additional measures such as nasal continuous positive airway pressure may be required.

Cerebellar Ataxia

Reference to unsteadiness of gait may be found in the earliest clinical descriptions of hypothyroidism. In a recent review of the literature, it was found that all patients develop significant broad-based gait, and other typical clinical features include, in decreasing frequency, incoordination of the limbs, cerebellar dysarthria, nystagmus, and vertigo. Rapid and complete or almost complete resolution of the cerebellar features usually occurs following achievement of euthyroidism.

The pathophysiologic basis of cerebellar dysfunction in hypothyroidism remains unknown. The rapid resolution of the ataxia with thyroid replacement therapy in most patients suggests a reversible metabolic factor. However there may be an immune-mediated mechanism of cerebellar degeneration inthose patients that have been noted to be ataxic despite being euthyroid. For this latter group, immunosuppression may be a therapeutic option. Pathologic reports are few, but depletion of Purkinje cells may occur. Changes on imaging are rare, but MRI may demonstrate atrophy of the vermis and cerebellar hemispheres.

Cranial Nerve Disorders

Primary thyroid failure may be associated with pituitary enlargement resulting from hyperplasia due to lack of negative feedback from circulating thyroid hormones. Pituitary enlargement, as determined on MRI, has been found in 70 percent of patients with primary hypothyroidism, and a reduction in pituitary size following treatment occurs in the majority. Visual evoked potentials may be abnormal in hypothyroid patients, but severe visual field loss and blindness are rare. The association between pituitary gland enlargement and primary hypothyroidism should be kept in mind when pituitary hyperplasia is detected on neuroimaging, so that unnecessary invasive interventions are avoided.

Some patients with hypothyroidism develop pseudotumor cerebri (idiopathic intracranial hypertension) resulting in headache and papilledema following the initiation of thyroxine replacement therapy. An atypical facial pain syndrome may also occur.

Hearing impairment and tinnitus commonly occur in patients with hypothyroidism. Estimations of reduced auditory acuity based on pure-tone audiometry vary, but it is likely that over half ofpatients suffer hearing impairment that may originate from the cochlea, central auditory pathways, or the retrocochlear region. The hearing loss associated with hypothyroidism is thought to be sensorineural in nature and may improve when the hypothyroidism is treated.

Dysphonia in patients with hypothyroidism appears to arise from local myxedematous changes in the larynx rather than from cranial nerve dysfunction.

Hypothyroid Myopathy

Clinical Features

Muscle involvement is common in clinical and subclinical hypothyroidism, with more than 60 percent of patients reported to have an elevated serum CKlevel. The level of increase correlates with the severity of hypothyroidism and corrects when thyroid function normalizes with treatment. Symptomatic muscle disease is less common. Clinical evidence of hypothyroid myopathy occurs in 30 to 80 percent of patients. A study of clinical and electrophysiologic features prior to commencement of thyroxine therapy revealed that 45 percent of patients with hypothyroidism had decreased or absent deep tendon reflexes, 30 percent had clinical muscle weakness, 15 percent had neuropathy, and 8 percent had evidence of myopathy on electromyography (EMG).

The major clinical features of hypothyroid myopathy include weakness, cramps, aching or painful muscles, sluggish movements and reflexes, and myoedema (mounding of the muscle on direct percussion). There may be a discernible increase in muscle bulk that is most obvious in the tongue, arms, and legs. The degree of weakness is usually relatively mild and tends to involve the pelvic- and shoulder-girdle muscles. The gait tends to be slowand clumsy. Occasionally, patients have been described with more severe myopathic symptoms, including the development of rhabdomyolysis and renal failure or, very rarely, respiratory insufficiency, which may respond to hormone replacement. Muscle pain, particularly during and after exertion, is a prominent feature, and hypothyroidism should be considered in patients presenting with musculoskeletal pains of uncertain cause.

Muscle pain, stiffness, cramps, and delayed relaxation of the tendon reflexes in adult hypothyroidism are sometimes referred to as Hoffmann syndrome. Kocher–Debré–Sémélaigne syndrome is the unusual association of muscle hypertrophy with childhood hypothyroidism. The patient may have the typical clinical features of CH, with the added feature of generalized muscular hypertrophy so that the child has an athletic, almost Herculean appearance.

A delay in the relaxation of muscle (pseudomyotonia) is commonly observed during assessment of the tendon reflexes in hypothyroid patients. All phases of the tendon reflex are delayed, although slowing of the relaxation phase is most apparent clinically. Pseudomyotonia differs from true myotonia in that there is reduction in the speed of both the contraction and relaxation phases, and this slowness is not increased after rest or relieved by repeated muscle contractions. EMG does not show the characteristic “dive-bomber” effect seen in true myotonia; in the pseudomyotonia of hypothyroidism, there is a continuous burst of action potentials that begins and terminates abruptly, with firing at a constant rate. Percussion of the muscle commonly causes a slow prolonged mounding effect (myoedema). This event, unlike myotonia, is electrically silent and has been attributed to derangement of intracellular calcium homeostasis.

The differential diagnosis of hypothyroid myopathy includes other causes of painful stiff muscles, such as polymyalgia rheumatica and polymyositis. Attention has been directed to the frequency ofneuromuscular symptoms in patients with subclinical hypothyroidism, and the suggestion has been made that such patients should be treated early, not only to prevent progression to frank hypothyroidism, but also to improve neuromuscular dysfunction.

Investigations

The majority of patients with hypothyroidism have an elevated serum CK level, even when the myopathic features are not clinically obvious. In symptomatic patients, the serum CK level may rise to more than 10 times the upper limit of normal. Due to the patchy nature of the myopathy, neurophysiologic assessment may show no significant abnormalities. However, up to one-third of patients with hypothyroidism may have “myopathic” short-duration, low-amplitude, polyphasic motor unit potentials on EMG.

Pathology

In many cases of hypothyroidism, pathologic changes in muscle are subtle and nonspecific. Light microscopy may reveal increased central nuclear counts, type I fiber predominance, or type II fiber atrophy; common abnormalities on electron microscopy include the accumulation of glycogen and lipids, abnormal and increased numbers of mitochondria in perinuclear and subsarcolemmal regions, dilated sarcoplasmic reticulum, and focal myofibrillar degeneration. There may be vacuolation in many large fibers, and crescents of material containing acid mucopolysaccharides may be found beneath the sarcolemmal sheath. Often these changes resolve with thyroxine replacement therapy.

Pathophysiology

Thyroid hormone is intimately linked to carbohydrate metabolism, mitochondrial function, and possibly to the function of the sarcoplasmic reticulum and intrinsic contractile properties of muscle. However, these structure–function relationships are still incompletely understood, although it is assumed that underlying biochemical changes in hypothyroidism lead to prolongation of the contraction and relaxation phases of muscle activity. Magnetic resonance spectroscopy of hypothyroid muscle shows a low intracellular pH in resting muscle and delayed glycogen breakdown in exercising muscle. In addition, mitochondrial oxidative capacity is reduced in hypothyroidism. Low levels of the mitochondrial transcription factor A (h-mtTFA), aproposed thyroid hormone target, occur in hypothyroid myopathy, and abnormal h-mtTFA turnover may be implicated in mitochondrial alterations in the condition. The decreased responsiveness to adrenergic stimulation and alterations in muscle carbohydrate metabolism may contribute to the impaired ischemic lactate production, weakness, exertional pain, and fatigue occurring in hypothyroidism. Hypothyroidism is associated with changes in myosin, lactate dehydrogenase, and myofibrillar ATPase activity. These changes may underlie the observed slowing of muscle contraction and relaxation. Both protein synthesis and breakdown are reduced in hypothyroidism, resulting in net protein catabolism.

Treatment and Prognosis

The only effective therapy for hypothyroid myopathy is to restore the patient to the euthyroid state. Most patients respond to thyroxine therapy with complete clinical and biochemical recovery; however, some patients require prolonged therapy with thyroxine before they recover from their muscle disorder and some may never regain full function. Serum CK levels correct rapidly with thyroxine replacement therapy. Some patients may develop increased muscle pain and weakness after starting thyroxine replacement, and the short-term addition of corticosteroid therapy may be helpful if this problem arises.

Peripheral Neuropathy

Hypothyroidism may be complicated by the development of entrapment mononeuropathies or a more diffuse peripheral neuropathy.

Entrapment Neuropathy

Evidence of entrapment neuropathy is found in around 35 percent of patients with hypothyroidism. The most common mononeuropathy is carpal tunnel syndrome involving compression of the median nerve at the wrist from deposition of acid mucopolysaccharides in the nerve and surrounding tissues. Surgical decompression for the median nerve entrapment is not usually required in patients with underlying hypothyroidism, as symptoms gradually resolve once euthyroidism is achieved.

Diffuse Peripheral Neuropathy

The peripheral neuropathy of hypothyroidism is usually a relatively mild, predominantly sensory axonal peripheral neuropathy. The symptoms of peripheral neuropathy in patients with hypothyroidism may be masked by more intrusive symptoms. Perhaps for this reason, the reported incidence of peripheral neuropathy has varied widely, ranging from 15 to 60 percent. Damage to small-diameter nerve fibers also occurs, and a minority of patients may have only small-fiber involvement. In patients with a generalized large-fiber neuropathy, the severity appears to correlate with the duration of the disease rather than the degree of the biochemical disorder. Multifocal motor neuropathy, associated with elevated titers of IgM antibodies against GM1 and responsive to intravenous immunoglobulin therapy, has also been associated with Hashimoto thyroiditis.

The pathologic changes described in hypothyroid neuropathy include axonal degeneration, segmental demyelination, and deposition of mucopolysaccharides in the endoneurial interstitium and perineurial sheath. Opinions have varied as to whether axonal degeneration or demyelination is the primary pathologic process, but most reports favor a primary axonal pathology.

Miscellaneous Associated Conditions

Myasthenia Gravis

An association between hypothyroidism and myasthenia gravis has been reported, although this is less common than the association of myasthenia gravis with hyperthyroidism. Myasthenic symptoms can appear before, with, or after the development of hypothyroidism, and the severity of the myasthenia may or may not improve following treatment of the hypothyroidism.

Giant Cell Arteritis and Polymyalgia Rheumatica

An association of giant cell arteritis and polymyalgia rheumatica with hypothyroidism has long been appreciated. Clinicians managing such patients should be careful not to misinterpret the musculoskeletal symptoms of hypothyroidism as an exacerbation of previously diagnosed polymyalgia rheumatica.

Hypothyroidism and Anticonvulsant Therapy

Subclinical hypothyroidism may occur in children with epilepsy treated with valproic acid or carbamazepine therapy. Rare cases of central hypothyroidism believed to be secondary to treatment with oxcarbazepine have been reported. Phenytoin may also impact thyroid function, either by inducing hypothyroidism or by worsening pre-existing hypothyroidism. Hypothyroidism also increases the risk of phenytoin toxicity.

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