NEURAL AND MENTAL CHANGES

Neural and mental findings are varied and striking. The patient complains of nervousness or irritability and appears to be restless and fidgety. It sometimes seems impossible for the thyrotoxic patient to remain still for an instant. The tendon reflexes tend to be brisk, and the reflex relaxation time is shortened. The reaction to all sorts of stimuli is distinctly excessive. When asked to sit up, the patient jumps into an upright position. He or she may wish to cooperate but rather overdoes it. The patient is, so to speak, "hypercooperative." Such behavior constitutes an almost pathognomonic pattern. In the clinic, we are familiar with what we call the "thyrotoxic entrance and exit." The thyrotoxic patient hops into the clinic room like a jack-in-the-box, often with staring eyes, sits very quickly in the clinic chair, bolt upright, looks rapidly about the room, and does whatever is asked with pathologic alacrity. His or her exit is equally precipitate. Often emotional instability is combined with this pattern, perhaps to the point of a significant change in personality. The patient is often given to fits of crying, but may have sufficient insight to realize that the crying is pathologic. Some patients become hyperirritable and combative, and this can precipitate accidents or even assaultive behavior.

In some patients, the emotional pattern is that of hypomania or pathologic well-being (euphoria). In others, hyperactivity seems to produce a state of exhaustion, and profound fatigue or asthenia chiefly characterizes the picture. The mind is often very active, and the patient is troubled with insomnia. Rarely, patients develop visual or auditory hallucinations or a frank psychosis. The latter may not completely clear up after thyrotoxicosis has been treated. It is probable that thyrotoxicosis makes manifest an abnormality already present rather than inducing a psychosis de novo.    Brownlie et al reported 18 cases of patients with thyrotoxicosis who had coincident psychotic disorder and concluded that, usually this was an effective psychosis, and that the incidence was above chance co-occurrence.  Thyrotoxicosis appeared to be a precipitant effect of psychosis ^165.1. 

Impairment of intellectual function has been found in patients with untreated hyperthyroidism. It is usually assumed that such abnormalities return to normal with therapy. However, Perild et al.¹⁶⁶ report that ten years after successful therapy of thyrotoxicosis a group of patients manifested abnormal neuropsychological tests, and half had significant intellectual impairment which was apparently permanent. This surprising observation awaits confirmation. Marked increase in fatigability, or asthenia, is often prominent. This increased weariness may be combined with hyperactivity. Patients remark that they are impelled to incessant activity, which, however, causes great fatigue.

A fine, rapid tremor of the outstretched fingers is classically found, and a generalized tremulousness, involving also the tongue, may be evident. Muscle fibrillations are not a usual part of the syndrome, but they may occur in chronic thyrotoxic myopathy. Polyneuropathy has also been reported.¹⁶⁷

More severe neurologic problems also occur during Graves' disease (Table 10-5). Patients who are known to have a convulsive disorder may become more difficult to control with the usual medications, and seizures may appear in patients who have never previously manifested such symptoms.¹⁶⁸ Electroencephalography¹⁶⁸ reveals increased fast wave activity, and occasionally bursts of tall spike waves. 
    Several reports describe a severe steroid responsive encephalopathy in patients with Hashimoto's thyroiditis (168.1). The same syndrome has been described in Graves' Disease^168.2. How directly related to Graves, or thyroiditis, is uncertain.  In animals, excess T4 decreases the threshold to convulsive stimuli.¹⁶⁹

C.H., 52-Year Old Woman: Psychosis with Thyrotoxicosis

This woman appeared in the emergency room  in a confused and agitated state. She refused to talk, but would on occasion answer questions. She appeared to be extremely paranoid and was resistant to offers of help.

She came to the emergency room alone, and after one interview disappeared. She returned a few hours later, again in the same agitated, confused, paranoid, and semimute condition. She stated that she heard voices quoting the Scripture and denied that these voices directed her to harm herself or others, but indicated that she was responsible for the bad problems of the world.

Relatives were contacted and indicated that the patient had been entirely well up to the previous few days, when she had become confused and agitated. It was determined that the patient had worked for more than 20 years and had lost her position about four years previously. She was married and had been separated from her husband intermittently during the past four years. She knew her address, was aware of the month and year but not the date, and was confused about current events.

The BP was 150/80 and the pulse rate 140. The patient was disheveled, thin, and hyperactive. The eyes were normal. Results of routine blood chemistry tests, complete blood count, and urinalysis were negative.

The patient was treated initially with haloperidol (Haldol), 1 mg twice a day, and gradually calmed. The diagnosis of hyperthyroidism was considered and confirmed by an FTI of 19. Antithyroid antibodies were absent.

During treatment, the patient's paranoia and anxiety subsided. She subsequently indicated that there had been a gradual increase in tiredness and weakness, weight loss of 10 lbs, heat intolerance, palpitations, and tremor over one to two years. Previous medical problems included a hysterectomy for fibroids and mild hypertension treated by diuretics. There was no history of previous psychiatric illness in the patient or her family.

On further examination, the thyroid was seen to be enlarged to about 35 g and was diffusely increased in size, without nodules; there was no bruit. Propranolol was added to the therapy, and Haldol was continued. The patient rapidly became psychologically normal and entirely cooperative, and regained control of her personal affairs.

An RAIU test was 49.7%. The patient received 4 mCi of radioactive 131I. After radioactive iodine therapy, the patient was given an antithyroid drug that brought her thyroid hormone levels back to normal. When this drug was discontinued, her FTI returned to 15.7. She was given 3.4 mCi of radioactive iodine again, and PTU was restarted. When last examined, her FTI was in the normal range.

There has been no return of any abnormal psychologic function, and the patient has received no further psychiatric care.

This episode appeared to be an acute psychotic reaction associated with severe hyperthyroidism, occurring in a patient with no previously known psychologic disease. It cleared promptly with medical therapy, including treatment of the hyperthyroidism, and the patient is now apparently well.

C.J., 43-Year-Old Woman: Thyrotoxic Neuropathy

This woman was referred for evaluation  with a history of obesity, hypertension for two years, prominence of the right eye for two years, and thyroid overactivity known for six months. She had gained 50 lbs during the interval preceding the examination because of excess eating. Increasing dyspnea and shortness of breath, present for the previous two years, had become worse in the previous two months. She came to the emergency room because of symptoms of asthma. Examination revealed a pulse rate of 120 and an enlarged heart. There was LVH and strain on the electrocardiogram, and on echocardiogram an enlarged left atrium and a left ventricle with decreased function, especially of the lateral and posterior inferior walls. Thyroid function tests showed a T4 level of 17 ug/dl, an FTI of 16.8, and a T3 level of 357 ng/dl. She received digoxin, 0.25 mg daily, furosemide, 40 mg daily, potassium chloride, and aminophylline.

On examination in the endocrine clinic, the BP was 170/100, and the patient was obese and hyperactive. There was moderate bilateral proptosis and inflamed insertions of the extraocular muscles. There was 22 mm proptosis bilaterally. The thyroid was diffusely enlarged to about 40 g. Neurologic examination showed weakness of ocular motility with diplopia on the left lateral gaze, bilateral nystagmus, marked proximal muscle weakness without fasciculations, and decreased touch, pinprick, and vibration sense in a glove distribution of both arms, the left greater than the right. There was no significant deficit in the feet. Weakness in the left upper extremity was marked. Deep tendon reflexes were absent. The differential diagnosis included Graves' disease, cardiomyopathy and peripheral neuropathy, congestive heart failure, and hypertension.

A neurologic consultant confirmed the neuropathy and noted mild choretic movements of the left hand and arm. Other known causes of neuropathy were excluded. The patient was treated for one month with antithyroid drugs and then given 2.7 mCi 131I. Because of continued hyperthyroidism, the patient was retreated with 3.2 mCi 131I seven months after the initial treatment. Three months later the FTI was normal at 10.4, and there were no symptoms or signs of congestive heart failure. Some decreased strength and clumsiness of the left hand persisted. The diplopia and proptosis were unchanged. The neuropathy in the hands had decreased, and the patient was euthyroid.

This patient exhibited profound cardiomyopathy and skeletal myopathy, choreiform movements, and peripheral neuropathy, all apparently related to severe thyrotoxicosis. She improved rapidly with appropriate treatment of the thyrotoxicosis.

The tremor of Parkinsonism is greatly intensified during thyrotoxicosis. Signs and symptoms of cerebellar disease or pyramidal tract lesions have been seen.^170,171 Rarely, patients manifest extreme restlessness, disorientation, aphasia, grimacing, chorioathetoid movements, symptoms suggestive of encephalitis,¹⁷² or episodes of hemiparesis or bulbar paralysis. These symptoms clear up completely after restoration of metabolism to normal. No definite lesions have been found in the brain. Rarely, polyneuropathy has been severe enough to cause paraplegia.¹⁷³

Most of the biochemical actions of thyroid hormone on the brain are related to developmental functions rather than function in the adult. These actions have recently been reviewed by Bernal (173a) .  All three forms of thyroid hormone receptor are expressed in the brain, especially in neurons.    Genes regulated by thyroid hormone include  myelin basic protein, mitochondrial genes such as cytochrome C oxidase, neurotrophins and their receptors, including NGF and trkA, cytoskeletal components such as tubulin, transcription factors such as NGF1a, extracellular matrix proteins, and adhesion molecules such as NCAM, genes involved in intracellular signaling such as RC3/neurogranin, and genes expressed in the cerebellum such as pcp-2. Interestingly, the brain of a thyrotoxic human subject does not have an elevated consumption of oxygen. Sensenbach et al.¹⁷⁴ found the cerebral blood flow to be increased, the cerebral vascular resistance decreased, arteriovenous (AV) oxygen difference decreased, and oxygen consumption unchanged in thyrotoxicosis. Reciprocal changes occurred in myxedema, and all reverted to normal after therapy. 
    Curiously, brain size was shown to decrease significantly during treatment of the hyperthyroid patients, and ventricular size increased.  This remarkable change is of uncertain cause but may involve osmotic regulation (174a). 

Although it is possible that some of the central nervous system irritability is a manifestation of elevated sensitivity to circulating epinephrine, this contention has not been proved. Epinephrine levels and catecholamine excretion are actually not elevated, but propranolol, presumably acting by inhibition of alpha-adrenergic sympathetic activity, certainly reduces anxiety and tremulousness in a very useful manner. The clinical applications of these findings are discussed in Chapters 11 and 12.

MUSCLES

The muscular symptoms vary from mild myasthenia to profound muscular weakness and atrophy, especially of proximal muscle groups. This weakness forms the basis of a useful clinical test. If a thyrotoxic patient seated in a chair is asked to hold one leg out straight and in a horizontal position, he or she may be able to do so for 25 - 30 seconds only; normal persons can maintain such a position for 60 - 120 seconds. Toe standing and step climbing may also bring out muscle weakness that is otherwise not so apparent. In the more extreme forms of muscular involvement, there is not only weakness but also atrophy. Wasting of the temporals and interossei may be noted in a considerable number of patients, and in a few, wasting of all skeletal muscles. This wasting may go so far as to bear a close resemblance to progressive muscular atrophy; occasionally the myopathy may shade into the picture of a polymyositis. Muscle cell necrosis and lymphocyte infiltration may be visible histologically, but usually are not found even when the symptoms of weakness are severe.¹⁷⁵ Tremor, which is usually present, is ascribed to altered neural function. Fasciculations are unusual.

The speed of both tension development¹⁷⁶ and relaxation of the muscles is increased, so that the reflex time is shortened. The electromyogram is normal in most instances but may occasionally resemble that of muscular dystrophy.¹⁷⁷ Work efficiency, measured in terms of the calories of heat produced while performing a given amount of work, has been reported to be both decreased¹⁷⁸ and normal. The question of metabolic efficiency of hyperthyroid muscle has been revisited by Erkintalo et al, using phosphorus-31 MRI spectroscopy, finding that toxic muscle required more energy to function than normal, presumably because of additional ATP-consuming mechanisms ^178.1. Creatine excretion is increased. The muscles have decreased ability to take up creatine, produced in the liver, from the blood^179-180.    Creatinine excretion is initially increased by the general catabolism of hyperthyroidism, but as muscle mass diminishes, creatinine excretion in the urine is depressed.

Myasthenia gravis may simulate thyrotoxicosis, and vice versa. ¹⁸³ It has been reported that neostigmine both strengthens the muscles in thyrotoxic myopathies and is without effect. Certainly, the response is small in comparison with the immediate and striking correction of weakness seen in myasthenia gravis. Thyrotoxicosis may rarely ameliorate myasthenia gravis, but typically it is accentuated by thyrotoxicosis and is also worsened by myxedema. The close relationship between these two diseases is apparent in the observation that thyrotoxicosis occurs in 3% of patients with myasthenia gravis. The pathogenic anti-acetylcholine receptor antibodies that occur in myasthenia gravis are clearly comparable to the anti-TSH receptor antibodies found in Graves' disease. In addition, it has been found that TG and acetyl- cholinesterase share epitopes recognized by B cells.  It is, however, uncertain that this plays any role in the pathogenesis of muscle disease in Graves' patients.

Periodic paralysis is precipitated and worsened by thyrotoxicosis.¹⁸⁴ This relationship has been extensively studied in Japan, where it is a familiar syndrome, particularly in men. The paralysis is usually associated with and due to hypokalemia. While the exact mechanism is not known, the hypokalemia is believed to be caused by a shift to the intracellular compartment. It has been demonstrated that thyrotoxicosis augments K+ uptake and release from cells. Experimental T4 treatment augments synthesis of membrane Na+-K+ activated ATPase. The episodes of paralysis tend to be infrequent and sporadic, but most commonly occur after a meal, following exercise, or start during sleep, and can be induced by administration of glucose and insulin. The onset following meals or exercise presumably relates to rapid K+ uptake by cells. Episodes last from minutes to hours, usually involving peripheral muscles, but can cause paralysis of the diaphragm and affect the heart. Serious episodes can be associated with extensive muscle cell damage and necrosis, EKG abnormalities such as ST and T wave changes, PVCs, first degree heart block, prolonged Q, T intervals, and even ventricular fibrillation.¹⁸⁵

Potassium treatment has some protective effect, and quickens recovery from attacks. Propranolol, for reasons not entirely clear, has prophylactic action. Therapy of the thyrotoxicosis almost always causes the rapid, and permanent disappearance of the syndrome.

Myotonia congenita and myotonia dystrophic do not occur with increased frequency with thyrotoxicosis.

SKELETON AND CALCIUM METABOLISM

Roentgenographic examination of the bones frequently discloses evidence of decalcification. Microdensitometry demonstrates this condition at all ages and in both sexes.^186-188  Patients with even mild increases in thyroid hormone lose bone mass, ¹⁸⁹ especially if postmenopausal and not receiving estrogen therapy.  Those with a history of thyrotoxicosis extending over a number of years may have osteoporosis that is severe and premature. Fractures are uncommon, with the most frequent being collapsed vertebra in a chronically thyrotoxic postmenopausal woman. Skeletal mass is augmented after therapy.^187-188 Treatment restores the density in younger patients, but not usually in the elderly.¹⁸⁷  Although most attention has been made to the effects of thyroid hormone on bone density in women, it is not surprising to know that thyroid hormone excess also has a mild deleterious effect in males (188a). A meta analysis of 289 published studies on the effect of hyperthyroidism causing bone fragility found that hyperthyroid patients had decreased bone mineral density and increased fracture risk.   The bone mineral density tended to return to normal after therapy (Vestergaard, P; Mosekilde, L.          Hyperthyroidism, bone mineral, and fracture risk – a meta-analysis.      Thyroid   13           585                2003).

Periarthritis of the shoulder (subacromial bursitis) is occasionally associated with thyrotoxicosis. Linear bone growth may be accelerated in children. The time of epiphyseal closure may be accelerated in children, and bone age may exceed chronologic age.

Thyrotoxicosis results in an accelerated turnover of bone calcium and collagen. ^197,190  TRa1, TRb1, and TRb2 proteins are expressed in human osteoblast cells and strongly in human bone marrow stromal cells.  Endogenous receptors in these cells are functional in in vitro test systems.  The specific function in vivo is unclear(190.1) .As described in the section on pathology, the histologic picture of bones from the thyrotoxic patient may suggest osteitis fibrosa with increased osteoclastic activity, fibrosis, and an increased number of osteoblasts.¹⁵⁶ Histomorphometric evaluations with tetracycline labelling demonstrates accelerated bone resorption and formation, both in spontaneous hyperthyroidism and in women treated with excess thyroid hormone. ^154,190,197 In bone biopsy specimens the thin trabeculae of osteoporosis are seen.¹⁵⁶ The serum calcium level is usually normal, but may be elevated sufficiently to produce nausea and vomiting¹⁹¹ and, rarely, renal damage.^192,193 It may be made clinically evident when thyrotoxic patients become relatively immobile, for example at bed rest during illness. In contrast to what occurs in hyperparathyroidism, the hypercalcemia can usually be corrected partially or totally by the administration of glucocorticoids,¹⁹⁴ but these have not been effective in all cases.¹⁹⁵ Phosphorus administration also lowers the concentration of calcium in serum and urine to normal.¹⁹⁶ The exchangeable calcium pool is remarkably increased.¹⁹⁷ Serum osteocalcin is increased in parallel with hormone levels.¹⁹⁹ The alkaline phosphatase level may be elevated, with a pattern showing the normal equal distribution of bone and liver isoenzymes. The changes in calcium and alkaline phosphatase correlate with serum T3 levels.²⁰⁰ After therapy, the alkaline phosphatase level tends to increase, and bone isoenzyme becomes predominant, probably due to skeletal repair.¹⁹⁹

Fecal and urinary calcium excretion is greatly augmented, and it is remarkable that renal stones are rarely formed. This is because there is a concomitant increase in excretion of colloids that stabilize the calcium. Urinary hydroxyproline and pyridium cross-link excretion are increased and fall to normal after therapy.¹⁹⁰ Serum carboxy-terminal-1-telopeptide and serum osteocalcin levels and urinary osteocalcin secretion are increased and return to normal with therapy. ^{198,202.1,202.2}

The serum phosphorus level is in the normal range or depressed. Renal phosphorus resorption is in the normal range or elevated.^193,194 Although some of the observations suggest the presence of hyperparathyroidism, it is most likely that the changes actually reflect the direct metabolic effects of thyroid hormone. The parathyroid glands are histologically normal. In fact, parathyroid hormone (PTH) levels tend to be suppressed in hyperthyroidism, apparently in response to the elevated calcium levels;²⁰¹ 1,25-dihydroxyvitamin D3 levels are likewise about 40% below normal.²⁰²

The increased fractional tubular phosphate reabsorption characteristic of hypoparathyroidism may also occur in thyrotoxicosis, probably because of reduced PTH levels. In one reported study,¹⁹² urinary phosphorus excretion was depressed after calcium infusion. Thus, a normal response was obtained rather than that found in hyperparathyroidism.

The hypercalcemia appears to be a direct manifestation of thyroid hormone action on bone metabolism, ^201,202 and calcium absorption from the intestine is usually reduced.²⁰³ Both catabolism and anabolism of bone are accelerated. Negative calcium balance can sometimes be corrected by administration of calcium, an observation that perhaps should be given more attention in the management of thyrotoxic patients. Hypercalcemia can be corrected by propranolol therapy in some patients.²⁰⁴ Bone turnover can be reduced by pamidronate and by calcitonin, which may therefore have a useful role in reducing thyrotoxicosis-induced osteopenia.^205,205.1

Two exceptional cases have been reported with coincident thyrotoxicosis and hypercalcemia with elevated PTH levels. Treatment of thyrotoxicosis eliminated all abnormalities, for reasons unknown.²⁰⁶