Graves’ Disease and the Manifestations of Thyrotoxicosis
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 affective psychosis, and that the incidence was above chance co-occurrence. Thyrotoxicosis appeared to be a precipitant effect of psychosis .
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. 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. 
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 . Electroencephalography  reveals increased fast wave activity, and occasionally bursts of tall spike waves. Several reports describe a severe steroid responsive encephalopathy (Hasshimoto’s Encephalopathy) in patients with Hashimoto's thyroiditis (281). The same syndrome has been described in Graves' Disease . A direct relation to Graves, or thyroiditis, seems probable, but is un-proven. In animals, excess T4 decreases the threshold to convulsive stimuli .
Table 5Neuromuscular Manifestations of Thyrotoxicosis
• Hyperactive reflexes
• Accelerated reflex relaxation
• Thyrotoxic neuropathy (rare)
• Acute thyrotoxic encephalopathy ( rare)
• Seizures (with or without an underlying abnormality)
• Neuropathy secondary to nerve entrapment by lesions of pretibial myxedema
• Corticospinal tract disease with pyramidal tract damage (rare)
• Chorea and athetoid movements (rare)
• Hypokalemic periodic paralysis
• (Myasthenia gravis -- associated)
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 , 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 .
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. 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.  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.
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 11and 12.