Hashimoto's encephalopathy.

We describe a 59-year-old female with Hashimoto's encephalopathy whose presentation was characterized by a subacute onset of confusion, depressed level of consciousness, tremor and pyramidal signs. She was euthyroid on presentation but antithyroid antibodies were elevated. Hashimoto's thyroiditis was confirmed by thyroid biopsy. There was a spontaneous remission of the neurological disorder. Subacute encephalopathy is often investigated with thyroid function tests only. In cases of unexplained encephalopathy, thyroid antibodies and/or thyroid biopsy should be performed to exclude this condition.

Peripheral neuropathy associated with simvastatin.

Four patients are described who developed sensorimotor neuropathy while being treated with simvastatin and had complete or partial resolution of clinical abnormalities after withdrawal of treatment. In one case onset was within days of commencing treatment, but in two cases symptoms did not develop for two years. The electrophysiological and pathological features of the neuropathy were those of axonal degeneration. Clinical evidence of proximal and distal weakness and muscle fasciculations and persistent abnormalities of sensory conduction after recovery suggest the possibility of toxic damage to anterior horn cells and dorsal root ganglia. Thirty eight other cases with symptoms suggestive of peripheral neuropathy have been reported to the Australian Adverse Drug Reactions Advisory Committee, 22 of whom recovered after cessation of treatment; in five cases there was recurrence after re-exposure to the drug. Simvastatin should be considered among the causes of peripheral neuropathy, and the drug should be withdrawn if patients receiving it develop muscle weakness or sensory disturbances.

Endemic cretinism: toward a unifying hypothesis.

Based on our data, the clinical picture of endemic cretinism results from the product of two pathophysiological events. Both events share a common feature, namely iodine deficiency, but act at different points in time. The first event occurs in all cretins and represents the prenatal action of thyroid hormone deficiency on brain development, transmitted vertically from mother to fetus, resulting in the neurological disorder of endemic cretinism. A consistent pattern and intensity of neurological, intellectual, and audiometric deficit is common to and equally present in all types of endemic cretin. The nature of these deficits points to an intrauterine insult to the developing fetal nervous system around the time of the midtrimester. The second event represents the postnatal action of thyroid hormone deficiency on somatic as well as brain development. Whereas previous workers had attributed the differences in the clinical presentation of endemic cretinism to the presence or absence of neurological features (i.e. prenatal hypothyroidism), the distinction between the types of endemic cretin can be related to the length and severity of postnatal thyroid hormone deficiency. Endemic cretins with predominant neurological features have had only transient hypothyroidism in the postnatal period, evidenced by their near normal thyroid function and by a lack of hypothyroid clinical features. By contrast, cretins with marked myxedematous features were characterized by permanent and severe postnatal thyroid hormone deficiency. These cretins, in addition to signs of neurological damage, were typically dwarfed, sexually immature, with marked clinical features of myxedema. This second event, influenced by the thyroid gland's morphologic response to its environment (goiter or thyroid atrophy), dictates the final clinical outcome. In conclusion, our hypothesis states that the clinical expression of endemic cretinism is determined by the sum of two pathophysiologic processes. The first process is fetal hypothyroidism which results in the neurological damage of the disorder and the second process is the duration and magnitude of postnatal hypothyroidism which dictates the final clinical appearance.

The neurology of endemic cretinism. A study of two endemias.

Endemic cretinism is the most severe manifestation of dietary iodine deficiency. Two forms of the syndrome are traditionally described: neurological and myxoedematous. Although this classification highlights the important neurological sequelae of the disorder it implies that myxoedematous cretins have an alternative mechanism. Further, the nature of the neurological deficit associated with both types of endemic cretinism has received scant attention in recent times considering that it remains a common disorder in many parts of the world. The nature and extent of the neurological deficit found in endemic cretinism was investigated in 104 cretins from a predominantly myxoedematous endemia in western China and in 35 cretins from central Java, Indonesia, a predominantly neurological endemia. We found a similar pattern of neurological involvement in nearly all cretins from both endemias, regardless of type (myxoedematous or neurological), and of current thyroid function. Hallmarks of the neurological features included mental retardation, pyramidal signs in a proximal distribution and extrapyramidal signs. Many patients exhibited a characteristic gait. This probably reflected pyramidal and extrapyramidal dysfunction, although joint laxity and deformity were important contributing factors. Other frequently encountered clinical features were squint, deafness, and primitive reflexes. Cerebral computerized tomography (CT) revealed basal ganglia calcification in 15 of 50 subjects. The presence of basal ganglia calcification was confined to cretins with severe hypothyroidism. Otherwise, cerebral CT scanning demonstrated only minor abnormalities which did not contribute to the localization of the clinical deficits. We conclude that the same neurological disorder is present in both types of endemic cretinism reflecting a diffuse insult to the developing fetal nervous system. These clinical findings support the concept of maternal and fetal hypothyroxinaemia, arising from severe iodine deficiency, as the primary pathophysiological event in endemic cretinism. Differences between the two types of cretinism may be explained by continuing postnatal thyroid hormone deficiency in the myxoedematous type, which results in impaired growth, skeletal retardation and sexual immaturity.

Supplementary iodine fails to reverse hypothyroidism in adolescents and adults with endemic cretinism.

The efficacy of supplemental iodine in correcting hypothyroidism in adults and older children with endemic myxedematous cretinism is not known. To investigate this issue we administered im iodized oil (1.5 mL) to 28 hypothyroid endemic cretins (TSH, greater than 5 mIU/L) from western China, aged 14-52 yr (mean = 29 SD = 11 yr). Clinical examination, intelligence testing (Hiskey Nebraska Test of Learning Aptitude and the Griffiths Mental Development Scales), and thyroid function tests were performed before and 6 months after iodine supplementation. We found that signs of thyroid hormone deficiency, dwarfism, and delayed sexual maturity persisted after iodine supplementation. Further, mental disability and other clinical features of neurological damage were not altered by treatment. The mean serum concentration of total T4 before treatment was 75 nmol/L (SD = 40) and fell after iodized oil administration to 56 nmol/L (SD = 29; P less than 0.001). Mean serum levels of TSH before and after iodine showed a paradoxical fall [85 mIU/L (SD = 102) and 46 mIU/L (SD = 46), respectively]. Serum TSH levels decreased into the normal range (less than 5 mIU/L) in only 1 of 28 patients (4%). We conclude that iodine supplementation does not reverse thyroid hormone deficiency or its sequelae in adolescents and adults with endemic myxedematous cretinism. Iodized oil in this age group of patients with endemic cretinism does not appear to be beneficial and should be used with caution.

Endemic cretinism: possible role for thyroid autoimmunity.

Thyroid atrophy, rather than goitre, is a characteristic feature of myxoedematous cretinism but its cause and nature are unknown. In this study, purified IgG fractions of serum from patients with myxoedematous endemic cretinism inhibited thyrotropin-induced DNA synthesis in guineapig thyroid segments in a sensitive cytochemical bioassay. IgG from patients with euthyroid neurological endemic cretinism or from normal subjects did not inhibit thyroid growth. Furthermore, in myxoedematous subjects, the presence of the thyroid-growth-blocking immunoglobulins showed a positive relation with thyroid atrophy found on ultrasound. These findings provide a pathogenic basis for the variable clinical expression of endemic cretinism.

Effects of protracted hypothyroidism on pituitary function and structure in endemic cretinism.

Pituitary function and structure were assessed in 69 endemic cretins from western China. In hypothyroid cretins (TSH greater than 10 mIU/l), CT imaging of the pituitary revealed adenoma in five of 20 (25%) and partially empty sella (PES) in a further eight of 20 (40%). The majority of tumours were microadenomas and showed a relation with higher levels of serum TSH but not with duration of hypothyroidism. Dynamic pituitary testing with TRH and GnRH in four patients with adenoma on CT gave a flat TSH response but significant rises in serum PRL, GH, LH and FSH concentrations. Hyperprolactinaemia (greater than 350 mIU/l) was present in hypothyroid cretins only (13 of 26; 50%) and serum PRL showed a curvilinear relation with serum TSH levels (r = 0.7, P less than 0.0001). Hypogonadism was seen in approximately half the cretins with high PRL levels. Our data suggest that severe protracted thyroid hormone deficiency may result in thyrotrophin adenomas of the pituitary gland. Disturbances of growth, puberty, and sexual function in endemic cretins are explained by the secondary effects of thyroid hormone deficiency on pituitary function.

A comparative study of neurological and myxedematous endemic cretinism in western China.

Endemic cretinism occurs in areas of severe iodine deficiency and is manifested by two major clinical patterns, myxedematous and neurological. The relationship between these types and the factors responsible for the clinical variability are not clear. We examined 69 endemic cretins, aged 4-52 yr, categorized clinically at the beginning of the study into the three traditional types of endemic cretins, myxedematous (n = 25), neurological (n = 15), and the mixed form (n = 29), from a previously unreported endemia in Qinghai Province, China. These patients underwent detailed endocrine and neurological examination, including intelligence assessment using the Hiskey-Nebraska Test of Learning Aptitude or the Griffiths Mental Development Scales, audiometry (in a subset of 37 patients); thyroid function testing and thyroid ultrasonography; and radiology of the skull, hand, and hip. We found that categorization of the cretins into the conventional types did not reflect the pathophysiology of the condition, since an identical pattern and intensity of neurological, intellectual, and audiometric deficits were common to and equally present in all three types of endemic cretins regardless of their thyroid function. Gait disorder (in 99%) and pyramidal signs such as patellar hyper-reflexia (in 91%) were the most common neurological abnormalities. There was no difference in mean intelligence test scores among the three groups [overall mean intelligence score (Hiskey or Griffiths tests), 28.8 +/- 12.8 (SD)]. The differing clinical manifestations of cretinism could be explained by the length and severity of thyroid hormone deficiency. Myxedematous cretins were severely thyroid hormone deficient, and as a result sexually immature, dwarfed, and had retarded skeletal maturity. They had clinical and sonographic thyroid atrophy, rather than goiter. Although neurological cretins were euthyroid, linear growth arrest lines (demonstrated radiologically) in the long bones of these cretins suggested previous hypothyroidism. Furthermore, all cretins were growth retarded when compared with peers of similar age and race. Our data therefore suggest that the different clinical types of endemic cretinism are in fact the same disorder phenotypically modified by the length and severity of postnatal hypothyroidism. The neurological manifestations are interpreted as reflecting the effects of maternal and fetal hypothyroxinemia, secondary to severe iodine deficiency, on the developing nervous system.

Galactosylceramide lipidosis: novel presentation as a slowly progressive spinocerebellar degeneration.

A 34-year-old woman was initially seen because of a progressive neurological disorder suggestive of a spinocerebellar degeneration. This condition had a late infantile onset and was unassociated with visual impairment or dementia. Nerve conduction velocity was severely reduced. A left hemiparesis later developed. A computed tomographic scan revealed multiple periventricular hypodense lesions, suggestive of a leukodystrophy. Sural nerve biopsy demonstrated changes of a chronic demyelinating neuropathy, with inclusions typical of Krabbe's disease. This diagnosis was confirmed by the finding of reduced leukocyte galactocerebrosidase activity.

Anticoagulants and cerebral venous thrombosis.

Three patients with cerebral venous thrombosis are described. The management of this rare condition is discussed and a case is made for using anticoagulant therapy provided the diagnosis is established before cerebral infarction or hemorrhage have occurred.