[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.166.74.94. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Neurocognitive Deficits in Hypothyroid Adults*
Neurocognitive Deficits in Hypothyroid Adults*
1.
Kamil  RJoffe  RT Neuroendocrine testing in electroconvulsive therapy. Psychiatr Clin North Am. 1991;14961- 970
2.
Nemeroff  CBLoosen  PT Handbook of Clinical Psychoneuroendocrinology.  New York, NY Guilford Press1987;
3.
Pharoah  PODButtfield  IHHetzel  BS Neurological damage to the fetus resulting from severe iodine deficiency during pregnancy. Lancet. 1971;1308- 310Article
4.
Alves  CEidson  MEngle  HSheldon  JCleveland  MM Changes in brain maturation detected by magnetic resonance imaging in congenital hypothyroidism. J Pediatr. 1989;115600- 603Article
5.
Bathia  VPoptani  HGupta  RKGujral  RB MRI of the brain in sporadic congenital hypothyroidism (SCH) and endemic iodine deficiency cretinism. Pediatr Res. 1993;33(suppl)593
6.
Siragusa  VBoffelli  SWeber  G  et al.  Brain magnetic resonance imaging in congenital hypothyroid infants at diagnosis. Thyroid. 1997;7761- 764Article
7.
Fisher  DALehman  HLackey  C Placental transport of thyroxine. J Clin Endocrinol Metab. 1964;24393- 400Article
8.
Legrand  J Morphogenetic action of thyroid hormones. Trends Neurosci. 1979;2234- 236Article
9.
Ruis-Marcos  ASanchez-Toscano  FEscobar del Rey  FMorreale de Escobar  G Severe hypothyroidism and the maturation of the rat cerebral cortex. Brain Res. 1979;162315- 329Article
10.
Klein  AHMeltzer  SKenney  FN Improved prognosis in congenital hypothyroidism treated before age 3 months. J Pediatr. 1972;81912- 915Article
11.
Raiti  SNewns  GH Cretinism: early diagnosis and its relation to mental prognosis. Arch Dis Child. 1971;46692Article
12.
Smith  DWBlizzard  RMWilkins  L The mental prognosis in hypothyroidism. Pediatrics. 1957;191011- 1022
13.
Hébert  RLaureau  EVanasse  M  et al.  Auditory brainstem response (ABR) audiometry in congenitally hypothyroid children under early replacement therapy. Pediatr Res. 1986;20570- 573Article
14.
Vanderschueren-Lodeweyckx  MDebruyne  FDooms  LEggermont  EEekels  R Sensorineural hearing loss in sporadic congenital hypothyroidism. Arch Dis Child. 1983;58419- 422Article
15.
Glorieux  JDussault  JHLetarte  JGuyda  HMorissette  J Preliminary results on the mental development of hypothyroid children detected by the Quebec Screening Program. J Pediatr. 1983;10219- 22Article
16.
Money  J Psychologic studies in hypothyroidism. Arch Neurol. 1956;76296
17.
Rovet  JWalker  WBliss  BBuchanan  LEhrlich  R Long-term sequelae of hearing impairment in congenital hypothyroidism. J Pediatr. 1996;128776- 783Article
18.
Walker  WBuchanan  LRovet  J Selective reading impairment in children with congenital hypothyroidism [abstract]. J Int Neuropsychol Soc. 1996;242
19.
Wolter  RNoel  PDeCock  P  et al.  Neuropsychological study in treated thyroid dysgenesis. Acta Paediatr Stockh. 1979;227(suppl)41- 46Article
20.
Kooistra  Lvan der Meere  JJVulsma  TKalverboer  AF Sustained attention problems in children with early-treated congential hypothyroidism. Acta Paediatr. 1996;85425- 429Article
21.
New England Congenital Hypothyroidism Collaborative, Effects of neonatal screening for hypothyroidism: prevention of mental retardation by treatment before clinical manifestations. Lancet. 1981;21095- 1098
22.
Rovet  JEhrlich  RMSorbara  D Intellectual outcome in children with fetal hypothyroidism. J Pediatr. 1987;110700- 704Article
23.
Tillotson  SLFuggle  PWSmith  IAdes  AEGrant  DB Relation between biochemical severity and intelligence in early treated congenital hypothyroidism: a threshold effect. BMJ. 1994;309440- 445Article
24.
Rovet  J Neurodevelopmental outcome in infants and preschool children following newborn screening for congenital hypothyroidism. J Pediatr Psychol. 1992;17187- 213Article
25.
Rovet  JEhrlich  RMDonner  E Long-term neurodevelopmental correlates of treatment adequacy in screened hypothyroid children. Pediatr Res. 1993;33(suppl)S91
26.
Rovet  JAlvarez  M Thyroid hormone and attention in school-age children with congenital hypothyroidism. J Child Psychol Psychiatry. 1996;37579- 585Article
27.
Rovet  JAlvarez  M Thyroid hormone and attention in congenital hypothyroidism. J Pediatr Endocrinol Metab. 1995;963- 66
28.
Rovet  JEhrlich  RM Long-term effects of L-thyroxine therapy for congenital hypothyroidism. J Pediatr. 1995;126380- 386Article
29.
Weiss  REStein  MATrommer  BRefetoff  S Attention-deficit hyperactivity disorder and thyroid function. J Pediatr. 1993;123539- 545Article
30.
Hauser  P The thyroid receptor beta gene and resistance T thyroid hormone: implications for behavioral and brain research. Psychoneuroendocrinology. 1994;19iii- viiArticle
31.
Hauser  PZametkin  AJMartinez  P  et al.  Attention deficit-hyperactivity disorder in people with generalized resistance to thyroid hormone. N Engl J Med. 1993;328997- 1001Article
32.
Ciaranello  RD Attention deficit-hyperactivity disorder and resistance to thyroid hormone: a new idea? N Engl J Med. 1993;3281038- 1039Article
33.
Elia  JGulotta  CRose  JR  et al.  Thyroid function attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1994;33169- 172Article
34.
Stein  MAWeiss  RERefetoff  S Neurocognitive characteristics of individuals with resistance to thyroid hormone: comparisons with individuals with attention-deficit hyperactivity disorder. J Dev Behav Pediatr. 1995;16406- 411
35.
Weiss  REStein  MADuck  SC  et al.  Low intelligence but not attention deficit hyperactivity disorder is associated with resistance to thyroid hormone caused by mutation R316H in the thyroid hormone receptor β gene. J Clin Endocrinol Metab. 1994;781525- 1528
36.
Maenpaa  JLiewendahl  K Peripheral insensitivity to thyroid hormones in a euthyroid girl with goiter. Arch Dis Child. 1980;55207- 212Article
37.
Glorieux  JDussault  JHMorissette  JDesjardins  MLetarte  JGuyda  M Follow-up at ages 5 and 7 years on mental development in children with hypothyroidism detected by Quebec Screening Program. J Pediatr. 1985;107913- 915Article
38.
New England Congenital Hypothyroidism Collaborative, Characteristics of infantile hypothyroidism discovered on infantile screening. J Pediatr. 1984;104539- 544Article
39.
New England Congenital Hypothyroidism Collaborative, Neonatal hypothyroidism screening: status of patients at 6 years. J Pediatr. 1986;107915- 919
40.
Money  JClarke  FCBeck  J Congenital hypothyroidism and IQ increase: a quarter century follow-up. J Pediatr. 1978;93432- 434Article
41.
Goodman  JF Medical diagnosis and intelligence levels in young mentally retarded children. J Ment Defic Res. 1977;21205
42.
Goodman  JFCameron  J The meaning of IQ constancy in young retarded children. J Gen Psychol. 1987;132109Article
43.
Spreen  OTupper  DRisser  ATuokko  HEdgell  D Human Developmental Neuropsychology.  New York, NY Oxford University Press Inc1984;
44.
Pharoah  PODConnolly  KJ Relationship between thyroxine levels during pregnancy and memory function in childhood. Early Hum Dev. 1991;2543- 51Article
45.
Pharoah  PODConnolly  KJHetzel  BEkins  R Maternal thyroid function and motor competence in the child. Dev Med Child Neurol. 1981;2376- 82Article
46.
Pharoah  PODConnolly  KJEkins  RPHarding  AG Maternal thyroid hormone levels during pregnancy and the subsequent cognitive and motor performance of the children. Clin Endocrinol (Oxf). 1984;21265- 270Article
47.
Connolly  KJPharoah  POD Iodine deficiency, maternal thyroxine levels in pregnancy and developmental disorders in children. DeLong  FRRobbins  JCondliffe  PGeds.Iodine and the Brain New York, NY Plenum Publishing Corp1989;317- 331
48.
Kooistra  LLaane  CVulsma  TSchellekens  JMvan der Meere  JJKalverboer  AF Motor and cognitive development in children with congenital hypothyroidism: a long-term evaluation of the effects of neonatal treatment. J Pediatr. 1994;124903- 909Article
49.
Rovet  JFEhrlich  RNSorbara  DL Intellectual outcome in children with fetal hypothyroidism. J Pediatr. 1987;110700- 704Article
50.
Crown  S Notes on an experimental study of intellectual deterioration. BMJ. 1949;2684- 685Article
51.
Haggerty  JJEvans  DLPrange  AJ Organic brain syndrome associated with marginal hypothyroidism. Am J Psychiatry. 1986;143785- 786
52.
Mennemeier  MGarner  RDHeilman  KM Memory, mood and measurement in hypothyroidism. J Clin Exp Neuropsychol. 1993;15822- 831Article
53.
Osterweil  DSyndulko  KCohen  SN  et al.  Cognitive function in non-demented older adults with hypothyroidism. J Am Geriatr Soc. 1992;40325- 335
54.
Whybrow  PCPrange  AJTreadway  CR Mental changes accompanying thyroid gland dysfunction: a reappraisal using objective psychological measurement. Arch Gen Psychiatry. 1969;2048- 63Article
55.
Peabody  CAThornton  JETinklenberg  JR Progressive dementia associated with thyroid disease. J Clin Psychiatry. 1986;47100
56.
Clarnette  RMPeterson  CJ Hypothyroidism: does treatment cure dementia? J Geriatr Psychiatry Neurol. 1994;723- 27
57.
Jeste  DVEastham  JHLacro  JPGierz  MField  MGHarris  MJ Management of late-life psychosis. J Clin Psychiatry. 1996;57(suppl 3)39- 45
58.
Livingston  EHHersman  JMSawin  CTYoshikawa  TT Prevalence of thyroid disease and abnormal thyroid tests in older hospitalized and ambulatory persons. J Am Geriatr Soc. 1987;35109- 114
59.
Freemon  FR Evaluation of patients with progressive intellectual deterioration. Arch Neurol. 1976;33658- 659Article
60.
Smith  JSKiloh  LG The investigation of dementia: results of 200 consecutive admissions. Lancet. 1981;1824- 827Article
61.
Fox  JHTopel  JLHuckman  MS Dementia in the elderly: a search for treatable illness. J Gerontol. 1975;30557- 564Article
62.
Freemon  FRRudd  SM Clinical features that predict potentially reversible progressive intellectual deterioration. J Am Geriatr Soc. 1982;30449- 451
63.
Cummings  JBenson  DFLoVerma  S  Jr Reversible dementia: illustrative cases, definition and review. JAMA 1980;2432434- 2439Article
64.
Clarfield  AM The reversible dementias: do they reverse? Ann Intern Med. 1988;109476- 486Article
65.
Larson  EBReifler  BVFeatherstone  HJEnglish  DR Dementia in elderly outpatients: a prospective study. Ann Intern Med. 1984;100417- 423Article
66.
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
67.
Barona  AReynolds  CRChastani  R A demographically based index of premorbid intelligence for the WAIS-R. J Consult Clin Psychol. 1984;52885- 887Article
68.
Blair  JRSpreen  O Predicting premorbid IQ: a revision of the national adult reading test. Clin Neuropsychol. 1989;3129- 136Article
69.
Johnstone  BCallahan  CDKapila  CJBouman  DE The comparability of the WRAT-R Reading Test and NAART as estimates of premorbid intelligence in neurologically impaired patients. Arch Clin Neuropsychol. 1996;11513- 519Article
70.
Kraken  DAGur  RCSaykin  AJ Reading on the Wide Range Achievement Test-Revised and parental education as predictors of IQ: comparisons with the Barona equation. Arch Clin Neuropsychol. 1995;10147- 157Article
71.
Wiens  ANBryan  JECrossen  JR Estimating WAIS-R FSIQ from National Adult Reading Test-Revised in normal subjects. Clin Neuropsychol. 1993;770- 84Article
72.
Wolff  ML Reversible intellectual impairment: an internist's perspective. J Am Geriatr Soc. 1982;30647- 650
73.
Geschwind  N Late changes in the nervous system: an overview. Stein  DGRosen  JJButters  Neds.Plasticity and Recovery of Function in the Central Nervous System Orlando, Fla Academic Press Inc1974;467- 471
74.
Ritter  FN The effects of hypothyroidism upon the ear, nose, and throat: a clinical and experimental study. Laryngoscope. 1967;771427- 1479Article
75.
Meyerhoff  WL Hypothyroidism and the ear: electrophysiological, morphological and chemical considerations. Laryngoscope. 1979;89(suppl 19)1- 25Article
76.
Glorig  ANixon  J Hearing loss as a function of age. Laryngoscope. 1962;721596- 1610Article
77.
Debruyne  FVanderschueren-Lodeweyckx  MBastijns  P Hearing in congenital hypothyroidism. Audiology. 1983;22404- 409Article
78.
Malloy  PFCummings  JLCoffey  CE  et al.  Cognitive screening instruments in neuropsychiatry: a report of the committee on research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci. 1997;9189- 197
79.
Jacobson  NSTrau  P Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. J Consult Clin Psychol. 1991;5912- 19Article
80.
Sawrie  SMChelune  GJNaugle  RILüders  HO Empirical methods for assessing meaningful neuropsychological change following epilepsy surgery. J Int Neuropsychol Soc. 1996;2556- 564Article
Review Article
July 13, 1998

Neurocognitive Aspects of Hypothyroidism

Author Affiliations

From the Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle.

Arch Intern Med. 1998;158(13):1413-1418. doi:10.1001/archinte.158.13.1413
Abstract

Hypothyroidism is associated with significant neurocognitive deficits that develop across the life span. This article discusses the patterns of cognitive deficits associated with congenital and adult-onset hypothyroidism. A review of the extant literature shows that the successful treatment of clinically evident thyroid gland hypofunction, resulting in a return to euthyroidism in both infants and adults, may be associated with only partial and typically inconsistent patterns of recovery of overall neurocognitive function. In addition to demonstrating different patterns of cognitive impairments, patients with congenital and acquired adult-onset hypothyroidism have variable responses to thyroid replacement therapy, which increases the risk of higher neurocognitive morbidity associated with congenital hypothyroidism. An evaluation of the commonly held view that hypothyroid dementia is an imminently reversible condition is only partially supported by the medical literature, which is fraught with methodological and conceptual shortcomings. I offer some recommendations for addressing the cognitive and behavioral management concerns of individuals with clinical hypothyroidism.

Many primary endocrine disorders have notable effects on cognition. Patients with a wide range of thyroid gland abnormalities often present with combined emotional and cognitive symptoms. Unfortunately, cognitive impairments associated with thyroid gland hypofunction are often overlooked by clinicians when patients do not overtly complain of changes in their neurocognitive status. Such errors of omission would be minimized if clinicians became more knowledgeable about the patterns of cognitive deficits that accompany hypothyroidism. The early recognition of conditions such as dementia, depression, and other neuropsychiatric abnormalities known to be associated with hypothyroidism are almost exclusively dependent on the routine and systematic assessment of cognition. Herein, I review the major neurocognitive deficits associated with hypothyroidism. Primarily, I will focus on the effects of clinical (rather than subclinical) hypothyroidism, the differential patterns of cognitive deficits in congenital and acquired hypothyroidism, and the impact of thyroid pharmacotherapy on the cognitive status of patients with hypothyroidism.

Although hypothyroidism has long been known to be associated with profound depression, this review will not address that issue because excellent reviews of hypothyroidism and depression are available elsewhere.1,2

CONGENITAL HYPOTHYROIDISM

The thyroid hormone is important to the functional development and maturation of the central nervous system; the association between the absence of thyroid hormones and congenital hypothyroidism and profound mental retardation has been recognized for more than a century. It is thought that the administration of supplementary iodine prior to conception in human mothers is effective in preventing the significant neuropsychological effects of thyroid gland dysfunction.3 Results from magnetic resonance imaging scans of cerebral morphologic features and myelination in infants diagnosed as having congenital hypothyroidism through neonatal screening reveal findings ranging from delayed and abnormal white matter myelination patterns4,5 to normal brain myelination and circumvolutions.6 The latter finding of no detectable morphological brain abnormalities has been attributed to the lingering neuroprotective effects of maternal thyroid hormones introduced to fetal transport by the placenta. However, there is evidence7 that very little thyroxine actually crosses the placental barrier, compelling the fetus to depend almost exclusively on its own thyroid gland, which, if underdeveloped, constitutes an imminent risk for congenital hypothyroidism. The story, however, is still not that simple: evidence from animal studies8,9 suggests a critical perinatal period during which deficiencies in thyroid gland function result in permanent morphological, histopathological, and behavioral abnormalities. While this window of opportunity has not been clearly delineated in humans, there are reports of normal intellectual function in patients with hypothyroidism who underwent thyroid replacement therapy (TRT) prior to 3 or even 7 months of age.1012 Despite these findings, the lack of a comprehensive evaluation of a wide variety of cognitive domains other than general intelligence (eg, attention, language, learning and memory skills) necessitates restraint in inferring that early intervention with TRT results in normal neurocognitive functioning. Evoked potential studies of auditory brainstem responses in children with congenital hypothyroidism who received postnatal TRT as early as 3 weeks of age showed significant audiometric deficits well into midchildhood.13 Consistent with these audiometric deficits are findings of hearing impairment14 and expressive language deficits,15 including difficulties with naming,16 in young children, which together call for more a comprehensive assessment of neurocognitive functioning across a broad range of domains in children with congenital hypothyroidism. Recent retrospective Canadian data17 report mild binaural conduction and sensorineural hearing loss in 20% of children with congenital hypothyroidism identified at neonatal screening, with strong indications that early treatment (within 2 weeks after birth) may reduce the incidence of hearing impairment. Although the children with congenital hypothyroidism and hearing impairment scored in the normal range on most general language tests, subtle impairments in their auditory speech-sound discriminations17 and reading skills18 were evident. Psychometric evidence of average IQ scores in children with hypothyroidism is not necessarily evidence that those children have normal cognitive abilities. For example, a Belgian study19 found notable deficits in the attention spans and cognitive information processing skills of children whose average IQ was a normal 100.1 (range, 87.6-113.8).

Pediatric hypothyroidism tends to be associated with attention deficits. While children with congenital hypothyroidism have demonstrated notable neurocognitive impairments based on objective cognitive tests designed to assess attention span20 (rather than on the basis of observer ratings of distractibility and inattention), it appears that numerous other factors, including overall treatment efficacy,21 disease onset,22 severity,23 and duration,24 as well as levels of thyroxine and thyrotropin,2528 contribute to the clinical manifestation of the attention deficits. A recent study29 of children diagnosed as having attention-deficit/hyperactivity disorder reported an unexpectedly higher incidence of hypothyroidism than hyperthyroidism, the latter indicated by resistance to thyroid hormone (RTH) disorder.3032 Resistance to thyroid hormone is, in fact, rare in community-based samples of individuals with attention-deficit/hyperactivity disorder.33 Although it appears that the profile of neurocognitive deficits associated with RTH disorder is not entirely consistent with that exhibited in attention-deficit/hyperactivity disorder,34,35 we are still far from understanding exactly how the neurocognitive deficits related to RTH disorder differ from children treated for congenital hypothyroidism, especially given the fact that some individuals with RTH disorder appear to be mildly hypothyroid.36

FOLLOW-UP STUDIES IN CONGENITAL HYPOTHYROIDISM

At least 2 study groups in North America, the Quebec Screening Program15,37 and the New England Congenital Hypothyroidism Collaborative,21,38,39 have reported prospective findings based on neonatal screening and TRT indicating that 10% to 15% of individuals with congenital hypothyroidism were resistant to treatment in their respective studies. These patients had IQ scores in the borderline impaired range or lower by the time they entered school (ie, at ages 5-7 years). In contrast, a 26-year follow-up study40 showed dramatic increases (at least 20 points) in the IQ test scores of 15% of individuals with congenital hypothyroidism who were assessed at 3 separate periods from childhood (ie, at ages 5-6 years) through adulthood. This finding was interpreted as evidence "that intellectual growth in treated congenital hypothyroidism may continue beyond the traditionally expected end point, well into adulthood."40 Unfortunately, the authors of the study failed to concede a potential difficulty that arises when predictions and assessments of changes in scores from baseline pediatric IQ tests are made: while initial test scores may be related to the condition and severity of the disease,41 they are not always accurate predictors of later cognitive (ie, IQ) performance in individuals both with and without mental retardation.42,43 Evidence from 4-year longitudinal studies of language and auditory processing skills in young children with congenital hypothyroidism shows essentially no difference in the expressive language skills between 7-year-olds with and without hearing impairments,17 although the cohorts with hearing impairments continued to exhibit receptive language and reading deficits on serial assessment.17

In a cross-cultural prospective study of nonverbal short-term memory span and pictorial serialposition memory in teenagers from Papua New Guinea (most of whom had an iodine deficiency and mothers who had received supplementary iodine during pregnancy),44 measured levels of total maternal thyroxine were not significantly associated with simple short-term memory span when the cohorts were 14 to 15 years old. However, on testing 2 year later, levels of total maternal thyroxine were significantly associated with more complex reverse order memory span operations and moderately associated (r=0.39) with serial position memory. This group of teenagers was also administered serial manual dexterity tests,4547 with results indicating consistent associations between total thyroxine levels and manual dexterity over time. Evidence of impairments in the development of motor skills in children with congenital hypothyroidism appears to be consistent with other follow-up studies.48 In another longitudinal follow-up study in which children with congenital hypothyroidism were assigned to groups on the basis of their skeletal maturity (an indicator of uterine hypothyroidism),49 it was found that beginning at ages 2 to 5 years, fine motor and visuoperceptual skills were significantly depressed in those with delayed skeletal maturity. Relative deficits in expressive and receptive language abilities emerged at ages 4 through 5 years, at which time cognitive assessments also indicated gross intellectual difficulties. Those authors concluded that while early detection and treatment of congenital hypothyroidism may be useful in preventing mental retardation, it may not be as effective in preventing other neurocognitive deficits.

In summary, untreated congenital hypothyroidism causes profound mental retardation characterized by severe cognitive deficits. Although early identification and treatment of congenital hypothyroidism has been known to improve scores on formal tests of intelligence, there is still evidence of neurocognitive deficits in attention, visuospatial processing, motor dexterity, and language comprehension skills that may persist through late childhood and in some cases adolescence. In addition, with the exception of studies4547 that found a consistent association between total thyroxine levels and motor dexterity over time, improvements in neurocognitive abilities do not generally appear to follow a predictable course, even with continued return to euthyroidism.

NEUROCOGNITIVE DYSFUNCTION IN ADULTS WITH HYPOTHYROIDISM

The onset of primary clinical hypothyroidism in adults has a variety of adverse effects on adaptive neurocognitive functioning. Table 1 shows some of the major patterns of cognitive deficits that have been documented in association with hypothyroidism.

Unfortunately, most of the published reports on neuropsychological functioning in adults with hypothyroidism are based on the assessment of only limited aspects of cognitive domains. For instance, there is a paucity of extant research on sustained and selective visual attention, speed of visual information processing, abstract concept formation and complex problem-solving abilities, academic achievement skills, tactile perception, and praxis/motor functions in patients with thyroid gland hypofunction. Of the cognitive domains that have been studied (Table 1), one may conclude that hypothyroidism is associated with deficits in memory, psychomotor slowing, and visuoperceptual and construction skills, none of which appear to show a consistent pattern of recovery following intervention with TRT. In contrast, sustained auditory attention abilities, language comprehension, and motor functions (ie, strength of grip) do not appear to be notably impaired in adults with hypothyroidism. Interestingly, the few studies that have used the Mini-Mental State Examination or variations of this general-purpose cognitive screening test (Table 1) have reported clinically significant and relentless impairments that seem to be refractory to treatment in patients with hypothyroidism. This, of course, raises important questions about the severity of the disease process, as well as the likelihood of other coexisting neuropsychiatric conditions at the time when those studies were undertaken. Another important observation in the current empirical literature that must be considered is the lack of adequate classification criteria by which different degrees of thyroid gland hypofunction may be associated with their respective neurocognitive sequelae. As a consequence, for example, there is no clear indication of how the cognitive profiles of patients with mild hypothyroidism may differ from those with more severe cases.

HYPOTHYROIDISM AND DEMENTIA

Myxedema traditionally has been classified as one of the reversible causes of dementia in the elderly. However, a recent review of the literature on hypothyroidism as a cause of dementia56 has found no strong evidence for complete reversibility. This, however, does not imply that the progressive and relentless neurocognitive decline usually seen in patients with untreated hypothyroidism cannot be averted or at least slowed with prompt and appropriate pharmacological management. Any discussion about health care management concerns with elderly patients necessitates addressing the following issues57 related to cognitive status and assessment: the prevalence of sensory defects such as reduced visual and auditory acuity, multiple drug treatments for the typically chronic physical illnesses that many older adults experience, the higher susceptibility among geriatric populations to the serious adverse effects of altering medications, and the increased likelihood of a latent coexisting dementia caused by something other than hypothyroidism. Older patients are particularly susceptible to developing primary hypothyroidism, a disease that becomes more common with age.58 Only a few empirical investigations of the neurocognitive effects of hypothyroidism in older populations have addressed these issues. Further studies will be necessary to assess intellectual decline in patients with late-onset hypothyroidism.

REVERSIBILITY OF HYPOTHYROID DEMENTIA

A number of researchers5963 have reported that between 10% and 30% of patients diagnosed as having syndromes that cause dementia have reversible or potentially treatable dementia. However, when these claims are subjected to critical scrutiny, one is led to believe that the actual incidence of reversible dementia may be much lower, probably in the order of 8% partial and 3% full-reversal64 over relatively brief periods. There is evidence from prospective follow-up data indicating that reversal to normal premorbid levels is the exception rather than the norm, and that many of the patients who show improvements in cognitive functioning after treatment may not have had dementia in the first place.65 Currently, to meet diagnostic criteria for dementia, an individual must have multiple cognitive deficits that include memory dysfunction severe enough to impair adaptive social or occupational functioning. Also, and perhaps more importantly, these cognitive impairments must have declined significantly from a higher level of functioning.66 Studies of neurocognitive aspects of hypothyroid dementia may need to demonstrate objective or estimated declines from premorbid levels using one of the many innovative assessment techniques now available.6771 Without such evidence, reports of dementia in the medical literature may be less defensible, particularly when the data presented indicate a complete reversal of the underlying degenerative process. Nevertheless, the fact that current pharmacotherapies may not be able to fully reverse the clinical complexes of patients with hypothyroidism does not mean that the progressive decline of their neurocognitive abilities cannot be slowed or stopped. Early reports50 regarding the reversibility of dementia have had to contend with spurious artifacts such as the practice effects that may accrue from serial testing over brief periods, thereby unduly overestimating actual cognitive abilities at retest. In addition, it has often been questioned whether reversals of dementia would be sustained if the patients were observed for extended follow-up periods,64 thus raising concerns about the duration of treatment effects.

In sum, the current empirical studies that claim that hypothyroidism is a fully reversible dementia are constrained by significant conceptual and methodological difficulties, and in many cases do not report consistent improvements to normal or premorbid levels of cognitive functioning following treatment. Unfortunately, one cannot always be sure that these neuropsychological findings are exclusively due to the effects of hypothyroidism, because the likelihood of comorbidity with neurodegenerative disorders or other factors influencing cognitive status57 may be quite high. It has often been argued that more emphasis should be placed on the appropriate social management of patients with cognitive decline related to hypothyroidism,72 and that classification of reversible and irreversible forms of dementia65 be avoided. Clearly, more data are needed to determine the extent to which hypothyroid dementia can be treated and the level of disease severity for which pharmacological intervention would be most effective.

CONGENITAL VS ACQUIRED HYPOTHYROIDISM

At first glance, congenital and adult-onset hypothyroidism may appear to be associated with similar patterns of neurocognitive deficits, especially with regard to short-term memory, visuospatial perception, and general intelligence. However, there are a number of factors that militate against making such an inference. One has to do with the extent and ability of the brain to recover lost function. In general, neuroplasticity varies directly with age, favoring infants over older individuals.43,73 Thus, although certain sensorineural deficits such as hearing loss may occur in both congenital and adult hypothyroidism,74,75 the developmentally based neurocognitive expression of such deficits, including treatment responses,76,77 may differ remarkably in these populations. This variability in treatment response and partial recovery may have more severe delayed neurobehavioral consequences in congenital hypothyroidism on TRT than may be expected in adult-onset hypothyroidism. Hence, the age at which hearing loss may have occurred in association with hypothyroidism is bound to have a differential impact on the nature and severity of subsequent language disorders exhibited on neurocognitive assessment in various age groups. In terms of motor deficits, the lack of comprehensive empirical data on manipulative dexterity and other pure motor functions in adults does not permit clear comparisons between congenital and acquired hypothyroidism.

While there is conflicting evidence in the literature on adult and congenital hypothyroidism regarding the extent and duration of recovery of cognitive functions following treatment with TRT, such recovery may not always be complete and does not seem to follow a consistent pattern in all cases. What is patently clear in both age groups, however, is the inexorable global decline in cognition when TRT is either delayed or absent.

CONCLUSIONS

Although the current empirical literature on the neurocognitive effects of clinical hypothyroidism is quite rudimentary, it is obvious that every individual diagnosed as having this disorder should be referred for comprehensive neuropsychological evaluation in view of the strong risk for cognitive morbidity. A number of methodological and conceptual issues need to be addressed to advance our understanding of the neurocognitive correlates of hypothyroidism. For instance, because the sole reliance of physicians on cognitive screening instruments such as the Mini-Mental State Examination tends to yield high misclassification rates,78 more comprehensive neurocognitive evaluations are essential to better determine the patterns of cognitive strengths and weaknesses associated with hypothyroidism. Also, issues pertaining to the confounding influence of test-retest constraints (including practice effects, statistical regression to the mean, etc) need to be seriously considered if serial evaluations are used to document changes in cognitive functioning following treatment. Recent innovative and promising techniques used to determine the reliability of data indicating neurocognitive change following intervention79 are currently being explored in clinical neuropsychological research80 and may be useful in assessing the reversibility of hypothyroid dementia. In concert with these and other methods, end points other than total reversal of cognitive decline related to hypothyroidism may have to be considered as viable clinical targets (eg, reduction in the negative slope of decline in treated patients compared with untreated cohorts) should future empirical research consensus indicate intractability of the hypothyroid dementia complex. Children diagnosed as having hypothyroidism have a greater likelihood of experiencing educational difficulties similar to what adults might experience in their vocational or occupational pursuits. Comprehensive neuropsychological evaluations can provide useful suggestions regarding the extent to which any difficulties with learning and memory, fine-motor skills (which influence writing abilities), phonetic, or other linguistic skills can be circumvented in the academic setting. Early assessment of cognition in adults can provide objective evidence for changes in their neuropsychological status over time, with ramifications for the establishment of long-term care planning and management. Whether an adult patient with hypothyroidism would need a restrictive level of management and care or be able to live independently in a supervised setting usually depends on the patient's cognitive and behavioral strengths and weaknesses, which are best determined by a comprehensive neurocognitive evaluation.

Back to top
Article Information

Accepted for publication December 12, 1997.

Reprints: Anthony T. Dugbartey, PhD, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Box 356560, Seattle, WA 98195-6560.

References
1.
Kamil  RJoffe  RT Neuroendocrine testing in electroconvulsive therapy. Psychiatr Clin North Am. 1991;14961- 970
2.
Nemeroff  CBLoosen  PT Handbook of Clinical Psychoneuroendocrinology.  New York, NY Guilford Press1987;
3.
Pharoah  PODButtfield  IHHetzel  BS Neurological damage to the fetus resulting from severe iodine deficiency during pregnancy. Lancet. 1971;1308- 310Article
4.
Alves  CEidson  MEngle  HSheldon  JCleveland  MM Changes in brain maturation detected by magnetic resonance imaging in congenital hypothyroidism. J Pediatr. 1989;115600- 603Article
5.
Bathia  VPoptani  HGupta  RKGujral  RB MRI of the brain in sporadic congenital hypothyroidism (SCH) and endemic iodine deficiency cretinism. Pediatr Res. 1993;33(suppl)593
6.
Siragusa  VBoffelli  SWeber  G  et al.  Brain magnetic resonance imaging in congenital hypothyroid infants at diagnosis. Thyroid. 1997;7761- 764Article
7.
Fisher  DALehman  HLackey  C Placental transport of thyroxine. J Clin Endocrinol Metab. 1964;24393- 400Article
8.
Legrand  J Morphogenetic action of thyroid hormones. Trends Neurosci. 1979;2234- 236Article
9.
Ruis-Marcos  ASanchez-Toscano  FEscobar del Rey  FMorreale de Escobar  G Severe hypothyroidism and the maturation of the rat cerebral cortex. Brain Res. 1979;162315- 329Article
10.
Klein  AHMeltzer  SKenney  FN Improved prognosis in congenital hypothyroidism treated before age 3 months. J Pediatr. 1972;81912- 915Article
11.
Raiti  SNewns  GH Cretinism: early diagnosis and its relation to mental prognosis. Arch Dis Child. 1971;46692Article
12.
Smith  DWBlizzard  RMWilkins  L The mental prognosis in hypothyroidism. Pediatrics. 1957;191011- 1022
13.
Hébert  RLaureau  EVanasse  M  et al.  Auditory brainstem response (ABR) audiometry in congenitally hypothyroid children under early replacement therapy. Pediatr Res. 1986;20570- 573Article
14.
Vanderschueren-Lodeweyckx  MDebruyne  FDooms  LEggermont  EEekels  R Sensorineural hearing loss in sporadic congenital hypothyroidism. Arch Dis Child. 1983;58419- 422Article
15.
Glorieux  JDussault  JHLetarte  JGuyda  HMorissette  J Preliminary results on the mental development of hypothyroid children detected by the Quebec Screening Program. J Pediatr. 1983;10219- 22Article
16.
Money  J Psychologic studies in hypothyroidism. Arch Neurol. 1956;76296
17.
Rovet  JWalker  WBliss  BBuchanan  LEhrlich  R Long-term sequelae of hearing impairment in congenital hypothyroidism. J Pediatr. 1996;128776- 783Article
18.
Walker  WBuchanan  LRovet  J Selective reading impairment in children with congenital hypothyroidism [abstract]. J Int Neuropsychol Soc. 1996;242
19.
Wolter  RNoel  PDeCock  P  et al.  Neuropsychological study in treated thyroid dysgenesis. Acta Paediatr Stockh. 1979;227(suppl)41- 46Article
20.
Kooistra  Lvan der Meere  JJVulsma  TKalverboer  AF Sustained attention problems in children with early-treated congential hypothyroidism. Acta Paediatr. 1996;85425- 429Article
21.
New England Congenital Hypothyroidism Collaborative, Effects of neonatal screening for hypothyroidism: prevention of mental retardation by treatment before clinical manifestations. Lancet. 1981;21095- 1098
22.
Rovet  JEhrlich  RMSorbara  D Intellectual outcome in children with fetal hypothyroidism. J Pediatr. 1987;110700- 704Article
23.
Tillotson  SLFuggle  PWSmith  IAdes  AEGrant  DB Relation between biochemical severity and intelligence in early treated congenital hypothyroidism: a threshold effect. BMJ. 1994;309440- 445Article
24.
Rovet  J Neurodevelopmental outcome in infants and preschool children following newborn screening for congenital hypothyroidism. J Pediatr Psychol. 1992;17187- 213Article
25.
Rovet  JEhrlich  RMDonner  E Long-term neurodevelopmental correlates of treatment adequacy in screened hypothyroid children. Pediatr Res. 1993;33(suppl)S91
26.
Rovet  JAlvarez  M Thyroid hormone and attention in school-age children with congenital hypothyroidism. J Child Psychol Psychiatry. 1996;37579- 585Article
27.
Rovet  JAlvarez  M Thyroid hormone and attention in congenital hypothyroidism. J Pediatr Endocrinol Metab. 1995;963- 66
28.
Rovet  JEhrlich  RM Long-term effects of L-thyroxine therapy for congenital hypothyroidism. J Pediatr. 1995;126380- 386Article
29.
Weiss  REStein  MATrommer  BRefetoff  S Attention-deficit hyperactivity disorder and thyroid function. J Pediatr. 1993;123539- 545Article
30.
Hauser  P The thyroid receptor beta gene and resistance T thyroid hormone: implications for behavioral and brain research. Psychoneuroendocrinology. 1994;19iii- viiArticle
31.
Hauser  PZametkin  AJMartinez  P  et al.  Attention deficit-hyperactivity disorder in people with generalized resistance to thyroid hormone. N Engl J Med. 1993;328997- 1001Article
32.
Ciaranello  RD Attention deficit-hyperactivity disorder and resistance to thyroid hormone: a new idea? N Engl J Med. 1993;3281038- 1039Article
33.
Elia  JGulotta  CRose  JR  et al.  Thyroid function attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1994;33169- 172Article
34.
Stein  MAWeiss  RERefetoff  S Neurocognitive characteristics of individuals with resistance to thyroid hormone: comparisons with individuals with attention-deficit hyperactivity disorder. J Dev Behav Pediatr. 1995;16406- 411
35.
Weiss  REStein  MADuck  SC  et al.  Low intelligence but not attention deficit hyperactivity disorder is associated with resistance to thyroid hormone caused by mutation R316H in the thyroid hormone receptor β gene. J Clin Endocrinol Metab. 1994;781525- 1528
36.
Maenpaa  JLiewendahl  K Peripheral insensitivity to thyroid hormones in a euthyroid girl with goiter. Arch Dis Child. 1980;55207- 212Article
37.
Glorieux  JDussault  JHMorissette  JDesjardins  MLetarte  JGuyda  M Follow-up at ages 5 and 7 years on mental development in children with hypothyroidism detected by Quebec Screening Program. J Pediatr. 1985;107913- 915Article
38.
New England Congenital Hypothyroidism Collaborative, Characteristics of infantile hypothyroidism discovered on infantile screening. J Pediatr. 1984;104539- 544Article
39.
New England Congenital Hypothyroidism Collaborative, Neonatal hypothyroidism screening: status of patients at 6 years. J Pediatr. 1986;107915- 919
40.
Money  JClarke  FCBeck  J Congenital hypothyroidism and IQ increase: a quarter century follow-up. J Pediatr. 1978;93432- 434Article
41.
Goodman  JF Medical diagnosis and intelligence levels in young mentally retarded children. J Ment Defic Res. 1977;21205
42.
Goodman  JFCameron  J The meaning of IQ constancy in young retarded children. J Gen Psychol. 1987;132109Article
43.
Spreen  OTupper  DRisser  ATuokko  HEdgell  D Human Developmental Neuropsychology.  New York, NY Oxford University Press Inc1984;
44.
Pharoah  PODConnolly  KJ Relationship between thyroxine levels during pregnancy and memory function in childhood. Early Hum Dev. 1991;2543- 51Article
45.
Pharoah  PODConnolly  KJHetzel  BEkins  R Maternal thyroid function and motor competence in the child. Dev Med Child Neurol. 1981;2376- 82Article
46.
Pharoah  PODConnolly  KJEkins  RPHarding  AG Maternal thyroid hormone levels during pregnancy and the subsequent cognitive and motor performance of the children. Clin Endocrinol (Oxf). 1984;21265- 270Article
47.
Connolly  KJPharoah  POD Iodine deficiency, maternal thyroxine levels in pregnancy and developmental disorders in children. DeLong  FRRobbins  JCondliffe  PGeds.Iodine and the Brain New York, NY Plenum Publishing Corp1989;317- 331
48.
Kooistra  LLaane  CVulsma  TSchellekens  JMvan der Meere  JJKalverboer  AF Motor and cognitive development in children with congenital hypothyroidism: a long-term evaluation of the effects of neonatal treatment. J Pediatr. 1994;124903- 909Article
49.
Rovet  JFEhrlich  RNSorbara  DL Intellectual outcome in children with fetal hypothyroidism. J Pediatr. 1987;110700- 704Article
50.
Crown  S Notes on an experimental study of intellectual deterioration. BMJ. 1949;2684- 685Article
51.
Haggerty  JJEvans  DLPrange  AJ Organic brain syndrome associated with marginal hypothyroidism. Am J Psychiatry. 1986;143785- 786
52.
Mennemeier  MGarner  RDHeilman  KM Memory, mood and measurement in hypothyroidism. J Clin Exp Neuropsychol. 1993;15822- 831Article
53.
Osterweil  DSyndulko  KCohen  SN  et al.  Cognitive function in non-demented older adults with hypothyroidism. J Am Geriatr Soc. 1992;40325- 335
54.
Whybrow  PCPrange  AJTreadway  CR Mental changes accompanying thyroid gland dysfunction: a reappraisal using objective psychological measurement. Arch Gen Psychiatry. 1969;2048- 63Article
55.
Peabody  CAThornton  JETinklenberg  JR Progressive dementia associated with thyroid disease. J Clin Psychiatry. 1986;47100
56.
Clarnette  RMPeterson  CJ Hypothyroidism: does treatment cure dementia? J Geriatr Psychiatry Neurol. 1994;723- 27
57.
Jeste  DVEastham  JHLacro  JPGierz  MField  MGHarris  MJ Management of late-life psychosis. J Clin Psychiatry. 1996;57(suppl 3)39- 45
58.
Livingston  EHHersman  JMSawin  CTYoshikawa  TT Prevalence of thyroid disease and abnormal thyroid tests in older hospitalized and ambulatory persons. J Am Geriatr Soc. 1987;35109- 114
59.
Freemon  FR Evaluation of patients with progressive intellectual deterioration. Arch Neurol. 1976;33658- 659Article
60.
Smith  JSKiloh  LG The investigation of dementia: results of 200 consecutive admissions. Lancet. 1981;1824- 827Article
61.
Fox  JHTopel  JLHuckman  MS Dementia in the elderly: a search for treatable illness. J Gerontol. 1975;30557- 564Article
62.
Freemon  FRRudd  SM Clinical features that predict potentially reversible progressive intellectual deterioration. J Am Geriatr Soc. 1982;30449- 451
63.
Cummings  JBenson  DFLoVerma  S  Jr Reversible dementia: illustrative cases, definition and review. JAMA 1980;2432434- 2439Article
64.
Clarfield  AM The reversible dementias: do they reverse? Ann Intern Med. 1988;109476- 486Article
65.
Larson  EBReifler  BVFeatherstone  HJEnglish  DR Dementia in elderly outpatients: a prospective study. Ann Intern Med. 1984;100417- 423Article
66.
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition.  Washington, DC American Psychiatric Association1994;
67.
Barona  AReynolds  CRChastani  R A demographically based index of premorbid intelligence for the WAIS-R. J Consult Clin Psychol. 1984;52885- 887Article
68.
Blair  JRSpreen  O Predicting premorbid IQ: a revision of the national adult reading test. Clin Neuropsychol. 1989;3129- 136Article
69.
Johnstone  BCallahan  CDKapila  CJBouman  DE The comparability of the WRAT-R Reading Test and NAART as estimates of premorbid intelligence in neurologically impaired patients. Arch Clin Neuropsychol. 1996;11513- 519Article
70.
Kraken  DAGur  RCSaykin  AJ Reading on the Wide Range Achievement Test-Revised and parental education as predictors of IQ: comparisons with the Barona equation. Arch Clin Neuropsychol. 1995;10147- 157Article
71.
Wiens  ANBryan  JECrossen  JR Estimating WAIS-R FSIQ from National Adult Reading Test-Revised in normal subjects. Clin Neuropsychol. 1993;770- 84Article
72.
Wolff  ML Reversible intellectual impairment: an internist's perspective. J Am Geriatr Soc. 1982;30647- 650
73.
Geschwind  N Late changes in the nervous system: an overview. Stein  DGRosen  JJButters  Neds.Plasticity and Recovery of Function in the Central Nervous System Orlando, Fla Academic Press Inc1974;467- 471
74.
Ritter  FN The effects of hypothyroidism upon the ear, nose, and throat: a clinical and experimental study. Laryngoscope. 1967;771427- 1479Article
75.
Meyerhoff  WL Hypothyroidism and the ear: electrophysiological, morphological and chemical considerations. Laryngoscope. 1979;89(suppl 19)1- 25Article
76.
Glorig  ANixon  J Hearing loss as a function of age. Laryngoscope. 1962;721596- 1610Article
77.
Debruyne  FVanderschueren-Lodeweyckx  MBastijns  P Hearing in congenital hypothyroidism. Audiology. 1983;22404- 409Article
78.
Malloy  PFCummings  JLCoffey  CE  et al.  Cognitive screening instruments in neuropsychiatry: a report of the committee on research of the American Neuropsychiatric Association. J Neuropsychiatry Clin Neurosci. 1997;9189- 197
79.
Jacobson  NSTrau  P Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. J Consult Clin Psychol. 1991;5912- 19Article
80.
Sawrie  SMChelune  GJNaugle  RILüders  HO Empirical methods for assessing meaningful neuropsychological change following epilepsy surgery. J Int Neuropsychol Soc. 1996;2556- 564Article
×