Differential Diagnosis of Functional Decline in Down's Syndrome

Robert J. Pary, M.D.
Associate Professor of Psychiatry
Southern Illinois University, School of Medicine
P.O. Box 19230
751 Rutledge Street
Springfield, IL 62794-9230
The Habilitative Mental Healthcare Newsletter
1992, Vol. 11, No. 6, p. 37-41.
© 1992 Pysch-Media, Inc.
  Reprinted with permission of Psych-Media, Inc., publishers of Psychiatric Aspects of Mental Retardation Reviews, Habilitative Mental Healthcare Newsletter, and the journal Mental Health Aspects of Developmental Disabilities.
Editor-in-Chief: Anne D. Hurley, Ph.D
E-mail: mhdd@emji.net
P.O. Box 57
Bear Creek, NC 27207-0057
(336) 581-3700
Fax: (336) 581-3766


     When an older adult with Down's syndrome (DS) shows a decline in production at a day program or a loss of hygiene and other self-help skills, is this Alzheimer's disease? Perhaps, but other conditions, including some reversible ones, can also cause a decline in function. This article will review Alzheimer's disease, the link between it and DS, and the differential diagnosis and treatment of functional decline in adults with DS.

Alzheimer's Disease
     Dementia is a syndrome of memory loss plus: a) an impairment in judgement; b) a personality change; or c) a loss of higher cortical functions (i.e., losing ability to dress oneself despite having sufficient motor strength to do so) resulting in an overall decline in functioning.1 Alzheimer's disease is a progressive form of dementia characterized by certain changes in the brain and results in a total inability to care for self and eventually to death. To date, no clinically accepted treatment can reverse the illness. Alzheimer's disease can be complicated by depression or delusions which may respond to psychoactive medications. Unfortunately, the diagnosis of Alzheimer's disease can only be confirmed at autopsy.

DS and Alzheimer Disease
     More than a century ago, Fraser and Mitchell observed "precipitated senility" in patients with DS.11 The link between Alzheimer's disease and DS was underscored when Wisniewski et al found that almost all individuals with DS, who die after 35 years of age, show evidence of Alzheimer-like changes in their brains.48 A relationship between DS and Alzheimer's disease is now accepted. 2,5,15,21 Clinically, however, dementia is not seen in everyone with DS after age 35. Alzheimer-like changes can be seen in brains of nondemented elderly in the general population.4,5
     Lai and Williams reported the prevalence of dementia in a mixed institutional and community population of DS individuals over the age of 35.23 About half (51%) had dementia with an average age at the onset of dementia to be 54.2 ± 6.1 years (range 43-68 years). Dementia occurred in two of 25 subjects between ages 35-49 years, 11 of 20 between 50-59 years, and 6 of 8 over 60.
     The initial phase of dementia in the higher functioning individuals was a personality change (e.g., irritability or mood lability), memory impairment, spatial disorientation (e.g., getting lost in the residence), or reduced talking. In the group, which had more severe disabilities prior to the onset of dementia, the first indications were apathy (lack of interest in previously enjoyable activities), inattention, and decreased social interaction. (As will be discussed later, the early signs of dementia such as a lack of interest and reduced social interactions can also be seen in depression.13)
     In the second phase of the dementing process, there was loss of ability to dress, use eating utensils, and toilet oneself. Also, gait became slow and shuffling, and workshop activity nonproductive. Seizures frequently occurred as well.
     Oliver and Holland reviewed eight articles with case reports describing the clinical changes in 14 individuals with DS and Alzheimer neuropathology.28 Nine of the 14 had "apathy", "depression", "lethargy", "withdrawn" or "lost interest". The authors concluded that clinical changes involved behavioral deterioration, loss of self-care skills, or loss of language.

TABLE 1. DIFFERENTIAL DIAGNOSIS OF FUNCTIONAL DECLINE IN DS

Disorders Which Are Common in DS
  • depression
  • hypothyroidism
  • infection folate or B12 deficiency
  • hearing impairment
  • visual impairment
  • malignancy such as leukemia
  • joint problems of the neck, knee or hip
  • Alzheimer disease
  • (?) sleep apnea

Miscellaneous Cerebral Conditions With No Apparent Predilection for Individuals with DS
  • subdural hematoma
  • brain tumors
  • normal pressure hydrocephalus
     Evenhuis also described the clinical course of 14 patients with DS and dementia (mean age of onset 51.9 years, range 45 to 60 years).9 In the initial phase, 13 of 14 had apathy and withdrawal, 9 had loss of self-help skills, 7 had daytime sleepiness, and 6 had gait deterioration. Myoclonus (brief, shock-like jerks), urinary incontinence, and seizures occurred at different phases depending on level of developmental disabilities. These symptoms were seen early, if the patient had severe disabilities, and usually not until after the second year in those with moderate disabilities.
     Not every person with DS over 35-years-old shows cognitive decline.14 Using serial Stanford-Binet Intelligence Scales,40 Hewitt et al found only 39% of 23 adults with DS over age 50 had a significant intellectual deterioration (suggestive of Alzheimer's disease).16 Furthermore, those who showed deterioration were significantly more likely to show visual impairment or hearing loss. Only 33% of adults with DS between 35-49 in the Fenner et al study had intellectual decline.10
     Thase et al assessed 165 DS individuals and 163 controls matched for age and IQ at time of institutionalization.44 Compared to controls, individuals with DS had deficits in orientation, attention span, memory, object naming, apathy and ability to follow commands. The deficits were most apparent in the 29 adults over 50-years-old. In a preliminary study from the same population, however, Thase et al noted that one individual aged 59-years had absolutely no evidence of dementia.43

Differential Diagnoses of Functional Decline
     Table 1 lists the differential diagnoses of functional decline in adults with DS.

Thyroid Disease
     Hypothyroidism can cause a decline in functioning by reducing one's energy, motivation, and enthusiasm, and by causing mental slowing. Thyroid disease is common in DS. Mani studied 55 patients ranging in age from 24 to 67 with a mean age of 43.3 years, and found that 50% had clinical features compatible with hypothyroidism and 22% (12 patients) had the disease.25 All 12 were 39-years or older. Dinani and Carpenter found that of 106 adults with DS, 43 (40.5%) had abnormal thyroid function; over 60% were 35-years or older.8

Major Depression
     Weight loss, withdrawal or loss of interest, sleep difficulty, tearfulness, anxiety, irritability, and depressed mood are commonly reported in case reports of depression in DS.6,19,24,29,32,35,37,42,47 Nevertheless, Sovner has emphasized that standard diagnostic criteria used in the general population may need to be modified for individuals with developmental disabilities.36 One feature of major depression in the developmentally disabled may be a loss of activity of daily living skills such as the onset of urinary incontinence. What emerges from the case reports and Sovner's criteria is that major depression, in this population, is characterized by withdrawal, a mood disturbance, and loss of personal care skills.
     The difficulty in diagnosing major depression from dementia is illustrated by Reid's description of a 50-year-old man with DS, who became "withdrawn and unsociable" and underwent what appeared to be a personality change.30 He started to sleep poorly and began to get up at night. Soon after he became ... incontinent [of urine and feces], progressively less capable of fending for himself, and terminally he began to eat rubbish ...he died at the age of 53... Changes characteristic of severe Alzheimer's disease were present in all sections of cerebral cortex examined microscopically. As noted above, Oliver et al,28 Lai et al,23 and Evenhuis have commented that depression, lethargy, personality change, withdrawal and loss of self-help skills often occur in individuals with DS and Alzheimer disease.
     Szymanski and Biederman mentioned that depression and dementia can coexist.37 This view is supported in studies of the general population.31,33 Zubenko et al have detected neurochemical changes in the brains of individuals with primary dementia who had depression that differed from those that had only primary dementia.49 Rovner et al found that the "subgroup of patients with Alzheimer's disease and depression were more cognitively impaired and more socially disabled than nondepressed patients.33 Jenike noted the benefit of monoamine oxidase inhibitor therapy for two patients with major depression and Alzheimer's disease, who did not benefit from standard antidepressants.20 Their improved mood allowed these patients to have a better quality of life despite the progressive memory loss.

TABLE 2. WORK-UP FOR FUNCTIONAL DECLINE IN DS

  • sleep and weight graphs
  • vital signs
  • complete blood count
  • screening blood chemistries
  • electrolytes
  • thyroid function tests
  • folate and B12 levels
  • urinalysis
  • electrocardiogram
  • chest X-ray
  • brain imaging study
  • neuropsychological testing
  • assessment of daily living skills
  • graph of work productivity
  • consider the following consultations:
    • audiologic
    • ophthalmologic
    • orthopedic
    • (?) sleep laboratory
     It appears that symptoms of major depression should be treated in individuals with DS, even if dementia is also suspected. Furthermore, it appears that the failure to respond to a single antidepressant agent may be inadequate to rule out depression. Jenike's case studies offer support for at least a second course of therapy with a different antidepressant in unresponsive individuals suspected of having depression.20

Sensory Impairment
     As one's eyesight or hearing significantly worsens, overall functioning may deteriorate. Unfortunately, adults with DS are at risk for both visual and auditory impairment.
     Keiser et al estimated that 40 to 77% of persons with DS suffer from the hearing loss.22 They concluded that adults with DS are prone to a variety of ear problems and may benefit from otological/audiological consultaion.
     In addition, up to 46% of patients with DS reportedly have cataracts.17 Odell has advised that cataracts should be ruled out as a cause for deterioration before diagnosing Alzheimer's disease.27

Infection
     Older adults with DS have impaired white blood cell function and are, therefore, susceptible to infection.26 It is not surprising that a leading cause of death in individuals with DS is pneumonia.7,41 At times, pneumonia will present as increased lethargy or confusion before clear respiratory signs appear. Useful clues include fever, rapid heart beat, increased respiratory rate, or elevated white blood cell.46

Other Conditions
     In the general population, vitamin B12 deficiency can cause confusional syndromes and dementia.46 Although vitamin B12 deficiency has not been reported in adults with DS, Cartlidge and Curnock described a 3-year-old girl with DS who was lethargic, irritable, had decreased appetite with weight loss, and withdrawal.3 She was found to have malabsorption of vitamin B12 and all of her symptoms disappeared following hydroxycobalamin therapy.
     Another potential cause for decline in functioning in individuals with DS is sleep apnea.34,39 Apnea is a temporary cessation of breathing and can cause excessive daytime sleepiness, lethargy and irritability. The diagnosis, however, may be difficult to confirm because many individuals with DS will not tolerate sleeping all night in a laboratory connected to a machine.
     Adults with DS are susceptible to joint problems in the neck, knee or hips.4,38 Joint pain may cause a decline in functioning by making it difficult to walk. This can result in reduced activity levels. An orthopedic consultation may be indicated if there are gait, posture or neck symptoms (neurologic consultation if the neck is involved).
     Leukemia occurs more often in adults as well as children with DS than in the general population.27 This blood cell cancer can present as tiredness, weight loss and an overall decline in functioning before the diagnosis is made. Cardiac disease can also produce a functional decline.12

Diagnostic Workup
     In addition to a history and physical examination. Table 2 lists a suggested work-up for functional decline in adults with DS. The work-up emphasizes ruling out three potentially reversible conditions of functional decline: infection; thyroid disease; and depression. A brain imaging study (computerized tomography or magnetic resonance) should probably be attempted to rule out tumors or other conditions such as subdural hematomas (clotted blood under the lining of the brain) all of which can lead to confusion, dementia and a decline in functioning.
     The clinician should consider audiologic, ophthalmologic, orthopedic, and possibly sleep laboratory consultations depending upon clinical circumstances. It is also important to establish the baseline level of psychosocial functioning through neuropsychological testing. Psychological testing, e.g., the Thematic Apperception Test, can be helpful in diagnosing depression (especially when baseline test results are available for comparison). An assessment of daily living skills and work productivity should also be included. These evaluations can help determine whether an intervention (e.g. an antidepressant trial) has had any impact on the decline.

Conclusion
     Functional decline in a person with DS does not necessarily presage the onset of a progressive and irreversible dementing process. A careful consideration of other reversible causes of impaired psychosocial function can provide persons with DS many years of meaningful life.

References

  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Third Edition -Revised. Washington DC: American Psychiatric Association, 1987.
  2. Ball M J, Nuttall K. Neurofibrillary tangles, granuovacuolar degeneration and neurone loss in Down's syndrome: quantitative comparison with Alzheimer's dementia. Ann Neurol 1980;7:462~465.
  3. Cartlidge PHT, Curnock DA. Specific malabsorption of vitamin B12 in Down's Syndrome. Arch Dis Child 1986;61:514-515.
  4. Collacott RA, Ellison D, Harper W, Newland C, Ray-Chaudhurt K. Atlanto-occipital instability in Down's syndrome. J Ment Defic Res 1989;33:499-505.
  5. Crapper DR, Dalton AL, Skopitz M, Eng P, Scott JH, Hachinski V. Alzheimer's degeneration in Down's syndrome. Arch Neurol 1975;32:618-623.
  6. Davies TS. "Niamid" in mongolism. Br J Med1959;2:1098.
  7. Deaton JG. The mortality rate and causes of death among institutionalized mongols in Texas. J Ment Defic Res 1973;17:117-122.
  8. Dinani S, Carpenter S. Down's syndrome and thyroid disorder. J Ment Defic Res 1991;34:187-193.
  9. Evenhuis HM. The natural history of dementia in Down's syndrome. Arch Neurol 1990;47:263-267.
  10. Fenner Me, Hewitt KE, Torpy DM. Down's syndrome: intellectual and behavioural functioning during adulthood. J Ment Defic Res 1987;31:241-249.
  11. Eraser J, Mitchell A. Kalmuc idiocy; report of a case with autopsy; with notes on sixty-two cases. J Ment Sci 1976;22:161.
  12. Goldhaber SZ, Brown WD, Robertson N, Rubin IL, St John Sutton MG. Aortic regurgitation and mitral valve prolapse with Down's syndrome: a case-control study. J Ment Defic Res 1988;32:333-336.
  13. Guze S, Robins E. Suicide and primary affective disorder. Br J Psychiatry 1970;117:437-483.
  14. Haxby JV. Neuropsychological evaluation of adults with Down's syndrome: patterns of selective impairment in non-demented old adults. J Ment Defic Res 1989; 33:193-210.
  15. Heston LL. Alzheimer's dementia and Down's syndrome: genetic evidence suggesting an association. Ann NY Acad Sci 1982;396:29-37.
  16. Hewitt KE, Carter G, Jancar J. Aging in Down's syndrome. Br J Psychiatry 1985;147:58-62.
  17. Hiles DA, Pettapiece MC, Biglan AW, Cheng KP. Ocular features of Down's syndrome. Down Syndrome Group Western Pennsylvania Newslett 1990;8:27-30.
  18. Hirschmann JV, Murray JF. Pneumonia and lung abscess. In Pertersdorf RG, Adams RD, Braunwald E, Isselbacher KJ, Martin JB, Wilson JD (eds), Harrison's Principles of Internal Medicine 10th Ed. NY: McGraw-Hill, 1982;1532-1537.
  19. Holt GM, Bouras N, Watson JP. Down's syndrome and eating disorders. Br J Psychiatry 1988;152:847-848.
  20. Jenike MA. Handbook of Geriatric Psychopharmacology. Littleton MA: PSG Publishing Company Inc, 1985.
  21. Jervis GA. Early senile dementia in mongoloid idiocy. Am J Psychiatry 1948;105:102-106.
  22. Keiser H, Montague J, Wold D, Maune S, Pattison D. Hearng loss of Down syndrome adults. Am J Ment Defic 1981;85:467-472.
  23. Lai F, Williams RS. A prospective study of Alzheimer disease in Down syndrome. Arch Neurol 1989;46:849-853
  24. Lazarus A, Jaffe RL, Dubin WR. Electroconvulsive therapy and major depression in Down's syndrome. J Clin Psychiatry 1990;51:422-425.
  25. Mani C. Hypothyroidism in Down's syndrome. Br J Psychiatry 1988;153:102-104.
  26. Nishida Y, Akaoka I, Suzuki T, Kabayashi M, Maruki K. Serum lymphocytotoxins and lymphocyte responses to mitogens of Down syndrome persons. Am J Ment Defic 1981;85:596:600.
  27. Odell JD. Medical consideration. ln C Tingey(ed), Down Syndrome A Resource Handbook. Boston: College-Hill Publication, 1988.
  28. Oliver C, Holland AJ. Down's syndrome and Alzheimer's disease: a review. Psychol Med 1986;16:307-322.
  29. Pary RJ. Pretreatment systolic orthostatic blood pressure depression in Down's syndrome. J Clin Psychopharmacol 1989;9:146-147.
  30. Reid AH. Psychiatric disturbances in the mentally handicapped. Proc Royal Soc Med 1976;69:509-512.
  31. Reifler BV. Depression with and without dementia. Hosp Practice 1990:25:47-66.
  32. Roith AI. Psychotic depression in a mongol. J Ment Subnorm 1961;7:45-47.
  33. Rovner BW, Broadhead J, Spencer M, Carson K, Folstein MF. Depression and Alzheimer's disease. Am J Psychiatry 1989;146:350-353.
  34. Silverman M. Airway obstruction and sleep disruption in Down's syndrome. Br Med J 1988;296:1618-1619.
  35. Singh I, Zolese G. Is mania really incompatible with Down's syndrome. Br J Psychiatry 1986;148:613-614.
  36. Sovner R. Limiting factors in the use of DSM-III criteria with mentally ill/mentally retarded persons. Psychopharmacol Bull 1986;22:1055-1059.
  37. Szymanski LS, Biederman J. Depression and anorexia nervosa of persons with Down syndrome. Am J Ment Defic 1984;89:246-251.
  38. Tangerud A, Hestnes A, Sand T, Sunndalsfoll S. Degenerative changes in the cervical spine in Down's syndrome. J Ment Defic Res 1990;34:179-185
  39. Telakivi T, Partinen M, Salmi T, Leinonen L, Harkonen T. Nocturnal periodic breathing in adults with Down's syndrome. J Ment Defic Res 1987;31:31-39.
  40. Terman LM, Merrill MA. Measuring Intelligence. Boston: Houghton Mifflin, 1937.
  41. Thase ME. Longevity and mortality in Down's syndrome. J Ment Defic Res 1982; 26:177-192
  42. Thase ME. Basal ganglia calcification and psychosis in Down's syndrome. Postgrad Med J 1984;60:137-139.
  43. Thase ME, Liss L, Smeltzer D, Maloon J. Clinical evaluation of dementia in Down's syndrome: A preliminary report. J Ment Defic Res 1982;26:239-244.
  44. Thase ME, Tigner R, Smeltzer D, Liss L. Age-related neuropsychological deficits in Down's syndrome. Biol Psychiatry. 1984;19:571-585.
  45. Tomlinson BE, Blessed G, Roth M. Observations on the brains of demented old people. J Neurol Sci 1970;11:205-242.
  46. Vickers R. Medical aspects of aging. In Lazarus LW (ed), Essentials of Geriatric Psychiatry. NY: Springer Publishing Co, 1988;65-101.
  47. Warren AC, Holroyd S, Folstein MF. Major depression in Down's syndrome. Br J Psychiatry 1989;155:202-205.
  48. Wisniewski KE, Wisniewski HM, Wen GY. Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome. Ann Neurol 1985;7:278-282.
  49. Zubenko GS, Moossy J, Kopp U. Neurochemical correlates of major depression in primary dementia. Arch Neurol 1990;47:209-214.
     Robert Pary, M.D. is an Assistant Professor of Psychiatry, University of Pittsburgh School of Medicine, Geriatric Health Services. Address all correspondence to Dr. Pary at 3811 O'Hara St., Pittsburgh, PA 15213.
 
  Revised: May 18, 2000.