Original Article Presenile Dementia Etiology, Clinical Profile and Treatment Response at Four Month Follow Up U Sundar*, A Sharma**, ME Yeolekar*** Abstract Dementia is the development of multiple cognitive deficits that includes memory impairment and at least one of the following - Aphasia, apraxia, agnosia or disturbances in executive functioning. The common causes of dementia among the elderly are Alzheimer s disease, vascular dementia, mixed dementia and Lewy body disease. The concept of reversible dementia was introduced in 1980 when a task force sponsored by National Institute of Ageing found 10-12% of dementia cases in older group to have reversible causes such as metabolic - nutritional, drugs, infections, psychiatric disorders etc. In our series of 76 patients in the presenile age group (<65 years), 34.21% (26/76) had a reversible condition underlying the dementia. 43.42% (33/76) had vascular dementia, 13.15% (10/76) had Alzheimer s disease and 9.21% (7/76) had mixed dementia. Hypertension, hyperlipidemia and diabetes mellitus were commoner in the vascular dementia group as compared to the Alzheimer s group. Evaluation of MRI as a tool in diagnosis of dementia showed increased sensitivity of MRI towards detecting lacunes. The potentially reversible dementias comprised infections 14.47% (11/76), metabolic-nutritional 14.47% (11/76) and autoimmune diseases 3.94% (3/76). These were characterized by a subcortical dementia. Four month follow up of MMSE in this group showed significant and sustained improvement in the metabolic nutritional group. INTRODUCTION Dementia is defined as the development of multiple cognitive deficits that include memory impairment, and at least one of the following - aphasia, apraxia or disturbance in executive functioning, the deficits being of sufficient magnitude to interfere with work or social activities. 1 The common causes of dementia, especially in the elderly age group, are Alzheimer s disease, vascular dementia, mixed dementia incorporating features of both, and Lewy body dementia: these are largely non-reversible. 2 The causes of dementia in a younger cohort (<65 years of age) would be expected to differ from that in senile dementia, with possibly, a larger proportion of reversible dementia being present. Some of the known causes of reversible dementia are neoplasms, infections, metabolic disturbances and underlying trauma causing structural alterations. Our study delineates the etiology of presenile dementia, its clinical subtypes, correlation with imaging features and treatment response. *Associate Professor; **Lecturer; ***Dean and Professor; Department of Medicine, Lokmanya Tilak Municipal Medical College and Lokmanya Tilak Municipal General Hospital, Sion, Mumbai - 22, India. Received : 29.7.2003; Revised : 17.4.2004; Accepted : 28.7.2004 MATERIAL AND METHODS To determine the etiology among patients with presenile dementia, to identify reversible dementias and to document improvement in dementia severity on treatment in this group. The period of study was of 3 years viz. from 1999 to 2002. Seventy six consecutive patients less than 65 years old referred to neurology services for cognitive dysfunction, were identified as having presenile dementia. DSM - 3 revised criteria were used to diagnose dementia. 1 All 76 had Folstein s MMSE score less than 24/30. 3 Criteria used to diagnose Alzheimer s dementia were the National Institute of Neurological disorder and stroke and Alzheimer s disease and related disorders association criteria for Alzheimer s disease. 4 A diagnosis of vascular dementia was made on the basis of clear history of at least one stroke with stepwise cognitive decline, not necessarily affecting memory in the early stages. 5 Mixed dementia was diagnosed in the presence of a pattern of cognitive decline suggestive of Alzheimer s disease (early and progressive memory involvement) followed by strokes affecting cognition further. 6 A subgroup of Potentially Reversible Dementia was identified, and monthly MMSE scores were repeated in this group, for four months. All patients had a CT brain and/or MRI done. Routine blood tests done in all included hemogram, JAPI VOL. 52 DECEMBER 2004 www.japi.org 953
liver and renal functions, and serum VDRL, serum TSH and HIV status. Appropriate additional investigations (CSF biochemistry and bacteriology, toxic screening, vitamin B 12 levels) were done in individual patients when indicated. All patients less than 65 years of age, satisfying the DSM- 3 revised criteria for dementia, were included in the study. Patients who were delirious or who could not co-operate for MMSE scoring due to shortened attention span or concentration were excluded. RESULTS Table 1 shows the etiology and mean age of 76 patients with presenile dementia. Thirty three patients had vascular dementia, 10 had Alzheimer s disease, seven had a potential mixed dementia, and 26 (33%) had a potentially reversible dementia. The mean age of the last group (39.2 yrs) was significantly lower than the other groups. (58.3 years - Mixed dementia). In the vascular dementia group 27/33 had a multiinfarct state. The five patients with single infarct presenting as dementia had the following etiopathogensis - two dominant thalamic infarcts, one angular gyrus infarct, one right hemispherical and one caudate nucleus infarct. Table 2 shows the correlation between clinical diagnosis (vascular dementia or Alzheimer s dementia), and CT findings / MRI findings of vascular involvement and atropy. Of the 33 patients clinically diagnosed as vascular dementia, five showed diffuse cerebral atropy. MRI confirmed this, and showed additional lacunae in six. Out of 10 clinical Alzheimer s dementia patients, eight had atrophy on CT and MRI, six being parieto temporal atrophy. Four out of these 10 patients Table 1 : Etiology of presenile dementia Etiology No. Median Age (years) 1. Vascular 33 58.3 Multi infarct 27 Single infarct 5 Haemorrhage 1 2. Degenerative 10 59.2 3. Mixed 7 58.6 4. Potentially reversible 26 39.2 Table 2 : Correlation of clinical and imaging diagnosis Clinical CT finding CT MRI MRI diagnosis (Vascular) (Atrophy) (Additional (Atrophy) lacunes) Vascular 33 5 6 5 dementia (33) Alzheimer s 8 4 8 dementia (10) Of the 33 patients clinically diagnosed as vascular dementia, five showed diffuse cerebral atrophy. MRI confirmed this, and showed additional lacunae in 6. 8/10 clinical Alzheimer s dementia patients had atrophy on CT and MRI, six being parieto temporal atrophy. 4/ 10 had periventricular lacunae on MRI. 5/33 dementia patients had a single infarct. (two dominant PCA territory, two dominant MCA territory, and one non-dominant MCA territory) had periventricular lacunae on MRI. Five out of 33 dementia patients had a single infarct. (two dominant PCA, two dominant MCA, and one non-dominant MCA). Table 3 shows a comparison of clinical profile between vascular dementia and Alzheimer s disease in our series. Median age, sex ratio, average MMSE, pattern of tobacco abuse, prevalence of IHD and alcoholism were comparable between the two groups. Hypertension, diabetes and hyperlipidemia were significantly commoner in the vascular dementia group. Table 4 delineates the details of reversible causes of presenile dementia. The average MMSE in this group was 22, median age being 39.5 years. Three patients had TB meningitis, two having additional communicating hydrocephalus on CT. Multiple tuberculomas were seen in two patients, neurocysticercosis lesions in three patients (one starry sky appearance, two multiple calcific and ring enhancing lesions) (Fig. 1), and three patients had HIV related CNS disease (one AIDS encephalopathy with cerebral edema, and two patients with Toxoplasmosis who had ring enhancing lesion and IgG positivity for toxoplasmosis) (Fig. 2). The patients with metabolic-nutritional causes had normal CT brains except the two patients with Korsakoff s psychosis and background alcoholism who demonstrated diffuse cerebral atrophy. Both the CRF patients were on dialysis. The two patients with systemic lupus erythematosis had significant imaging findings, venous infarcts in one case with a secondary anti-phospholipid antibody syndrome (Fig. 3), and basal meningitis with vasculitis causing MCA territory penetrating branch infarct in the other. Table 5 shows the correlation between etiology of presenile dementia and clinical subtype of dementia. Cortical dementias resulted in prominent memory and language dysfunction with apraxia and agnosia, and were seen in vascular and degenerative conditions. Infective and metabolic causes led mainly to sub-cortical dementia, characterized by bradyphrenia and personality changes. Table 6 shows the follow-up of MMSE scores at one month, and four months review in the Reversible Dementia group. Table 3 : Comparison of clinical profile in presenile dementia between vascular dementia and Alzheimer s disease Sr Clinical profile Vascular Alzheimer s No. dementia (33) Dementia (10) 1. Median age (years) 58.3 59.2 2. M:F 23:10 6:4 3. Average MMSE 20 16 4. Hypertension (No.) 25 3* 5. Diabetes mellitus (No.) 20 2* 6. Tobacco abuse (No.) 21 5 7. IHD (No.) 16 2 8. Alcoholism (No.) 16 4 9. Hyperlipidemia (No.) 19 2* *p value < 0.05; Hypertension, diabetes and hyperlipidemia were significantly commoner in vascular dementia group as compared to Alzheimer s group. 954 www.japi.org JAPI VOL. 52 DECEMBER 2004
Table 4 : Reversible causes of presenile dementia - 26 patients A) Infective Median age - 39.5 years, Average MMSE-22 Etiology Imaging TB meningitis (3) Basal meningitis (1) Communicating hydrocephalus (2) Tuberculoma (2) Multiple tuberculomas Neurocysticercosis (3) Multiple calcific and ring enhancing lesions HIV related (3) Toxoplasmosis (2)? AIDS encephalopathy (1) B) Metabolic - Nutritional Hypothyroidism (3) Normal Chronic renal failure Normal Korsakoff s psychosis (2) Cerebral atrophy Megaloblastic anaemia (2) Normal C) Autoimmune- systemic lupus erythematous SLE with secondary Multiple venous infracts antiphospholipid antibody syndrome SLE Basal meningitis with vasculitis Table 5 : Correlation of etiology and clinical subtypes of dementia Fig. 2 : Multiple ring enhancing lesions in a contrast CT scan brain - CNS toxoplasmosis in a HIV +ve patient Etiology (no.) Dementia sub-types Cortical Sub-cortical Vascular (33) 25 8 Degenerative (10) 10 Infective (11) 3 8 Metabolic (11) 2 9 Autoimmune (3) 2 1 Cortical dementis included prominent memory and language dysfunction with apraxia and agnosia, and were seen in vascular and degenerative conditions. Infective and metabolic causes led mainly to sub-cortical dementia, characterized by bradyphrenia and personality changes. Fig. 3 : Venous infarcts - contrast CT brain in a patient with SLE with secondary antiphospholipid antibody syndrome Fig. 1 : Multiple punctate calcific and hypodense lesionsneurocysticercosis Three patients had expired at 1-month follow-up and 10 were lost to follow-up at four months. One patients each of HIVrelated CNS disease, CRF dialysis and SLE, expired at 30 days follow-up. Treatment of the infetious diseases constituted standard treatment of CNS tuberculosis, neurocysticercosis and toxoplasmosis. The two patients with obstructive hydrocephalus were both shunted. The patients with HIV related dementias were treated for Toxoplasmosis in two cases and one patient with AIDS dementia was on HAART therapy. Standard treatment for chronic renal failure (CRF), including dialysis twice weekly was continued in the two patients with CRF. Vitamin B 12 and folate therapy, and thyroxine replacement, were initiated in the patients with dementia related to megaloblastic anemia and hypothyroidism, respectively. The patients with SLE were on methyl JAPI VOL. 52 DECEMBER 2004 www.japi.org 955
Table 6 : 4-month follow up of MMSE score in treatable dementia Etiology Baseline 1st month 4 month MMSE MMSE MMSE TB meningitis Tuberculoma Neurocysticercosis HIV related Systemic lupus erythematous Chronic renal failure Hypothyroidism Megaloblastic anemia Korsakoff s psychosis 18 26 27 20 27 15 24 26 20 23 25 22 26 19 24 27 16 17 26 18 21 16 17 14 14 17 (E) 21 26 27 22 29 19 (E) 14 18 20 17 22 23 21 (E) 18 24 25 19 26 26 21 26 26 17 24 27 20 25 13 22 17 24 24 Three patients expired before 1 month follow up. Ten patients lost to follow up at 4 months average MMSE rose from baseline 17.3 to 23 at 1-month follow up. Poorest response in HIV-related dementia, best response in metabolic-nutritional prednisolone and cyclophosphamide. The patients with SLE and venous infarcts received Heparin in addition. No patient was given any additional neuroprotective agent or preparation to improve cognition. Average MMSE rose form 17.3 at baseline to 23 at 1-month follow-up. DISCUSSION Although there are over 70 causes of dementia, the majority of cases is accounted for by Alzheimer s dementia. Other common causes are vascular dementia, mixed dementia and Lewy body disease. 2 All these are mainly seen in the older age group and are largely irreversible, although some degree of response may be expected with newer drugs such as the acetylcholinesterase inhibitors. In contrast, dementia may be reversible in a subgroup of patient where underlying etiology such as metabolic nutritional infective or neoplastic causes may be identified. 7 In our study which examines dementia in the presenile age group (<65 yrs), vascular dementia and Alzheimer s dementia together accounted for >65% of our patients. Alzheimer s disease is the most common cause of dementia in the west. 2 Vascular dementia, on the other hand is the predominant cause of dementia among the elderly, in eastern countries. The entity of mixed dementia, 6 which incorporates the early memory disturbance in Alzheimer s disease, along with the typical cognitive dysfunction following strokes in vascular disease, may not be easy to quantify due to difficulties with case definition. In our group of presenile vascular dementia patients (43.42%), multi-infarct state accounted for the majority. Vascular dementia was diagnosed when the ischemic score was more than seven, 4 there was CT/MRI evidence of at least 1 infarct, and there was a history of at least one stroke with stepwise cognitive decline subsequently, with or without memory decline in the early stages. 5,8 The volume of infarct causing the multi infract dementia state is probably not crucial, as evidenced by our five patients with a single discrete strategic infarct in isolation, presenting as dementia. Mixed dementia was diagnosed in 7/76 patients, with a pattern consisting of early memory decline followed by strokes and worsening cognition. This is a questionable group, as there are no validated criteria for identifying mixed dementia, and the ischemic score does not discriminate between mixed dementia and other groups. 6 In addition, in our series the diagnosis was made clinically, aided by neuroimaging, without the benefit of histopathology. On correlation of clinical and imaging diagnosis in the vascular dementia group, MRI and CT showed diffuse atrophy in 5/33 patients, in addition to infarcts. The atrophy was not localized to any particular lobe, and appeared to be secondary to the infarcts. Of the 10 clinically diagnosed Alzheimer s disease patients, eight had CT and MRI proven atrophy, six of these being parietotemporal. Two patients had no apparent atrophy, but had periventricular lacunes on MRI. However, their clinical ischemic score was less than four, and prolonged and early memory changes and personality alterations mandated their inclusion in the Alzheimer s dementia group. MRI was evidently more sensitive in detecting lacunar infarcts than CT brain, as a total of 10 patients in both groups together had additional lacunes on MRI scanning. Presently, structural brain imaging, especially MRI remains the imaging method of choice for in vivo assessment of cerebrovascular disease, although functional brain imaging is important in assisting with the differentiation of Alzheimer s disease with concomitant brain infarction from vascular dementia. 9 A comparison of the clinical profile between the vascular dementia and Alzheimer s disease group in our series, yielded background diabetes mellitus (vascular dementia 20/33 vs Alzheimer s 2/10, p < 0.05), hyperlipidemia (vascular dementia 25/33 vs Alzheimer s 3/10, p < 0.05) as being significantly commoner among the vascular dementia group. These are all risk factors for stroke, which is a presenting factor inbuilt into the diagnostic criteria for vascular dementia, and may hence reflect an inclusion bias. In addition, various risk factors have now been shown to be shared between vascular dementia and Alzheimer s disease, including hypertension, 956 www.japi.org JAPI VOL. 52 DECEMBER 2004
atherosclerosis, ischemic heart disease, smoking and diabetes. 10,11 Vascular amyloid angiography is the commonest vascular lesion reported in Alzheimer s disease. The MMSE score was not significantly different in the two groups, being 20 in the vascular dementia group and 16 in the Alzheimer s disease group. Previous studies by Fitcher et al 12 and Kertesz et al 13 where higher functions were studied in detail showed that patient with Alzheimer s disease performed better on measures of attention, executive function and fine motor control, while patients with cerebrovascular disease demonstrated better orientation, recalled and language function. 26/76 patients had potentially reversible dementia (11 infective, 11 metabolic and 3 auto-immune). In a review by Clarfield,7 32 studies (2889 subjects) that investigated prevalence of causes of dementia were critically reviewed. Potentially reversible causes made up 13.2% of all cases, and in 11 studies that provided follow-up, 11% of dementias resolved, the commonest reversible causes being drugs (28.2%), depression (26.2%) and metabolic (15.5%). These series in general did not analyse presenile dementia in particular, and their mean age was 72.3 years. In one of the series, a sub analysis showed that investigation for reversible causes was more rewarding in younger patients, 20.7% of patients aged less than 65 years having a potentially reversible cause as compared to 5.4% of patients greater than 65 years of age. 14 Fully a third of presenile dementia patients in our series had a potentially reversible cause, 44% of these being infective, reflecting the high burden of tuberculosis, HIV and neurocysticercosis in our population. Due to the referral pattern to a speciality OPD, and screening by initial treating physician, some of the common causes of reversible dementia in the general population (depression, drugs, post-head injury), were not reflected in our series. Infective disorders of the CNS may present with a wide range of symptoms, including a picture of meningeal irritation, focal seizures or neurological deficits, secondary hydrocephalus and less commonly encephalopathy or progressive cognitive dysfunction. Tuberculosis, the commonest infective process affecting the CNS in our country, usually presents with a picture of chronic meningitis with or without vasculitis or focal deficit/seizures secondary to tuberculomas. 15 The neurological manifectations of AIDS are protean- a diagnosis of HIV dementia is made in the appropriate setting after confounding medical conditions (drugs, sepsis, metabolic derangements) and opportunistic processes and neurosyphilis have been excluded. 16 Parenchymal neurocysticercosis is usually manifested by seizures and focal deficits, epilepsy being by far the most common clinical finding. Intellectual deterioration is also a frequent manifestation of parenchymal neurocysticercosis; particularly in patients with multiple cysts- these patients have a chronic neurologic disorder in which dementia and motor dysfunction predominate. 17 The potentially reversible dementias, taken as a whole showed a predominantly subcortical form of dementia, (72%), characterized by bradyphrenia and personality changes. Vascular and Alzheimer s dementia on the other hand, had predominant cortical features such as memory and language dysfunction, agnosia and apraxia. Marked psychomotor retardation, relatively preserved language function, and poor attention and concentration characterized the subcortical dementias 18 - this pattern as been found in various conditions, such as Parkinson s disease, Wilson s disease, Huntington s disease, infarctions of the basal ganglia, post-encephalitic sequale, and metabolic conditions such as parathyroid dysfunction. 18 The causes among the 26 patients with subcortical dementia included diffuse cerebral edema (AIDS), basal meningitis with hydrocephalus (TB), multiple ringenhancing lesions (tuberculomas, neurocysticercosis and toxoplasmosis), CRF, hypothyroidism, nutritional anemia and eight vascular dementia cases, six of which were subcortical lacunar strokes. Twenty three patients were followed up for one month, and 13 patients for four months, in the reversible dementia group. A rise of average MMSE score from 17.3 to 23 was seen at one-month follow up. Three patients had expired at 1- month follow up (Tuberculoma - 1, CRF - 1, SLE-1). Ten more patients were lost to follow up at four months duration. The infective cases, apart from HIV related disease; showed a good response, average MMSE rising to 26 to 4 months. HIV related dementia showed the poorest response, whereas nutritional-metabolic causes showed early and sustained response to treatment. The entity of reversible dementia has been debated in the past- a critical question is whether patients with reversible dementias stay well or relapse if followed up for long enough. In Larson s series 19 of dementia due to depression, hypothyroidism and medicational toxicity, initial improvement was followed by progressive intellectual decline suggestive of Alzheimer s disease. Again with respect to dementia reversibility, the issue of alcohol abuse is problematic, e.g. although some improvement can be expected in alcoholic patients with Wernicke-Korsakoff syndrome following vitamin infusion and abstinence, complete resolution of all clinical symptoms is usually not possible as evidenced in our patients. In our study, we have not followed up the patients of vascular dementia or Alzheimer s dementia on treatment (in the case of the former, treatment constituted control of various risk factors coupled with aspirin - clopidogrel, and in the case of the latter, donepezil in three patients), as these are not generally considered to be potentially reversible. At best, stabilization of symptoms can be expected. CONCLUSION 26/76 (34.7%) patients had a potentially reversible cause of presenile dementia in our series, etiology being infective, metabolic or autoimmune. Vascular, degenerative and mixed dementia accounted for 67% of patients. The potentially reversible group had a predominantly subcortical type of dementia, and this group showed a significant rise in MMSE JAPI VOL. 52 DECEMBER 2004 www.japi.org 957
scores on treatment. Hence, a zealous search for treatable causes of dementia in the presenile age group would be warranted, given the substantial proportion and significant treatment response of this group. REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, ed. 4, Washington DC American Psychiatric Association, 1994. 2. Lobo A, Lanner LJ, Fratigtiom L. Prevalence of dementia and major subtypes in Europe a collaborative study of population based cohorts - neurologic disease in the elderly research group. Neurology 2000;54(Supplement):4-9. 3. Folstein MF, Folstein SE, McHugh RR. Mini-mental state a practical method for grading cognitive state of patient for clinician. J Psychiatr Res 1975;12:196-8. 4. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer s disease. Report of NINCDS: ADRDA workgroup under auspices of DHHS task force on Alzheimer s disease. Neurology 1984;34:939-44. 5. Pohjasvaara T, Mantyla R, Ylikoski R, Kaste M, Erkinjutti T. Comparison of different clinical criteria (DSM-III, ADDTC, ICD-10, NINDS-AIREN, DSM-IV), for diagnosis of vascular dementia: National Institute of Neurological Disorders and Stroke. Stroke 2000;50:1431-8. 6. Zekry D, Hauw JJ, Gold G. Mixed dementia: epidemiology, diagnosis, and treatment. J Am Geriatr Soc 2002;50:1431-8. 7. Clarfield AM. The Reversible Dementias. Do they reverse? Ann Int Med 1988;109:476-86. 8. Roman GC, Tatemichi TK, Erkinjuntti T. Vascular dementia; diagnostic criteria for research studies; report of the NINDS- AIREN international workshop. Neurology 1993;43:250-60. 9. Mori E, Tshri K, Hashimoto M, et al. Role of functional brain imaging in the evaluation of vascular dementia. Alzheimer s Dis Assoc Dissorderol 1999;B(suppl.3):91-101. 10. Premkumar DRD, Cohen DL, Hedera P, et al. Apolipoprotein E e4 alleles in cerebral amyloid angiopathy and cerebrovascular pathology is Alzheimer s disease. Am J Pathol 1996;148:2083-95. 11. Hofman A, Ott A, Breteler NMB, et al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer s disease in the Rolterdam study. Lancet 1997;349:151-4. 12. Fischer P, Gatterer G, Marterer A, Danielczyk W. Nonspecificity of semantic impairment in dementia of Alzheimer s type. Arch Neurol 1988;45:1341-3. 13. Kertesz A, Clydesdale S. Neuropsychological deficits in vascular dementia VS Alzheimer s disease : frontal lobe deficits prominent in vascular dementia. Arch Neurol 1994;51:1226-31. 14. Smith JS, Kiloh LG. The investigation of dementia. Results in 200 consecutive admissions. Lancet 1981;1:824-7. 15. Prabhakar S, Thussu A. CNS tuberculosis. Neurol India 1997;45:132-40. 16. Mc Arther JC. Neurological manifestations of AIDS. Medicine 1987;66:407-37. 17. Julio Sotela, Oscar H Del Brutto, Gustavo C Roman. Cysticercosis. Current Clinical Topics in Infectious Diseases. Edited. JS Remington, MN Swartz 1996:240-59. 18. Cummings JL. Review subcortial dementia-neuropsycology, neuropsychiatry and pathophysiology. Br J Psychiatry 1986;149:682-97. 19. Larson EB, Reifler BV, Sumi SM, Canfield CG, Chinn NM. Diagnostic evaluation of 200 elderly outpatients with suspected dementia. J Gerontol 1985;40:536-43. Announcement APICON 2005 : We are closing Due to overwhelming response, the final last date of registration is 31st December 2004. No registration will be entertained after this date. The inconvenience is regretted. Siddharth N Shah Ketan K Mehta Organising Chairman, APCON 2005 Organising Secretary, APICON 2005 958 www.japi.org JAPI VOL. 52 DECEMBER 2004