Downloaded from http://ebmh.bmj.com/ on February 6, 2015 - Published by group.bmj.com
Evidence-based case conference
Diagnostic test for dementias Toshi A Furukawa Departments of Health Promotion and Human Behavior and of Clinical Epidemiology, Kyoto University Graduate School of Medicine/ School of Public Health, Kyoto 606-8501, Japan
INTRODUCTION This is the second of a series of evidence-based case conferences. The main aim of this new series of papers is help clinicians learn and apply the evidence-based approach in their own clinical practices. The clinical question that we seek to solve in each of this series emanates from a real clinical case. I have completely anonymised the scenario but I still hope it remains as real as it was. The presentation in this series may appear too brief and rushed, but this is how EBM can be practiced by busy clinicians once you are familiar with the process. This issue’s clinical question is about diagnosis. The case conference below illustrates how to critically appraise and apply an article about a diagnostic test. We anticipate that the third of the series will deal with a clinical question of prognosis.
CLINICAL CASE Patient: 77-year-old woman Present illness: The patient is a mother of four children who have all gotten married and left home. After her husband passed away with lung cancer several years earlier, she had been living alone, occasionally attending the elderly people’s gatherings but generally leading a quiet life. Two of her daughters live in the neighbourhood and come by several times a month for a chat. It has been almost a year that the patient talked to her family about ‘children visiting her in her room’ and that she saw them hiding in the tree outside the window of her house too. At first, the patient’s daughters did not take it seriously, but the patient described them very vividly with no apparent doubt as to their veracity. The patient seems to have had repeated falls in the house but, on questioning by her daughters, could not recall the details. She has become forgetful and sometimes cannot even recall the family’s phone calls or visits from yesterday. Worried about dementia, the daughters consulted the family doctor who found a low score on the Mini-Mental State Examination (MMSE)i and sent the patient to the Memory Clinic in our hospital. Present status: On presentation, the patient is a very agreeable old lady. She admits that her memory has become weak recently but she still manages her own house chores. On being questioned, she talks of ‘children visiting her in her room’ and also of falling down occasionally but cannot recall any details. The family has noticed no fluctuation in her alertness or no abnormal sleep behaviour, but they also admit that they may have missed such. Her MMSE score is 22. Her family doctor reported high blood pressure, which is well controlled, and history of breast cancer operation in her 50s but no other major illness. Neurological examination shows only equivocal presence of parkinsonism. Having confirmed gradually progressing cognitive decline, the list of her differential diagnoses now includes Alzheimer’s disease, vascular dementia, dementia with Lewy bodies (DLB),ii
i
MMSE is the most commonly used test for examining cognitive functions and screening for dementia. It has 11 questions and its maximum score is 30, with the commonly used threshold to raise suspicion of dementia is 24/23. ii DLB is a neurocognitive disorder characterised by progressive cognitive impairment, fluctuations in attention and alertness, recurrent complex visual hallucination, REM sleep behaviour disorders and/or spontaneous features of parkinsonism. When parkinsonism precedes onset of dementia, it is often differentiated from DLB and is called Parkinson’s disease with dementia (PDD). Evid Based Mental Health May 2014 Vol 17 No 2
frontotemporal and other dementias. We order some further neuropsychological tests for memory and executive functions and an MRI. If these are not suggestive of Alzheimer’s disease or vascular dementia, we would strongly suspect DLB and wonder if metaiodobenzylguanidine (MIBG) myocardial scintigraphyiii will be helpful in differentiating DLB from other dementias.
FORMULATE YOUR CLINICAL QUESTION Patients: Patients suspected with dementia. Intervention: MIBG myocardial scintigraphy. Comparison: Long-term follow-up diagnoses and/or neuropathological diagnoses of DLB. Outcomes: Sensitivity/specificity and/or likelihood ratios (LRs).
LITERATURE SEARCH First we searched the most important secondary sources of evidence (The Cochrane Library, Evidence-Based Mental Health, EvidenceUpdates websites) with the keyword ‘Lewy OR MIBG’. Neither the Cochrane Library nor Evidence-Based Mental Health had any diagnostic accuracy review for DLB. EvidenceUpdates had a diagnostic accuracy study of single photon emission CT for DLB but not MIBG. Then we searched PubMed: the first step was to identify MeSH terms for DLB, then entered its combination with ‘MIBG’ on the Clinical Queries page, setting category to diagnosis and scope to narrow. This quick search retrieved 3 systematic reviews and 12 diagnostic studies. One systematic review1 focused on differential diagnosis between DLB and other dementias and looked very promising. On browsing the review, however, we found that many of the included diagnostic studies had the so-called ‘case– control diagnostic design’ in which clearly diagnosed cases were compared with healthy non-cases. Such studies cannot inform clinical practices where we perform a diagnostic test because the diagnoses are uncertain and we need to differentially diagnose among several possibilities. Only one study recruited a consecutive series of patients suspected of DLB.2
CRITICAL APPRAISAL OF THE LITERATURE ON DIAGNOSTIC TEST See box.
iii MIBG is an analogue of norepinephrine and its uptake by the heart is hampered under local myocardial sympathetic nerve damage, not only in primary heart disease but also in neurological disorders with autonomic failure, such as Parkinson’s disease or DLB.
45
Downloaded from http://ebmh.bmj.com/ on February 6, 2015 - Published by group.bmj.com
Evidence-based case conference
the LR for the positive test result (LR+) is calculated as the proportion of people with positive test results among people with the disease, divided by the proportion of people with positive test results among people without the disease, that is
CRITICAL APPRAISAL OF THE LITERATURE ON DIAGNOSTIC TEST ARE THE RESULTS AT RISK OF BIAS?
LRþ ¼ [a=(a þ c)]=[b=(b þ d)]
Did participating patients present a diagnostic dilemma? YES. This study enrolled ‘all 105 outpatients’ referred to the Memory Clinic of the study authors’ secondary care hospital who fulfilled the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for dementia. Did investigators compare the test to an appropriate, independent reference standard? YES. The reference diagnosis was made in accordance with international clinical diagnostic criteria such as DLB consortium consensus guidelines, NINCDS-ADRDA and NINDS-AIREN. None of them include MIBG as a diagnostic criterion. Were those interpreting the test and reference standard blind to the other results? UNCLEAR. There is no mention of ‘blindness’ or ‘independence’ between measurements for the MIBG and the clinical diagnoses of dementia. It is possible that the personnel who provided the final clinical diagnoses were aware of the MIBG results. Did investigators perform the same reference standard to all patients regardless of the results of the test under investigation? YES. All the patients received MIBG scans and the clinical diagnosis. WHAT ARE THE RESULTS? What LRs were associated with the range of possible test results? When the heart-to-mediastinum ratio (H/M ratio) in the delayed phase below 1.73 (the mean minus 2×SD of the elderly normal controls) was used as the threshold, we obtain the following 2×2 table for differentiating DLB from other dementias.
10 or
Evidence-based case conference
Diagnostic test for dementias Toshi A Furukawa Departments of Health Promotion and Human Behavior and of Clinical Epidemiology, Kyoto University Graduate School of Medicine/ School of Public Health, Kyoto 606-8501, Japan
INTRODUCTION This is the second of a series of evidence-based case conferences. The main aim of this new series of papers is help clinicians learn and apply the evidence-based approach in their own clinical practices. The clinical question that we seek to solve in each of this series emanates from a real clinical case. I have completely anonymised the scenario but I still hope it remains as real as it was. The presentation in this series may appear too brief and rushed, but this is how EBM can be practiced by busy clinicians once you are familiar with the process. This issue’s clinical question is about diagnosis. The case conference below illustrates how to critically appraise and apply an article about a diagnostic test. We anticipate that the third of the series will deal with a clinical question of prognosis.
CLINICAL CASE Patient: 77-year-old woman Present illness: The patient is a mother of four children who have all gotten married and left home. After her husband passed away with lung cancer several years earlier, she had been living alone, occasionally attending the elderly people’s gatherings but generally leading a quiet life. Two of her daughters live in the neighbourhood and come by several times a month for a chat. It has been almost a year that the patient talked to her family about ‘children visiting her in her room’ and that she saw them hiding in the tree outside the window of her house too. At first, the patient’s daughters did not take it seriously, but the patient described them very vividly with no apparent doubt as to their veracity. The patient seems to have had repeated falls in the house but, on questioning by her daughters, could not recall the details. She has become forgetful and sometimes cannot even recall the family’s phone calls or visits from yesterday. Worried about dementia, the daughters consulted the family doctor who found a low score on the Mini-Mental State Examination (MMSE)i and sent the patient to the Memory Clinic in our hospital. Present status: On presentation, the patient is a very agreeable old lady. She admits that her memory has become weak recently but she still manages her own house chores. On being questioned, she talks of ‘children visiting her in her room’ and also of falling down occasionally but cannot recall any details. The family has noticed no fluctuation in her alertness or no abnormal sleep behaviour, but they also admit that they may have missed such. Her MMSE score is 22. Her family doctor reported high blood pressure, which is well controlled, and history of breast cancer operation in her 50s but no other major illness. Neurological examination shows only equivocal presence of parkinsonism. Having confirmed gradually progressing cognitive decline, the list of her differential diagnoses now includes Alzheimer’s disease, vascular dementia, dementia with Lewy bodies (DLB),ii
i
MMSE is the most commonly used test for examining cognitive functions and screening for dementia. It has 11 questions and its maximum score is 30, with the commonly used threshold to raise suspicion of dementia is 24/23. ii DLB is a neurocognitive disorder characterised by progressive cognitive impairment, fluctuations in attention and alertness, recurrent complex visual hallucination, REM sleep behaviour disorders and/or spontaneous features of parkinsonism. When parkinsonism precedes onset of dementia, it is often differentiated from DLB and is called Parkinson’s disease with dementia (PDD). Evid Based Mental Health May 2014 Vol 17 No 2
frontotemporal and other dementias. We order some further neuropsychological tests for memory and executive functions and an MRI. If these are not suggestive of Alzheimer’s disease or vascular dementia, we would strongly suspect DLB and wonder if metaiodobenzylguanidine (MIBG) myocardial scintigraphyiii will be helpful in differentiating DLB from other dementias.
FORMULATE YOUR CLINICAL QUESTION Patients: Patients suspected with dementia. Intervention: MIBG myocardial scintigraphy. Comparison: Long-term follow-up diagnoses and/or neuropathological diagnoses of DLB. Outcomes: Sensitivity/specificity and/or likelihood ratios (LRs).
LITERATURE SEARCH First we searched the most important secondary sources of evidence (The Cochrane Library, Evidence-Based Mental Health, EvidenceUpdates websites) with the keyword ‘Lewy OR MIBG’. Neither the Cochrane Library nor Evidence-Based Mental Health had any diagnostic accuracy review for DLB. EvidenceUpdates had a diagnostic accuracy study of single photon emission CT for DLB but not MIBG. Then we searched PubMed: the first step was to identify MeSH terms for DLB, then entered its combination with ‘MIBG’ on the Clinical Queries page, setting category to diagnosis and scope to narrow. This quick search retrieved 3 systematic reviews and 12 diagnostic studies. One systematic review1 focused on differential diagnosis between DLB and other dementias and looked very promising. On browsing the review, however, we found that many of the included diagnostic studies had the so-called ‘case– control diagnostic design’ in which clearly diagnosed cases were compared with healthy non-cases. Such studies cannot inform clinical practices where we perform a diagnostic test because the diagnoses are uncertain and we need to differentially diagnose among several possibilities. Only one study recruited a consecutive series of patients suspected of DLB.2
CRITICAL APPRAISAL OF THE LITERATURE ON DIAGNOSTIC TEST See box.
iii MIBG is an analogue of norepinephrine and its uptake by the heart is hampered under local myocardial sympathetic nerve damage, not only in primary heart disease but also in neurological disorders with autonomic failure, such as Parkinson’s disease or DLB.
45
Downloaded from http://ebmh.bmj.com/ on February 6, 2015 - Published by group.bmj.com
Evidence-based case conference
the LR for the positive test result (LR+) is calculated as the proportion of people with positive test results among people with the disease, divided by the proportion of people with positive test results among people without the disease, that is
CRITICAL APPRAISAL OF THE LITERATURE ON DIAGNOSTIC TEST ARE THE RESULTS AT RISK OF BIAS?
LRþ ¼ [a=(a þ c)]=[b=(b þ d)]
Did participating patients present a diagnostic dilemma? YES. This study enrolled ‘all 105 outpatients’ referred to the Memory Clinic of the study authors’ secondary care hospital who fulfilled the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for dementia. Did investigators compare the test to an appropriate, independent reference standard? YES. The reference diagnosis was made in accordance with international clinical diagnostic criteria such as DLB consortium consensus guidelines, NINCDS-ADRDA and NINDS-AIREN. None of them include MIBG as a diagnostic criterion. Were those interpreting the test and reference standard blind to the other results? UNCLEAR. There is no mention of ‘blindness’ or ‘independence’ between measurements for the MIBG and the clinical diagnoses of dementia. It is possible that the personnel who provided the final clinical diagnoses were aware of the MIBG results. Did investigators perform the same reference standard to all patients regardless of the results of the test under investigation? YES. All the patients received MIBG scans and the clinical diagnosis. WHAT ARE THE RESULTS? What LRs were associated with the range of possible test results? When the heart-to-mediastinum ratio (H/M ratio) in the delayed phase below 1.73 (the mean minus 2×SD of the elderly normal controls) was used as the threshold, we obtain the following 2×2 table for differentiating DLB from other dementias.
10 or
