(1)
Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool, UK
Abstract
This chapter considers important aspects in the clinical history, including family history, in the diagnosis of cognitive disorders, and also examines the diagnostic utility of various non-canonical neurological signs (attended alone, head turning, applause).
Keywords
DementiaDiagnosisHistoryNeurological signs3.1 History Taking
History taking and physical examination are the touchstone of all neurological assessments and the first step in all diagnostic pathways (Larner et al. 2011). This is as true for individuals with cognitive complaints as for those with sensory and/or motor problems. History taking is by far the most important method of assessment.
A semi-structured approach to the history, sufficiently flexible to accommodate the variety of clinical presentation, is required. Application of Kipling’s “six honest serving men” (what, why, when, how, where, who) may be useful (Fisher and Larner 2006; Larner 2007a; Box 3.1). This may also flesh out the social, occupational, and past medical history which will contextualise the current problems.
Box 3.1: Suggested Approach to the History Taking in the Cognitive Clinic (Adapted from Larner 2007a)
What are the problems? Frequent repetition of questions or comments suggests organic amnesia. Loss of instrumental activities of daily living such as handling finances or medications, travelling by public or private transport, and using the telephone, should arouse concern since epidemiological studies show them to be predictive of dementia.
Why has the patient presented now? Have problems been worsening over some months? Or has some particular incident triggered consultation? An acute episode of confusion (delirium) occurring during febrile illness or post-operatively may be the harbinger of progressive cognitive decline.
When did this happen? Many years of forgetfulness are less alarming than a history of 6–12 months of progressive decline. Also, when in the lifespan: pathological causes of memory complaint are much more common in later life, although 2.2 % of dementia cases occur before the age of 65 years.
How do the patient and family cope with the situation? Have there been work or domestic repercussions because of forgetfulness, e.g. complaints that work is not being done or even dismissal from work, others needing to take over the patient’s usual household chores?
Where do the problems occur? Are they more noticeable in new or unusual situations? Does the patient prefer to be at home, to the extent that social withdrawal has occurred? Has occupational function been impaired?
Who makes the complaint of forgetfulness? Does it emanate primarily from the patient, or from relatives, friends and carers? If the latter, whilst the patient makes little of the difficulties, the clinical index of suspicion should be increased, likewise if patients are unable to give examples of memory lapses. Patients attending alone very seldom have dementia.
Some centres use a history proforma to ensure that all potentially relevant issues are addressed, including not only cognitive symptoms but also behavioural and psychiatric features. Key history points (Larner 2011a) will include:
The specific complaint: if memory problems, ask for some examples of how the patient’s memory lets her/him down.
Age at onset (and hence duration) of the problem.
Onset and course of the problem: sudden or gradual onset? Fluctuating or steadily progressive course?
In addition, the importance of obtaining collateral history from a knowledgeable informant cannot be overemphasized. In some centres a provisional diagnosis of Alzheimer’s disease (AD) in pre-dementia stage is based largely on informant report (Burns and Morris 2008).
Enquiries about the impact of cognitive problems on occupational and/or social functions should be made, since impairment in these domains is a sine qua non for a DSM-IV diagnosis of dementia (American Psychiatric Association 2000). Further insights may be gained by enquiring about the impact of symptoms on activities of daily living (ADL), both instrumental and basic activities (Box 3.2). Dedicated screening instruments for the assessment of ADLs are available (see Sect. 5.1).
Box 3.2: History Taking in the Cognitive Clinic: ADLs
Instrumental activities:
Ability to use public and private transport
Handling monetary transactions
Using the telephone, e.g. recalling messages
Managing medications
Basic activities:
Feeding
Dressing
Toileting
Additional points worth enquiring about in the history include:
Education and employment: extent of education and employment history may give some pointers to premorbid cognitive function, and hence expectations about appropriate performance on cognitive testing.
Appetite: may be poor, and associated with some weight loss, in the early stages of some dementias (e.g. Alzheimer’s disease); change in dietary habit with a predilection for sweet foods may occur in behavioural variant frontotemporal dementia (bvFTD).
Mood: anxiety and depression can impact on memory function, and may be potentially reversible with appropriate medication (see Sect. 5.2).
Sleep pattern: disturbed sleep may impair memory, for example in depression or specific sleep-related disorders such as obstructive sleep apnoea syndrome or restless legs syndrome (see Sect. 5.3).
Drug use: both prescription and recreational drugs may impair cognition, for example due to anticholinergic or soporific effects.
Specific aspects of the history may have positive predictive value for specific dementia disorders (see Chap. 8). These include:
Motor slowing, visual hallucination, REM sleep behaviour disorders in dementia with Lewy bodies and Parkinson’s disease dementia.
Early speech production problems, or impaired comprehension in the linguistic variants of frontotemporal lobar degeneration (FTLD).
Personality change, either apathy or disinhibition; increased tendency to routines; development of sweet tooth; wandering without getting lost in bvFTD.
Getting lost early; lack of confidence; early amnesia in Alzheimer’s disease.
Prior transient ischaemic attacks/strokes, emotional incontinence in vascular cognitive impairment and vascular dementia.
History taking may be envisaged as a conversion of the patient (and collateral) episodic account into a semantic formulation. The key question which history taking should seek to answer is whether the account is one of self-reported lapses in memory retrieval in the absence of collateral verification, or an informant report of memory impairment with loss of self-appreciation by the patient, the latter being more in keeping with a neurodegenerative disorder (Burns and Morris 2008:53; Larner 2011a).
Pattern recognition and deductive skills, perhaps akin to the methodology used by the fictional detective Sherlock Holmes, who encountered various neurological disorders in his practice (Larner 2011b), and whose skills have been adduced to the service of interpretive (Hunter 1991) and evidence-based medicine (Nordenstrom 2007), are central to diagnostic formulation, supplemented where necessary by further investigations (discussed in Chaps. 4, 5 and 6).
3.1.1 Family History of Dementia
Taking a family history is an integral part of the history taking process in all domains of medicine, not only neurology.
Many individuals attending cognitive disorders clinics with complaints of poor memory prove, following clinical and cognitive testing, to have no evidence for underlying cognitive impairment indicative of a neurodegenerative disorder, prompting diagnostic labels such as “worried well” and “subjective memory complainers” (see Sect. 1.4). What prompts these individuals to be sufficiently concerned about memory function to consult medical opinion is not entirely clear. Factors which may contribute to subjective memory impairment include affective disorders, such as anxiety and depression (Sect. 5.2.2; Hancock and Larner 2009a), sleep disturbance (Sect. 5.3.1; Hancock and Larner 2009b), and self-perception of impaired self-efficacy (Sect. 7.3). Another possible factor is the presence of a family history of a dementing disorder (see Case Study 3.1). This concern may be well justified in light of the increasing number of recognised genetically determined causes of dementia (Sect. 6.3). Although the family history may emerge or be volunteered during history taking, specific questions about this aspect may need to be addressed to the patient.
Case Study 3.1: Family History of Dementia
A 43 year-old lady was referred to the clinic by her general practitioner with memory complaints. She attended alone. Her specific complaints were of difficulty with peoples’ names and forgetting ongoing tasks if distracted. There was a prior history of a seizure disorder, exact nature unspecified, but she was receiving neither antiepileptic nor any other medication. On direct questioning, she admitted to poor sleep, with sleep maintenance insomnia resulting in an estimated 4 h sleep per night, leaving her tired during the day. She was not working, and had lost interest in hobbies, but activities of daily living were preserved.
Her family history was positive for dementia. The patient (see Fig. 6.4, patient III.7) was one of seven siblings, all brothers, the three eldest of whom were affected, all with onset in their early 40s. Their mother was also affected. The brothers had been diagnosed with probable Alzheimer’s disease (AD) on the basis of their clinical phenotype.
The patient’s neurological examination was normal. Cognitive status was examined with the Mini-Mental State Examination (see Sect. 4.1) on which she scored 29/30 (1 point dropped out of 3 on delayed recall) and with the Montreal Cognitive Assessment (see Sect. 4.9) on which she scored 27/30 (normal ≥ 26/30; 1 point dropped out of 5 on delayed recall). Structural brain imaging was normal. In the absence of an objective measure of cognitive impairment, the patient was diagnosed with subjective memory impairment.
Following the death of one of her brothers, it became evident from post-mortem examination that he in fact had a tauopathy and not AD. Further investigation with neurogenetic testing showed that this was due to a splice site mutation in the gene encoding the microtubule associated protein tau on chromosome 17 (IVS10+16C>T), and hence his diagnosis was frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17; Doran et al. 2007). A cousin later presented with a clinical phenotype more typical of behavioural variant frontotemporal dementia but with the same tau gene mutation (Larner 2009a). In light of this information, the patient was offered referral to clinical genetics services for consideration of counselling prior to predictive genetic testing, but she declined this in light of the reassuring cognitive and neuroradiological findings.
To investigate what effect a positive family history of dementia might have on referrals to the Cognitive Function Clinic (CFC), a prospective observational study was undertaken, based on a clinical impression that a positive family history of dementia might be more common in clinic attenders without dementia (Larner 2013a). As part of clinical history taking, enquiry for a family history of dementia and/or AD was made in consecutive new patients attending the clinic over a 6-month period (April-September 2011 inclusive). The following definitions were used (after Cruts et al. 1998):
“Autosomal dominant disease”: ≥3 affected family members in at least two generations.
“Familial disease”: at least one first degree family relative affected.
“Sporadic disease”: no family history.
Of the 139 patients assessed (M:F = 66:73, 47 % male; age range 18–88 years, median 61 years), 63 were judged to be either demented by DSM-IV criteria (American Psychiatric Association 2000) or to have mild cognitive impairment (MCI) by Petersen criteria (Petersen et al. 1999), hence the prevalence of cognitive impairment was 45 %; 76 patients were not demented. Forty-three patients reported a positive family history of dementia. In only four instances were the criteria for “autosomal dominant disease” fulfilled, the remainder (39) having only “familial disease”.
Of the 63 patients who received a diagnosis of dementia or MCI, 14 had a positive family history (all “familial disease”). Of the 76 patients who were judged to have neither dementia nor MCI, 29 had a positive family history (either “autosomal dominant disease”, 4, or “familial disease”, 25). Hence the frequencies of a positive family history in the two groups were 14/63 (=22.2 %) and 29/76 (=38.2 %) respectively. The relative risk or risk ratio of a patient with neither dementia nor MCI having a positive family history of dementia was 1.72 (95 % confidence interval [CI] = 1.00–2.96). The null hypothesis that the proportion of patients with a positive family history of dementia was the same in the cognitively impaired and non-impaired groups was not rejected, although a trend was observed (χ2 = 3.41, df = 1; 0.1 > p > 0.05). Using the Z test, the null hypothesis was rejected (Z = 2.02, p < 0.05).
As the data on family history of dementia in this study were based on patient report, with or without input from other family member, friend or carer, they are obviously subject to recall bias, which might be deemed a shortcoming. Nonetheless, since this reported family history is the one with which the patient operates, the data have ecological validity. They suggest that a positive family history of dementia may be one stimulus for concerns about memory leading to consultation and onward referral.
A potential confounder of this result may be that patients with cognitive impairment might underreport a positive family history, for example as a consequence of an amnesic syndrome. However, since these individuals almost invariably attend the clinic with a relative, friend or carer (see Sect. 3.2.1), the risk of this confound may be minimised by the availability of collateral report.
It might be argued that using a more stringent definition of autosomal dominant disease (e.g. >3 affected family members in three generations, and/or disease age at onset <61 years) might alter the study conclusions (certainly this increases the chances of finding deterministic genetic mutations, e.g. Cruts et al. 1998; Campion et al. 1999; Janssen et al. 2003). However, experience of eight families with deterministic genetic mutations for dementia seen in CFC (four with tau gene mutations, four with presenilin 1 gene mutations) found that in only three of these families was there a clear autosomal dominant pattern of disease transmission (using the same definition as used in this study); in four others there was familial disease, and one case was apparently sporadic, possibly due to de novo mutation. All but one of these families had early-onset (i.e. before 65 years of age) dementia (Doran and Larner 2009; see Sect. 6.3 for further details). All four of the patients in the family history study with a reported family history suggestive of autosomal dominant disease did not have cognitive impairment (Larner 2013a).
A study of first-degree relatives of patients with AD reported more subjective memory complaints than in the spouses of AD patients, especially in those with a prior history of depression (Tsai et al. 2006). Another study found this relationship only in the relatives of patients with early-onset AD, suggesting that increased monitoring of memory performance might occur when relatives enter the age range in which parents or siblings developed dementia (McPherson et al. 1995). It may be that these individuals are sensitized to the symptoms of memory impairment, or over-attend to apparent signs of cognitive loss, including memory lapses, as a consequence of their family history.
3.2 Neurological Examination
Neurological examination is guided by diagnostic hypotheses generated by history taking, which will contextualise and give meaning (relevant, irrelevant) to the many signs which may be detected on neurological examination (Larner 2011c, 2014). There are no neurological signs which are pathognomonic of dementia, in part because there is overlap with signs which may emerge with normal ageing (Larner 2006, 2011c:7–8, 2012a). In the appropriate setting certain features may be suggestive of the diagnosis, such as carphologia or floccillation (Larner 2007b).
A normal neurological examination may be anticipated in those with subjective memory impairment, but this is also the norm in neurodegenerative disorders such as Alzheimer’s disease in its early stages. A number of neurological signs should be specifically looked for (Box 3.3; Larner 2011a, 2014), since they may suggest specific disorders (also known as “secondary” dementias; Kurlan 2006) and/or broaden the differential diagnosis to the many neurological disorders which may have cognitive impairment as part of their phenotype (Larner 2013b). Measurement of blood pressure and auscultation for cardiac sounds and possible carotid bruits may be indicated if vascular dementia or vascular cognitive impairment is suspected.
Box 3.3: Neurological Signs to Look for in Patients Attending the Cognitive Clinic (Adapted from Larner 2011a, 2014)
Parkinsonism: Parkinson’s disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal syndrome; may also be seen in Alzheimer’s disease.
Muscle wasting +/− fasciculations; cachexia may be common to many dementias in their later stages, but concurrent fasciculations in the tongue or around the shoulder girdle suggest frontotemporal lobar degeneration with motor neurone disease.
Myoclonus: occurs early in sporadic Creutzfeldt-Jakob disease, late in Alzheimer’s disease.
Chorea: Huntington’s disease.
Sensory complaints: prion disease, especially variant CJD; multiple sclerosis.
The methodology used for assessing the diagnostic utility of neurological signs is similar to that used for cognitive and non-cognitive screening instruments (see Chap. 2).
3.2.1 “Attended Alone” Sign
The importance of collateral history from a knowledgeable informant when assessing individuals complaining of memory problems and in the diagnosis of dementia syndromes, particularly AD, has been emphasized in diagnostic guidelines (e.g. Knopman et al. 2001; Waldemar et al. 2007). Formalised input to the diagnostic process from a caregiver may be achieved through the use of structured interviews of informants, or informant scales (see Sect. 5.4).
Because of the importance of collateral history in the assessment of cognitive problems, all patients referred to CFC are sent written instructions, printed in bold type, requesting them to attend the clinic with someone who knows them well and can give information about them. These instructions are included with the letter giving the details of the clinic appointment (date, time, location).
Failure to attend CFC consultation with an informant, despite the prior provision of written instructions to do so, has been examined as a possible (“Attended alone”) sign of absence of dementia in two consecutive studies over a 6-year period (September 2002-August 2008) (Larner 2005a, b, 2009b). The results (Table 3.1) showed that attending alone was a robust sign of the absence of dementia, with very high sensitivity, negative predictive value and negative likelihood ratio, but low specificity, positive predictive value and positive likelihood ratio, and clinical utility indices which were only adequate (rule in) or poor (rule out).
“Attended alone” | |
|---|---|
N | 735 |
Prevalence dementia | 45 % |
Accuracy | 0.66 (0.61–0.72) |
Sensitivity (Se) | 0.99 (0.91–1.07) |
Specificity (Sp) | 0.40 (0.37–0.43) |
Y | 0.39 |
PPV | 0.57 (0.53–0.62) |
NPV | 0.98 (0.90–1.06) |
PSI | 0.55 |
LR+ | 1.65 (1.52–1.78) = unimportant |
LR− | 0.030 (0.027–0.033) = large |
DOR | 54.3 (50.1–58.9) |
CUI+ | 0.56 (adequate) |
CUI− | 0.39 (poor) |
The utility of the attended alone sign may be dependent in part on the location where patients are being seen. In the study of the Instrumental Activities of Daily Living (IADL) Scale (see Sect. 5.1.1; Hancock and Larner 2007), of the patients completing the instrument without an informant present (n = 63), most did not have dementia (56, of whom 5 had mild cognitive impairment). Six of the seven patients adjudged to have dementia but attending the clinic alone lived close to the hospital, the only medical institution in the town (Runcorn, Cheshire) where they were seen; the other patient travelled by ambulance arranged by his primary care practitioner.
A subsequent study (Larner 2012b) of the “attended alone” sign in a large, independent outpatient cohort was undertaken to evaluate its utility as a simple screening test for the absence of dementia, as previously reported. Since “absence of dementia” may include individuals with MCI, the utility of the “attended alone” sign for identification of cognitively healthy individuals within the subjective memory impairment (SMI) group was also examined, by excluding MCI patients. Over the 3-year study period (September 2008-August 2011), a total of 726 new patients were assessed. The majority of referrals came from primary care physicians (500/726, =68.9 %), the other major sources being psychiatry services (106/726, =14.6 %) and other neurologists (88/726, =12.1 %). Compared with the prior 6 year-period (September 2002-August 2008), this suggested an increased (approximately doubled) referral rate (see Sect. 1.1).
Of the 726 patients, 480 (=66.1 %) attended with an informant as requested, of whom 216 were diagnosed with either dementia or MCI, and 264 were diagnosed as cognitively healthy. In the attended alone group (n = 246), no patient was diagnosed as suffering from dementia but 16 patients were diagnosed with MCI and hence at possible risk of progressing to dementia, leaving 230 individuals diagnosed as cognitively healthy in this group. Prevalence of dementia/MCI (i.e. cognitive impairment) in the study population was therefore 31.9 % (232/726). Dementia prevalence in previous studies (2002–2008) was 45.0 % (331/735; MCI diagnoses not recorded). The null hypothesis that the proportion of patients with dementia/MCI in the study period versus the proportion with dementia in the historical cohort was the same was rejected (χ2 = 26.6, df = 1; p < 0.001; see Sect. 1.4).
Diagnostic parameters for the “attended alone” sign for the absence of dementia (Table 3.2, left hand column) showed excellent sensitivity, negative predictive value, and negative likelihood ratio, as previously (Table 3.1).
“Attended alone” | ||
|---|---|---|
N | 726 | |
Prevalence cognitive impairment | 32 % | |
M:F (% male) | 383:343 (52.7) | |
Age range | 16–92 (median 61) | |
Diagnosis of no dementia | Diagnosis of subjective memory impairment (i.e. no dementia or MCI) | |
Accuracy | 0.64 (0.60–0.67)
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