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Introduction
Cognitive impairment, sometimes amounting to dementia, may accompany many neurological disorders1; thus, any neurological sign2 might, in theory, be associated with a cognitive deficit. However, in practice, only a few are relevant because of the limited number of conditions that typically present to cognitive disorders clinics. In addition to these textbook (canonical) neurological signs, a number of others that are easily observed and categorised may help in deciding whether there is cognitive impairment or not. These signs, therefore, also merit inclusion here; indeed, they are discussed first, since in practice, the differentiation of cognitively healthy and cognitively impaired individuals should precede any further investigations.
This article does not presume to be exhaustive, but focuses on those signs that I have found useful in practice. Clearly, any neurological examination must follow a detailed history in order to contextualise any examination findings.
The pattern of neuropsychological deficits evident on cognitive testing, either performed by the neurologist3 or more formally by a neuropsychologist, may help more than neurological signs in establishing an aetiological diagnosis.
Non-canonical signs
Many referrals to the cognitive disorders clinic—possibly an increasing number following high-profile directives on dementia (whether in consequence or subsequence)—are of cognitively healthy individuals with memory complaints, a group variously labelled as worried well, memory complainers, or those with subjective memory impairment. This heterogeneous group includes healthy people intuiting the memory inefficiency which we all will develop with ageing (perhaps from the mid-40s onwards4), as well as those with mood disorders or sleep impairment. Clinical assessment must try to identify these individuals, and to differentiate them from those harbouring the early stages of a neurological disorder, so that they may be appropriately reassured.
The following easily observed and categorised signs, not generally found in neurological textbooks, may help this initial differentiation of the cognitively healthy from the cognitively impaired, although there have been few reported pragmatic diagnostic accuracy studies of these signs.
‘Attended alone’ sign
A collateral history is absolutely essential for assessing patients with memory complaints (as for blackouts). For this reason, patients referred to cognitive clinics are usually requested to attend with a knowledgeable informant (spouse, relative, friend, carer). Despite this, experience shows that many patients attend alone, an observation which in itself may powerfully predict the absence of dementia.5 ,6
A 3-year study of consecutive new referrals to a cognitive disorders clinic examined the value of the ‘attended alone’ sign to identify subjective memory impairment.7 Of the 726 patients, 480 (66%) attended with an informant as requested, of whom 216 had either dementia or cognitive impairment without dementia; 264 patients had subjective memory impairment. In the ‘attended alone’ group (n=246), no one had dementia, but 16 had cognitive impairment without dementia and, hence, were at possible risk of progressing to dementia, leaving 230 individuals with subjective memory impairment. Hence, the ‘attended alone’ sign was very sensitive (0.93) for a diagnosis of subjective memory impairment, with a high negative predictive value (also 0.93), a measure of the probability of the absence of disease (see table 1, left hand column).7
The ‘attended alone’ sign, therefore, has excellent sensitivity for the absence of cognitive impairment,5 ,6 and also for identifying subjective memory impairment.7 It may, therefore, be a useful screening observation, indicating in many cases that reassurance rather than further investigation may be the most appropriate clinical management. Attending alone may reflect preserved activities of daily living as well as memory and executive functions, and hence, a marker of an Alzheimer's disease mimic.8
Head-turning sign
While taking the history from a patient with possible cognitive impairment
the physician may observe that the patient exhibits the head turning sign (looking at his care-giver when asked a question), which is a common sign in Alzheimer's disease.9
The head-turning sign may be operationalised as the observation that the patient turns her or his head away from the interlocutor and towards the accompanying person(s) when first invited to describe symptoms, or when specifically asked about them. Note that this operationalisation differs from that used by the authors of another study, namely head turning while performing cognitive screening tests, such as the Mini-Mental State Examination.10
Two non-overlapping pragmatic diagnostic accuracy studies examined the head-turning sign (table 1, middle column).11 ,12 The sign was only modestly sensitive for the diagnosis of cognitive impairment (0.63–0.68) but had excellent specificity (0.94–0.95); in other words, it is reliably absent in those without cognitive impairment. The head-turning sign had correspondingly excellent positive predictive value (0.94–0.96), a measure of the probability of disease in a patient with a positive test.11 ,12 The sign's exact neuropsychological correlates are not currently defined; it might possibly be a somatic marker of amnesia.
Applause sign
The applause sign (signe d'applause) is elicited by asking a patient to clap their hands three times as quickly as possible, as demonstrated by the examiner; clapping more than three times is abnormal. The applause sign was first shown in progressive supranuclear palsy,13 and later in other parkinsonian disorders such as Parkinson's disease, dementia with Lewy bodies, corticobasal degeneration and multiple system atrophy.14 It also occurs in cortical dementias, such as Alzheimer's disease and frontotemporal lobar degeneration, albeit less frequently than in progressive supranuclear palsy and dementia with Lewy bodies.15 ,16 The applause sign may be a motor perseveration, indicating frontal lobe dysfunction.
A prospective observational study of the diagnostic value of the applause sign in day-to-day clinical practice17 showed it to have poor sensitivity for the diagnosis of cognitive impairment (0.26) but better specificity (0.91). Unlike in the experimental studies of selected patient groups, this pragmatic study of consecutive clinic attenders showed that the sign was specific—that is, its absence effectively ruled out dementia or cognitive impairment—but not sensitive. As in previous studies, the applause sign was not specific to a particular disease (table 1, right hand column).17
Canonical signs
In considering the potential value of textbook, canonical neurological signs in assessing patients attending the cognitive clinic, I use the traditional Holmesian order of the neurological examination (appearance, tone, power, coordination, reflexes sensation). Of course, these do not occur in isolation, but in the context of a clinical history and the observation of the aforementioned non-canonical signs, which may have raised clinical suspicion of a dementing disorder.
Appearance
Focal muscle wasting with concurrent muscle fasciculation, for example in the shoulder girdle (more often than in the tongue), suggests an anterior horn cell disorder, as in frontotemporal dementia with motor neurone disease. Generalised muscle wasting (cachexia) may be common to many dementias in their later stages, often from poor nutrition.
Movement disorders may be obvious on initial clinical observation or on examining the gait, but sometimes may be subtle. Parkinsonism (akinesia more often than tremor) occurs in Parkinson's disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, and corticobasal syndrome, which has heterogeneous neuropathology, including corticobasal degeneration as well as Alzheimer's disease and frontotemporal lobar degenerations. Parkinsonism also occurs in Alzheimer's disease—usually late in the course—and occasionally in prion diseases. In a large cohort of patients with vascular dementia, parkinsonian gait disorder and hypokinesia were associated with small vessel disease, while hemiplegic gait associated more often with cerebral infarction.18 Mild akinesia and parkinsonian gait or posture were common among a small cohort of patients with frontotemporal dementia.19
Choreiform movements always raise the possibility of Huntington's disease. Myoclonus occurs early in sporadic Creutzfeldt–Jakob disease, but generally late in Alzheimer's disease, and is rare in frontotemporal lobar degenerations. The alien limb phenomenon occurs with corticobasal degeneration, but has been described on occasion in Alzheimer's disease and prion disease.
Tone
Limb rigidity typical of parkinsonism may develop in the classical parkinsonian disorders and also in later stages of Alzheimer's disease, in vascular dementia as a consequence of small vessel disease,18 and in frontotemporal dementia.19 Some patients with dementia with Lewy bodies have no extrapyramidal signs at the time of cognitive presentation.20
Spasticity may occur in vascular dementia associated with cerebral infarction.18 Spastic paraparesis may occur in ‘variant Alzheimer's disease’ in association with presenilin-1 gene mutations, particularly, but not exclusively, those clustered around exons 8 and 9.21
Gegenhalten (German: to counter or stand one's ground) or paratonia, is a resistance to passive limb movement, which increases with attempts to get the patient to relax; it may indicate bilateral frontal lobe disease.2 Gegenhalten occasionally occurs in patients with Alzheimer's disease with dyspraxia, and in those with frontal lobe disorders, such as cerebrovascular disease.
Power
Patients with the frontotemporal dementia of motor neurone disease may show weakness consistent with muscle wasting, although sometimes their strength may be surprisingly well preserved despite wasting. Hemimotor dysfunction may be a feature of vascular dementia associated with cerebral infarction.18
Coordination
Cerebellar ataxia may develop in some forms of prion disease, and in association with some presenilin-1 mutations causing early onset Alzheimer's disease.21 Cognitive impairment may develop in some forms of spinocerebellar ataxia, particularly SCA2 and SCA17.1
Reflexes
Patients with vascular dementia due to cerebral infarction are more likely to have reflex asymmetry than those with small vessel disease.18
Primitive reflexes (eg, grasp, snout, palmomental, rooting) may be defined as reflexes that are present in infancy but which disappear with brain maturation; re-emergence in adulthood suggests brain pathology.2 Though sometimes classified with the primitive reflexes, the pout reflex may be more appropriately categorised as an upper motor neuron facial reflex.22 One study of 31 patients with mild-to-moderate frontotemporal dementia found that the palmomental reflex was the only primitive reflex present in 7% of the patients.19 Although sometimes denoted as ‘frontal release signs’, a retrospective chart review of 204 dementia patients found primitive reflexes did not positively predict frontotemporal dementia. Primitive reflexes—of which the palmomental was the most common—were more likely in dementia with Lewy bodies and Alzheimer's disease than in frontotemporal dementia.23 However, others have noted grasp and rooting reflexes in frontal disorders, with the rooting reflex being much more common in orbitofrontal degeneration than in dementia with Lewy bodies and Alzheimer's disease.
Environmental dependency behaviours, such as imitation behaviour and utilisation behaviour, are much more common in the behavioural variant frontotemporal dementia than in Alzheimer's disease, particularly when information gathered is from observation in the clinic and from caregiver history. Imitation behaviour may be exclusive to behavioural variant frontotemporal dementia.24 Environmental dependency behaviours may result from a frontoparietal network dysfunction.25
Sensation
Hemisensory dysfunction may characterise vascular dementia associated with cerebral infarction.18 Sensory complaints may occur in prion disease, especially variant Creutzfeldt–Jakob disease—in which persistent and unpleasant pain (hyperpathia) may affect the limbs, trunk, or face.26 Agraphaesthesia may occur in corticobasal syndrome.
Conclusion
In addition to patient and collateral history and cognitive testing, several neurological signs may help in assessing patients referred to cognitive clinics. If the patient attends alone, the index of clinical suspicion will be low (ie, threshold for concern is high) since this seems to be a robust indicator of subjective memory impairment. By contrast, observation of either the head-turning sign or the applause sign during clinical assessment should increase the index of clinical suspicion for the presence of cognitive impairment. In that case, clinicians should search for other neurological signs that might permit refinement of dementia subtype/neurological diagnosis.
References
Footnotes
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Competing interests None.
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Provenance and peer review Commissioned; externally peer reviewed. This paper was reviewed by Martin Rossor, London, UK.
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