A systematic review and meta-analysis of neurological soft signs in relatives of people with schizophrenia

Neurological soft signs are subtle but observable impairments in motor and sensory functions that are not localized to a specific area of the brain nor characteristic of any specific neurological condition [1]. Typically they are classified into signs relating to: motor co-ordination, sequencing of complex motor tasks, sensori-motor integration, and disinhibition [2]. Neurological soft signs are known to correlate with a range of neuro-cognitive and neuro-anatomical abnormalities, and it has been proposed that they represent an underlying defect in neural integration [3]. Until recently neurological soft signs have been considered of little practical clinical significance, but the prospect that they could be an endophenotype of schizophrenia has led to a resurgence of interest [4].

Endophenotypes are defined as trait-markers that are present independent of the manifestation of a disease [5]. They represent a phenotype "within" the patient below the level of overt behavioural or psychopathological symptoms. Five criteria for an endophenotype have been put forward: (i) association with illness (higher rates of endophenotype in people with the illness than that found in the general population); (ii) state independence (presence of endophenotype irrespective of the disease state); (iii) familial association (the endophenotype is present at higher rates in unaffected family members than in the general population); (iv) co-segregation (higher prevalence of the endophenotype in ill relatives of ill probands than in well relatives of ill probands); and (v) heritability (the extent of variation of the endophenotype that is attributable to the genetic variation) [6]. It has been proposed that endophenotypes may be of particular value to genetic research on mental disorders because they are more closely related to underlying gene expression than is psychopathology [7]. For example, endophenotypes could be used for the discovery of genes associated with schizophrenia [8].

Neurological soft signs are a potential endophenotype for schizophrenia, because: they are common in people with the disorder (ranging from 50 to 65% of people with schizophrenia [1], predate the onset of the disorder [9], and can be plausibly linked to the underlying brain abnormalities postulated by the neurodevelopmental theory of schizophrenia [1, 10]. It has been established, in a systematic review and meta-analysis [3], that neurological soft signs in schizophrenia meet two criteria for an endophenotype: association with illness (because they occur much more frequently in people with schizophrenia than in controls); and state-independence (because they are present whether or not the illness is active).

This systematic review and meta-analysis aimed to determine how far soft signs in schizophrenia met a further criterion for an endophenotype, namely familial association. It was hypothesized that if familial association were present then neurological soft signs would be: (a) more common in first-degree relatives of people with schizophrenia than in controls; and (b) more common in people with schizophrenia than in their first-degree relatives.

The search strategy identified 8678 articles, of which 120 referred to studies that were thought to potentially satisfy the inclusion criteria. After obtaining the full text of these articles, it was found that 105 referred to studies that did not meet inclusion criteria. Seven studies, described in 15 articles, met inclusion criteria and offered data for the meta-analysis [14, 18‐31] (for details see study flowchart Figure 1).

All seven included studies compared levels of soft signs amongst people with schizophrenia, relatives, and normal controls, within the same design, using the same assessment method and the same raters. The participants in the included studies comprised: 558 people with schizophrenia or schizophrenia-like disorders, 471 first-degree relatives (there were no studies of second degree relatives), and 524 normal controls (see table 2). One study [28] included two independent samples from different countries (France and Tunisia). Within the meta-analysis, this study was treated as two separate studies. Of the remaining six studies the country of origin of two studies was USA [24, 25] and there was one study each from Sweden [27], Italy [14], Turkey [29] and France [26].

The Neurological Evaluation Scale [2] was used in 3 studies, whilst the Rossi Scale [14] and the Standardised Neurological Examination [15] were each used in 2 studies (see table 2).

The group of first -degree relatives was categorised as a "mixed" group in 2 studies [14, 24] as they included a combination of offspring, siblings and/or parents. In the first of these studies [14], the ages of all three groups were similar, suggesting that the relatives group were principally siblings and that there was little chance of an age difference between groups confounding the comparison. In the second study [24], the relatives group were 11 years older on average than the schizophrenia group, whilst the control group were 12 years older on average. This suggested a risk of an age confound, as neurological soft signs could increase with age. In 4 studies the first degree relatives group consisted only of siblings [25, 27‐29] and in one study consisted only of parents [26]. In this study, parents were on average 32 years older than people with schizophrenia, whereas controls were 10 years older, again suggesting the possibility of an age confound.

It was hypothesized that if soft signs showed evidence of familial association, then they would be more common in people with schizophrenia versus their first-degree relatives; and in first-degree relatives versus normal controls. Both these hypotheses were confirmed. As anticipated, it was also found that soft signs were more common in people with schizophrenia than normal controls. Thus, in summary, soft signs appear to be distributed across people with schizophrenia and their first-degree relatives in a manner that is consistent with familial association.

A key limitation of this review was the finding of significant heterogeneity across all comparisons. The variance among studies could be due to factors such as variation among sample size of studies, source of normal controls, kind of first degree relatives, scales used and clinical factors such as being on medication. Insufficient studies were available to permit investigation of this heterogeneity using meta-regression. Likewise, higher scores for some signs in patients may be due to use of anti-psychotic medication and we could not conduct moderator analysis exploring the extent of its effects. Despite some similar labels, it should be kept in mind while interpreting the meta-analysis that the rating and the tasks that correspond to the individual NSS items vary between the different scales. However, all studies in the review had the same direction of effect, and the findings were stable to analysis using a random effects model. Moreover, with the exception of one comparison (first degree relatives versus controls, where the effect size remained stable but no longer statistically significant), the findings were also stable to a rigorous sensitivity analysis which ruled out those studies with poor age matching of controls, lack of reliability testing, and unblinded raters. Thus it is probable that the findings reflect true differences between the comparison groups, rather than bias or fundamental differences in study methodology. A further limitation is the possibility that the findings could be explained by publication bias. Tests for publication bias suggest that this is unlikely, but it cannot be ruled out completely.

Hence, the findings of this review add weight to the idea that neurological soft signs are an endophenotype of schizophrenia. Contrary, to other developmental markers such as 'minor physical anomalies' were early environmental factors are indicated, soft signs reflect familial association [26]. There is evidence to suggest that certain neurological soft signs correlate with region-specific structural brain deficits in people with schizophrenia [33, 34]. Future research should explore the potential of these individual signs as endophenotype of schizophrenia.

Neurological soft signs can be elicited quickly, reliably and cheaply [13], they could be used in ordinary clinical settings to establish that an individual had progressed along the neuro-developmental pathway to schizophrenia. There is evidence to suggest association of neurological soft signs in relatives with schizotypal personality scores, symptom severity and neuropsychological measures [30]. The presence of higher rates of soft signs has the potential to augment the predictive power of psychopathological tests for the prodrome of schizophrenia, such as: the SIP/SOPS [35], Comprehensive Assessment of At Risk Mental States (CAARMS) [36], or Basic Symptoms [37]. Our meta-analysis highlights the meaning of neurological soft signs in the context of neurodevelopmental theory of schizophrenia. Neurological soft signs have important clinical implications and they open an avenue for future research.

Neurological soft signs show a pattern of familial association in schizophrenia that is compatible with the status of an endophenotype for the disorder. The findings are based on a small number of studies. There is a need for more studies using a consensual rating tool and homogeneous sample to establish that neurological soft signs are an endophenotype of schizophrenia. Prospective diagnostic studies are required to establish how far the identification of soft signs in at risk patients can augment the predictive power of established psychopathological tests.