Minor physical anomalies in schizophrenia: cognitive, neurological and other clinical correlates

Abstract

Minor physical anomalies (MPAs) are minor congenital malformations which are found with significantly increased frequency among both patients with schizophrenia and their siblings, suggesting the effect of early developmental disturbance in their families. The aim of this study was to explore the relationship between these signs of early dysmorphogenesis and cognitive and neurological dysfunction in the patients and their siblings as well as the clinical characteristics of the patients. Sixty patients with schizophrenia, 21 nonpsychotic siblings and 75 normal comparison subjects were studied. Increased rates of cognitive and neurological dysfunction and high MPA scores were found in both the patients and their siblings. High rates of MPAs were not significantly related to cognitive or neurological dysfunction in the patients or siblings, or to premorbid history or other characteristics of the clinical disease process in the patients. These results suggest that MPAs are possibly markers of general early neuromaldevelopment rather than markers of a specific cognitive/neurological or clinical subtype of schizophrenia.

Introduction

In recent years, a neurodevelopmental theory of schizophrenia has received increased attention (O'Callaghan et al., 1995, Waddington and Buckley, 1996). In short, this theory assumes that neuromaldevelopment occurring during the pre- and perinatal periods, and possibly also early childhood, may be a basis for the etiopathological changes that underlie the premorbid and morbid manifestations seen in schizophrenia spectrum disorders including the subtle subclinical forms. In support of this theory, considerable evidence has been obtained that factors present in very early development influence an individual's risk for becoming ill with schizophrenia later in life (Weinberger, 1995).

One of the early developmental phenomena related to schizophrenia is minor physical anomalies (MPAs), which are slight anatomical deviations occurring during early gestation and evident throughout the individual's life cycle. The pathogenesis of these anomalies would appear to be the result of inherited genetic defects, chromosomal aberration and environmental teratogenic agents interacting through as yet unknown mechanisms (Jones and Murray, 1991, Cantor-Graae et al., 1994a, Cantor-Graae et al., 1994b). The special psychiatric relevance of these anomalies is that they are assumed to be markers of parallel fetal CNS maldevelopment, as the target organs of these anomalies share their embryonic ectodermal origin with the brain, and evidence has been found for an intimate relationship between the morphogenesis of the brain and the craniofacial region (Diewert et al., 1993). MPAs have been found to be associated with a wide range of neurodevelopmental disorders including schizophrenia (Lohr and Flynn, 1993, McGrath et al., 1995). The results of 11 previous studies of MPAs in schizophrenia patients show these patients to have an average of more than four Waldrop Scale MPAs, a rate more than double that in the general population (Ismail et al., 1998b). Our recent study showed 60% of schizophrenia patients and 38% of their nonpsychotic siblings to have a total (expanded scale) MPA score of at least 6, while only 5% of normal comparison cases showed such a level (Ismail et al., 1998b). The patients showed significant increases in MPA scores both in total and in each of five specific body areas, i.e. global head, eyes, ears, mouth and hands. No discriminating ‘cranio-facial’ pattern was found among specific MPAs in patients, MPAs in the hand contributing as much or more to the discrimination of patients vs. comparison subjects as did specific MPAs in eye and mouth regions.

The role of MPAs in the subsequent development of schizophrenia remains unclear, and the investigation of the relationship between MPAs and the clinical characteristics of these patients, as well as signs of cognitive and neurological dysfunction in both the schizophrenic patients and their relatives, may potentially provide insight into the origin of the pathological changes in this disorder.

The burgeoning literature on cognitive dysfunction in schizophrenia suggests a variable degree of cognitive impairment in this syndrome, with a generalized cognitive deficit. Neuropsychological tests have not provided a ‘pathognomonic’ discrimination of schizophrenic patients from others, but schizophrenic patients show primarily functional deficits related to attentional tasks, reaction time, motor speed, verbal and working memory and executive functions (Blanchard and Neale, 1994, Flashman et al., 1996). Many studies have shown similar patterns of cognitive dysfunctions in the relatives of schizophrenic patients, especially the siblings (Cannon et al., 1994, Keefe et al., 1994, Faraone et al., 1995, Seidman et al., 1997).

Similarly, neurological abnormalities (NA) are a well documented phenomenon with high frequency in schizophrenic patients and their relatives, and are estimated to be present in 50–65% of patients with this disease (Heinrichs and Buchanan, 1988). Our recent study found 82% of the same sample of schizophrenics and 38% of their siblings to have increased neurological abnormalities, a result found in only 5% of the comparison subjects (Ismail et al., 1998a).

Previous studies of the relationship between MPAs and the clinical characteristics of schizophrenics have shown generally negative or inconsistent findings (see Table 1). Abnormal premorbid personality was positively related to MPAs in one study (Guy et al., 1983) but not in two others (Alexander et al., 1994, McGrath et al., 1995). Early age of onset was found by Green et al. (1989) to be related to high rates of MPAs, while six other studies failed to do so. Regarding the different parameters of illness severity, Lohr and Flynn (1993) found no relationship between MPAs and the amount of negative and positive symptoms. O'Callaghan et al. (1995) found a positive correlation between high MPA scores and high scores for negative symptoms, while two other studies (Torrey et al., 1994, McGrath et al., 1995) found no such relationship. McGrath et al. (1995) found a significant positive relationship between the MPA scores and the number of admissions and, non-significantly, duration of total hospitalization. Nizamie et al. (1989) found no difference in MPA level between patients with chronic (an illness duration of at least 2 years) or acute (an illness duration of less than 3 months) courses. Two studies (Alexander et al., 1994, Torrey et al., 1994) found no relationship between MPAs and the duration of illness. To our knowledge no previous study has examined the relationships between MPAs and patients' educational attainment or the current medication dose.

The relationship between MPAs and cognitive dysfunction in schizophrenic patients is similarly unclear. Four studies (Green et al., 1989, Green et al., 1994, Alexander et al., 1994) found no relationship between MPAs and cognitive dysfunction, while three others (Guy et al., 1983, O'Callaghan et al., 1991, McGrath et al., 1995) found a positive relationship. O'Callaghan et al. (1991) found higher scores of MPAs to be positively related to poor performance on Trail making B. Utilizing graphaesthesia as an indicator of cognitive function, McGrath et al. (1995) found some support for the postulated relationship between cognitive impairment and MPA score. Further, O'Callaghan et al. (1995) found a negative association between MPAs and estimated level of premorbid intelligence, while McGrath et al. (1995) found no relationship at all. Further investigation of the relation between MPAs and cognitive dysfunction is clearly indicated.

Finally, although a model of fetal maldevelopment occurring parallel in the ectoderm and in the CNS in schizophrenia would predict a positive relationship between MPAs and neurological abnormality, of the two studies (Nizamie et al., 1989, Torrey et al., 1994) which have examined this issue one found such a relationship (Nizamie et al. 1989).

To our knowledge, the relationship between the MPAs and neurocognitive and neurological dysfunction in the relatives of patients has not been studied previously.

The purpose of the current study was to investigate the role of MPAs in the development of schizophrenia, by studying the relationship between MPAs and clinical characteristics of the patients as well as cognitive and neurological dysfunctions in patients and their non-psychotic siblings. The clinical parameters of interest were educational attainment, abnormal premorbid personality, age of onset and severity of illness, as represented by duration of the illness, clinical course, global function and the amount and duration of medication needed. The hypothesis tested in this study is that high rates of MPAs are related to increased cognitive and neurological abnormality, low educational attainment, abnormal premorbid personality, early illness onset and greater severity of illness in patients. Similar relationships between MPAs and cognitive and neurological dysfunction are hypothesized to be found in the nonpsychotic siblings of these patients.

As compared with previous work, this is apparently the first study to investigate the relationship between MPAs and cognitive/neurological dysfunction in siblings of patients, it includes not previously studied patient characteristics (educational attainment and medication dose), and also uses an extended MPA scale consisting of both Waldrop Scale items and other MPAs in the same body areas, thus providing a broader scope of prenatal maldevelopment.