© 2011 John Wiley & Sons A/S
Acta Neuropsychiatrica 2011 All rights reserved DOI: 10.1111/j.1601-5215.2011.00636.x
ACTA NEUROPSYCHIATRICA
Obstetric complications and neurological soft signs in male patients with schizophrenia Bersani G, Clemente R, Gherardelli S, Bersani FS, Manuali G. Obstetric complications and neurological soft signs in male patients with schizophrenia. Objective: The study investigated the relationship between neurological soft signs (NSS) and obstetric complications (OCs) in patients with schizophrenia. Methods: Sixty-three male patients with schizophrenia were divided into two subgroups, based on the OCs presence or absence, which were compared in relation to NSS prevalence. After that, a Person’s correlation test was performed to explore the correlation between NSS and OCs severity. Results: The subgroup with OCs showed more NSS, but there were not significant correlations between NSS and OCs severity. Conclusions: It seems that any OC, without distinction in typology and severity, could unspecifically impair the neurodevelopment and inducing NSS expression. Our findings confirm the hypothesis that neurodevelopment alterations, such as those probably induced by OCs, can contribute to a premorbid brain dysfunctional state expressed by NSS.
Giuseppe Bersani, Roberta Clemente, Simona Gherardelli, Francesco Saverio Bersani, Giorgiana Manuali Department of Medical – Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy Keywords: neurodevelopment; neurological soft signs; obstetric complications; schizophrenia Prof. Giuseppe Bersani, Department of Medical – Surgical Sciences and Biotechnologies, Sapienza University of Rome, via di Torre Argentina 21, 00186 Rome, Italy. Tel: +39 06 4454765; Fax: +39 06 6875237; E-mail: [email protected] Accepted for publication October 31, 2011
Significant outcomes • • •
Neurological soft signs (NSS) and obstetric complications (OCs) show higher incidence in schizophrenic male patients. We used a homogeneous sample of male patients. This study suggests a role of OCs in neurodevelopment alterations. The results suggest the meaning of NSS as markers of the neurodevelopment impairment.
Limitations • • •
We used a small sample of schizophrenic patients. The sample was not antipsychotic naïve. We relied on maternal recall to retrospectively ascertain a history of OCs.
Introduction
Schizophrenia is a loose and complex neuropsychiatric syndrome characterised by a range of cognitive (1,2) and psychophysiological deficits (3,4). Even if the full physiopathology of schizophrenia is still unknown, the study of NSS has provided an additional and increasingly important perspective
on the illness. NSS involve observable defects in sensorial integration, motor coordination and inhibition. NSS are present in approximately 60% of schizophrenic patients (5) and they are considered a neurodysfunctional correlation of schizophrenia (6). NSS have also been described in children at risk of schizophrenia (7), in drug-naïve patients at first psychotic episode (8) and appear to be related to 1
Bersani et al. cognitive impairment (9). The role of NSS in schizophrenia is still unclear: Tsuang et al. (10,11) have argued that these defects reflect genetic and non-genetic processes underpinning the predisposition to psychotic illness. On the other hand, current views consider these signs as covariates of attention (12,13), verbal ability (14,15) and visual-spatial memory (16,17). OCs constitute an early environmental factor that is a well-known source of neurological and behavioural abnormalities in non-psychotic populations (18,19). OCs have been considered possible risk factors of schizophrenia (20,21): there is considerable evidence that exposure to OCs is associated with an increased risk of developing schizophrenia in later life (22–24). Nevertheless, it remains unclear whether OCs represent an independent risk factor for schizophrenia, interact with genetic risk to increase liability, are themselves a manifestation of genetic liability for schizophrenia or are epiphenomena of developmental compromise in individuals who are already on a trajectory towards psychotic illness in adult life. Despite evidences about the association between OCs and neurological abnormalities in the nonpsychotic population, few studies explored the possible role of OCs in the expression of NSS in schizophrenia (25) and these studies gave controversial results. Moreover, NSS and OCs show higher incidence in male patients with schizophrenia (26,27), providing the hypothesis that males are more sensitive to environmental factors and more prone to a neurodevelopmental subtype of schizophrenia. For these reasons, the aim of the study is to investigate the relationship between NSS and OCs in male patients with schizophrenia. Materials and methods Patients
Sixty-three male inpatients meeting diagnostic and statistical manual of mental disorders IV text revision (DSM-IV-TR) diagnostic criteria for Schizophrenia (28) were consented and enrolled in the study (Table 1). Seventeen patients had schizophrenia of paranoid type, 14 of disorganised type, 3 of catatonic type, 15 of undifferentiated type and 14 of residual type. All the patients had been treated with the same antipsychotic drugs for at least 6 months. Fifty patients were treated with one antipsychotic medication while 13 patients with two. More details about the antipsychotic treatments are given in Table 1. The following exclusion criteria were applied: history of alcohol or drug abuse, neurological disorders and meaningful somatic disease. 2
Table 1. Antipsychotic treatment of enrolled patients Antipsychotic drug Haloperidol Risperidone Olanzapine Trifluoperazine Quetiapine Chlorpromazine
Number of patients
Chlorpromazine equivalents
23 14 16 10 5 8
150–300 150–250 200–300 120–180 200–300 100–200
Clinical measures
Schizophrenia diagnosis was made according to DSM-IV-TR criteria and confirmed through the Structured Clinical Interview (SCID-I and SCID-II) for DSM-IV-TR criteria (29), during which patients’ demographic and clinical characteristics were collected. NSS were assessed through the Neurological Evaluation Scale (NES) (30) by a unique senior psychiatrist blind to the results of the mother’s interview. The NES includes 28 items listing the more frequent and significant soft neurological signs; the results are expressed as total score and as three main subscale scores (sensorial integration, motor coordination and sequencing of complex motor acts), that we considered in the statistical analysis. The OCs were assessed interviewing the patients’ biological mothers. The interviewer was blind to neurological evaluation. The Lewis–Murray Scale (LMS) (31) and the Midwife Protocol (MP) (32) were used for a comprehensive evaluation of both prevalence and severity of OCs. The LMS rates 24 potential OCs in order to examine their absence or presence (definite-14 or equivocal-10); it describes patients with presence or absence of OCs. The MP is a semistructured interview that examines a wide set of OC scored, according to the severity, from 0 (none) to 4, providing a total score that represents the sum of the scores of the items describing the single complications. There is not a complete overlapping between the OCs listed in the LMS and in the MP. Study design
The research protocol was approved by the Ethics Committee of Policlinico Umberto I Hospital, Sapienza University of Rome, and it was conform to the Declaration of Helsinki. All the patients gave their voluntary informed consent. The sample was divided into two subgroups on the basis of the absence or presence of OCs as evaluated by the LMS. A compared analysis between the NES scores of the two subgroups was performed through the t-test. After that, a Pearson’s correlation test between NES scores and MP scores was performed
Obstetric complications and neurological soft signs in the group of patients with OCs to explore the correlation between NSS and OCs severity. Even if there is a known relationship between age and NSS (33), we did not consider the age in comparing the two subgroups because the mean ages of both were very similar. Results
The mean age of patients was 31.11 ± 9.21, the mean duration of illness was 10.19 ± 7.77 years and the mean educational level was 10.9 ± 3.26 years of school. Patients mothers’ age was comprise between 41 and 65. They did not present any psychiatric or cognitive disorder and they were considered reliable in providing the requested information. Thirty-seven subjects did not show OCs and 26 subjects showed OCs, both definite (19 subjects) and equivocal (7 subjects). In particular, 37 patients scored 0 to LMS, 7 patients scored 1 (equivocal) and 19 patients scored 2 (definite). The results of the comparison analysis showed that the group characterised by history of OCs exhibited more NSS: the differences were significant in the NES total score and in the Complex Motor Acts subscale score (Table 2). MP total score was 0 in non-OCs group; the results of MP total score in the patients of OCs group are given in Table 3. No significant relationship emerged between NES and MP scores. Discussion
Some studies already explored the relationship between OCs and NSS in Schizophrenia, reporting controversial results. Lane et al. assessed that male schizophrenic patients whose mothers experienced OCs had higher NSS scores (34); Cantor-Graae et al. demonstrated that the degree of neurological impairment in the well-discordant monozygotic twins was significantly positively related to history of both neonatal and total OCs (35); Boks et al. found significantly more NSS in the group of patients without a history of OCs (36). The use of not clinically homogeneous samples, the use of different Table 2. NES scores in groups of patients without OC and with OC
Total score Motor coordination Complex motor acts Sensorial integration ∗
p ≤ 0.05.
Patients without OC (n = 37)
Patients with OC (n = 26)
t
p -Value*
23.7 ± 11.9 0.78 ± 1.00 3.29 ± 2.59 2.8 ± 2.86
30.7 ± 15.01 1.26 ± 1.63 5.26 ± 1.63 2.65 ± 2.34
−2.07 −1.45 2.44 0.35
0.042 0.15 0.017 0.72
Table 3. MP total scores Number of patients 5 2 5 6 7 8 9 10 11
MP total score 1 2 3 8 8 2 3 1 1
NSS assessment scales and the use of mixed samples (male and female patients) could potentially have confounding effects. For example, NSS and OCs showed a higher incidence in schizophrenic male patients (37,38), confirming the hypothesis that males are more sensitive to environmental factors and more prone to a neurodevelopment subtype of schizophrenia, for which OCs are believed to play an aetiologic role (39). To our knowledge, this work is the first exploring the relationship between NSS and OCs in a sample of only male patients with schizophrenia. The results of this study confirm the association of the presence of OCs history and NSS in schizophrenic patients. Neurodevelopment alterations such as those probably induced by OCs, in fact, can contribute to a premorbid brain dysfunctional state expressed by NSS (40,41), associated to an increased risk of adult schizophrenia. From this point of view, NSS can be seen as early markers of the neurofunctional impairment. Although OCs seem to act as a factor of overall increased brain developmental abnormalities and disease risk, it seems that various brain regions can be differently involved in the consequences of different type or severity of OCs; this fact can contribute to the heterogeneous expression of NSS. The prevalence in our sample of the Sequence of Motor Act subscale impairment can be intended in this sense. The absence of a significant increase of motor coordination and sensorial integration subscales in the group with OCs respect to the group without OCs shows that OCs represent a group of factors very heterogeneous and variable in terms of typology and intensity. This variability can affect very deeply the brain organisation and the connected neurological manifestations such as NSS. For this reason, a negative result cannot exclude definitively that in groups of patients with different distribution of OCs may exist a relationship between these and the scores of the two subscales. The association between OCs history and NSS is in agreement with the general neurodevelopmental 3
Bersani et al. hypothesis of schizophrenia and can shed some light on the heterogeneity of neurologic and clinical features of the illness. On the other hand, the lack of a proportional relationship between the severity of OCs and NSS suggests that any OCs, apart from their typology and severity, could unspecifically impair the early physiologic neurodevelopment, resulting in expression of NSS. Other factors, both genetically determined and related to post-natal environmental events, probably concur to NSS etiopathogenesis and they should be further considered for a more comprehensive view of the etiopathogenetic mechanisms of Schizophrenia. Some potential limitations of our study should be considered. First, the sample was not antipsychotic naïve. It is possible to assume, however, the independence of NSS from antipsychotic treatment or side effects: NSS are also present in neuroleptic-naïve patients (42) and it is well established in literature that they are not associated to antipsychotic type or dosage (43). Second, we relied on maternal recall to ascertain a history of OCs; this method has proved to be reliable in several studies (44,45).
10.
11.
12.
13.
14.
15.
16.
17.
References 1. Heinrichs RW, Zakzanis KK. Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 1998;12:426–445. 2. Cocchi L, Bosisio F, Berchtold A et al. Visuospatial encoding deficits and compensatory strategies in schizophrenia revealed by eye movement analysis during a working memory task. Acta Neuropsychiatrica 2009;21:75–83. 3. De Wilde OM, Bour LJ, Dingermans PM, Koelman JHTM, Linszen DH. A meta-analysis of the P50 studies in patients with schizophrenia and relatives: differences in methodology between research groups. Schizophr Res 2007;97:137–151. 4. Yamada M, Yukawa E, Taketani F, Matsuura T, Hara Y. Multifocal visual-evoked potentials in patients with schizophrenia during treatment. Acta Neuropsychiatrica 2011;23:31–34. 5. Buchanan RW, Heinrichs DW. The neurological evaluation scale (NES): a structured instrument for the assessment of neurological signs in schizophrenia. Psychiatry Res 1989;27:335–350. 6. Ota M, Obu S, Sato N, Mizukami K, Asada T. Progressive brain changes in schizophrenia: a 1-year follow-up study of diffusion tensor imaging. Acta Neuropsychiatrica 2009;21:301–307. 7. Marcus J, Hans SL, Lewow E, Wilkinson L, Burack CM. Neurological findings in high risk children: childhood assessment and 5-year follow up. Schizophr Bull 1985;11:85–100. 8. Gupta S, Andreasen NC, Arndt S et al. Neurological soft signs in neuroleptic-naïve and neuroleptic treated schizophrenic patients and in normal comparison subjects. Am J Psychiatry 1995;152:191–196. 9. Bersani G, Clemente R, Gherardelli S, Pancheri P. Deficit of executive functions in schizophrenia: relationship
4
18.
19.
20.
21.
22.
23.
24.
25.
26.
to neurological soft signs and psychopathology. Psychopathology 2004;37:118–123. Tsuang MT, Gilberson MW, Faraone SV. The genetics of schizophrenia: current knowledge and future directions. Schizophr Res 1991;4:157–171. Tsuang MT, Faraone SV. The concept of target features in schizophrenia research. Acta Psychiatr Scand Suppl 1999;395:2–11. Mohr F, Hubmann W, Cohen R et al. Neurological soft signs in schizophrenia: assessment and correlates. Eur Arch Psychiatry Clin Neurosci 1996;246:240–248. Cuesta MJ, Peralta V, De Leon J. Neurologicalfrontal signs and neuropsychological deficits in schizophrenic patients. Schizophr Res 1996;20:15–20. Merriam AE, Kay SR, Opler LA, Kushner SF, Van Praag HM. Neurological signs and the positive-negative dimension in schizophrenia. Biol Psychiatry 1990;28: 181–192. Flashman LA, Flaum M, Gupta S, Andreasen NC. Soft signs and neuropsychological performance in schizophrenia. Am J Psychiatry 1996;153:526–532. Arango C, Bartko JJ, Gold JM, Buchannan RW. Prediction of neuropsychological performance by neurological signs in schizophrenia. Am J Psychiatry 1999;156: 1349–1357. Sanders RD, Schuepbach D, Goldstein G, Haas GL, Sweeney JA, Keshavan MS. Relationships between cognitive and neurological performance in neuroleptic-na¨ıve psychosis. J Neuropsychiatry Clin Neurosci 2004;16: 480–487. Breslau N, Chilcoat HD, Johnson EO, Andreski P, Lucia VC. Neurologic soft signs and low birthweight: their association and neuropsychiatric implications. Biol Psychiatry 2000;47:71–79. Hediger ML, Overpeck MD, Ruan WJ, Troendle JF. Birthweight and gestational age effects on motor and social development. Pediatr Perinatol Epidemiol 2002;16: 33–46. Lewis SW, Murray RM. Obstetric complications, neurodevelopment deviance, and risk of schizophrenia. J Psychiatr Res 1987; 21:413–421. Bersani G, Taddei I, Manuali G. Severity of obstetric complications and risk of adult schizophrenia in male patients: a case-control study. J Matern Fetal Neonatal Med 2003;14:35–38. Cannon M, Jones PB, Murray RM. Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiat 2002;159:1080–1092. Geddes JR, Lawrie SM. Obstetric complications and schizophrenia: a meta-analysis. Br J Psychiatry 1995;167: 786–793. Verdoux H, Geddes JR, Takei N et al. Obstetric complications and age at onset in schizophrenia: an international collaborative meta-analysis of individualpatient data. Am J Psychiat 1997;154:1220–1227. Mrad A, Mechri A, Slama H, Mokni S, Letaief M, Gha L. Correlations between obstetric complications and neurological soft signs in Tunisian patients with schizophrenia. Psychiatry Clin Neurosci 2010;64:645–648. Boks MP, Selten JP, Leask S, Castelein S, Van Den Bosch RJ. Negative association between a history of obstetric complications and the number of neurological soft signs in first-episode schizophrenic disorder. Psychiatry Res 2007;149:273–277.
Obstetric complications and neurological soft signs 27. O’Callaghan E, Gibson T, Colohan H et al. Risk of schizophrenia in adult born after obstetric complications, and their association with early onset of illness: a controlled study. Br Med J 1992;305:1256–1259. 28. AAVV. Diagnostic criteria from DSM IV TR, 4th edn. Washington DC: American Psychiatric Association, 2002. 29. First MB, Donovan S, Frances A et al. Nosology of chronic mood disorders. Psychiatr Clin North Am 1996;19: 29–39. 30. Buchanan RW, Heinrichs DW. The Neurological Evaluation Scale (NES): a structured instrument for the assessment of neurological signs in schizophrenia. Psychiatry Res 1989;27:335–350. 31. Lewis SW, Murray RM. Obstetric complications, neurodevelopment deviance, and risk of schizophrenia. J Psychiatr Res 1987;21:413–421. 32. Parnas J, Schulsinger F, Teasdale TW, Schulsinger H, Feldman PM, Mednick SA. Perinatal complications and clinical outcome within the schizophrenia spectrum. Br J Psychiatry 1982;140:416–420. 33. Chen EYH, Lam LCW, Chen RYL, Nguyen DGH. Neurological signs, age, and illness duration in schizophrenia. J Nerv Ment Dis 1996;184:339–345. 34. Lane A, Colgan K, Moynihan F et al. Schizophrenia and neurological soft signs: gender differences in clinical correlates and antecedent factors. Psychiatry Res 1996;64:105–114. 35. Cantor-Graae E, Mcneil TF, Rickler KC et al. Are neurological abnormalities in well discordant monozygotic co-twins of schizophrenic subjects the result of perinatal trauma? Am J Psychiatry 1994;151:1194–1199. 36. Boks MP, Selten JP, Leask S, Castelein S, Van Den Bosch RJ. Negative association between a history of obstetric complications and the number of neurological soft signs in first-episode schizophrenic disorder. Psychiatry Res 2007;149:273–277. 37. O’Callaghan E, Gibson T, Colohan H et al. Risk of schizophrenia in adult born after obstetric complications,
38.
39.
40.
41.
42.
43.
44.
45.
and their association with early onset of illness: a controlled study. Br Med J 1992;305:1256–1259. Boks MP, Selten JP, Leask S, Castelein S, Van Den Bosch RJ. Negative association between a history of obstetric complications and the number of neurological soft signs in first-episode schizophrenic disorder. Psychiatry Res 2007;149:273–277. Goldstein JM, Seidman LJ, Santangelo S, Knapp PH, Tsuang MT. Are schizophrenic men at higher risk for developmental deficits than schizophrenic women? Implications for adult neuropsychological functions. J Psychiatr Res 1994;28:483–498. Peralta V, De Jalon EG, Campos MS, Basterra V, Sanchez-Torres A, Cuesta MJ. Risk factors, pre-morbid functioning and episode correlates of neurological soft signs in drug-naive patients with schizophrenia-spectrum disorders. Psychol Med 2010;22:1–11. Heuser M, Thomann PA, Essig M, Bachmann S, ¨ Schroder J. Neurological signs and morphological cerebral changes in schizophrenia: an analysis of NSS subscales in patients with first episode psychosis. Psychiatry Res 2011;192:69–76. Gupta S, Andreasen NC, Arndt S et al. Neurological soft signs in neuroleptic-naive and neuroleptic-treated schizophrenic patients and in normal comparison subjects. Am J Psychiatry 1995;152:191–196. Bersani G, Gherardelli S, Clemente R et al. Neurological soft signs in schizophrenic patients treated with conventional and atypical antipsychotic. J Clin Psychopharmacol 2005;25:372–375. Walshe M, Mcdonald C, Boydell J et al. Long-term maternal recall of obstetric complications in schizophrenia research. Psychiatry Res 2011;187:335–340. Hidalgo BR, Zandio M, Zarzuela A. Validit`a of maternal recall of obstetric complications in mothers of patients with schizophrenia spectrum disorders and their healthy siblings. Schizophr Res 2011;126:308–309.
5
Acta Neuropsychiatrica 2011 All rights reserved DOI: 10.1111/j.1601-5215.2011.00636.x
ACTA NEUROPSYCHIATRICA
Obstetric complications and neurological soft signs in male patients with schizophrenia Bersani G, Clemente R, Gherardelli S, Bersani FS, Manuali G. Obstetric complications and neurological soft signs in male patients with schizophrenia. Objective: The study investigated the relationship between neurological soft signs (NSS) and obstetric complications (OCs) in patients with schizophrenia. Methods: Sixty-three male patients with schizophrenia were divided into two subgroups, based on the OCs presence or absence, which were compared in relation to NSS prevalence. After that, a Person’s correlation test was performed to explore the correlation between NSS and OCs severity. Results: The subgroup with OCs showed more NSS, but there were not significant correlations between NSS and OCs severity. Conclusions: It seems that any OC, without distinction in typology and severity, could unspecifically impair the neurodevelopment and inducing NSS expression. Our findings confirm the hypothesis that neurodevelopment alterations, such as those probably induced by OCs, can contribute to a premorbid brain dysfunctional state expressed by NSS.
Giuseppe Bersani, Roberta Clemente, Simona Gherardelli, Francesco Saverio Bersani, Giorgiana Manuali Department of Medical – Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy Keywords: neurodevelopment; neurological soft signs; obstetric complications; schizophrenia Prof. Giuseppe Bersani, Department of Medical – Surgical Sciences and Biotechnologies, Sapienza University of Rome, via di Torre Argentina 21, 00186 Rome, Italy. Tel: +39 06 4454765; Fax: +39 06 6875237; E-mail: [email protected] Accepted for publication October 31, 2011
Significant outcomes • • •
Neurological soft signs (NSS) and obstetric complications (OCs) show higher incidence in schizophrenic male patients. We used a homogeneous sample of male patients. This study suggests a role of OCs in neurodevelopment alterations. The results suggest the meaning of NSS as markers of the neurodevelopment impairment.
Limitations • • •
We used a small sample of schizophrenic patients. The sample was not antipsychotic naïve. We relied on maternal recall to retrospectively ascertain a history of OCs.
Introduction
Schizophrenia is a loose and complex neuropsychiatric syndrome characterised by a range of cognitive (1,2) and psychophysiological deficits (3,4). Even if the full physiopathology of schizophrenia is still unknown, the study of NSS has provided an additional and increasingly important perspective
on the illness. NSS involve observable defects in sensorial integration, motor coordination and inhibition. NSS are present in approximately 60% of schizophrenic patients (5) and they are considered a neurodysfunctional correlation of schizophrenia (6). NSS have also been described in children at risk of schizophrenia (7), in drug-naïve patients at first psychotic episode (8) and appear to be related to 1
Bersani et al. cognitive impairment (9). The role of NSS in schizophrenia is still unclear: Tsuang et al. (10,11) have argued that these defects reflect genetic and non-genetic processes underpinning the predisposition to psychotic illness. On the other hand, current views consider these signs as covariates of attention (12,13), verbal ability (14,15) and visual-spatial memory (16,17). OCs constitute an early environmental factor that is a well-known source of neurological and behavioural abnormalities in non-psychotic populations (18,19). OCs have been considered possible risk factors of schizophrenia (20,21): there is considerable evidence that exposure to OCs is associated with an increased risk of developing schizophrenia in later life (22–24). Nevertheless, it remains unclear whether OCs represent an independent risk factor for schizophrenia, interact with genetic risk to increase liability, are themselves a manifestation of genetic liability for schizophrenia or are epiphenomena of developmental compromise in individuals who are already on a trajectory towards psychotic illness in adult life. Despite evidences about the association between OCs and neurological abnormalities in the nonpsychotic population, few studies explored the possible role of OCs in the expression of NSS in schizophrenia (25) and these studies gave controversial results. Moreover, NSS and OCs show higher incidence in male patients with schizophrenia (26,27), providing the hypothesis that males are more sensitive to environmental factors and more prone to a neurodevelopmental subtype of schizophrenia. For these reasons, the aim of the study is to investigate the relationship between NSS and OCs in male patients with schizophrenia. Materials and methods Patients
Sixty-three male inpatients meeting diagnostic and statistical manual of mental disorders IV text revision (DSM-IV-TR) diagnostic criteria for Schizophrenia (28) were consented and enrolled in the study (Table 1). Seventeen patients had schizophrenia of paranoid type, 14 of disorganised type, 3 of catatonic type, 15 of undifferentiated type and 14 of residual type. All the patients had been treated with the same antipsychotic drugs for at least 6 months. Fifty patients were treated with one antipsychotic medication while 13 patients with two. More details about the antipsychotic treatments are given in Table 1. The following exclusion criteria were applied: history of alcohol or drug abuse, neurological disorders and meaningful somatic disease. 2
Table 1. Antipsychotic treatment of enrolled patients Antipsychotic drug Haloperidol Risperidone Olanzapine Trifluoperazine Quetiapine Chlorpromazine
Number of patients
Chlorpromazine equivalents
23 14 16 10 5 8
150–300 150–250 200–300 120–180 200–300 100–200
Clinical measures
Schizophrenia diagnosis was made according to DSM-IV-TR criteria and confirmed through the Structured Clinical Interview (SCID-I and SCID-II) for DSM-IV-TR criteria (29), during which patients’ demographic and clinical characteristics were collected. NSS were assessed through the Neurological Evaluation Scale (NES) (30) by a unique senior psychiatrist blind to the results of the mother’s interview. The NES includes 28 items listing the more frequent and significant soft neurological signs; the results are expressed as total score and as three main subscale scores (sensorial integration, motor coordination and sequencing of complex motor acts), that we considered in the statistical analysis. The OCs were assessed interviewing the patients’ biological mothers. The interviewer was blind to neurological evaluation. The Lewis–Murray Scale (LMS) (31) and the Midwife Protocol (MP) (32) were used for a comprehensive evaluation of both prevalence and severity of OCs. The LMS rates 24 potential OCs in order to examine their absence or presence (definite-14 or equivocal-10); it describes patients with presence or absence of OCs. The MP is a semistructured interview that examines a wide set of OC scored, according to the severity, from 0 (none) to 4, providing a total score that represents the sum of the scores of the items describing the single complications. There is not a complete overlapping between the OCs listed in the LMS and in the MP. Study design
The research protocol was approved by the Ethics Committee of Policlinico Umberto I Hospital, Sapienza University of Rome, and it was conform to the Declaration of Helsinki. All the patients gave their voluntary informed consent. The sample was divided into two subgroups on the basis of the absence or presence of OCs as evaluated by the LMS. A compared analysis between the NES scores of the two subgroups was performed through the t-test. After that, a Pearson’s correlation test between NES scores and MP scores was performed
Obstetric complications and neurological soft signs in the group of patients with OCs to explore the correlation between NSS and OCs severity. Even if there is a known relationship between age and NSS (33), we did not consider the age in comparing the two subgroups because the mean ages of both were very similar. Results
The mean age of patients was 31.11 ± 9.21, the mean duration of illness was 10.19 ± 7.77 years and the mean educational level was 10.9 ± 3.26 years of school. Patients mothers’ age was comprise between 41 and 65. They did not present any psychiatric or cognitive disorder and they were considered reliable in providing the requested information. Thirty-seven subjects did not show OCs and 26 subjects showed OCs, both definite (19 subjects) and equivocal (7 subjects). In particular, 37 patients scored 0 to LMS, 7 patients scored 1 (equivocal) and 19 patients scored 2 (definite). The results of the comparison analysis showed that the group characterised by history of OCs exhibited more NSS: the differences were significant in the NES total score and in the Complex Motor Acts subscale score (Table 2). MP total score was 0 in non-OCs group; the results of MP total score in the patients of OCs group are given in Table 3. No significant relationship emerged between NES and MP scores. Discussion
Some studies already explored the relationship between OCs and NSS in Schizophrenia, reporting controversial results. Lane et al. assessed that male schizophrenic patients whose mothers experienced OCs had higher NSS scores (34); Cantor-Graae et al. demonstrated that the degree of neurological impairment in the well-discordant monozygotic twins was significantly positively related to history of both neonatal and total OCs (35); Boks et al. found significantly more NSS in the group of patients without a history of OCs (36). The use of not clinically homogeneous samples, the use of different Table 2. NES scores in groups of patients without OC and with OC
Total score Motor coordination Complex motor acts Sensorial integration ∗
p ≤ 0.05.
Patients without OC (n = 37)
Patients with OC (n = 26)
t
p -Value*
23.7 ± 11.9 0.78 ± 1.00 3.29 ± 2.59 2.8 ± 2.86
30.7 ± 15.01 1.26 ± 1.63 5.26 ± 1.63 2.65 ± 2.34
−2.07 −1.45 2.44 0.35
0.042 0.15 0.017 0.72
Table 3. MP total scores Number of patients 5 2 5 6 7 8 9 10 11
MP total score 1 2 3 8 8 2 3 1 1
NSS assessment scales and the use of mixed samples (male and female patients) could potentially have confounding effects. For example, NSS and OCs showed a higher incidence in schizophrenic male patients (37,38), confirming the hypothesis that males are more sensitive to environmental factors and more prone to a neurodevelopment subtype of schizophrenia, for which OCs are believed to play an aetiologic role (39). To our knowledge, this work is the first exploring the relationship between NSS and OCs in a sample of only male patients with schizophrenia. The results of this study confirm the association of the presence of OCs history and NSS in schizophrenic patients. Neurodevelopment alterations such as those probably induced by OCs, in fact, can contribute to a premorbid brain dysfunctional state expressed by NSS (40,41), associated to an increased risk of adult schizophrenia. From this point of view, NSS can be seen as early markers of the neurofunctional impairment. Although OCs seem to act as a factor of overall increased brain developmental abnormalities and disease risk, it seems that various brain regions can be differently involved in the consequences of different type or severity of OCs; this fact can contribute to the heterogeneous expression of NSS. The prevalence in our sample of the Sequence of Motor Act subscale impairment can be intended in this sense. The absence of a significant increase of motor coordination and sensorial integration subscales in the group with OCs respect to the group without OCs shows that OCs represent a group of factors very heterogeneous and variable in terms of typology and intensity. This variability can affect very deeply the brain organisation and the connected neurological manifestations such as NSS. For this reason, a negative result cannot exclude definitively that in groups of patients with different distribution of OCs may exist a relationship between these and the scores of the two subscales. The association between OCs history and NSS is in agreement with the general neurodevelopmental 3
Bersani et al. hypothesis of schizophrenia and can shed some light on the heterogeneity of neurologic and clinical features of the illness. On the other hand, the lack of a proportional relationship between the severity of OCs and NSS suggests that any OCs, apart from their typology and severity, could unspecifically impair the early physiologic neurodevelopment, resulting in expression of NSS. Other factors, both genetically determined and related to post-natal environmental events, probably concur to NSS etiopathogenesis and they should be further considered for a more comprehensive view of the etiopathogenetic mechanisms of Schizophrenia. Some potential limitations of our study should be considered. First, the sample was not antipsychotic naïve. It is possible to assume, however, the independence of NSS from antipsychotic treatment or side effects: NSS are also present in neuroleptic-naïve patients (42) and it is well established in literature that they are not associated to antipsychotic type or dosage (43). Second, we relied on maternal recall to ascertain a history of OCs; this method has proved to be reliable in several studies (44,45).
10.
11.
12.
13.
14.
15.
16.
17.
References 1. Heinrichs RW, Zakzanis KK. Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 1998;12:426–445. 2. Cocchi L, Bosisio F, Berchtold A et al. Visuospatial encoding deficits and compensatory strategies in schizophrenia revealed by eye movement analysis during a working memory task. Acta Neuropsychiatrica 2009;21:75–83. 3. De Wilde OM, Bour LJ, Dingermans PM, Koelman JHTM, Linszen DH. A meta-analysis of the P50 studies in patients with schizophrenia and relatives: differences in methodology between research groups. Schizophr Res 2007;97:137–151. 4. Yamada M, Yukawa E, Taketani F, Matsuura T, Hara Y. Multifocal visual-evoked potentials in patients with schizophrenia during treatment. Acta Neuropsychiatrica 2011;23:31–34. 5. Buchanan RW, Heinrichs DW. The neurological evaluation scale (NES): a structured instrument for the assessment of neurological signs in schizophrenia. Psychiatry Res 1989;27:335–350. 6. Ota M, Obu S, Sato N, Mizukami K, Asada T. Progressive brain changes in schizophrenia: a 1-year follow-up study of diffusion tensor imaging. Acta Neuropsychiatrica 2009;21:301–307. 7. Marcus J, Hans SL, Lewow E, Wilkinson L, Burack CM. Neurological findings in high risk children: childhood assessment and 5-year follow up. Schizophr Bull 1985;11:85–100. 8. Gupta S, Andreasen NC, Arndt S et al. Neurological soft signs in neuroleptic-naïve and neuroleptic treated schizophrenic patients and in normal comparison subjects. Am J Psychiatry 1995;152:191–196. 9. Bersani G, Clemente R, Gherardelli S, Pancheri P. Deficit of executive functions in schizophrenia: relationship
4
18.
19.
20.
21.
22.
23.
24.
25.
26.
to neurological soft signs and psychopathology. Psychopathology 2004;37:118–123. Tsuang MT, Gilberson MW, Faraone SV. The genetics of schizophrenia: current knowledge and future directions. Schizophr Res 1991;4:157–171. Tsuang MT, Faraone SV. The concept of target features in schizophrenia research. Acta Psychiatr Scand Suppl 1999;395:2–11. Mohr F, Hubmann W, Cohen R et al. Neurological soft signs in schizophrenia: assessment and correlates. Eur Arch Psychiatry Clin Neurosci 1996;246:240–248. Cuesta MJ, Peralta V, De Leon J. Neurologicalfrontal signs and neuropsychological deficits in schizophrenic patients. Schizophr Res 1996;20:15–20. Merriam AE, Kay SR, Opler LA, Kushner SF, Van Praag HM. Neurological signs and the positive-negative dimension in schizophrenia. Biol Psychiatry 1990;28: 181–192. Flashman LA, Flaum M, Gupta S, Andreasen NC. Soft signs and neuropsychological performance in schizophrenia. Am J Psychiatry 1996;153:526–532. Arango C, Bartko JJ, Gold JM, Buchannan RW. Prediction of neuropsychological performance by neurological signs in schizophrenia. Am J Psychiatry 1999;156: 1349–1357. Sanders RD, Schuepbach D, Goldstein G, Haas GL, Sweeney JA, Keshavan MS. Relationships between cognitive and neurological performance in neuroleptic-na¨ıve psychosis. J Neuropsychiatry Clin Neurosci 2004;16: 480–487. Breslau N, Chilcoat HD, Johnson EO, Andreski P, Lucia VC. Neurologic soft signs and low birthweight: their association and neuropsychiatric implications. Biol Psychiatry 2000;47:71–79. Hediger ML, Overpeck MD, Ruan WJ, Troendle JF. Birthweight and gestational age effects on motor and social development. Pediatr Perinatol Epidemiol 2002;16: 33–46. Lewis SW, Murray RM. Obstetric complications, neurodevelopment deviance, and risk of schizophrenia. J Psychiatr Res 1987; 21:413–421. Bersani G, Taddei I, Manuali G. Severity of obstetric complications and risk of adult schizophrenia in male patients: a case-control study. J Matern Fetal Neonatal Med 2003;14:35–38. Cannon M, Jones PB, Murray RM. Obstetric complications and schizophrenia: historical and meta-analytic review. Am J Psychiat 2002;159:1080–1092. Geddes JR, Lawrie SM. Obstetric complications and schizophrenia: a meta-analysis. Br J Psychiatry 1995;167: 786–793. Verdoux H, Geddes JR, Takei N et al. Obstetric complications and age at onset in schizophrenia: an international collaborative meta-analysis of individualpatient data. Am J Psychiat 1997;154:1220–1227. Mrad A, Mechri A, Slama H, Mokni S, Letaief M, Gha L. Correlations between obstetric complications and neurological soft signs in Tunisian patients with schizophrenia. Psychiatry Clin Neurosci 2010;64:645–648. Boks MP, Selten JP, Leask S, Castelein S, Van Den Bosch RJ. Negative association between a history of obstetric complications and the number of neurological soft signs in first-episode schizophrenic disorder. Psychiatry Res 2007;149:273–277.
Obstetric complications and neurological soft signs 27. O’Callaghan E, Gibson T, Colohan H et al. Risk of schizophrenia in adult born after obstetric complications, and their association with early onset of illness: a controlled study. Br Med J 1992;305:1256–1259. 28. AAVV. Diagnostic criteria from DSM IV TR, 4th edn. Washington DC: American Psychiatric Association, 2002. 29. First MB, Donovan S, Frances A et al. Nosology of chronic mood disorders. Psychiatr Clin North Am 1996;19: 29–39. 30. Buchanan RW, Heinrichs DW. The Neurological Evaluation Scale (NES): a structured instrument for the assessment of neurological signs in schizophrenia. Psychiatry Res 1989;27:335–350. 31. Lewis SW, Murray RM. Obstetric complications, neurodevelopment deviance, and risk of schizophrenia. J Psychiatr Res 1987;21:413–421. 32. Parnas J, Schulsinger F, Teasdale TW, Schulsinger H, Feldman PM, Mednick SA. Perinatal complications and clinical outcome within the schizophrenia spectrum. Br J Psychiatry 1982;140:416–420. 33. Chen EYH, Lam LCW, Chen RYL, Nguyen DGH. Neurological signs, age, and illness duration in schizophrenia. J Nerv Ment Dis 1996;184:339–345. 34. Lane A, Colgan K, Moynihan F et al. Schizophrenia and neurological soft signs: gender differences in clinical correlates and antecedent factors. Psychiatry Res 1996;64:105–114. 35. Cantor-Graae E, Mcneil TF, Rickler KC et al. Are neurological abnormalities in well discordant monozygotic co-twins of schizophrenic subjects the result of perinatal trauma? Am J Psychiatry 1994;151:1194–1199. 36. Boks MP, Selten JP, Leask S, Castelein S, Van Den Bosch RJ. Negative association between a history of obstetric complications and the number of neurological soft signs in first-episode schizophrenic disorder. Psychiatry Res 2007;149:273–277. 37. O’Callaghan E, Gibson T, Colohan H et al. Risk of schizophrenia in adult born after obstetric complications,
38.
39.
40.
41.
42.
43.
44.
45.
and their association with early onset of illness: a controlled study. Br Med J 1992;305:1256–1259. Boks MP, Selten JP, Leask S, Castelein S, Van Den Bosch RJ. Negative association between a history of obstetric complications and the number of neurological soft signs in first-episode schizophrenic disorder. Psychiatry Res 2007;149:273–277. Goldstein JM, Seidman LJ, Santangelo S, Knapp PH, Tsuang MT. Are schizophrenic men at higher risk for developmental deficits than schizophrenic women? Implications for adult neuropsychological functions. J Psychiatr Res 1994;28:483–498. Peralta V, De Jalon EG, Campos MS, Basterra V, Sanchez-Torres A, Cuesta MJ. Risk factors, pre-morbid functioning and episode correlates of neurological soft signs in drug-naive patients with schizophrenia-spectrum disorders. Psychol Med 2010;22:1–11. Heuser M, Thomann PA, Essig M, Bachmann S, ¨ Schroder J. Neurological signs and morphological cerebral changes in schizophrenia: an analysis of NSS subscales in patients with first episode psychosis. Psychiatry Res 2011;192:69–76. Gupta S, Andreasen NC, Arndt S et al. Neurological soft signs in neuroleptic-naive and neuroleptic-treated schizophrenic patients and in normal comparison subjects. Am J Psychiatry 1995;152:191–196. Bersani G, Gherardelli S, Clemente R et al. Neurological soft signs in schizophrenic patients treated with conventional and atypical antipsychotic. J Clin Psychopharmacol 2005;25:372–375. Walshe M, Mcdonald C, Boydell J et al. Long-term maternal recall of obstetric complications in schizophrenia research. Psychiatry Res 2011;187:335–340. Hidalgo BR, Zandio M, Zarzuela A. Validit`a of maternal recall of obstetric complications in mothers of patients with schizophrenia spectrum disorders and their healthy siblings. Schizophr Res 2011;126:308–309.
5
