a prospective study of offspring of women with psychosis: visual dysfunction in early childhood...

A prospective study of offspring of womenwith psychosis: visual dysfunction in earlychildhood predicts schizophrenia-spectrumdisorders in adulthood

Introduction

Children with visual dysfunction (i.e. strabismus,ocular motor apraxia, retinopathy) have beenshown to be characterized by increases in prema-ture birth, low birth weight, neurological abnor-malities, brain abnormalities, and impairments invisual perception and cognitive function (1–5). Thevisual-spatial difficulties observed in children withcongenital ocular motor apraxia have been pro-posed to be caused by developmentally inappro-priate sensory input because of the abnormalsaccades seen in this illness (2). Visual dysfunctionsin childhood may well negatively influence thedevelopment of visual perception and cognitivefunction (2, 3). These diverse deviations are alsosimilar in some respects to those frequently foundin patients with schizophrenia (6–11).

Schizophrenia is now widely conceived of as abrain disorder resulting from disturbed neurode-velopment (11). The neurodevelopmental hypothe-sis of schizophrenia proposes that an earlyanomaly in the brain, mediated by genetic and/orenvironmental factors, such as obstetric complica-tions and/or viral infections, results in disturbedneurodevelopment. This process manifests itself inschizophrenia in adolescence or young adulthood,when the brain completes its maturation (12, 13).Neurological abnormality, which is a frequent andwell-established finding among patients with schi-zophrenia or schizophrenia-spectrum disordersand their non-ill relatives (7, 14–21), may beanother manifestation of this proposed disturbedneurodevelopmental process.Such disturbed neurodevelopment could also

underlie the well-known and repeated findings of

Schubert EW, Henriksson KM, McNeil TF. A prospective study ofoffspring of women with psychosis: visual dysfunction in earlychildhood predicts schizophrenia-spectrum disorders in adulthood.Acta Psychiatr Scand 2005: 112: 385–393.� 2005 BlackwellMunksgaard.

Objective: Children with visual dysfunction have perinatal,neurological, visual-perceptual and cognitive abnormalities, similar toschizophrenia patients. We prospectively investigated whether visualdysfunction in childhood selectively predicts adult schizophrenia-spectrum disorders, and is related to childhood neurologicalabnormality.Method: Offspring of mothers with and without a history of psychosiswere prospectively assessed with vision tests at 4 years, neurologicalexaminations at 6 years, and interviews for psychiatric disorders atfollow-up (93% effective, n ¼ 166) at 22 years.Results: In the total sample and high-risk (HR) offspring, visualdysfunction at 4 years, and its severity, were associated only withschizophrenia-spectrum disorders in adulthood, and with neurologicalabnormality at 6 years.Conclusion: Visual dysfunction at 4 years of age selectively predictsschizophrenia-spectrum disorders in adulthood among HR offspring,this likely reflecting disturbed neurological development.

E. W. Schubert, K. M. Henriksson,T. F. McNeilUnit of Psychiatric Epidemiology, University Hospital,Lund University, Lund, Sweden

Key words: childhood; high-risk study; neurologicalabnormality; psychiatric disease; psychosis;schizophrenia; visual dysfunction

Thomas McNeil, Unit of Psychiatric Epidemiology,Barngatan 2, University Hospital, S-221 85 Lund,Sweden.E-mail: [email protected]

Accepted for publication May 3, 2005

Acta Psychiatr Scand 2005: 112: 385–393All rights reservedDOI: 10.1111/j.1600-0447.2005.00584.x

Copyright � 2005 Blackwell Munksgaard

ACTA PSYCHIATRICASCANDINAVICA

385

smooth pursuit eye movement dysfunction,impaired visual perception, and impaired visualworking memory among patients with schizophre-nia-spectrumdisorders and their relatives (8, 22–26).These various visual and neurological disturb-ances have been related primarily to schizophre-nia-spectrum disorders and not to other psychiatricdisorders (27, 28). Especially neurological abnor-mality and smooth pursuit eye movement dysfunc-tion have been pointed out to be biological markersfor the liability for schizophrenia-spectrum disor-ders, and even to predict that type of illness inoffspring of parents with schizophrenia (21).The Swedish High-Risk Study, which began

before the subjects’ births, is a prospective, longi-tudinal investigation of high-risk (HR) offspring ofwomen with schizophrenic, schizoaffective, affect-ive and unspecified functional psychoses, as well asnormal-risk (NC) offspring of women with nohistory of psychosis (29). Congruent with findingsin other studies (21, 30–33), we have previouslyfound that offspring of mothers with schizophreniahave more neurological abnormalities in infancy,early childhood and adulthood than do offspringof mothers with affective psychosis and offspring ofmothers with no history of psychosis (34–36). Inaddition, schizophrenia-spectrum disorders in theoffspring at risk for psychosis were found predom-inantly among offspring of mothers with schizo-phrenia-related psychoses in follow-up of thissample at about 22 years of age (29).At 4 years of age the children were assessed with

a standardized test of vision. The total HR groupand the offspring of mothers with schizophreniawere found to have more visual dysfunction by thisage than did NC offspring (37). To our knowledge,nothing is known concerning whether visual dys-function in early childhood relates to the develop-ment of psychiatric disorders in young adulthood,and whether early visual dysfunction is related toneurological abnormality in children at risk forpsychosis. Our prospectively collected data con-cerning neurological abnormality, visual dysfunc-tion and psychiatric outcome in young adultoffspring of mothers with psychosis yield aunique opportunity to study this question.

Aims of the study

The aim of the study was to investigate whether:

i) the presence of visual dysfunction by 4 yearsof age, and its severity, predict schizophrenia-spectrum disorders in young adulthood bothin general and in offspring with heightenedrisk for psychosis,

ii) visual dysfunction by 4 years of age, and itsseverity, predict other psychiatric disorders inyoung adulthood both in general and inoffspring with heightened risk for psychosis,and

iii) visual dysfunction by 4 years of age, and itsseverity, are related to neurological abnormal-ity in infancy, childhood and young adult-hood.

Material and methods

Subjects

The sample comes from the Swedish High-RiskStudy, which is a prospective, longitudinal inves-tigation of offspring of women with psychosis, aswell as NC offspring of women with no history ofpsychosis (29). The project was begun in 1973–1977 during the mothers’ pregnancies. Heightenedoffspring risk for psychopathology was defined onthe basis of a history of psychosis in the (index)mother, while NC was defined on the basis of anabsence of a psychosis history in both the (control)mother and biological father (as determinedthrough medical records). Both index and controlmothers were selected from among women regis-tered at the local prenatal clinics in a largegeographical area in southwest Sweden. Controlswere chosen to have the same prenatal clinic,maternal age (±1 year in 75% of cases, ±2 yearsin the remaining), parity (0 vs. 1 vs. 2+), socialclass (upper, middle, lower) and formal maritalstatus in pregnancy as the index case.The offspring and their environment were stud-

ied from before birth until 2 years, at 6 years of age(38, 39), and at the recently completed first adultfollow-up at 22 years of age (29).In total, 166 (93.3%) of the 178 offspring (80

HR, 98 NC) potentially participating in the projectwere followed up at 22 years of age. The total HRgroup consisted of 28 offspring of mothers withschizophrenia (Sc), 22 offspring of mothers withaffective psychosis (Aff, with 16 bipolar and sixunipolar depressive mothers), 15 offspring ofmothers with schizoaffective psychosis (Scaff),and 10 offspring of mothers with unspecifiedfunctional psychosis (Unsp), all defined byResearch Diagnostic Criteria (40).The project was approved by the Research

Ethics Board of Lund University.

Procedure and assessment of childhood visual dysfunction

At both national and local levels, Sweden has avery long tradition of preventive child healthcare.

Schubert et al.

386

As this has gained high acceptance, all familieswith preschool age children take part in theseactivities (41, 42). The program includes repeatedrecordings at Well Baby Clinics (WBC) of overallbody and head growth, medical physical examina-tions (performed by specially trained physicians),psychosocial observations, and testing of gross andfine motor acquisitions, and speech, hearing andvisual functions. Special attention is paid to thevisit at 4 years of age. Child examiners at the WBCfollowed standard routines for all surveys and werenever provided with extra information about themothers or offspring in this project.The subjects had an average of 25 WBC contacts

from birth to 4 years of age, these contactsconstituting mainly offspring visits to the healthclinics, home visits by a nurse and in a few casestelephone contacts. We were able to retrieve dataon vision and hearing checkups at age 4 years for110 of the 166 offspring, whereas the remainingcases had incomplete data due primarily to nothaving reached 4 years of age at the time thesemedical record data were collected. No significantdifferences existed in rates of 4-year checkups forNC vs. total HR or the specific risk groups. Thesubsample with data consisted of 52 HR offspring(19 Sc, 9 Scaff, 16 Aff, 8 Unsp) and 58 NCoffspring.All children participating in the test at 4 years of

age were assessed with a standard test of vision(Bostrom Nordlow-Joachimsson or Schnellens E-test), performed by specially trained nurses. Thesubjects who passed the test at the first or secondtesting (not more than 3 months apart) wereconsidered to have normal vision. Children whodid not fulfill these criteria, or children who hadbeen referred to a specialist because of visionproblems prior to 4 years, were considered ashaving visual dysfunction. The rate of referral toeye specialists was 21% among the participatingchildren, which was similar to rates from anational survey conducted in the same age groupduring at the same time period (43). Visualdysfunction was present in 34 of the offspring inthe present sample.The level of severity of visual dysfunction was

operationally defined according to the followingfour levels: 0 ¼ no known visual dysfunction, 1 ¼deviant vision test without referral to specialist,2 ¼ referral to eye specialist after vision test, and3 ¼ eye disorder diagnosed, wearing eyeglasses,and/or repeatedly controlled by eye specialist. Thecategorization of the presence and level of severityof visual dysfunction was performed (by K.M.H.)blindly with respect to psychiatric outcome inadulthood.

Procedure and assessment of offspring adolescent/adultpsychiatric diagnosis

The subjects were followed-up at 22 years of ageduring a full day of assessment at their localgeneral practitioners’ offices (29). The standardizedprocedure during the morning session constitutedextensive neuropsychological testing, a neurologi-cal examination, and completion of self-reportscales concerning mental health, life events andfamilial and social environment. DSM-III-R-baseddiagnostic interviews were conducted during theafternoon.The Swedish version of the structured clinical

interview for DSM-III-R (SCID I and II) was usedto diagnose Axis I and Axis II disorders in theoffspring (44). Axis I disorders could occur at anytime during adolescence and adulthood untilfollow-up. The Axis II personality disorders thatwere scored were those existing at the time offollow-up.Occurrence of Axis II personality disorders was

calculated in terms of Cluster A (Paranoid, Schiz-oid, Schizotypal), Cluster B (Antisocial, Border-line, Histrionic, Narcissistic) and Cluster C(Avoidant, Dependent, Obsessive-Compulsive,NOS) types.The psychiatric disorders in the current offspring

sample were grouped into the following categoriesfor the present analysis: schizophrenia-spectrumdisorders (schizophrenia, schizoaffective psychosis,Cluster A personality disorders) (n ¼ 7 cases),depressive disorders (n ¼ 25), anxiety disorders(n ¼ 12), substance abuse disorders (n ¼ 9), clusterB personality disorders (n ¼ 12) and cluster Cpersonality disorders (n ¼ 8).All subjects were assessed by one examiner (E.

W. S.) with extensive psychiatric diagnostic experi-ence. He received no information on the pasthistory of the subject including his/her HR- vs.NC-status or any previous project data includingprevious visual disorder and neurological abnor-mality, or whether the subject even had data forthese variables. Inter-rater reliability in diagnosisof psychiatric patients with various psychoticconditions was tested (with R. Bernce, MD) bothbefore (n ¼ 5) and after (n ¼ 5) the current follow-up (Kappa 1.0, P < 0.0001).

Neurological examinations

Neonatal exam. Standardized neurological exami-nations were blindly performed by one assessor atthe delivery hospitals on the third to fourth dayafter birth (34). The examination was basedprimarily on methods by Prechtl and colleagues

Visual dysfunction and schizophrenia risk

387

and Hagberg (45–47) and included evaluation ofmuscle tone, motor movements, simple and com-plex reflexes, activity level and sensitivity tostimulation. A summary score composed of devi-ation points compiled across 19 different itemsrepresented the subject’s degree of total neonatalneurological abnormality. As in our previous study(34), a subject was classified as neurologicallydeviant if the total neurological abnormality scorewas >5. In total, 78 (32 HR, 46 NC) subjects haddata on both neonatal neurology and visualfunction at 4 years.

Six-year exam. In the follow-up investigation at6 years of age, neuromotor assessment wasblindly conducted in the subjects’ homes by adifferent examiner (35). The neuromotoric assess-ment was primarily based on Touwen and Prec-htl’s neurological examination of children (48),and included 26 test items (35). A subject with atotal neurological abnormality score of >7 (the94th percentile for the NC subjects) was classifiedas neurologically deviant at that age. In total, 97(42 HR, 55 NC) subjects had data on bothneurology at 6 years and visual function at4 years of age.

Adult exam. A third examiner (E.W.S.), blind to allprevious data, performed all neurological assess-ments at 22 years of age. This neurological exam-ination was based on a comprehensive,standardized assessment scale (18), previouslyused by us to study adult schizophrenia patientsand their siblings. The scale consists of 44 items,and includes 21 items from Woods et al. (16), all 19items of Rossi et al. (15), two items (right-leftconfusion and finger-thumb opposition) fromQuitkin et al. (14), and two items (finger–nosetest, crossing body midline) from McNeil et al.(35). The neurological assessment scale comprisesinvestigation of motor coordination, musclepower, muscle tone, sensory functions, reflexes,and cognitive functions. The total neurologicalabnormality score was the sum of the scores on all44 items (potentially ranging from 0 to 124).A score above the 90th percentile on the total

neurological assessment scale for the NC cases (i.e.a score >7) was operationally defined as deviant.In total, 108 (52 HR, 56 NC) subjects had data onboth neurology at 22 years and visual function at4 years of age.The inter-rater reliability for this neurological

assessment was determined by testing agreementon the total scores with an experienced physician(18) (B. Ismail, MD) on 20 subjects (10 patientswith psychosis and 10 hospital personnel). The

inter-rater coefficient (intraclass correlation) was0.97 (F ¼ 65.44, d.f. ¼ 9, 10, P < 0.001).

Statistical methods

In the total sample (HR + NC) and among HRoffspring, both the rate and the level of severity ofvisual dysfunction at 4 years of age were comparedfor (a) offspring with each specified psychiatricdiagnostic category vs. offspring without thatparticular disorder (22-year follow-up), and (b)neurologically deviant offspring vs. neurologicallynormal offspring at each of the three assessmentages.Fisher exact test, with odds ratios (OR) and 95%

confidence intervals (CI), was used for analysis ofcategory data, while analysis of quantitative datawas done by Wilcoxon and Mann–Whitney tests.Statistical significance was defined as P £ 0.05 two-tailed, with 0.10 ‡ P > 0.05 denoting non-signifi-cant trends.

Results

Visual dysfunction in early childhood and psychiatric diagnosisin young adulthood

In the total sample and among HR offspring,subjects with visual dysfunction at 4 years of agehad a significantly increased frequency of schizo-phrenia-spectrum disorders at 22 years of age,compared with subjects with no visual dysfunctionat 4 years of age (Table 1). Visual dysfunction at4 years was not related to any other psychiatricdiagnostic category at 22 years.In both the total sample and among HR

offspring, subjects with schizophrenia-spectrumdisorders at 22 years of age had a significantlyincreased level of severity of visual dysfunction at4 years, as compared with subjects without schi-zophrenia-spectrum disorders (Table 2). No othercategory of psychiatric disorder at 22 years wasrelated to level of severity of visual dysfunction at4 years.

Visual dysfunction in early childhood and neurologicalabnormality at different ages

Both rate and level of visual dysfunction at 4 yearsof age were significantly positively related toneurological abnormality at 6 years of age in thetotal sample, with a similar tendency in the HRgroup (Tables 3 and 4). All subjects with visualdysfunction at 4 years of age and later schizophre-nia-spectrum disorder showed neurological abnor-malities at 6 years of age (Table 5).

Schubert et al.

388

In contrast, neither rate nor level of visualdysfunction at 4 years was significantly related toneurological abnormality in infancy or in youngadulthood, in the total sample or in the HRgroup.

Secondary analyses of possible confounders

Other early developmental problems by 4 years ofage in total HR offspring showed no significantrelationships between adult schizophrenia-spec-

Table 1. Rate of psychiatric diagnoses in adulthood in high-risk and normal-risk control offspring with visual dysfunction at 4 years of age

Diagnosis Total (n) HR + NC (n ¼ 110) [n (%)]

Statistical analysis

Total (n) HR (n ¼ 52) [n (%)]


P OR, CI P OR, CI

Any schizophrenia-spectrum disorder 7 6 (86) 0.003 16.07, 1.85–139.6 6 5 (83) 0.034 9.37, 1.01–87.33No schizophrenia-spectrum disorder 103 28 (27) 46 16 (35)Any depressive disorder 25 9 (36) ns 1.35, 0.53–3.46 19 7 (37) ns 0.79, 0.25–2.53No depressive disorder 85 25 (29) 33 14 (42)Any anxiety disorder 12 2 (17) ns 0.41, 0.09–1.99 8 2 (25) ns 0.44, 0.08–2.42No anxiety disorder 98 32 (33) 44 19 (43)Any substance abuse disorder 9 4 (44) ns 1.89, 0.48–7.55 7 4 (57) ns 2.20, 0.44–11.03No substance abuse disorder 101 30 (30) 45 17 (38)Any Cluster B personality disorder 12 4 (33) ns 1.13, 0.32–4.06 9 4 (44) ns 1.22, 0.27–5.22No Cluster B personality disorder 98 30 (31) 43 17 (40)Any Cluster C personality disorder 8 3 (37) ns 1.37, 0.31–6.11 7 3 (43) ns 1.12, 0.22–5.64No Cluster C personality disorder 102 31 (30) 45 18 (40)

Statistical analysis: rate of psychiatric diagnosis in offspring with vs. without VD; Fisher exact P, two-tailed, OR, 95% CI.NC, normal-risk controls; HR, total high-risk offspring; n, number of subjects; VD, group with visual dysfunction at 4 years of age (% ¼ % of total n); ns, not significant.

Table 2. Severity of visual dysfunction at 4 years of age in high-risk and normal-risk control offspring with psychiatric diagnoses in adulthood

Diagnosis Total (n) HR + NC (n ¼ 110) [mean (sd)]

Statisticalanalysis

Total (n) HR (n ¼ 52) [mean (sd)]

Statisticalanalysis

Z P Z P

Any schizophrenia-spectrum disorder 7 1.71 (1.25) 3.08 0.002 6 1.50 (1.22) 2.06 0.039No schizophrenia-spectrum disorder 103 0.58 (1.06) 46 0.67 (1.08)Any depressive disorder 25 0.68 (1.07) 0.43 ns 19 0.63 (1.01) 0.55 nsNo depressive disorder 85 0.65 (1.12) 33 0.85 (1.18)Any anxiety disorder 12 0.17 (0.39) 1.36 ns 8 0.25 (0.46) 1.24 nsNo anxiety disorder 98 0.71 (1.15) 44 0.86 (1.17)Any substance abuse disorder 9 0.78 (1.09) 0.70 ns 7 1.00 (1.15) 0.41 nsNo substance abuse disorder 101 0.64 (1.11) 45 0.73 (1.12)Any Cluster B personality disorder 12 0.67 (1.15) 0.14 ns 9 0.89 (1.27) 0.75 nsNo Cluster B personality disorder 98 0.65 (1.10) 43 0.74 (1.09)Any Cluster C personality disorder 8 0.38 (0.52) 0.06 ns 7 0.43 (0.53) 0.36 nsNo Cluster C personality disorder 102 0.68 (1.14) 45 0.82 (1.17)

Statistical analysis: severity of VD in offspring with vs. without psychiatric diagnosis; Mann–Whitney, two-tailed.NC, normal-risk controls; HR, total high-risk offspring; n, number of subjects, Severity of VD (visual dysfunction) at 4 years of age; ns, not significant.

Table 3. Rate of visual dysfunction at 4 years of age in neurologically deviant (vs. normal) offspring in different ages

Total (n) HR + NC n (%)


Total (n) HR n (%)


P OR, CI P OR, CI

ND in infancy 26 7 (27) ns 1.00, 0.35–2.89 15 4 (27) ns 0.67, 0.14–3.04Not ND in infancy 52 14 (27) 17 6 (35)ND at 6 years 11 7 (64) 0.01 5.77, 1.53–21.77 8 5 (62) (0.11) 4.00, 0.79–20.02Not ND at 6 years 86 20 (23) 34 10 (29)ND at 22 years 28 7 (25) ns 0.69, 0.26–1.84 15 4 (27) ns 0.43, 0.11–1.59Not ND at 22 years 80 26 (32) 37 17 (46)

Statistical analysis: rate of VD in offspring with vs. without ND; Fisher exact P, two-tailed, OR, 95% CI.NC, normal-risk controls; HR, total high-risk offspring; n, number of subjects; VD, presence of visual dysfunction at 4 years of age (% ¼ % of total n); ND, neurologicallydeviant; ns, not significant.


389

trum disorders and impaired hearing (P ¼ 1.00,OR 0.73, CI 0.07–7.95), language disorders (P ¼0.33, OR 0.32, 0.50–2.12), disturbed behavior(P ¼ 0.66, OR 0.72, CI 0.13–4.00) or late walking(P ¼ 1.00, OR 1.00, CI 0.18–5.48). Gender was notsignificantly related to visual dysfunction at 4 yearsof age (P ¼ 0.57, OR 0.66, CI 0.21–2.03) or laterschizophrenia-spectrum disorder (P ¼ 1.00, OR1.20, CI 0.26–5.43) in HR offspring.

Discussion

In this prospective, longitudinal HR study, begin-ning before birth, we show for the first time thatvisual dysfunction in early childhood predictsschizophrenia-spectrum disorder in adulthood,and no other psychiatric disorder. This associ-ation was found in both the total sample and theHR sample per se, but mostly concerns theoffspring of mothers with psychosis, as six ofthe seven schizophrenia-spectrum cases comefrom the HR group. Visual dysfunction wassignificantly related to neurological abnormalityat the most proximal examination age in child-hood (6 years) and may thus constitute a form of

early neuro-maldevelopment. Visual dysfunctionwas not gender-related and apparently not part ofmore general developmental disturbance, as noneof the four other selected early developmental orsensory disturbances (walking, hearing, language,behavior) were related to schizophrenia-spectrumdisorder.While visual dysfunction could potentially have

resulted from attention or behavioral problemsduring the vision test (26, 49), this is very unlikelyas disturbances on the hearing test performed at4 years of age were totally unrelated to schizo-phrenia-spectrum disorder in adulthood. The hear-ing test requires an even higher degree ofconcentration and cooperation by the children.Even more importantly, the offspring with schizo-phrenia-spectrum disorders also had a significantlyhigher level of severity of visual dysfunction,reflecting unequivocal eye disorders (Table 2),which are not the result of attention or behavioralproblems.Visual dysfunction may thus represent a biolo-

gical marker and an early indicator for the liabilityfor schizophrenia-spectrum disorders, found pri-marily in children at risk for psychosis.

Table 4. Severity of visual dysfunction at 4 years of age in neurologically deviant (vs. normal) offspring in different ages

Total (n) HR + NC [mean (sd)]


Total (n) HR [mean (sd)]


Z P Z P

ND in infancy 26 0.58 (1.06) 0.34 ns 15 0.53 (1.06) 0.68 nsNot ND in infancy 52 0.60 (1.09) 17 0.59 (0.94)ND at 6 years 11 1.27 (1.27) 2.67 0.008 8 1.25 (1.28) 1.80 (0.072)Not ND at 6 years 86 0.50 (1.00) 34 0.53 (0.96)ND at 22 years 28 0.61 (1.13) 0.53 ns 15 0.60 (1.12) 1.03 nsNot ND at 22 years 80 0.65 (1.08) 37 0.84 (1.12)

Statistical analysis: severity of VD in offspring with vs. without ND; Mann–Whitney, two-tailed.NC, normal-risk controls; HR, total high-risk offspring; n, number of subjects; Severity of VD (visual dysfunction) at 4 years of age; ND, neurologically deviant; ns, notsignificant.

Table 5. Characteristics of subjects with visual dysfunction at 4 years and schizophrenia spectrum disorder at 22 years

Sex Subjects' diagnosis at 22 years Mothers' disorder Visual disorder at 4 years Type of neurological abnormalities at 6 years

F Schizoaffective psychosis Schizophrenia-spectrum Impaired vision bilat Clumsy and awkward movements; poor finger-nose accuracy,balance, diadochokinesia, crossing body midline and copyingpattern with finger; choreiform movements,finger tremor, mirror movements

M Schizotypal personality disorder Normal-risk control Strabism Continual, non-goal-directed gross and small movements

F Schizotypal personality disorder Schizophrenia-spectrum Strabismabducens paresis

Poor balance; choreiform movements,mirror movements, abnormal co-movements

M Paranoid personality disorder Affective-spectrum Impaired vision unilat Poor diadochokinesia & balance; mirror movements, abnormal co-movements

M Schizotypal personality disorder Schizophrenia-spectrum Impaired vision bilat Poor diadochokinesia; mirror movements, abnormal co-movements

F Schizoid personality disorder Affective-spectrum Strabism Continual, rapid, clumsy, non-goal-directed movements;poor finger-nose accuracy, diadochokinesia, crossing body midline andcopying patterns with finger; choreiform and athetoid movements,finger tremor, mirror movements and abnormal co-movements

F, female; M, male.

Schubert et al.

390

Previous studies report that neurological abnor-mality reflecting cerebellar dysfunction, eye-move-ment dysfunction and impaired visual perceptioncharacterizes patients with schizophrenia and theirrelatives, rather than patients with other psychi-atric disorders and their relatives (7, 8, 14–26, 30–36, 50, 51). The current findings are partiallydiscrepant with this, in that visual dysfunction wasassociated only with adult schizophrenia-spectrumdisorders in the offspring themselves, but therelationship did not breed true at the maternalrisk-group level. Among the six offspring with bothvisual dysfunction at 4 years of age and schizo-phrenia-spectrum disorder, three had mothers withschizophrenia-spectrum disorders, two had moth-ers with affective-spectrum disorders and one was aNC control case (Table 5) (a majority of the HRcases had mothers with psychoses other thanschizophrenia). One possible interpretation of thisdiscrepancy between maternal diagnosis and off-spring visual dysfunction/schizophrenia-spectrumdisorder is that the combination of visual dysfunc-tion in childhood and later development of schi-zophrenia-spectrum disorder is not only, or evenprimarily, the result of genetic risk for schizophre-nia-spectrum disorders, but rather reflects earlyabnormal neurodevelopment resulting from othergenetic factors or environmental influences (such asinfections or obstetric complications) that spanacross the different risk and control groups.For example, studies of NC groups have found

visual dysfunction to be related to a history ofobstetric complications (3, 4). Exploratory analysesprovided, however, no evidence for an associationbetween visual dysfunction and OCs in the currentsample. Selected complications (investigatedthrough personal observations by the last author(T.F.M.) and obstetric record information) werenot more frequent in HR subjects with (vs.without) visual dysfunction. These two subgroupsshowed little difference on mean length of labor(4.08 ± 1.75 h vs. 4.62 ± 3.04 h), rate of fetaldistress (28.6% vs. 22.6%), mean birthweight(3544 ± 434 g vs. 3540 ± 619 g), deviant birth-weights (<2.5 or >4.5 kg) (9.5% vs. 16.1%),prolonged labor (0% vs. 12.9%), instrumentaldelivery (4.8% vs. 12.9%), low 1-min Apgarscore (0% vs. 14.8%), abnormal gestational age(4.8% vs. 7.4%) and abnormal birthweight pergestational age (0% vs. 9.7%).In congruence with previous findings in studies

of children with ocular disorders (1–5), visualdysfunction was related to neurological abnormal-ity. This association was found at the mostproximal examination age (6 years), but not ininfancy or adulthood, and statistical significance

was dependent on inclusion of both NC and HRsubjects (Table 3). In general, the subjects did notshow personal stability on level of neurologicalabnormality from neonatal to 6-year examinations(35), and personal stability from 6 to 22 years wasof only moderate degree (but statistically signifi-cant) in both HR (rs ¼ 0.38) and NC (rs ¼ 0.26)offspring (52). The changes occurring in thenervous system over this 22 years age span wellencompass the possibility that visual dysfunctionwould relate to other signs of neurological devi-ation at the temporally most contiguous time(6 years) but not at two other, more distal ages,as observed here.Further investigation showed that visual dys-

function had no selective relation to the particulartype of neurological abnormality at 6 years of age[disturbed coordination vs. overflow movement(53)]. In total, these findings might suggest tenta-tively that disturbed neurodevelopment lies behindboth visual dysfunction and neurological abnor-mality, visual dysfunction likely being a furthermanifestation of disturbed neurodevelopment thatis already detectable in early childhood. Therelation between visual dysfunction and neurolog-ical abnormality in early childhood, and schizo-phrenia-spectrum disorders in adulthood, supportsthe neurodevelopmental hypothesis of the patho-genesis of schizophrenia-related disorders.

Strengths and limitations

The strengths of the study were the prospectivedesign with early neurological assessments andvision tests; the high adult follow-up rate; thenarrow age range at follow-up; the use of stan-dardized examination routines; and examinationby investigators who were blinded to the subject’sstudy group and previous project data. The studydesign was especially demanding, as visual dys-function was compared for individuals with a givenpsychiatric categorization vs. those without thatparticular categorization, even if many subjects inthe latter group had other psychiatric diagnoses.The major limitations of this study lie in the non-selective loss of 33% of the sample for vision tests(because of not having reached 4 years of age atdata collection) and the small number of subjectswith schizophrenia-spectrum disorders.In summary, visual dysfunction in early child-

hood predicted the development of schizophrenia-spectrum disorder later in life primarily amongoffspring at risk for psychosis, and was related toneurological abnormality in mid-childhood. Thesefindings yield support for a neurodevelopmentaletiology for schizophrenia-spectrum disorders.


391

Given the apparent uniqueness of these results andthe small sample size, future research should retestthese findings and further focus attention on theantecedents of visual dysfunction and its relevancefor the later development of serious psychopathol-ogy.

Acknowledgements

This study was supported by grants from the Stanley MedicalResearch Institute USA, the NIMH USA (grant no.MH18857), the Swedish Medical Research Council (no.3793), and the Medical Faculty of Lund University, Sweden.

References

1. Garbutt S, Harris CM. Abnormal vertical optokinetic ny-stagmus in infants and children. Br J Ophthalmol 2000;84:451–455.

2. Jan JE, Kearney S, Groenveld M, Sargent MA, Poskitt KJ.Speech, cognition, and imaging studies in congenital ocularmotor apraxia. Dev Med Child Neurol 1998;40:95–99.

3. Weisglas-Kuperus N, Heersema DJ, Baerts W et al. Visualfunctions in relation with neonatal cerebral ultrasound,neurology and cognitive development in very-low-birth-weight children. Neuropediatrics 1993;24:149–154.

4. Holmstrom G, el Azazi M, Kugelberg U. Ophthalmologicalfollow up of preterm infants: a population based, pros-pective study of visual acuity and strabismus. Br J Oph-thalmol 1999;83:143–150.

5. Ohtsuki H, Yoshifumi K, Hasebe S, Kono R, Harada Y.Comparative study of brain lesions detected by magneticresonance imaging between strabismus and nonstrabismusin infancy. Ophthalmologica 2000;214:105–110.

6. McNeil TF, Cantor-Graae E, Ismail B. Obstetric compli-cations and congenital malformation in schizophrenia.Brain Res Brain Res Rev 2000;31:166–178.

7. Heinrichs DW, Buchanan RW. Significance and meaning ofneurological signs in schizophrenia. Am J Psychiatry 1988;145:11–18.

8. Tek C, Gold J, Blaxton T et al. Visual perceptual andworking memory impairments in schizophrenia. Arch GenPsychiatry 2002;59:146–153.

9. Blanchard JJ, Neale JM. The neuropsychological signatureof schizophrenia: generalized or differential deficit? Am JPsychiatry 1994;151:40–48.

10. Levin S, Yurgelun-Todd D, Craft S. Contributions ofclinical neuropsychology to the study of schizophrenia.J Abnorm Psychol 1989;98:341–356.

11. Waddington JL. Neurodynamics of abnormalities in cer-ebral metabolism and structure in schizophrenia. Schiz-ophr Bull 1993;19:55–68.

12. Murray RM, Lewis SW. Is schizophrenia a neurodevelop-mental disorder? BMJ 1987;295:681–682.

13. Weinberger DR. Implications of normal brain developmentfor the pathogenesis of schizophrenia. Arch Gen Psychi-atry 1987;44:660–669.

14. Quitkin F, Rifkin A, Klein DF. Neurologic soft signs inschizophrenia and character disorders. Organicity in schi-zophrenia with premorbid asociality and emotionallyunstable character disorders. Arch Gen Psychiatry 1976;33:845–853.

15. Rossi A, De Cataldo S, Di Michele V et al. Neurological softsigns in schizophrenia. Br J Psychiatry 1990;157:735–739.

16. Woods BT, Kinney DK, Yurgelun-Todd D. Neurologicabnormalities in schizophrenic patients and their families.I. Comparison of schizophrenic, bipolar, and substanceabuse patients and normal controls. Arch Gen Psychiatry1986;43:657–663.

17. Wolff AL, O’Driscoll GA. Motor deficits and schizo-phrenia: the evidence from neuroleptic-naive patients andpopulations at risk. J Psychiatry Neurosci 1999;24:304–314.

18. Ismail B, Cantor-Graae E, McNeil TF. Neurologicalabnormalities in schizophrenic patients and their siblings.Am J Psychiatry 1998;155:84–89.

19. Asarnow JR. Children at risk for schizophrenia: converginglines of evidence. Schizophr Bull 1988;14:613–631.

20. Lawrie SM, Byrne M, Miller P et al. Neurodevelopmentalindices and the development of psychotic symptoms insubjects at high risk of schizophrenia. Br J Psychiatry 2001;178:524–530.

21. Erlenmeyer-Kimling L. Neurobehavioral deficits inoffspring of schizophrenic parents: liability indicatorsand predictors of illness. Am J Med Genet 2000;97:65–71.

22. Iacono WG, Lykken DT. Two-year retest stability of eyetracking performance and a comparison of electro-oculo-graphic and infrared recording techniques: evidence ofEEG in the electro-oculogram. Psychophysiology 1981;18:49–55.

23. Holzman PS, Solomon CM, Levin S, Waternaux CS. Pursuiteye movement dysfunctions in schizophrenia. Family evi-dence for specificity. Arch Gen Psychiatry 1984;41:136–139.

24. Mather JA. Eye movements of teenage children of schizo-phrenics: a possible inherited marker of susceptibility tothe disease. J Psychiatr Res 1985;19:523–532.

25. Levy DL, Holzman PS, Matthysse S, Mendell NR. Eyetracking and schizophrenia: a selective review. SchizophrBull 1994;20:47–62.

26. Rosenberg DR, Sweeney JA, Squires-Wheeler E et al. Eye-tracking dysfunction in offspring from the New YorkHigh-Risk Project: diagnostic specificity and the role ofattention. Psychiatry Res 1997;66:121–130.

27. Levy DL, Yasillo NJ, Dorus E et al. Relatives of unipolarand bipolar patients have normal pursuit. Psychiatry Res1983;10:285–293.

28. Cannon M, Caspi A, Moffitt TE et al. Evidence for early-childhood, pan-developmental impairment specific toschizophreniform disorder: results from a longitudinalbirth cohort. Arch Gen Psychiatry 2002;59:449–456.

29. Schubert E, McNeil T. Prospective study of adult mentaldisturbance in offspring of women with psychosis. ArchGen Psychiatry 2003;60:473–480.

30. Hanson DR, Gottesman II, Heston LL. Some possiblechildhood indicators of adult schizophrenia inferred fromchildren of schizophrenics. Br J Psychiatry 1976;129:142–154.

31. Marcus J, Hans SL, Lewow E, Wilkinson L, Burack CM.Neurological findings in high-risk children: childhoodassessment and 5-year followup. Schizophr Bull 1985;11:85–100.

32. Marcus J, Hans SL, Nagler S et al. Review of the NIMHIsraeli Kibbutz-City Study and the Jerusalem InfantDevelopment Study. Schizophr Bull 1987;13:425–438.

33. Hans SL, Marcus J, Nuechterlein KH et al. Neurobehavi-oral deficits at adolescence in children at risk for schizo-phrenia: The Jerusalem Infant Development Study. ArchGen Psychiatry 1999;56:741–748.

Schubert et al.

392

34. Blennow G, McNeil TF. Neurological deviations in newb-orns at psychiatric high risk. Acta Psychiatr Scand 1991;84:179–184.

35. McNeil TF, Harty B, Blennow G, Cantor-Graae E. Neu-romotor deviation in offspring of psychotic mothers: aselective developmental deficiency in two groups of chil-dren at heightened psychiatric risk? J Psychiatr Res1993;27:39–54.

36. Schubert EW, Cantor-Graae E, McNeil TF. Neurologicaldeviation in offspring of women with psychosis: from in-fancy to childhood. Schizophr Res 2002;53:S232.

37. Henriksson KM, McNeil TF. Health and development in thefirst 4 years of life in offspring of women with schizo-phrenia and affective psychoses: Well-Baby Clinic infor-mation. Schizophr Res 2004;70:39–48.

38. McNeil TF, Kaij L. Offspring of women with nonorganicpsychoses. In: Watt NF, Anthony EJ, Wynne LC, Rolf JE,eds. Children at risk for schizophrenia: a longitudinalperspective. New York, NY: Cambridge University Press,1984:465–481.

39. McNeil TF, Kaij L. Swedish high-risk study: sample char-acteristics at age 6. Schizophr Bull 1987;13:373–381.

40. Spitzer R, Williams J, Gibbon M, First M. Instructionmanual for the structured clinical interview for DSM-IIIR(SCID, 5/1/89 Revision): Biometric Research Department.New York, NY: New York State Psychiatric Institute,1989.

41. Social styrelsen. Child health services for children at 4 yr ofage. Report. Stockholm: Socialstyrelsen (the Swedish Na-tional Board for Health and Welfare), 1974.

42. Kornfalt R. Survey of the pre-school child health surveil-lance programme in Sweden. Acta Paediatr 2000;434(Suppl.):2–7.

43. Kohler L, Stigmar G. Vision screening of four-year-oldchildren. Acta Paediatr Scand 1973;62:17–27.

44. American Psychiatric Association. Diagnostic and statis-tical manual of mental disorders. Revised 3rd edn (DSM-III-R). Washington, DC, USA: APA, 1987.

45. Prechtl HFR, Beintema D. The neurological examination ofthe fullterm newborn infant. London: Heinemann, 1964.

46. Hagberg B. Neurologisk diagnostik i nyfoddhetsperioden(Neurological diagnostics in the neonatal period). Lakar-tidningen 1964;32:2232–2238.

47. Beintema DA. A neurological study of newborn infants.London: Heinemann, 1968.

48. Touwen BCL, Prechtl HFR. The neurological examinationof the child with minor nervous dysfunction. London:Heinemann, 1970.

49. Cornblatt B, Obuchowski M, Roberts S, Pollack S,Erlenmeyer-Kimling L. Cognitive and behavioral precursorsof schizophrenia. Dev Psychopathol 1999;11:487–508.

50. Andreasen NC, Paradiso S, O’Leary DS. ��Cognitivedysmetria’’ as an integrative theory of schizophrenia: adysfunction in cortical-subcortical-cerebellar circuitry?Schizophr Bull 1998;24:203–218.

51. Avila MT, Weiler MA, Lahti AC, Tamminga CA, ThakerGK. Effects of ketamine on leading saccades duringsmooth-pursuit eye movements may implicate cerebellardysfunction in schizophrenia. Am J Psychiatry 2002;159:1490–1496.

52. Schubert EW, McNeil TF. Prospective study of neurologi-cal abnormalities in offspring of women with psychosis:birth to adulthood. Am J Psychiatry 2004;161:1030–1037.

53. McNeil TF, Cantor-Graae E, Blennow G. Mental correlatesof neuromotoric deviation in 6-year-olds at heightened riskfor schizophrenia. Schizophr Res 2003;60:219–228.


393

a prospective study of offspring of women with psychosis: visual dysfunction in early childhood...

Documents