Magnetic resonance imaging abnormalities in young euthymic patients with bipolar affective disorder

Temporal lobe and limbic structures may be abnormalin bipolardisorder. T2-weighted magnetic resonance imaging (MRI) scansfrequently show deep white matter lesions. MRI was performedon 50 young (19-39 years) euthymic patients with bipolar disorderand 26 controls. Mean temporal lobe volumes were reduced inpatients (right, 9.42 cm³; left, 6.33 cm³) but this could notbut this could not be ascribed to a specific structure. Deepwhite matter lesions were present in 5 patients but no controlsraising questions of their aetiological significance.

INTRODUCTION

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INTRODUCTION

Despite many magnetic resonance imaging (MRI) studies of thetemporal lobe in bipolar disorder, consistent findings areyet to emerge. Early findings of reduced temporal lobe volumesremain unconfirmed (Swayze et al, 1992; Altshuler et al, 2000).Deep and periventricular white matter lesions observed on T2-weightedMRI scans are 3.3 times more prevalent in bipolar disorder (Altshuler et al, 1995),although they are present in only a minority of patients. Herewe compare temporal lobe and ventricular volumes and deep whitematter lesions in young, physically healthy euthymic patientswith bipolar disorder and controls.

METHOD

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METHOD

We invited 121 patients with bipolar I disorder attending clinicsin north-east England to participate in the study. After assessmentand explanation of the study's aims and methods, 53 gave writteninformed consent. Three were excluded because of scanning difficulties,leaving 50 (15 males; mean age 30.2 years (s.d.=6.2, range20-39); mean illness duration 8.9 years (s.d.=3.3)) to completethe study. We recruited 26 controls (13 males, 13 females;mean age 30.2 years (s.d.=6.2, range 20-39), with no currentor past psychiatric disorder matched for mean age and premorbidIQ (NART; Nelson, 1982).

Patients met DSM-IV criteria (American Psychiatric Association, 1994)for bipolar I disorder only and had experienced at least twoepisodes of illness. Exclusion criteria (Moore et al, 2001a)designed to eliminate white matter abnormalities unrelatedto bipolar disorder were applied to patients and controls. Both groups were euthymic at the time of scanning; this was confirmedby a mental state examination supplemented by the Beck DepressionInventory (Beck et al, 1961).

Axial T2-weighted, coronal inversion recovery and sagittal,coronal and axial T1 scans were recorded using a General Electrics(Slough, UK) MR max plus 0.5 tesla scanner. Details of volumetricmeasurements from coronal inversion recovery scans have beenpublished previously (Moore et al, 2001a). The rostral limitof the temporal lobe was taken to be the last slice showingthe Sylvian fissure.

Intracranial volumes could not be measured directly. Head sizewas measured as the product of three mutually perpendicularskull diameters, the posterior-anterior diameter, the left-rightdiameter and the vertical height of the skull above the sella.White matter hyperintensities on MRI were evaluated independentlyby two investigators. Only hyperintensities present on bothT2 and proton density scans and, for deep white matter lesionsat least 3 mm in diameter, were included. Investigators werein complete agreement about whether an individual scan showeddeep or periventricular white matter lesions. Scans were ratedusing the scale of Fazekas et al (1993).

Data were analysed using the statistical package Minitab 10.2for Windows (Minitab Inc., Pennsylvania, USA). Data that werenormally distributed were analysed using ANOVA and Student'st-test. A Bonferroni correction was applied, making P $<=$ 0.007significant and 0.05 > P > 0.007 a trend.

RESULTS

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RESULTS

Patients had smaller temporal lobe volumes than controls (left,mean 54.9 cm³ (s.d.=9.9) v. 61.3 (s.d.=8.3), F=7.7, P=0.007and right, mean 59.5 cm³ (s.d.=10.8) v. 68.1 (s.d.=8.2), F=12.55,P=0.001) with right volumes being greater than left (pairedt=7.28, P<0.001) (Fig. 1). Lateral ventricle volumes didnot differ between patients and controls (left, mean 8.7 cm³(s.d.=4.3) v. 8.0 (s.d.=2.8) and right, mean 8.21 cm³ (s.d.=4.4)v. 7.3 (s.d.=2.4). Illness (F=9.81, P=0.003) and gender (F=7.37, P=0.008) contributed significantly to differences in temporallobe volume. Post hoc pairwise comparisons of temporal lobevolumes in males, females, patients and controls found significantly(F=9.3, P=0.003) smaller left volumes (mean 52.2 cm³ (s.d.=8.8)) in female than male (mean 61.0 cm³ (s.d.=9.6)) patients. Therewere trends (0.05 > P > 0.007) for female patients tohave smaller temporal lobes (left or right) than controls,and for the right temporal lobes of female patients to be smallerthan those of males (F=4.99, P=0.03).

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Fig. 1 Left and right temporal lobe volumes in patients and controls., •, male patient;, ${blacksquare}$ , male control;, ${circ}$ female patient;, ${square}$ female control.

Age and skull volume may be confounding variables. Age was similarin patient and control groups and was not a significant confounder.When temporal lobe volumes were analysed using a general linearmodel with illness presence and gender as categorical variablesand head size as covariate (with interactions allowed), theadjusted left mean temporal lobe volumes of patients (55.7cm³ (s.d.=1.6)) and controls (61.7 cm³ (s.d.=1.6)) differedsignificantly (F=13.8, P<0.001). An interaction betweenillness group and head size contributed significantly (F=12.4,P=0.001) to the left temporal lobe volume variance.

Similarly, the adjusted right mean temporal lobe volume in patients(60.0 cm³ (s.d.=1.7)) was smaller (F=10.6, P=0.002) than incontrols (68.5 (s.d.=1.8)). Again an interaction between illnessgroup and head size parameter was observed (F=10.6, P=0.002).No other group/covariate interactions significantly contributedto the variance of left or right temporal lobe volumes.

Deep white matter lesions were observed in 5 out of 50 patients(10%) but no controls (Fisher's exact test, two-tailed, P=0.115).Two were graded as 2 (moderate severity) and three were gradedas 1 (mild) on the Fazekas scale. Two patients with deep whitematter lesions had periventricular white matter lesions (Fazekasgrade 3 and 1). No controls exhibited white matter abnormalities.

DISCUSSION

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DISCUSSION

Patients with bipolar disorder had significantly reduced rightand left temporal lobe volumes even after controlling for skullvolumes. Our mean temporal lobe volume in males (125.6 cm³(s.d.=18.9)) agrees well with a recently published value (139.5cm³ (s.d.=15.5)) despite differences in MRI methods and problemsdefining the temporal lobe rostral boundary (Altshuler et al, 2000).

Published, mixed-gender studies of bipolar disorder have reportedsmaller (Swayze et al, 1992), unchanged (Hauser et al, 2000)or increased (Harvey et al, 1994) temporal lobe volumes. Altshuleret al (2000) were unable to replicate an earlier finding ofreduced temporal lobe volume in males. We found temporal lobevolume reductions predominantly in females, which may explaindifferences in male only and mixed-gender studies.

Generalised or specific structural atrophy, changes in grey/whitematter density, or abnormal temporal lobe neurodevelopmentcould cause reduced temporal lobe volumes. Measured mean hippocampaland amygdala volumes lie in the ranges of 2.0-3.8 cm³ and 1.3-3.4cm³, respectively (Swayze et al, 1992; Altshuler et al, 2000).As these are much less than our measured reductions in temporallobe volumes, such reductions could not result solely from hypoplasticityof the amygdala and hippocampus. Although patients exhibited minimally enlarged lateral ventricles, this was not statisticallysignificant. Thus, there was little evidence of generalisedcerebral atrophy in young patients with bipolar disorder, addingto the consensus of negative studies (Soares & Mann, 1997). Grey matter density may be reduced by up to 9.6% and mightcontribute to reduced temporal lobe volume (Lim et al, 1999).

We are confident that the deep white matter lesions observedin 10% (P=0.115) of patients are linked to bipolar disorder.In this and an earlier study with similar exclusion criteria (Moore et al, 2001a), deep white matter lesions were absentin controls under 50 years, reinforcing the association, albeitweak, between the lesions observed here and bipolar disorder.Furthermore, studies of younger (or first-episode) patients(Swayze et al, 1992; Strakowski et al, 1993) also showed anon-significant 10% frequency of deep white matter lesions.Supporting these observations, post-mortem studies have reportedmicrotubule protein and oligoden-drocyte abnormalities in bipolardisorder (for review see Harrison, 2002), which may contributeto the formation of deep white matter lesions.

The low prevalence of deep white matter lesions suggests thatthey have a limited but unknown contribution to the pathogenesisof bipolar disorder. Associations with winter birth (Moore et al, 2001b),cognitive difficulties (Dupont et al, 1995) and especiallytreatment resistance (Moore et al, 2001a) may provide startingpoints for future examination of their importance.

REFERENCES

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