Leukoencephalopathy in elderly depressed patients referred for ECT

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1988;24:143-161

Leukoencephalopathy in Elderly Depressed Patients Referred for ECT C. Edward Coffey, Gary S . Figiel, William T. Djang, Martha Cress, William B . Saunders, and Richard D. Weiner

Using brain magnetic resonance imaging (MRI) and high-resolution computed tomography (CT), we identified changes in the subcortical white matter in 44 of 67 elderly depressed inpatients (66%) referred for electroconvulsive therapy (ECT). This “leukoencephalopathy” was frequently associated with other structural brain changes, including cortical atrophy, lateral ventricular enlargement, and lacunar infarctions of the basal ganglia and thalamus. Many (58%) of the patients had developed late-onset depressive disorders, and the majority (86%) had been refractory to andlor intolerant of antidepressant drug therapy. Nevertheless, all but I of the 44 patients subsequently responded to a course of ECT, which in general was well tolerated. Although the precise etiology of the leukoencephalopathy remains unclear, clinical data suggest that it may result from arteriosclerotic disease of the medullary arteries that supply the subcortical brain regions. Several lines of evidence suggest that leukoencephalopathy may have implicationsfor the pathophysiology of depressive illness, at least in some elderly patients.

Introduction Subcortical white matter changes are often seen on magnetic resonance imaging (MRI) or high-resolution computed tomography (CT) of the brain in elderly or demented subjects (Zimmerman et al. 1986; Coffey et al. 1987a; Fazekas et al. 1987; Hachinski et al. 1987). Typically, these changes appear as areas of increased “T2-signal” on MRI or decreased density on CT. In the absence of other systemic or intracranial disease, the leukoencephalopathy is felt to reflect abnormal water (hydrogen) content and/or myelin structural changes resulting from progressive arteriosclerotic disease of the medullary arteries that supply the subcortical brain regions (Kinkel et al. 1985; Coffey et al. 1987a). Recently, we have observed similar subcortical white matter changes in a small number of elderly patients referred for electroconvulsive therapy (ECT) of severe depression (Coffey et al. 1987a). This finding is of interest given the well-known association between affective disorder and syndromes associated with subcortical brain disease (e.g., Huntington’s disease, Parkinson’s disease, multiple sclerosis, etc.) (Cummings 1986). The

(W.T.D.), Duke University Medical Center, and the Dwham Vetcmns Hospital (R.D.W.), Durham, NC. Address reprint tqoests to Dr. C. Edward Coffey, Box 3920, Duke University Medical Center, D&am, NC 27710. Supported in pU by NthU-I Grants MH 41803. MH 30723, end MH 40159 and the North Carolina United Way. Pmsented in part at the Annual Meeting of the Society of Biological Psychiatry, Chicago, IL, May 9, 1987. Received August 20, 1987; revised October 13, 1987. 0 1988 Society of Biological Psychiatry

COO6-3223/88/$03.50

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relative frequency of leukoencephalopathy in patients with affective illness is unclear, however, and precisely how such changes affect clinical presentation and response to ECT has never been studied. To determine the occurrence of leukoencephalopathy in this population, we reviewed the brain MRJ and CT scans of all elderly inpatients who recently received ECT at our institution. The relationship of these brain imaging findings to selected features of the patients’ clinical status and response to ECT were also examined.

Methods From July 1, 1985 to December 31, 1986, 168 consecutive inpatients received a course of ECT at Duke University Medical Center. Of these, 89 (53%) were 60 years of age or older (“elderly”), and all met DSM-III criteria for major depression. At the time of referral for ECT, most (86%) of these patients were determined by the referring physician to have been either refractory to and/or intolerant of antidepressant medications.

Subjects Advanced brain imaging studies were obtained in 67 (75%) of these elderly depressed patients prior to their course of ECT-36 received MRJ and 39 received CT (8 patients received both studies). The brain imaging studies were obtained for one or more of the following reasons: an abnormal neurological examination, as part of a diagnostic evaluation to exclude an organic affective disorder (e.g., brain tumor, cortical stroke), and as part of a research protocol. The mean age of this population was 71.6 years (range 60-86), and there were 41 women and 26 men. In addition to major depression, two of these patients had been previously diagnosed as having primary degenerative dementia. Many of these patients were taking medications for one or more of the following medical illnesses: ischemic heart disease and/or hypertension (n = 35)) diabetes mellitus (n = 8), chronic obstructive pulmonary disease (n = 4), hypothyroidism (n = 4), deep vein thrombosis (n = 2), and severe malnutrition (n = 2). There were 19 medically healthy patients on no medications. Brain Imaging Studies The brain MRJ and CT scans of these 67 elderly depressed inpatients were analyzed retrospectively to determine the occurrence and severity of white matter changes and any other structural brain abnormalities. Formal rating scales were employed to assess the most frequent findings, and the medical records of each patient were reviewed to investigate potential clinical correlates. BrainMRZ (n = 36).All brain MRJ studies were performed on a General Electric 1.5 Tesla Signa system. For each study, spin echo pulse sequences were used to generate both “Tl-weighted” (TR = 500 msec, TE = 20 msec) and “TZweighted” (TR = 2000 msec, TE = 40 and 80 msec) axial brain images. The axial imaging planes were obtained parallel to the orbitomeatal baseline (0”). For both the Tl- and T2-weighted images, a series of 20 5-mm thick sections with a 2.5-

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mm interscan gap was performed. Gther technical parameters included 128 x 256 matrix, field of view (FOV) 20 cm, and number of excitations (NEX) 2. The brain MRI scans were analyzed independently by a board-certified neuroradiologist (W.T.D.) and a neurologist/psychiatrist (C.E.C.), both of whom were blind to the clinical intetpretation of each study. Using formal rating instruments suited to MRI, each patient’s MRI study was assessed for the presence and extent of the following findings: 1. Leukoencephalopathy, including periventricular hyperintensity (PVH) and deep white matter hyperintensity (DWMH)-Both PVH and DWMH were rated from the T2-weighted images using a modification of the Cpoint scale described by Far&as et al. (1987). Periventricular hyperintensity (PVH) was graded as 0 = absent, 1 = “caps” or pencil-thin lining, 2 = smooth “halo,” and 3 = irregular PVH extending into the deep white matter. Separate deep white matter hyperintensity signals (DWMH) were rated as 0 = absence, 1 = punctuate foci, 2 = beginning confluence of foci, and 3 = large confluent areas. Pmdefined visual standards for each grade were established for comparison. 2. Lacunae of the subcortical gray matter (basal ganglia, thalamus)-Abnormalities were rated as either punctate, multipunctate, or diffuse, and any left-right asymmetries were noted. 3. Lateral ventricular enlargement (Drayer et al. 1985; Steingart et al. 1987)-A lateral ventricular enlargement score (LVES) was determined from a 5-point rating scale: 0 = none, 1 = slight enlargement, 2 = mild enlargement, 3 = moderate enlargement, and 4 = severe enlargement. Ventricular enlargement was rated only if it was considered to be more extensive than would be expected for the patient’s age. Predefined visual standards for each grade were established for comparison. The LVES for each patient was defined as the average score of the two raters, and fractions were rounded to the nearest integer. Any left-right asymmetries were also recorded. 4. Cortical atrophy (Largen et al. 1984)-A cortical atrophy score (CAS) was determined from a 5-point rating scale: 0 = no atrophy, 1 = slight atropy, 2 = mild atrophy, 3 = moderate atrophy, and 4 = severe atrophy. Specific definitions of each anchor point are given in the Appendix. Predefined visual standards for each grade were established for comparison. The CAS for each patient was defined as the average score of the two raters (fractions were rounded to the nearest integer). Any left-right asymmetries were also recorded. 5. Other abnormalities (e.g., brain stem, cerebellum) were described and recorded. Bruin CT (n = 39). All brain CT scans wete performed on either a GE 9800 or a GE 9000 series system. Each patient received a CT scan consisting of 12-15 contiguous slices collimated at 10 mm each. The scanning angle was parallel to the canthomeatal line, and the examinations were performed without contrast. The brain CT images were analyzed independently by the same board-certified neuroradiologist (W.T.D.) and neurologist/psychiatrist (C.E.C.). Again, both were blind to the clinical imerpmtation of each study. Using formal rating scales appropriate for CT, each patient’s study was assessed for the presence and extent of the following: 1. Leukoencephalopathy, including leukoaraiosis and focal lacunar infarctions of the internal capsule-leukoaraiosis is a descriptive eponym coined by Ha&in&i et al. (1987) to refer to illdefined, patchy, diffuse, low-density (on CT) lesions of

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2.

3. 4.

5.

C.E. Coffey et al.

the white matter, without cortical extension or local changes in ventricle or sulcus. The severity of leukoaraiosis was rated on a 4-point scale (0 = none, 1 = mild, 2 = moderate, 3 = severe) (Lotz et al. 1986), with anchor points defined for each rating (see Appendix). Predefined visual standards for each grade were also established for comparison. These measures provided an assessment of subcortical white matter disease that could be compared to MRI ratings of PVH and DWMH. Lacunae of the subcortical gray matter (basal ganglia, thalamus)--As with MRI, these abnormalities were rated as either punctuate, multipunctuate, or diffuse, and any left-right asymmetries were noted. Cortical atrophy (Largen et al. 1984). Lateral ventricular enlargement (Drayer et al. 1985)--A CAS and LVES were obtained for each patient using the same rating scales as described for the MRI studies. Other abnormalities (e.g., brain stem, cerebellum, etc.) were described and recorded.

ECT Treatment Technique Psychotropic medications were tapered and discontinued prior to ECT in all patients. The ECT treatment technique was similar for each patient. ECT was administered three mornings a week on a Monday-Wednesday-Friday schedule. Patients received glycopyrrolate (Robinul) ,0.002 mg/lb im, at least 30 min prior to ECT . Anesthesia was induced with methohexital (Brevital), 1 mg/kg iv, followed by succinylcholine (Anectine), 1 mgl kg iv, to produce subtotal neuromuscular blockade. All patients were preoxygenated with 100% oxygen via a mask, and once apneic, their respirations were maintained at a rate of 20-25/min with positive-pressure ventilation by bag. Choice of stimulus electrode placement was made by the attending physician. For unilateral nondominant (UL) ECT, the d’Elia placement technique was used (d’Elia 1970). Thirty-four patients received UL ECT exclusively, 4 were switched from UL to bilateral (BL) ECT because of poor therapeutic response, and the remaining 29 patients received only BL ECT. The total number of ECT treatments was determined by the attending physician; the average number of ECTs was 9 (range 6-14). The pulse ECT stimulus was administered by either the MECTA C, the MECTA SRl , or the Thymatron device. A previously described “moderately suprathreshold” stimulus dosing strategy was employed (Coffey et al. 1987~). For each ECT treatment, seizure duration was determined from a one-channel electroencephalogram (EEG) using standard criteria (Weiner 1979) to insure that all patients received seizures of adequate length (Coffey et al. 1987~).

Clinical Data The medical records of each patient were reviewed by a psychiatrist (G.S.F.) who was blind to the results of all brain imaging studies. Clinical data on each patient were obtained for the following: 1. Past psychiatric and medical histories, including risk factors for atherosclerotic disease (hypertension, diabetes, tobacco use, hyperlipidemia, and history of cardiovascular, cerebrovascular, or peripheral vascular disease).

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2. Current psychiatric illness, including type, severity, and duration of symptoms and response to therapies. 3. Results of physical and mental status examinations. 4. Any current laboratory studies, including the Dexamethasone Suppression Test (DST), and neuropsychological evaluations. Prior to beginning ECT, each patient underwent a systematized neurological evaluation by a neurologist (C.E.C.) blind to the results of all brain imaging studies. Only those findings that clearly indicated involvement of the upper motor neuron at or above the brain stem were analyzed. The findings from the neurological examinations were given global ratings of either normal or abnormal in terms of cranial nerves, muscle tone, muscle power, gait, deep tendon reflexes, and plantar responses. The occurrence (present or absence) of involuntary movements and primitive reflexes (rooting, sucking, snout, glabellar, and palmomental) were also recorded. Therapeutic outcome from ECT was determined retrospectively from a review of the medical records and was based on the global assessment of the patient’s treatment course as determined by the attending physician and ward treatment team (Black et al. 1987). The patient was rated as having an excellent response if the medical records indicated that the patient was “back to baseline” or showed a “dramatic”, “marked”, or “very good” response. The patient was rated as having a good response if the medical record stated that the patient showed a “good” or “moderate” response. The patient was rated as having a “fair” response if the medical record stated that the patient showed a “mild” or “fair” response. Those who were reported to be “unimproved” were rated as such. In order to investigate any potential relationships between preexisting brain abnormalities and encephalopathic side effects of ECT, the occurrence of post-ECT delirium and interictal confusion were also recorded.

Statistical Analysis A logistic regression model suitable for ordinal data was used to address the following questions: (1) Is there an association between the severity of leukoencephalopathy on MRI (PVH or DWMH) or CT (leukoaraiosis) and (A) cortical atrophy (CAS) or (B) lateral ventricular enlargement (LVES)? (2) Is there an association between a prior history of ECT (yes or no) and the severity of (A) leukoencephalopathy (PVH, DWMH, or leukoaraiosis), (B) cortical atrophy (CAS), or (C) lateral ventricular enlargement? Given the differences in rating scales and relative sensitivities of the imaging techniques, statistical analyses were conducted separately for the patients with leukoencephalopathy who received MRI scans (n = 31) and those patients with leukoencephalopathy who received CT scans (n = 20).

Results Brain Imaging Abnormalities Of the 67 elderly depressed patients who received brain MRI and/or CT, 14 patients (21%) had normal studies (Table 1). There were three normal MRI scans and 12 normal CT scans. One patient had both a normal MRI and a normal CT scan. Brain imaging abnormalities were present in 53 (79%) of the 67 elderly depressed

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Table 1. Brain Imaging Findings in Elderly Patients with Depression (n = 67)” All patients

Brain MRI (n = 36)

BrainCT (n

Normal Subcortical abnormalities

14 45

3

12

Leukoencephalopatby Gray matter lacwae Basal ganglia only Tbalamus only Both Lateral ventricular ealargementb Cortical abnormalities

44 21 10 1 10 45 46

31 16 7 1 8 28

20 6 4 0 2 20

Atrophy’ Infarction Other

46 3

31 0

22 3

13 5

13 3

0 2

Brain stem lacunae Cerebellar infarction

= 39)

“[email protected] nxeivcd both an MRl scaa and a CT scan. Most patients had more than one ahno&@. bLatcralventricularenlargementis detkd aa a rating of 1 or greater. ‘Atrophy is defined as a cortical atrophy score of 2 or greater.

patients. Of the 36 MRI scans, 33 were abnormal (92%); 27 of the 39 CT scans were abnormal (69%). The most common findings were abnormalities of the subcortical white and gray matter (45 patients), lateral ventricular enlargement (45 patients), and cortical atrophy (46 patients). Most patients had various combinations of these findings. Other less common abnormalities included apparent infarctions of the cerebral cortex (3 patients), cerebellum (5 patients), and brain stem (presumed lacunar infarctions of the pons in 13 patients). Leukoencephalopathy was observed in 44 (66%) of the 67 patients (Table 1). On T2weighted brain MRI (Table 2), these abnormalities consisted of PVH and/or DWMH (n = 31). The PVH was characterized either by caps or a pencil-thin lining (grade 1) in 15 patients, by a smooth halo (grade 2) in 11 patients, and by irregular extension into the deep white matter (grade 3) in 5 patients (Table 2). The DWMH consisted of punctuate foci (grade 1) in 11 patients, small areas of confluent foci (grade 2) in 11 patients, or large confluent areas (grade 3) in 5 patients. In 9 of these 31 patients with white matter abnormalities (PVH or DWMH) on MRI, the lesions were felt to be asymmetric, with greater involvement of the left than right hemisphere in 7 of the 9 patients (Table 2). On brain CT (Table 3), the leukoencephalopathy consisted of discrete lacunar infarctions (n = 2 patients with left internal capsule infarcts) or leukoaraiosis (n = 18 patients). The extent of leukoaraiosis was rated as mild in 7 patients, moderate in 9 patients, and severe in 2 patients. The leukoaraiosis was symmetric in 15 patients; however, in 2, the leukoaraiosis was more extensive in the right hemisphere, and in 1 patient, the left hemisphere was more involved (Table 3). White matter abnormalities were apparent on both MRI (TZweighted) and CT scans in 7 of the 8 patients who received both studies (1 patient had a normal MRI and CT scan). The leukoencephalopathy was generally rated as more extensive and severe on the MRI studies than on the CT scans, however. In addition, in 4 patients, the n-weighted MRI scans revealed lacunar infarctions of the basal ganglia, thalamus, and/or pons that were not apparent on brain CT. Leukoencephalopathy was frequently associated with other structural brain changes,

Pat&&

1 1

1

1 1 (R > L)

(78,F) (77,M)

(46.~)

(69.M) (72,m

27 28 29 30 31

> R)

> R)

> R)

> R)

> L)

1 0 0 0 0

2 2 2 1 (L > R) 1 (L > R) 1 1 1 1 1

3(R 3 3 2 (L 2 3 (L 3 2 (L 2 2 2 2 2 1 (L

DWMH

1 1 1 (L > R) 1

THAL, PGNS

BGL, PONS I’I-LU (R) PONS

PONS

BGL,THAL BGL (L > R), THAL, PONS BGL (L > R), THAL, PONS PONS PONS

F’ONS BGL

BGL

1 1 (L > R) 0 1 2 0 1 1 1 2 2 1 2

2 2 2 1 3 (L > R) 2

2 (R > L) 1 3 1

Lateral ventricular enlargement

THAL, PONS (L > R), ‘l-HAL. F’ONS PONS

LaCUnae’

BGL, THAL BGL, PONS BGL, (R > L)

BGL, BGL BGL, BGL BGL BGL,

F, female; M, male. bPVH, pcriventricdar hyperintensity; DWHM, deep white matter hypxintensity; L, left, R, right. ‘BGL, basal ganglia; THAL, tbakunus.

I 1

(80,M) WM) (75,M) (73,F) (64.F) (i%F) (79,F) (70,M) @OF)

16 17 18 19 20 21 22 23 24

3(R > L) 3 3 3 3 2 2 2 2 2 2 2 2 2 2 2 1 1 1 1 1 1 (L > R) 1 1

PVH

25 (73,F) 26 (65,M)

WF) (7&F) (74,M) (77.F) (73,M) (67,F) (72,E) (72,F) @Q,m WM) (74,E) (78.F) (74,M)

3 4 5 6 7 8 9 10 11 12 13 14 15

2 o%F)

1 wm

(age, sex)

LeukoencephalopathqP

Table 2. Brain MRI Findings in 31 Patients with Leukoencephalopathy atrophy

p L-. 8

3 4 3 3 3 3 4 4 3 4 3 4 2 2 2 2 4 1 3 3 2 3 3 3 3

Is

1 Y

d

i!

u

P

L(2) > R(1) 4 4

3 3

4

SCOR

Cortical

F

150

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Table 3. Brain CT Findings in 20 DepressedPatients with Leukoencephalopathy Patient”

(age,sex) 1 w3,F) 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

(75,F) (77,FI (74-F) (72.F) (68,F) (74.F) (7O.F) (68,M) (66,F) (80,F) (74,M) (78,M) (72,F) (77.F) (73,F) (74,M) (70,M) (72,M) (61.F)

Lacunae’

Leukoaraiod R(3) > L(1) 3 2 (R > L) 2 (L > R) 2 2 2 2 2 2 2 1

I I I 1 1 1 0 0

BGL, THAL BGL (R), THAL BGL (L)

I I 2 (R > L) 1 3 I 2 1

BGL (L > R) BGL (L > R)

LIC LIC

Cortical atrophy score

Lateral ventricular enlargement

2 3 (L > R) 1 I I 1 0 0 I 1 (L > R)

Brain MRId

2 L(3) ’ R(2) R(4) > L(3) L(3) > R(2) 3 3 3 L(2) > R(1) 2 2

10 3 4

3 3 3 3

11 15

2 1 1 4 3

19

9

“F, female; M. male. “R, right; L, left. ‘BGL, basal ganglia; THAL, thalamus; LIC, left internal capsule. “Patient number from Table 2 for those subjects who also received brain MRl

including subcortical gray matter abnormalities, lateral ventricular enlargement, and cortical atrophy. Subcortical gray matter abnormalities were observed in 20 (45%) of the 44 patients with leukoencephalopathy (1 patient with gray matter abnormalities had no evidence of leukoencephalopathy on brain CT) (Table l-3). These gray matter abnormalities consisted of punctate or multipunctate areas of high signal intensity on T2weighted MRI (n = 16 patients) or low density on CT (n = 5 patients). The abnormalities involved both the basal ganglia and thalamus in 9 patients, the basal ganglia only in 10 patients, and the thalamus only in 1 patient. The two cerebral hemispheres were symmetrically involved in 12 patients; 5 patients showed greater left hemisphere involvement and 3 patients greater rightsided involvement (Tables 2 and 3). The anatomic distribution and brain imaging characteristics of these gray matter abnormalities were felt to be most consistent with lacunar infarctions. Lateral ventricular enlargement was observed in 40 (91%) of the 44 patients with leukoencephalopathy, and in the majority, was of a slight (grade 1) or mild (grade 2) degree. Moderate ventricular enlargement was seen in only 2 patients. The lateral ventricular enlargement was symmetric in 34 patients; in 4 patients, there was greater enlargement of the left lateral ventricle, and in 2 patients, the right lateral ventricle was larger (Tables 2 and 3). All 20 patients with leukoencephalopathy and lacunae of the basal ganglia/thalamus also had lateral ventricular enlargement. There was no significant association between severity of leukoencephalopathy and extent of lateral ventricular enlargement.

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Table 4. comparison of Selected Clinical Data in Patients with Leukoencephalopathy(n = 44) Mesa age (range) Sex

Onset of depression after age 60 Drug refractory/drug intolerance Unipolar depression Suicidal ideation Psychotic ideation Family history of depression DST nonsuppressed at baseline Prior history of ECT Dementia Vascular risk factors Focal neurological exam

73 years (60-86) 60% Female 58% 86% 95% 17% 15% 43% 82% 18% 5% 91% 61%

Cortical atrophy (defined as a CAS of 2 or greater) was observed in 40 (91%) of the 44 patients with leukoencephalopathy. The cortical atrophy was rated as mild (grade 2) in 9 patients, moderate (grade 3) in 20 patients, and severe (grade 4) in 11 patients (Tables l-3). The cortical atrophy was diffuse and symmetric in the majority of patients (Tables 2 and 3); however, in 3, the atrophy was greater in the left hemisphere, and in 1, it was greater in the right hemisphere (this patient also had an old right parietal lobe infarction). In 2 patients, the atrophy was felt to be especially prominent in the frontal lobes. For the 31 patients who received MRI scans, the degree of cortical atrophy was significantly (p = 0.03) associated with the severity of PVH. There was no association between cortical atrophy and severity of DWMH on MRI or leukoaraiosis on CT scan. Clinical Correlates of Leukoencephalopathy Table 4 presents a summary of selected clinical data for the 44 patients with leukoencephalopathy. There were too few patients with other lesions (e.g., cortical atrophy only) to include for comparison. Similarly, comparisons with the 14 patients with “normal” brain imaging studies have not been made given that (1) only 3 of these 14 patients received MRI scans, and as CT is less sensitive than MRI, brain lesions (especially those of the white matter) may have been missed; and (2) of the 12 patients with “normal” CT scans, 7 had abnormal neurological examinations. The average age of our patients with leukoencephalopathy was 73 years, and the majority (60%) were female. Many (58%) of these patients did not develop their first episode of depression until after the age of 60 years. The depressions were typically unipolar (95%) and occasionally were associated with suicidal (17%) and/or psychotic (15%) ideations. Family history of affective disorder in a first- or second-degree relative was noted in 43% of the patients. An abnormal DST (nonsuppression) was observed in 32 of the 39 patients (82%) who received the test prior to ECT. Eight patients (18%) had received a course of ECI for a pmvious episode of depmssionthe total number of prior ECT treatments could not be reliably determined. There was no significant association between a prior history of ECT and either the type or severity of any of the brain imaging abnormalities (i.e., leukoencephalopathy , cortical atrophy, and ventriculomegaly) . Only two patients with leukoencephalopathy had clear histories of dementia prior to

IS2

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et al.

the onset of their current depression. Both had leukoencephalopathy and gray matter lacunae, together with ventriculomegaly and moderately severe (grade 3) cortical atrophy. Neither of these patients had received ECT previously. The neurological examination was abnormal in both cases. Risk factors for atherosclerosis were common (9 1%), but their presence did not appear to be related to the type or severity of any of the brain imaging abnormalities. The neurological examination was abnormal in 61% of the patients. This finding did not appear to be related to the type or severity of the brain imaging abnormalities. All but one of the patients (98%) with leukoencephalopathy showed a good (44%) or excellent (54%) response to the course of ECT therapy. Follow-up DSTs after completion of the course of ECT were obtained in 28 of the 32 patients with abnormal (nonsuppression) baseline DSTs; normalization (suppression) was observed in 13 (46%) of the 28 followup studies. The majority of patients with leukoencephalopathy tolerated the ECT treatments without major encephalopathic side effects. Inter&al confusion was observed in 6 patients (14%), all of whom were at least 72 years old (mean 74.6 years). One of these patients also developed a marked delirium associated with diffuse background slowing of the EEG, together with focal slowing in the left temporal area. All six of these patients had hypertensive cardiovascular disease, and two patients had a history of dementia (one mild and one severe) that preceded the onset of their depression. Neurological examinations were abnormal in each of these patients. In addition, all six of these patients had lateral ventricular enlargement and subcortical white matter and gray matter disease, and five of the six also had cortical atrophy (CAS of 2 or greater). Inter&al confusion did not appear to be related to the number of ECT treatments (mean = 9) nor to the stimulus electrode placement (five patients received UL, one patient received BL). In each of the six patients, the confusion had cleared by the time of discharge from the hospital.

Discussion Brain Imaging Findings Leukoencephalopathy.Leukoencephalopathy was identified in 44 (66%) of 67 elderly depressed inpatients referred for ECT using brain MRI and high-resolution CT. White matter changes were observed on 86% of the MRI scans and 50% of the CT scans. This surprisingly high frequency of leukoencephalopathy was unexpected and stands in marked contrast to the previously reported occurrence of similar changes in a small number of “normal” elderly patients studied with MRI (2046-632) (Brant-Zawadzki et al. 1985; Fazekas et al. 1987; Rezeket al. 1987) and CT (946-1696) (Hachinski et al. 1987; Steingart et al. 1987a). Indeed, the actual overall occurrence of leukoencephalopathy in our study may have been underestimated, as 31 of the patients received brain CT only. In this regard, it should be noted that 7 of the 12 patients with “normal” CT scans had abnormal neurological exammations. None of the 3 patients with a normal brain MRI scan had any abnormalities on their neurological examinations. We can only speculate on the etiology of the leukoencepha@athy in our patients. The white matter lesions typically involved the perivenhicular and deep white matter and appeared as foci of increased signal intensity on T2-weighted MRI (PVH, DWMH) and as areas of low density on brain CT. These lesions were commonly associated with cortical atrophy (9 l%), lateral ventricular enlargement (91%), and lacunae of the subcortical gray matter (45%). Although similar white matter changes have been reported in patients with a variety of disease processes (including head trauma, supratentorial

neoplasms, hydrocephalus, systemic malignancy, and demyelinating diseases such as multiple sclerosis, etc.) (Coffey et al. 1987a), there was no evidence of any of these conditions in our patients. Several lines of evidence would support a vascular-ischemic etiology for the leukoencephalopathy seen in our patients. First, the MRI and CT patterns of white matter disease seen in our patients have been shown at autopsy of other patients to be associated with atherosclerotic changes in the small, deep, penetrating arterioles that supply subcortical brain regions (De Reuck et al. 1980; Goto et al. 1981; Loizou et al. 1981; Friedland et al. 19&1, Kinkel et al. 1985). Second, the finding of white matter changes in our study was associated with a high occurrence (91%) of risk factors for atherosclerosis, including hypertension, diabetes mellitus, and ischemic heart disease. A similar association has been reported by others (Kinkel et al. 1985; Geratd and Weisberg 1986; In&u-i et al. 1987). Third, in 50% of our patients with leukoencephalopathy, there was frank evidence of atherosclerotic cerebrovascular disease, as indicated by the presence of lacunar infarctions in the brain stem (pons) and subcortical gray matter structures (basal ganglia, thalamus) (Caplan and Schoene 1978). In summary, although pathological verification is not available, the clinical and radiographic findings in our patients with leukoencephalopathy are most consistent with subcortical arteriosclerotic encephalopatby (SAB), which is an increasingly recognized form of cerebrovascular disease produced by atherosclerosis of the medullary arteries. The diagnosis of SAE is #~~~ on ne~pa~ology by the findings of multiple periventricular lactmar infarctions and ischemic demyelination of the subcortical white matter with gliosis (Burger et al. 1976). The resultant abnormal water (hydrogen) content and/ or myelin structural changes presumably account for the appearance of increased “‘I2 signal” on brain MRl and the low density on CT (Coffey et al. 1987a; Hachinski et al. 1987). The most consistently reported clinical findings of leukoencephalopathy secondary to SAE include hypertension, stroke, focal neurological abnormalities, and cognitive impairment/dementia (Caplan et al. 1978; Goto et al. 1981; Loizou et al. 1981; Kinkel et al. 1985). Many (50%) of our patients with leukoencephalopathy were hypertensive, but the majority gave no history of either a transient ischemic attack (TIA) or stroke. Over half (61%) of these patients had abnormal ~~logic~ ex~ations. ~uk~~~ph~opa~y is very common in patients with rn~~~~t dementia (Fazekas et al. 1987; Hershey et al. 1987; Steingart et al. 1987b), but has also been found in patients with Alzheimer’s disease (Brant-Zawadzki et al. 1985; Fazekas et al. 1987; Steingart et al. 1987b). In addition, leukoencephalopathy has recently been shown to be associated with cognitive impairment in elderly, nonclinically demented normal subjects (Steingatt et al. 1987a). Only two of our patients had clearly established histories of dementia prior to ECT, however. Furthermore, many of our nondemented patients had relatively extensive white matter changes (e.g., grades 2 and 3 PVH and DWMH), which have been previously reported to be highly associated with clinical dementia (Fazekas et al. 1987). Thus, our clinical findings indicate that le~~nceph~opa~y in depressed patients is not likely to be p~o~omonic for dementia. Still, the diagnosis of dementia in severely depressed patients may be difficult, and further study is requited to dete~e whether or not depressed patients with le~~nceph~opa~y might be at increased risk for clinical dementia (Coffey et al. 1987a). Enlargement of the lateral ventricles. This was common and was seen in 91% (40/ 44) of our depressed patients with leukoencephalopathy. Although the severity of the

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ventriculomegaly was not closely related to the extent of leukoencephalopathy, this could have been because most patients had only “slight” or “mild” ventricular enlargement. An association between ventriculomegaly and severity of white matter disease has been reported iu patients with dementia (Bradley et al. 1984; Brant-Zawadski et al. 1985; Kinkel et al. 1985; Hershey et al. 1987; Steingart et al. 1987b). In support of these findings, our only patient with severe (grade 4) lateral ventricular enlargement was also demented. This latter finding is consistent with the hypothesis that ventricular enlargement in leuk~nceph~opa~y may reflect an advanced stage of the disease process in which progressive shrinkage of the ~~ven~cul~ white matter and gray matter structures permits ex vacua expansion of the lateral ventricles (Kinkel et al. 1985). In at least some patients, this disease process might be manifested clinically as dementia (Caplan and Schoene 1978; Kinkel et al. 1985) or possibly as an affective disorder (see below). Additional studies using quantitative assessments of lateral ventricular size are currently in progress to address these questions. CorticaE atrophy. Cortical atrophy was observed in 40 of the 44 patients (91%) with leukoencephalopathy, and the severity of the atrophy was significantly associated with the extent of white matter disease (PVH) on MRI. All patients with basal ganglia lesions had cortical atrophy, as did both patients with dementia. A small number of studies have described a similar association between cortical atrophy and le~~nceph~opa~y, especially in patients with dementia (Hershey et al. 1987; Sarpel et al. 1987; Steingart et al. 1987b). Surprisingly, many brain imaging studies a~empting to establish clinical correlates of le~~nceph~opa~y do not comment on the occurrence of associated cortical atrophy. Our results suggest that cortical atrophy is common in patients with leukoencephalopathy (at least those that are depressed) and thus should be considered in any discussion of its clinical effects, especially in elderly patients. The etiology of the cortical atrophy in our subjects is unclear. Atrophy is common in patients with degenerative brain syndromes such as Alzheimer’s disease (Drayer et al. 1985), and gray matter degeneration may produce secondary changes in white matter (Brun and England 1986). These changes in myelin are typically quite mild @run and England 1986), however, and as mentioned above, only two of our patients had clear evidence of dementia. Al~ough the precise occurrence of cortical atrophy in leukoenceph~opathy is not known, our imaging observations suggest that atrophy, like ventricular enlargement, may be an accompaniment of more severe stages of this form of white matter disease. In this regard, the same vascular-ischemic processes that produce leukoencephalopathy might also be postulated to have cortical effects, either directly (e.g., decreased cerebral blood flow and/or metabolism) (Hachinski et al. 1975; Rogers et al. 1986) and/or indirectly by remote (transsynaptic) effects of degenerating subcortical structures (Torch et al. 1977; Kemper 1984). These and additional mechanisms could be illuminated with studies of in vivo brain metabolism in patients with leukoencephalopathy and with animal investigations of the cortical effects of subcortical lesions.

C~i~icul Correlates of ~~~oe~ce~~~o~ut~

and A~e~t~ve ~i~o~~e~

Our finding that le~~nceph~opa~y is common in elderly patients with severe depression raises several important questions that cannot yet be fully answered. (i) Are the brain imaging findings

no more than evidence

of a normal aging pro-

~~~n~ph~opa~y

in Depression

EIOLPsYcwATRY 1988;24:143-161

IS5

cess? Although changes in the subcortical white matter are more common in the elderly, currently available data do not allow any conclusions regarding the precise occurrence of such changes in the “normal elderly.” Furthermore, it is not known how severe such changes must be before they are associated with s~ptoms, either ~~logic~ or psychiatric. Cerebral atrophy and lateral ventricularenlargement are also known to accompany “normal aging” (Zatz et al. 1982; Bird et al. 1986), but generally are of a slight or mild degree. In our patients, ventricular enlargement was rated only if it was considered to be moK: extensive than would be expected for the patient’s age, and cortical atrophy was not considered to be significant unless the CAS was 2 or greater. Even with these conservative criteria, the majority of our elderly depressed patients had moderate or severe cortical atrophy and lateral ventricular enlargement. Thus, it would appear unlikely that the brain imaging abnormalities observed in our study represent “normal” aging alone. Clearly, further studies of the elderly using detailed clinical and radiological assessments are needed to address these questions. (ii) How Hoes the presence of 1e~encep~loFath~ affect the clinical presentation, treatment, and course of the depressive illness ? Most (95%) of our patients with leukoencephalopathy were described as having unipolar depression that was occasionally associated with suicidal (17%) and/or psychotic (15%) ideation. All seven of our patients with leukoencephalopathy and psychotic depression had lateral ventricular enlargement and cortical atrophy. These finings are consistent with previous studies that have reported an association between enlarged lateral ventricles and delusional depression (Luchins and Meltzer 1983; Targum et al. 1983; Schlegel and Kretzschmar 1987). A prospective study is currently underway to define more precisely the clinical phenomena of depression in patients with leukoencephalopathy. The DST showed nonsupp~ssion in 32 of the 39 patients (82%) with leukoencephalopathy who received the test. Al~ough there were too few patients with negative (normal or suppressed) DSTs to compare statistically with the DST-positive patients, we observed no trends to support an association between type or severity of brain imaging abnormalities (leukoencephalopathy, cortical atrophy, or lateral ventricular enlargement) and DST results (positive versus negative). Our findings are consistent with previous studies that have found no association between DST response and lateral ventricle size in depression (Targum et al. 1983; Schlegel and Kretzschmar 1987). The clinical interpretation of DST results in our patients with leukoencephalopathy remains difficult, however, because of the complex effects of the brain lesions on the hypothalamic-pituitary-adrenal axis (Fogel 1986). Additional studies have been initiated to help define more clearly the clinical correlates of DST results in patients with leuk~nceph~opa~y, using secure psychome~c assessments and the absolute values of postdexamethasone cortisol concentrations (Fogel 1986). Despite the high rate of clinical response observed in our patients, normalization of DST occurred in only 46% (13/28) of patients who received the test following completion of the ECT course. Previous studies have suggested that ECT has no uniform effect on the DST, and changes in the DST (from positive to negative, or vice versa) during a course of ECT appear to have little or no predictive value with respect to clinical outcome (Coryell 1986). Precisely how baseline and follow-up DST results relate to clinical outcome from a course of ECT in patients with leukoencephalopathy is currently under investigation. Of interest was the finding that 58% of our patients with leukoencephalopathy and

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cortical atrophy had experienced no depressive episodes prior the age of 60. These observations are consistent with those of Jacoby and Levy (1980) and Bird et al. (1986), who described ventricular enlargement on CT scans in a small group of elderly patients with late-age onset depression. (These authors did not comment on the presence of leukoencephalopathy in their patients.) As late-onset depression in the elderly appears to be relatively uncommon (Dorzab et al. 1987), these data suggest that structural brain changes may interact with the aging process to facilitate the emergence of depression in late life. The majority (86%) of our depressed patients with leukoencephalopathy had been refractory to and/or intolerant of antidepressant medications. All but one of these 44 patients (98%) subsequently responded to a course of ECT. These findings are consistent with previous reports that depressed patients with organic brain disease may show a good clinical response to ECT (Coffey et al. 1987a,c, 1988; Weiner and Coffey 1987). Despite the small sample size and obvious selection bias, our data raise the consideration that patients with leukoencephalopathy and depression may be relatively less responsive to and/or more intolerant of standard antidepressant chemotherapy. Prospective, randomized studies with a larger number of patients are required to evaluate more completely the relative efficacy and toxicity of ECT and drug therapy in patients with leukoencephalopathy and depression. The long-term prognosis of depression in patients with leukoencephalopathy has not been studied. At least some elderly patients who develop depression appear to have a relatively poor prognosis (Post 1972; Murphy 1983), and Jacoby et al. (1981) have reported a higher 2-year mortality in depressed patients who had previously been found to have ventricular enlargement on brain CT. These data suggest that brain imaging studies may provide important prognostic information for at least some elderly patients with depression and indicate the need for long-term prospective studies. The degree to which patients with leukoencephalopathy may be at increased risk for developing ECT-related encephalopathic side effects (confusion, amnesia, EEG slowing) remains unknown, Although the majority of our patients did well, six experienced interictal confusion, and one of these also developed a delirium. All six of these patients had leukoencephalopathy, lateral ventricular enlargement, and gray matter lacunae, and five had cortical atrophy. Further studies are required to determine the relative contribution of these various brain lesions to the risk of encephalopathic side effects and whether or not such effects can be reduced with modifications in ECT technique, such as the use of UL electrode placement and administering treatments on a less frequent basis (e.g., a Monday and Friday schedule). These studies will need to take into account the fact that the natural history of cognitive changes in patients with leukoencephaiopathy is not known. At least some patients may go on to develop cognitive dysfunction as the white matter disease progresses and becomes associated with cortical atrophy and ventricular enlargement (Caplan et al. 1978), and the effects of ECT on the course of this disease process will need to be examined. In this regard, it is interesting to note that both of our patients with dementia experienced inter&al confusion following their ECT. (iii) Are the structural brain changes related to previous treatment? Although a small number of retrospective studies have suggested a relationship between ECT and brain changes on CT (Weinberger et al. 1979; Calloway et al. 1981), these reports remain controversial and are limited by a number of significant methodological difficulties (Wei-

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ner 1984; Coffey et al. 1988). In the present study, there was no association between a prior history of ECT and either the presence or severity of any structural brain abnormality, including leukoencephalopathy, lateral ventricular enlargement, and cortical atrophy. Similar negative results have been reported by many others, including recent prospective studies of ECT using brain MRI (Coffey et al. 1987b,d). Thus, it seems unlikely that there is a causal relationship between ECT and structural brain changes. Rather, any association may simply reflect the possibility that patients with leukoencephalopathy, ventriculomegaly, and/or cortical atrophy are more likely to have the type of clinical depressions that require ECT (Coffey et al. 1988). Consistent with this hypothesis was the finding that a large percentage (86%) of our patients with leukoencephalopathy had been refractory to and/or intolerant of antidepressant drug therapy. One important observation from our study was that brain abnormalities are common in patients referred for ECT, including those without any prior exposure to the therapy. For this reason, retrospective studies that report an apparent association between prior ECT and current brain imaging abnormalities must be interpreted cautiously, as such findings may have been present before ECT. Clearly, only prospective imaging studies can adequately address the important question of whether or not ECT is associated with structural brain changes (Weiner 1984; Coffey et al. 1988). (iv) Is leukoencephaiopathy related to the pathophysiology of depressive illness in the elderly? As discussed above, disturbances of affect are common in many syndromes associated with diseases of the subcortical gray and/or white matter (Cummings 1986). Affective disturbances have also been described in patients with SAE (Caplan and Schoene 1978; Summergrad 1985; Coffey et al. 1987a), but many recent studies using advanced brain imaging technologies have generally neglected any systematic evaluation of the patients’ emotional status. Our results suggest that leukoencephalopathy may be more closely associated with affective changes than has been previously considered. Still, whether or not the structural changes of leukoencephalopathy are actually associated with neurochemical and/or functional alterations underlying the presence of affective disorder will require further study. Most of our elderly depressed patients with leukoencephalopathy also had lateral ventricular enlargement, a finding that has been frequently described in other studies of patients with depression (Targum et al. 1983; Nasrallah and Coffman 1985; Schlegel and Kretzschmar 1987) and which we have suggested may be causally related to the presence of leukoencephalopathy. A pathophysiological relationship between lateral ventricular enlargement and depression has been suggested by reports of alterations in catecholamine concentrations in the cerebrospinal fluid (CSF) of patients with enlarged ventricles (Standish-Barry et al. 1986). Furthermore, a recent study of depressed patients using positron emission tomography (PET) demonstrated reduced glucose metabolism in the caudate nuclei, which border the anterior horns of the lateral ventricles (Baxter et al. 1985). One could speculate that mild atrophy of the caudate nuclei in leukoencephalopathy might be associated with enlarged lateral ventricles and a reduction in regional metabolic activity of the caudate and other periventricular structures. In the majority of our patients (all of whom were right-handed), the leukoencephalopathy involved both cerebral hemispheres equally. Of the 31 patients with PVH and/or DWMH on MRI, however, 7 had greater left hemisphere involvement, and 2 had greater involvement of the right hemisphere. These findings are consistent with other data sug-

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other data suggesting an association between depression and lesions of the left hemisphere (Coffey 1987). Still, in contrast to a previous report by Fromm et al. (1985), we found no predominance of left-sided basal ganglia/thalamic lesions in our depressed patients. These authors failed to mention whether or not their patients also had leukoencephalopathy.

Conclusion In summary, our experience suggests that leukoencephalopathy is common in elderly depressed patients referred for ECT and is frequently associated with other structural abnormalities. Little is known about the clinical and laboratory features of depression in these patients, however, and follow-up studies are required to assess more completely the effects of leukoencephalopathy on long-term prognosis in the depressed elderly. Although many of our depressed patients with leukoencephalopathy had been refractory to and/or intolerant of antidepressant medications, ECT proved to be a highly effective and relatively well-tolerated form of therapy. Several lines of evidence suggest that leukoencephalopathy may have implications for the pathophysiology of depression, at least in some elderly patients. Given the increased recognition of leukoencephalopathy and the frequency of depression in the elderly, psychiatrists are likely to see more patients like those we have described.

Appendix Cortical Atrophy Score The CAS consisted of a rating of sulcal size, irrespective of the patient’s age, using the 5-point rating scale of Largen et al. (1984).

0 = (N) None, questionable 1 = (Q) Slight, questionable 2 = (M) Mild

3 = (MO) Moderate

4 = (S) Severe

No atrophy of cortex and no abnormally wide sulci. Sulci not very abundant. In uppermost cuts an occasional prominent sulcus may be seen. Edges of cortex slightly atrophied and/or slight widening in one or two sulci. No evidence of sulcal widening or atrophy on lower cuts. Defined atrophy that is not very extensive, and sulcal widening in several sulci. Some evidence of atrophy and/or sulcal widening in lower cuts. Definite atrophy of cortex that extends in a moderate distance from the edges. Atrophy does not engulf entire brain area (e. g , entire frontal brain), and marked atrophy is often limited to one area of the brain. Marked sulcal widening and/or enlarged sulci characteristic of much of the brain. Interhemispheric fissure is widened. Large areas of atrophy accompanied by general widening of most of the sulci. Atrophy and sulcal widening are prominent in lower cuts. Brain looks definitely shrunken. Interhemispheric fissure widened.

BIOL PSYCHIATRY 1988;24:14~161

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159

Rating for L.eukoencephalopathy on CT 1 = (M) Mild 2 = (MO) Moderate 3 = (S) Severe

Minimal white matter lucencies confined to periventricular regions. More extensive periventricular white matter lucencies, with some extension into the deep white matter. Extensive involvement of large contiguous areas of periventricular and deep white matter.

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