Comorbidity of panic disorder and seizures: Affinity or artifact?

Journal oJ.4wxiety Disonlcrr. Vd. 7. pp. 21-35.1993 Printedin the USA. All r&hta rexned.

a387-61w93 $6.00 + .oa Capyright 8 1993Pcqamon Press Ltd.

Comorbidity of Panic Disorder and Seizures: Affinity or Artifact? RICHARD NEUGEBALJER, ~H.D. Gertrude H. Sergievsky Centes Faculty of Medicine, Columbia University, and Deparhnent of Epidemiology of Developmental Brain Disorders, New York State Psychiatric Institute

MYRNA M. WWSSMAN, PH.D. College of Physicians and Surgeons and School of Public Health of Columbia University, and Director, Division of Clinical and Genetic Epidemiology, New York State Psychiatric Institute

ROBERTOCJELLEITE,M.PHIL New York State Psychiatric Institute; presently at Tandy Corporation

JIM JOHNSON, PH.D.* New York State Psychiatric Institute, and College of Physicians and Surgeons of Columbia University

JEFFREYMARKOWITZ, DR. P.H. College of Physicians and Surgeons of Columbia University. and New York State Psychiatric Institute; presently at E. R. Squibb and Sons, Inc.

Abstract - Case reports of the co-occurrence of panic attacks and seizures in the same individuals have prompted speculation about a shared neuropathophysiology. We investigated the association of a history of panic disorder and of seizures using community data from the Epidemiologic Catchment Ama (ECA) studies, a multisite,

*Deceased. Address reprint requests and correspondence to Dr. Richard Neugebauer, Associate Research Scientist, Gertrude H. Sergievsky Center, Faculty of Medicine, Columbia University, 630 West 168th Street, New York, NY 10032, U.S.A. This work was supported in part by grants from NIMH, no. MH43525 and no. 5ROl MH28274-14. We appreciate the helpful comments of Gerald L. Klerman, M.D.; Robert Post, M.D.; Stephen Ng, M.B., Dr. PH.; Sir Martin Roth; W. Allen Hauser, M.D.; Mervyn Susser, M.B., B.Ch.; Dale Hesdorffer, M.P.H.; and Tiiothy Pedley, M.D. 21

22

R. NEUGEBAUER

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population-based survey of psychiatric disorders. At one site (New Haven) post hoc data inspection disclosed a strong association between lifetime prevalence of panic disorder and of seizures (OR=15), which persisted in controlled analyses. The adjusted odds of persons with panic disorder reporting a seizure history was 5.9-fold (95% CI, 2.2-15.5) that of persons with no lifetime psychiatric disorder and 5.5-fold (95% CI, 2.0-15.3) that of persons with other psychiatric disorders. This association was also found in a second, independent sample, comprising the other four ECA sites, using a different measure of seizure history. In this second sample, the corresponding odds ratios were 5.1 (95% CI, 3.045) and 1.9 (95% CI, 1.1-3.3). respectively. These findings must be interpreted with extreme caution, since they were not hypothesized at study inception and may arise from several spurious and artifactual causes. For example, subjects with panic disorder may mistakenly label theii attacks as seizures. Additionally, this association appears to characterize panic disorder only when complicated by other psychiatric conditions. Nonetheless, these suggestive results argue for further controlled investigations of this question.

INTRODUCTION Over the years, clinical investigators have noted the similarity between specific types of anxiety attacks (now recognized as expressions of panic disorder) and of seizures and their co-occurrence within the same individual (Williams, 1956; Bingley, 1958; Harper & Roth, 1962; Uhde et al., 1985; Edlund et al., 1987; Weilburg et al., 1987; Devinsky et al., 1989). In general, the seizures have been complex partial and hence, of presumed temporal lobe origin. These findings have prompted speculation that these two conditions share a common neuropathophysiology (Harper & Roth, 1962; Weilburg et al., 1987; Stein & Uhde, 1989). The latter hypothesis is consistent with a constellation of heterogeneous biological findings. Direct electrical stimulation of limbic structures, notably, the amygdala, produces experiences of fear and anxiety (Gloor, 1972). Panic disorder patients undergoing PET scans exhibit abnormal hemispheric asymmetry of parahippocampal blood flow, blood volume, and oxygen metabolism (Reiman et al., 1986). Panic attacks, susceptible to induction by sodium lactate infusion, are reported following surgical procedures affecting the temporal lobe (Wall et al., 1985, 1986). Ample evidence also exists that argues against any association of these two disorders beyond chance or errors of misclassification. To date, investigators have failed to find unequivocal epileptiform EEG abnormalities in panic disorder patients (Roy-Byrne et al., 1986; Lesser et al., 1985; Mellman & Uhde, 1989). Although there are case accounts of effective treatment of panic attacks with nonbenzodiazepene anticonvulsants, these patients usually report atypical The ECA is a series of epidemiological research studies performed by independent research teams in collaboration with NIMH. Rockville, MD. The NIMH Principal Collaborators were Darrel A. Regier, M.D.; Ben 2. Locke, M.S.P.H.; and Jack D. Burke, Jr. The NIMH Project Officers were Carl A. Taube, Ph.D., and William Huber. The Principal Investigators and CoInvestigators from the five sites were: Yale University: Jerome K. Myers, Ph.D., and Gary L. Tischler, M.D.; Johns Hopkins University: Morton Kramer, D.Sc., Ernest Gruenberg, M.D., and Sam Shapiro, MS.; Washington University: Lee N. Robins, Ph.D., and John Helzer, M.D.; Duke University: Linda George, Ph.D., and Dan Blazer, M.D.; UCLA: Marvin Kamo, M.D., Richard L. Hough, Ph.D., Javier I. Escobar, M.D., M. Audrey Burnam, Ph.D., and Dianne M. Tiibers, Ph.D.

COMORBKXTY OF PANIC DISORDER AND SEIZURE3

23

panic attacks (Edlund et al., 1987; Weilburg et al., 1987). By contrast, Uhde et al. (1988) found no therapeutic benefit for carbamazepine for panic attacks in a controlled trial involving 14 persons with uncomplicated panic disorder. Furthermore, the clinical resemblance of panic disorder and seizures, with both conditions involving paroxysmal episodes without apparent precipitants and autonomic nervous system involvement, also raises concern about problems of differential diagnosis (Raj & Sheehan, 1987). Symptoms arising from one condition may be incorrectly attributed to both. The Epidemiologic Catchment Area (ECA) studies, which surveyed psychiatric disorders in the community and included questions on seizures, permit investigation of the comorbidity of panic disorder and reported seizures, free from problems of selection bias. Three epidemiologic criteria for evaluating causal associations (Susser, 1973) - strength, consistency, and specificity of the association - are investigable with these data. Preliminary evidence for the biological plausibility of the connection, a fourth criterion, has already been mentioned. The question of time sequence must await separate investigation. Despite the methodologic advantage of community-based samples for study of comorbidity, these strengths are offset by the absence of detailed clinical and laboratory assessment. We emphasize, too, that the association of panic disorder and seizures reported here represents a comorbid relationship not hypothesized at study inception.

METHODS The ECA studies estimated rates of psychiatric disorders in a probability sample of more than 18,000 persons over age 17, residing in five U.S. communities: New Haven, CT; St. Louis, MO; Baltimore, MD; Durham, NC; and Los Angeles, CA. Data on the institutionalized samples in the ECA are not included in this report. Response rates for the initial assessment ranged from 68% to 79% across sites. (See Regier et al., 1984, Eaton et al., 1984, and Robins & Regier, 1991, for further details.)

Psychiatric Assessment At each site lay personnel administered the Diagnostic Interview Schedule (DIS) (Robins et al., 1981), a highly structured research instrument. The items pertaining to panic disorder began: “Have you ever had a spell or attack when all of a sudden you felt frightened, anxious, or very uneasy in situations when most people would not be afraid?’ Individuals reporting such an attack were then asked about 12 predominantly autonomic nervous system symptoms keyed to DSM-III criteria for panic disorder, focusing on their “worst attack.” These symptoms included palpitations, sweating, faintness, dizziness, hot and cold flashes, trembling, feelings of unreality, or a fear of dying or going crazy. Subjects were asked whether the attack was severe enough to lead them to seek help from a doctor or other health professional or take medication more than once, and whether the attack significantly interfered with daily life. If the attack was severe by any of these three criteria, another series of questions probed for potential nonpsychiatric explanations (e.g., ingestion of drugs or

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R. NEUGEBAUER

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medication, use of alcohol, other physical illness or injury). Age of onset was also obtained. Individuals having severe and frequent attacks (at least three attacks in three weeks), accompanied by four or more of the 12 specific symptoms not explained by nonpsychiatric causes and occurring at least once in the absence of a phobic stimulus, met lifetime DIS/DSM-III criteria for panic disorder. Subjects meeting criteria for other disorders were not precluded from receiving a diagnosis of panic disorder as well. Subjects diagnosed with panic disorder in the ECA were not dissimilar from persons so diagnosed in a clinic setting in age of onset, symptom picture, and degree of comorbidity (Klerman et al., 1991).

Seizure Assessment New Haven site. At New Haven, a health survey administered

before the DIS inquired about various medical conditions (e.g., cancer, stroke, trouble with bowel/bladder control, heart attacks, severe head injury, hardening of the arteries, and seizures). The first seizure question was: “Have you ever had epilepsy, convulsions, or seizures ?,’ Individuals responding affirmatively were asked if they were currently under treatment by a physician or other health professional for this condition and whether on medication for it. Information on the type of physician and name of the medication was not obtained. Data on psychoactive medication use for emotional disturbance in the preceding six months were also obtained.

Other ECA sites. At the other four ECA sites, a seizure question appeared only in the DIS section on Somatization Disorder. It read: “Have you ever had a seizure or convulsion of any kind since you were 12 where you were unconscious but your body jerked?” Subjects attributing these reported seizures to physical illness and not to drugs or alcohol were classified as having a history of seizure disorder. Neither age of onset nor data on number of seizures was obtained at any of the five sites. (In New Haven, a gate question that excluded over 90% of respondents preceded the Somatization Section, thereby precluding comparison of responses on this item with the other sites.) Statistical Analysis Post hoc bivariate inspection of New Haven ECA data disclosed a strong association between reports of seizures and panic disorder. These results prompted the following analyses. In each sample (New Haven and at the other four sites combined) subjects were divided into three hierarchic, mutually exclusive, psychiatric diagnostic groups. The first group comprised all subjects with “Panic Disorder,” irrespective of whether they met DSM-III criteria for one or more other psychiatric disorders. The second group consisted of subjects without panic disorder but with a lifetime diagnosis of any other DISIDSM-III disorder (“Other Psychiatric Disorders”), namely, major depression, dysthymia, bipolar disorder, obsessive-compulsive disorder, schizophrenia or schizophreniform disorders, somatization disorder, phobias, and alcohol or drug abuse. The third group contained individuals without a lifetime diagnosis of any of the preceding disorders, including panic disorder (“No Disorder”).

COMORBIDITY OF PANIC DISORDER AND SEIZURES

25

We assess the strength of association between panic disorder and seizures (i.e., a seizure history) by comparing the odds of reporting seizures among persons with panic disorder to the odds of reporting seizures among persons with no psychiatric disorder. We examine specificity of the association by comparing the odds of having seizures among persons with panic disorder with the same odds among persons with other psychiatric disorders. Both observed odds ratios (OR) and those adjusted for potentially confounding variables are presented, together with 95% confidence intervals (95% CI). Adjusted odds ratios are produced using logistic regression. These foregoing analyses were performed first at New Haven. Consistency was then examined by performing the same analyses in the second sample, the other four ECA sites combined. In selecting covariates for the logistic regression analysis we included factors suspected a priori of being linked both to seizures and to panic disorder. Hence, in both samples, alcohol abuse, schizophrenia/schizophreniform disorders, and obsessive-compulsive disorder were used as covariates in analyses comparing the diagnostic groups: panic disorder with the other psychiatric disorders (Boyd et al., 1984; Ng et al., 1988; Toone, 1981; Bear & Fedio, 1977). At New Haven, stroke and head injury, available from the medical questionnaire, were included as control variables in all analyses because of their previously reported association with seizures (Shinton et al., 1987; Viitanen et al., 1988; Olsen et al., 1987; Annegers et al., 1980; Rocca et al., 1987) and with panic disorder in our data set. Sex, age, socioeconomic status, race, and marital status were controlled as well. To insure that no important unsuspected confounding variables had been missed, we introduced as covariates all other psychiatric disorders, including drug abuse (e.g., cocaine; Anthony et al., 1989). In the New Haven sample, we were also able to introduce psychoactive medications used in the preceding six months (e.g., tranquilizers, sleeping pills, and anti-depressants; Markowitz et al., 1989) into the model. None of these additional factors altered the odds ratios produced by the simpler logistic models, indicating that neither illicit drug use nor recent psychoactive medication use played a detectable role in the association of panic disorder and seizures. Accordingly, these factors were excluded from further consideration. (Overall, less than 0.2% of subjects reported cocaine abuse; 9%, use of minor tranquillizers, with information on the latter available only at Yale. The infrequent reported use of these substances in our adult community sample, combined with the expectedly low prevalence of panic disorder and seizure history, limits either the ability of these substances to affect the panic-seizure association substantially or at least our ability to detect such effects.) The statistical tests utilized have assumed that subjects were derived by simple random sampling. Since the ECA design employed cluster sampling, the sample variances are somewhat underestimated, albeit not substantially (Eaton et al., 1984). As a result, an odds ratio with a 95% confidence interval that only trivially exceeds 1 at the lower bound is probably not statistically significant at a p c .05 level. However, major interest focuses on the magnitude and consistency of the associations between seizures and panic disorder. Whether a particular estimate of an odds ratio is statistically significant at the p c .05 level or only at p c .lO is not of primary concern at this exploratory research stage (Walker, 1986; Rothman, 1986).

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RESULTS Characteristics of the Samples The two samples differed somewhat in sociodemographic distribution. The New Haven sample was disproportionately white and, by design, markedly older (Table 1). At New Haven, 1.2% of the subjects had panic disorder; in the other four sites, 1.5%. Within each sample, persons with panic disorder were

TABLE 1 S~CIODEM~GF~APHIC CHARA~~ERIS~~~ OF

THE Two

ECA STUDY

SAMPLFS

New Haven (N = 5034)

Other Four ECA Sites (N = 13,267)

Characteristic Sex Male Female

N

(%)

N

(%)

2062 2972

(41.0) (59.0)

5453 7814

(41.1) (58.9)

Race White Black Other

4440 420 174

(88.2) (08.3) (03.5)

7544 3783 1940

(56.9) 03.5) (14.6)

Age (YP 18-34 35-64 t 65

1168 1290 2576

(23.2) (25.6) (51.2)

5119 5183 2958

(38.6) (39.1) (22.3)

2492 1231

(49.5) (24.5)

6088 1960

(45.9) (14.8)

517 794

(10.3) (15.8)

2238 2981

(16.9) (22.5)

1032 1647 1531 801

(20.6) (32.9) (30.6) (16.0)

3306

(25.1)

4480 3630 1769

(34.0) (27.5) (13.4)

Marital Status Married Widowed Separated/ divorced Single Socioeconomic Status (in quartiles)b Bottom Second Third Top

21

COMORBIDITY OF PANIC DISORDER AND SEIZURES

TABLE 2 SOCIODEMOGRAFWC C~FMXERISTI~SOFTHETHREEPs~ammc THETWOECA SAMPLJ3

New Haven Psychiatric Disorders Panic N = 60

OthfX N = 1137

Sex Female

80.0

56.0

Race White Black Other

90.0 8.3 1.7

85.8 9.0 5.2

40.3 (14.7)

49.6 (21.4)

41.7 10.0

44.0 18.9

31.7

16.7

16.7

Socioeconomic Status (in quartiles) Bottom 12.1 second 20.7 Third 46.6 20.7 TOP

Characteristic

Mean Age (SD) Marital Status Married Widowed Separated/ divorced Single

DIAGNOSTIC GROUPSIN

Other Four ECA Sites Psychiatric Disorders

N= 193

Other N = 4525

59.6***

74.1

55.1

60.6***

88.9*** 8.2 3.0

64.2 23.8 11.9

53.7 32.1 14.1

58.3*** 26.7 14.9

N = 3837

58.5* (19.8)

44.3 (18.6)

None N = 8549

* $:b

38.3 8.3

40.2 13.9

49.1*** 15.4

8.0

30.6

22.4

13.6

20.4

14.4

22.8

23.6

21.9

20.4 33.9 29.4 16.3

20.8 32.8 30.6 15.8

28.4 30.0 32.1 9.5

28.6 34.8 25.9 10.7

23.1*** 33.6 28.3 14.9

51.3*** 26.3

l P < .05 forwithin-sample F tats. *** P < ,006forwithin-umplc 22tats

younger, and a greater proportion were female compared with the other two study groups (Table 2). The overall seizure rate in New Haven and in the other sample was 1.6% and 2.7% respectively (Table 3). Within each sample, rates did not differ by sex but were higher for blacks, although significantly so only in the New Haven sample. Approximately 85% of study subjects with panic disorder met criteria for at least one other psychiatric disorder. For example, about 35% of subjects met criteria for any substance abuse or dependence; 30% for major depressive disorder. The following analyses present results for each sample regarding all subjects with panic disorder, irrespective of whether they met

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TABLE 3 LEEIWE

PREVALENCE

SOCIODEMOGRAMC

RA?ES OF SEIZURES BY

CHAFMXRI~TICS

SELECIED ECA

IN THE Two

SAhrPLEs

Prevalence Rate per 100 Scciodemographic Characteristic

New Haven N=ll

Other Four ECA Sites N=351

1.58

2.12

Male

1.55

Female

1.51

2.70 2.59

Overall Sex

Race White

1.22**

Black Other Age (years) 18-34 35-64 65+ Socioeconomic (in quartiles) Bottom Second Third Top l

*P <

3.81 3.60

2.40 3.05 2.15

2.05 2.09 1.01

2.18 3.39 2.14

1.69 1.84 1.48 0.83

3.69 2.78 2.20 1.43

Status

.Ol kx X2 testof witi-sample

d~fferenccs.

criteria for other disorders. A concluding with uncomplicated panic disorder.

section presents results for persons

Panic disorder and reported seizures in the New Haven sample. The seizure rate is markedly greater in the panic disorder group, and modestly higher in persons with other psychiatric disorders, than in persons with no psychiatric disorder (Table 4). The observed odds of an individual with panic disorder reporting seizures is approximately 15 times that of an individual with no psychiatric disorder (Table 5A). The adjusted odds ratio is 5.9-fold. The observed and adjusted odds ratios for persons with panic disorder reporting seizures compared to persons with other psychiatric disorders are 5.7 and 5.5, respectively. Subjects with other psychiatric disorders and no disorder did not differ on odds of reporting seizures in controlled analyses.

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COMORBIDITY OF PANIC DISORDER AND SE3ZURFiS

TABLE4 LIFETIMEPREVALENCERATESOF SEIZURESBY PSYCHLGRIC GROUPS IN lHE TWO ECA !+fUDY SAMPLES

DLWJNOSTIC

Percent (%) with Seizures (Ns/Nt)a

Study Group

New Haven

Other Four ECA Sites

(8/60)

9.3

(181193b)

2.6

(30/1137)

3.9

(1771452Y)

1.0

(39/3837)

1.9

(16Z8549d)

Panic Disorder

13.3

Other Disorders No Disorder

YN&) = Numberof pasms with seizur.e.sToal number of persons in the diagnwic pup. bFar each of the four sites. lhcsc figures wax as follows: Bdtimon 6.5% (3/46): Durham 14% (7/50): St. Louis 10.4% (5/48): Las Angclea 6.1% (3/49). FFor each of the four site. lk.u. figures WCICas follows: Bdtimac 3.4% (43/128 I); Durham 3.6% (46’1262): St Louis 5.0% (47/948): Las Angclca 4.0% (4/1034). dFa epch of the fau sitw. these figurea were. as follows: Baltimore 2.4% (490,015); Durham 1.2% (35i-2519); St Louis 1.8% (3511974): Los Angeled 2.1% (43/2041).

Among the New Haven subjects with seizures, approximately half (N = 37) reported being medicated for this condition. In controlled analyses, the odds of a person with panic disorder having medicated seizures was 6.6-fold that of a person with no psychiatric disorder (95% CI. 1.50-28.81); the same odds ratio for persons with panic disorder compared with persons with other psychiatric disorders was 2.58 (95% CI, 0.58-l 1.55). Panic disorder and reported seizures in the four-site sample. In Baltimore, Durham, St. Louis, and Los Angeles, the odds ratios (and 95% confidence intervals) for seizures in persons with panic disorder compared with persons with no psychiatric disorder were 2.80 (0.84-9.33). 11.55 (4.86-27.46). 6.44 (2.41-17.24), and 3.03 (0.91-10.12), respectively. These point estimates for the odds ratio all exceeded 1 and did not vary significantly across sites using a lenient rejection value for the Mantel-Haenzel test for homogeneity (p c.05) (Fleiss, 1981). Consequently, data from the four sites were merged despite the variation in the observed odds ratios and the limited statistical power to reject the null hypothesis. (See Table 4 note for sample sizes.) As in the New Haven sample, the seizure rate is considerably higher in the panic disorder group than in persons with no psychiatric disorder. The rate in persons with other psychiatric disorders falls between the other two. The overall observed odds ratio for persons with panic disorder compared with persons with no disorder was 5.33; the adjusted odds ratio was 5.06 (Table 5B). The observed odds ratio for persons with panic disorder compared with persons with other psychiatric disorders was 2.53; the adjusted odds ratio was 1.90. The parallel odds ratios for persons with other psychiatric disorders compared with persons with no psychiatric disorder also exceeded 1.

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R. NEUGEBAUER ET AL.

TABLE 5 OBSERVED

m

AND hlU!TlEII

ODDS

&WloS

FOR SEZUWS

AMONG

thJBlE?CIS

WTIH PANIC

DISORDER,

F’SYCXLUFUC DISORDEMANDNo PSY~HLX’IC DEOIUXXINTHE‘lh’o ECA STUDY SAhlFiXS (NEW

HAVEN

SEPARATELY; Foua Bonier Srnx.sCOMBINED) Study Groups Compared:

Odds Ratio (95% Confidence Interval) P Value Panic Disorder vexslls No Disorder

Panic Disorder versus Other Disorder

Other Disorder versus No Disorder

A. New Haven Observed 14.99 (6.68-33.63) < .OOOO Adjusted 5.88ab (2.23-15.49) c .0005

5.68 (2.48-12.99) < .ODOO 5.50abf (1.97-15.34)<.0014

2.64 (1.6U.27 ) < 001 1.22ab (0.62.49) n.s.

B. Four Other Sites Observed 5.33 (3.20-8.86) c 0000 Adjusted 5.06a (3.00-8.54) <.OOOl

2.53 (1.52-4.20) < .0004 1.90ab (109-3 . .30) < .0250

2.11 (1.70-2.62) < .OOl 1.73* (1.32-2.28) < .Ol

Adjusted for the following fwors: sScciodcmopphic. bMcdical cmditims. (i.e. stroke pod had injury) Wtha psychiabic dkordas. (ag.. alcd~~l abuse).

Uncomplicated

Panic Disorder and Reported Seizures

In an attempt to elaborate further the association of panic disorder with seizures, we examined the frequency of reported seizures in persons with uncomplicated panic disorder and panic disorder complicated with other psychiatric disorders. Both at New Haven and at the other four sites, 19 persons had uncomplicated panic disorder. None of them reported seizures. Among persons with panic disorder complicated with other psychiatric disorders, 19.5% at New Haven and 10.3% at the other four sites reported seizures. However, the strength of association of seizures with panic disorder did not vary significantly by category of panic disorder (complicated/uncomplicated) in a formal statistical test. DISCUSSION In multivariate analyses the odds of persons with panic disorder having a seizure history compared with the odds of persons with no lifetime psychiatric disorder having a seizure history was 5.9-fold in New Haven and 5.1-fold in the other four sites. The strength and consistency of this association in samples differing sociodemographically and in seizure questions enhances the plausibility of these results. The greater odds of persons with panic disorder reporting seizures compared to the odds of persons with other psychiatric disorders also suggests that the association with panic disorder does not reflect simply a raised seizure rate for psychiatric disorders generally. However,

COMORBIDI’IY OF PANIC DISORDER AND SFJZURES

31

seizures were not found in excess among persons with uncomplicated panic disorder. Interpretation of this statistically nonsignificant result is problematic, given the small numbers and limited statistical power. Nonetheless, it raises the real possibility that the increased odds of a seizure history pertains to panic disorder only when complicated by other psychiatric conditions and, hence, that panic disorder by itself is not associated with a history of seizures. Examining the implications of this possible result for etiologic explanations of the association between panic disorder and seizures must await replication. Despite the internal coherence of our findings, they must be viewed as at best exploratory, since they were prompted by post hoc data inspection at New Haven. The ECA’s use of lay interviewers to secure symptom data should occasion additional caution in interpreting these results because of the diagnostic difficulty of distinguishing panic symptoms from certain ictal phenomena. Two related questions merit attention. First, in general, did the seizure items truly discriminate people with and without a seizure history? Second, more specifically, were persons with panic disorder but no seizures or persons with seizures but no panic disorder mistakenly classified under both conditions? This study lacks a diagnostic gold standard against which to evaluate the seizure items. However, the correlation of positive responses with risk factors, medical conditions, and sociodemographic characteristics known to be associated with seizures affords evidence of construct validity. Thus, at New Haven, endorsement of the seizure item was strongly, directly associated with severe head injury (OR = 7.09, 95% CI, 4.38-11.5). stroke (OR = 4.94, 95% CI, 2.65-9.20), and trouble with bowel/bladder control (OR = 2.29, 95% CI, 1.33-3.92). In both samples a seizure history was strongly associated with alcohol abuse. Equally important, the seizure item was not associated with cancer, heart attacks, hardening of the arteries - conditions for which no current evidence demonstrates a link with seizures. Furthermore, in both samples, the ratio of seizure rates for males/females, blacks/whites, and persons under 60 years old/60+ agrees broadly with findings from specialized neuroepidemiologic surveys of lifetime prevalence rates of recurrent afebrile seizures (Haerer et al., 1986; Brewis et al., 1966; Bharucha et al., 1988; Hauser & Kurland, 1975; Neugebauer & Susser, 1979; Logan, 1962; Crombie et al., 1960; Levy, 1970; Leibowitz & Alter, 1968; Gudmundsson, 1966; deGraaf, 1974; Cowan et al., 1989; Shamansky & Glaser, 1979; Hollingsworth, 1978). (We interpret the pattern of lower lifetime seizure rates in older age groups as an artifact of differentially greater forgetting of earlier seizures among older adults.) The lifetime prevalence rates of recurrent, afebrile seizures in the two U.S. population-based neuroepidemiologic surveys permitting age, race, and sex adjustment of rates to the 1980 U.S. adult population are approximately 1.3 1% (Hollingsworth, 1978) and 1.30% (Haerer et al., 1986), respectively. Had these other studies included single seizures within their purview, as did the ECA, their rates could range anywhere from 1.3% to 4% (Shinnar et al., 1990; Annegers et al., 1986; Hauser et al., 1982), depending upon subjects’ completeness of recall of single seizures. The adjusted rates for New Haven and the other four ECA sites are 1.67 and 2.59, respectively.

32

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Despite this evidence for construct validity, the diagnostic imprecision of the seizure items remains. Neither item distinguishes febrile from afebrile; symptomatic from idiopathic seizures; pseudoseizures from true ictal phenomena. Furthermore, to what extent did persons with panic disorder only or seizures only engage in double attribution of their symptoms? On the one hand, it seems unlikely that a substantial proportion of persons with panic disorder only would report having “epilepsy, convulsions or seizures” (New Haven) or attacks when they “were unconscious but your body jerked” (other sites). It also seems unlikely that a large proportion of patients with partial complex seizures, especially those on anticonvulsants, would report ictal phenomena in the DIS panic disorder section without attributing them to a medical condition. However, several investigators have reported that panic disorder patients do on occasion refer to their attacks as “seizures” or “spells” (Uhde, T. W., personal communication, 1991), and only a modest degree of misclassification is required to produce the present findings. For example, the observed odds ratio of 1.5 at New Haven would result from just 12% of persons with panic disorder providing a false positive response to the seizure item. (Such false positive responses to the seizure items by persons with panic disorder and subthreshhold panic disorder, the latter comprising 3.7% of the total sample, may also serve to inflate the seizure rates in the ECA data.) Additionally, syncopal episodes, common in some panic patients (Reiman et al., 1986), if incorrectly reported as seizures, would create a spurious association of seizures and panic. Also, subjects with panic disorder, as compared to persons with other psychiatric disorders or without any disorder, may be more inclined to recall fear-inducing episodes of other illnesses. However, there is no evidence of the latter phenomenon in our data. At a minimum, these results are meant to prompt greater efforts at differentiation of panic attacks and seizures in future surveys of psychiatric and of neurological disorders. Although compromised by possible problems of diagnostic misclassification, we find these results sufficiently strong to motivate further research in this area. Previous clinical research has left unresolved whether seizures precede panic disorder in the causal sequence or vice versa. Although the ECA had a one-year follow-up, the relative rarity of these two disorders has precluded a prospective analysis of this association using incident cases of panic disorder (Key1 & Eaton, 1990). However, Key1 and Eaton did find an association of seizures, as reported in the baseline Somatization section of the DIS, with incident panic attacks, but only for attacks in which psychological symptoms predominated (e.g., feelings of unreality). Interpretation of these findings and their direct relevance for panic disorder proper, remain unclear. If seizures and panic disorder are the product of a shared antecedent neurophysiological disturbance, neither disorder may be necessarily precedent. Therefore, a next research effort in psychiatric epidemiology might entail a dual case-control study using incident cases both of panic disorder and of adult seizure disorders. A reasonable strategy would be to recruit both case groups from primary care settings. Controls for the panic disorder cases would be heterogeneous patients attending the same medical facility and service, free of a history of panic attacks and of medical conditions known a priori to be associated

COMORBIDITY OF PANIC DISORDER AND SEZURES

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