Carbon Dioxide Inhalation Challenges in Multiple Chemical Sensitivity

Naveen Poonai

A thesis submiaed in conformity with the requfrements for the dwee Master of Science

lnstltute of Media1 Sciences Univenity of Toronto

1999

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Acknowldgemtnts

The author wishes to thank Susan Tarlo, Frances Silvenaan, Karen Binkley, Martin Antony,

Peter Stem, and Richard Swinsoq for their expert guidance, encouragement, and patience;

Justina Greene and Paul Corey, for their statisticai advice and insight; Inrin Broder, for his

helpful suggestions; the stafTat the Aaxiety Disorders Cfinic, Clarke Institute ofpsychiatry, for

their time cornmitment; Pat Brown, for her administrative assistance, aad especially Bruce Urch,

for his technical assistance and advice.

1 also wish to thank rny parents Saras and Norman and my sister Aarti for their ongoing

understanding, love, support and encouragement during my research and the writing of îhis

manuscript.

Table of Contents

Acknowledgernents

Table of Contents

List of Tables

List a f Figures

List ofAbbreviations

Abstract

Cfia~ter One: introduction

I .O Background - 1 .1 Hypothesis and Study Ratiode - 1 -2 Chicai EcoIogy Theories - 1 -3 Case Definitions of MCS - 1 -4 Aiieged Etiologicai Agents - 1.5 Prevalence of hfCS - 1.6 Theories of MCS -

1.6.1 Immunologie Theories of MCS - 1 -6 -2 Neurobiological Theories of MCS - 1 -6.3 Overview of Anxiety and Mood Disorders - 1.6.4 Literaîure Supporting the Psychogenic Theory of MCS - 1.6 -5 The Classicai Conditioning Theory of MCS - 1.6.6 Evidence of Anxiety Reactions in MCS Patients Challengeci with their -

Purported Triggers

Cha~ter Two: Methods

2.1 Subjects - 2.2 Diagnostic Measures - 2.3 Self-Report Measures -

Table of Contents (Contiaued)

2.4 Measwes of Response to the Challenges -

2.5 Procedure -

2.6 Statistical Analysis -

2.7 Sampie Size -

Chamer Three: R a i t s

3.1 Instrument Validation -

3.2 Demographic Variab les -

3.3 Iliaess History -

3 -4 Medication Use - 3 -5 Health Care Needs -

3.6 Effects of Environmental Exposuxes (MCS Subjects) -

3.7 S ymptoms Experienced -

3 -8 Tests for S ymptoms

3.9 Lifestyle Activities -

3.1 0 Lifestyle Limitations -

3.1 1 Life Circumstance Dissatisfktion -

3.12 Effect of Age and Gender -

3.13 Effect of Recruitment Source - 3.14 Psychologid Scores -

3.1 5 Gas inhalation Chaiienges - 3.1 5 (a) Baseline Measures 78

3.15 Ib) Response to Air Inhaiat;on 83

3.15 (c) Response to Carbon Dioxide rnhiilation 87

3.1 8 Effèct of Age, Gender, Employment Status and Psychologid Quesoiowe Scores 94 -

Table of Contents (Continued)

3.1 9 Differences in Panic S ymptomatology, PhysioIogic Responses, and MCS - 97 S ymptomatology Between Panickers and Non-Panickers

3.20 Effect of Recruitment Source on Responses to 35% C a in Oxygen - 99

3.21 Results fiom Five MCS Patients who Received the Chaltenges in the Reverse Order 101 - 3.22 Resuits Erom Four MCS Patients who received an Air / Air Sequence - 101

3.23 Structured Clinical Interviews for Major DSM-IV Disorders - 101

Cha~ter 4: Discussion

References

Appendix I

Appendix LI

List of Tables

Table 1 - 1. Frequency of Chernical SensitiMty in Four Prevalence Studies

Table 3-1. Accuracy Validation of Flow Spirometer Over 8 Triais

Table 3-2. Health and Demographics Questionnaire: Demographic Variables

Table 3-3. IlInesses Present on Either a Continuhg or Intermittent Basis and Medication Use

Table 3-4. Medication Use

Table 3-5. Health Care U W o n in the Past Two Years

Table 3-6. Onset of Environmental Sensitivities in MCS Subjects

Table 3-7 Locations of Environmental Exposures in MCS Subjects

Table 3 -8 Environmentai Sensitivity S yxnptorns in MCS Subjects

Table 3-9. Symptoms Experienced on an Ongoing Basis

Table 3 -IO. Mean Number of Ongoing S ymptoms

Table 3-1 1. Test(s) for Syrnptoms Listed Î n Table 3-9

Table 3- 12. Lifiestyle Activities

Table 3 - 1 3. Limitations in Lifestyle Capabilities

Table 3 - 14, Dissatisfaction in Life Cucumstances

Table 3-15. Illness and Symptom History between Males and Females in MCS and Controls

Table 3-16. Illness History and Environmentai Perceptions in MCS Subjects RecruÏted fiom Two

Sources

Table 3-1 7. Mean Psychological Self-Report Questionmire Scores in MCS and Control Subjects

Table 3-1 8. Demographic Parameters and Mean Psychological Self-Report Questionnaire Scores

in MCS and Control Subjects who Completed Gas hidations

Table 3- 19. Pulmonary Function Parameters in Challenged Subjects

Table 3-20. Physiological and Subjective Parameters Immediately Pnor to Air inhalation

Table 3-2 1. Baseline SeIf-Report DSM-IV Panic Attack Symptom Ratmgs

Table 3-22. Absolute Physiological and Subjective Parameters after Compressed Air Inhalation

List o f Tables (Continued)

Table 3-23. Change in Physioiogical and Subjective Parameters after Compressed Air Inhalation

Table 3-24. Seif-Report Panic Symptom Ratings afkr Compressed Air Inhalation

Table 3-25. Absolute Physiological and Subjective Paramerers before 35% C a in ûxygen

inhalation

Table 3-26. Absolute Physiologid and Subjective Parameters after 35% C a in Oxygen

Inhalation

Table 3 -27. Change in Physiological and Subjective Parameters after 35% C a in Oxygen

Miaiation

Table 3 -28. P hysiological Responses and SUD Before and A f k Gas Challenges in MCS Subjects

and cokrols

Table 3-29. Self-Report Panic Symptorn Ratings afkr 35% C a in Oxygen inhalation

Table 3-30. Subjective Responses Comparing 35% C a to Air In)inlat;on Between MCS and Control

Subjects

Table 3-3 1. Effect of Self-Report Psychologicaî Symptom Scores and Gender on Panic Outcorne after

3 5 % COz Inhalation in Controls

Table 3-32. Dflerences in Self-Report Psychological Symptom Scores and Gender in MCS Subjects

Fulfilling and not FulfiUing Panic Criteria after C a ùihalation

Table 3-33. Physiological and Subjective Parameters Between MCS Panickers and Non-Panickers

Table 3-34. Physiological and Subjective Parameters Between Control Panickers and Non-Panickers

Table 3-35.35% Carbon Dioxide Challenge Parameters in MCS Subjects Recniited fiom Two

Sources

Table 3-36. Current and Past Psychiatrie Findings in 2 1 MCS Subjects

List of Figures

Figure 1 . Subject Recruitment (heaIthy coatrols)

Figure 2. Patient Recniltment (MCS subjects)

Figure 3. Agoraphobic Cognitions Questionnaire

Figure 4. Aauiety Sensitivity Index

Figure 5. Depression Anxiety Stress Scala

Figure 6. Mobili~, Inventory for Agoraphobia

Figure 7. Heahb aud ~emo&hics QnestiOnlfaftC

Figure 8. Panic Frequency Questionnaire

Figure 9. Diagnostic Symptom Questionnaire

Figure 10. Taped Preliminary Instructio~~

Figure 1 1. Sample Size Calculation

List of Abbrcviations

AC Q Agorap hobic Cognitions Questionnaire

AS1 Anxiety Sensitivity Index

COz Carbon Dioxide

D AS S Depression Anxiety Stress Scales

DSM-IV Diagnostic and Statistical Mawal of Mental Disorders Version IV

DSM-III Diagnostic and Statistical Manual o f Mental Disorders Version III

DSM-III-R Diagnostic and Statistical Manual of Mental Disorders Version III Revised

FEV, Forced Expiratory Volume in 1 Second

FVC Forced Vital Capacity

FEFSo Forced Expiratory Volume at 50%

HDQ Health and Demographics Questionnaire

IEI Idiopathic Environmental intolerances

IVC Inspiratory Vital Capacity

MCS Multiple Chernical Sensitivity

MI Mobility Inventory for Agoraphobia

MV Minute Ventilation

PA Panic Attack

PD Panic Disorder

PEF Peak Expiratoq Flow

Carbon Dioxide Inhalation Challenges in Multiple Chernical Sensitivity B y Naveen Poonai

A thesis submitted in conformity wïth the rapkmcnts for the degree Master of Science Lnstitute of Mtdicai Sciences, University of Toronto

Abstract

Backaround: Multiple chemical sensitivity (MCS), recently reaamed idiopathic

environmental intolerances (1) is a condition of unknown cause and associated with a variety of

unexplained physical symptoms attributed to exposure to environmental substances at levels

generally considered to be non-noxious. There is Lunitecl data regardhg its prevalence, etiology,

diagnostic criteria and treatment. Clllùcally, the symptoms of MCS overlap considerably with

those of panic disorder (PD), such as breathing difnculties, ditwiess, and nausea (16). Providing

preiiminary evidence to support a link between MCS san PD, Binkley et al. (1997) reported on

five patients with MCS who experienced a panic response foliowing a sodium lactate infusion, a

reliable panic induction challenge (16). The present study utilized a less invasive single-breath

3 5% carbon dioxide 1 65% oxygen (herein referred to as "CO<) inhalation to expand on these

preliminary findings with a larger, controiled sample. COI inhalation has previously been

demonstrated to trigger a panic attack in roughly 70% of patients with PD compared to 5% of

healthy controls (26-29). Obiective: This study tested the hypothesis that patients with symptoms

to suggest multiple chemical sensitivity (MCS) exhîbit features of panic disorder (PD) in

response to non-noxious environmental stimuli. It was expected that MCS patients, but not

controls, would fiilfiIl panic criteria foliowing a CO2 inhalation challenge. Method: Thirty-six

patients with symptoms to suggest MCS and 37 heaithy controls with no pre-existing psychiatrie

history were compared in (i) scores on seK-report psychological cpestiomaires assessing

psychological morbidity physiological and (ii) subjective responses to a single-breath inhalation

of 3 5% CO2 1 65% 02. Subjects underwent one vital capacity inhalation of air foilowed 10

minutes later by one vital capacity inhalation of COz through a one-way demand valve. Outcome

measures hcluded the Diagnostic Syrnptom Questiomaire @SQ) which lists the 13 panic attack

symptoms found in the Diagnostic and Statistical Manual of Mental Disorders, Version IV

@SM-IV). A panic attack was dehed as fi) the presence of at least 4 DSM-N panic attack

symptoms, at least one of which must be a cognitive symptom and 0 a sensation of panic or

fear. Results: MCS subjects scored significantly higher than controls on the number of pre-visit

pauic attacks, Agoraphobie Cognitions Questionnaire (ACQ), Anxiety Sensitivity Index (ASI),

Depression Anxiety Stress Scales @ASS), and Mobility Inventory for Agoraphobia (Mi)

(Student's t, p < 0.05). Twenty-two of 3 1 (71%) of MCS subjects and 8 of 3 1 (26%) of controls

fulfilled panic attack critena in response to CO2 inhalation (Fisher's exact test, p c 0.001).

Physiological responses to the CO2 challenge which included heart rate, minute ventilation, and

respiratory rate were not significantiy different between MCS and controls or between subjects

who fulfilled and did not fuW panic criteria in either the MCS or control group. However,

compared to controls, MCS subjects reported significantly more DSM-IV panic attack symptoms

(Student' s t, p < 0.05) in response to CO2 and rated them as signifcantly more severe (Student' s

t, p < 0.05). Within the MCS group, subjects who fulfilled panic cnteria foliowing CO2

inhalation showed a signif~cantly higher pre-visit score on the AS1 and reported significantly

more panic attacks in the month preceding their visit compared to MCS subjects who didn't

fûlfill panic criteria following COI inhalation. These distinctions were not seen between controls

who fulfilled and did not fuüill panic criteria. A subset of MCS subjects (n = 21) undenvent the

Structureci Clinical interview for DSM-IV psychiatnc disorders (SCID-IV). Eleven of the 2 1

MCS subjects fùlfilled past or curent DSM-N aiteria for a cumnt anxiety or curent or past

mood disorder. conclusion^: This study has shown that a gnater proportion of patients with

symptoms to suggest MCS compareci to fontrols W i e d panic attack critena foiiowing a single,

vital capacity inhalation of 35% C a . The response to CO2 inhalation is suggestive of a tendency

to over-report and possibly catastrophicaiiy misinterpet physicai symptoms, featrues consistent

with that of PD. Furthemore, the fact that MCS subjects scored higher than controis on a

meanire of anxiety sensitivity (MI) indicate a fear of anxietyd ated physicai sensations arnong

MCS subjects, auother consistent feature in patients with PD. Findings of high anxiety sensitivity

and panic in response to CO2 inhalation are consistent with the hypothesis that MCS shares an

underlying diathesis similar with if not identical to that of PD. This suggests a ratiode for

intervention studies to assess components of PD management in MCS patients with features of

PD.

Chapter One: Introduction

1.1 Background -

Multiple chemical sensitivity (MCS) - or a more recently suggested name "idiopathic

environmental intolerances (IEI)" (1) - is a controversiai diagnosis for which there is Limited data

with respect to its prevalence, diagnostic critena, etiology, and therapeutic strategies. Many

individuals suffering tiom MCS have severed their ties to conventional medicine in favor of

alternative therapies. There is a need for a more complete pichire conceming MCS.

At present, there exists no universaily accepted clinical definition and no published, vaiid

estimates of the prevalence of MCS (2). AUergists and immunologists oAen reject the diagnosis

of MCS because comesponding diagnostic critena are lacking and because patients have no

consistent physical or immunological abnormaiitia (3,4). Funhermore, there is substantid

heterogeneity in exposure, illness history, and presentation among persons with MCS (5).

On average, MCS patients are between 40 -50 years of age with approximately four times

as many women affected as men Furthermore, no singie chemical or psychosocial situation can

be defmed as being more prevaient than any other for onset of symptoms (6). The moa frequent

symptoms include anxiety, lightheadedness, impaired mentation, poor coordination,

breathlessness (without wheezing), tremor, and abdominal discodort (7). MCS patients attribute

their symptoms to various environmental chernicals (8).

A number of hypotheses have been generated as to the etiology of MCS such as toxicant-

induced loss of tolerance (9), tirne-dependent sensitization (IO), neurogenic infiammation (1 1),

immune dysfùnction (12) aiid psychogenic causes (4,13-16). A central question has been whether

individuais characterized with MCS are suffering firom a toxic or aiiergic disorder or whether

psychological factors cause at les t some to develop physical symptoms, which they attribute to

aiiergy or toxic mechanisms. Since aliergy has not ben clearly demonnrated, and m e n t

toxicological paradigms for exposure-symptom relationships do not readily accommodate MCS,

psychogenic theories have recently been the focus of a number of investigations (3,12).

There are a number of hdings of increased psychiatric morbidity among MCS patients

(4,13.14,16). Clinically, the symptoms of MCS overlap considerably with those of panic disorder

(PD). This overlap includes the particular physical sensations expenenced by MCS patients

(chest tightness, breathlessness, palpitations, nausea, etc.), apprehension about symptom

occurrence and avoidance of situations where symptoms occur (16). PD is a psychiatric

disturbance with lifetime prevalence estimates rmging £rom 24% in large community samples

(1 7). Accordhg to the 4& edition of the Diagnosîic and Stafiistiaf MmaI of Mental Disorders

@SM-IV), the central feature of PD is the recurrence of unexpected panic attacks accornpanied

by persistent fears or worries about the attacks or their consequences or changes in behaviour

(e.g. avoidance) due to the attacks (18). PD is often linked to agoraphobia which is the fear of

being in places or situations from which escape might be diff~cult (or embarrassing) or in which

help might not be available in the event of a panic attack. Panic attacks may occasionally become

paired with non-noxious stimuli (eg., a certain activity), which the patient may corne to regard as

causing symptoms (1 9).

According to the widely held cognitive-behaviod mode1 of panic, the fm of and

rnisinterpretation of anxiety-related physicai sensations, temied "anxiety sensitivity" is believed

to be a central component of panic attacks. Individuals who panic appear to be more fearful of

anxiety-related interoceptive nies aich as dyspnea, tachycardia, or chest tightness. These

individuals may then contemplate the worst coosequences or catastrophize about the siWcance

of these symptoms, leading to a vicious cycle of escalating h e t y as autonomie arousal

increases and culminates in a panic attack (20). Simiiarly, a fear of uncornfortable physical

sensations, brought about by exposure to an aiîeged environmental substance, may underlie MCS

symp tomatology.

A number of studies suggest that patients with PD and control subjects have similar

physiological reactions to panic-provoking agents such as sodium lactate and carbon dioxide but

differ in the tendency to catastrophicaiiy misinterpret and panic during these sensations

(2 1,22,23). Evidence in MCS patients (24) suggests a simiiar response. Specifically, Lemoff

(24) found that in 1 1 of 15 MCS patients challenged with their tngger substances, there was an

objective measurement of hypocarbia to account for symptoms, evidence of an anxiety reaction.

In addition, a pilot study, Binkley and Kutcher (16) reported that al1 five MCS patients

experieaced a symptomatic panic respome following intravenous sodium lactate infusion, a

challenge that has been shown to trigger panic attacks in patients with PD (25). Independent

psychiatnc assessrnent resulted in the diagnosis of PD on the basis of DSM-III-R criteria in each

of the five patients (16). This evidence supports the concept that panic symptomatology may be

involved in MCS.

Carbon dioxide in an inhaid challenge hss been shown to reproduce panic symptoms in

45%-92% of panic disorder patients and approximately 5% of controis (26,27,28,29). Inhaied

carbon dioxide has severai advantages over infised sodium lactate. Carbon dioxide is less

invasive and may render studying a larger sample more feasible. Carbon dioxide may aiso be

easily administered to a subject via a one-way demand valve. Although the carbon dioxide

challenge is not necessarily diagnostic of PD, a panic response may be indicative of an

underlying diathesis consistent with PD. The purpose of the m e n t study is to assess the role of

panic disorder in MCS using self-report measures of anxiety and a carbon dioxide panic induction

challenge in a larger case-control patient sample than used in the pilot study by Binkley et al.

(1 6). Furthemore, the current study examines the ciifferences between MCS patients and healthy

controls on self-report meanires of anxiety and various demographic variables.

I -1 Hypothesis and S tudy Rationde -

Given the elevated rates of psychopathology in MCS patients (4,13,14,16), the

overlapping presentation between MCS and PD patients (16) and the hdings that sodium lactate

infusion reproduces symptoms in both MCS and PD patients (16), it is hypothesized that some

individuals with symptoms to suggest MCS may exhibit feaaues of PD in response to non-

noxious environmental stimuli- Consistent with our hypothesis, we expect MCS subjects to

evidence higher rates of carbon dioxide-induced panic and higher scores on self-report measures

of anxiety compared to otherwise healthy control subjects. The extent to which PD and MCS are

related rnay suggest a ratiode for intemention studies to assess the enicacy of panic disorder

management in patients with MCS.

1.2 Chical Ecology Theories - Since the 1960's, a growing number of individuals have presented with symptoms in

many organ systems aiiegedly resulting fiom chronic exposure to low levels of synthetic and

naturai organic and inorganic environmental chemicais, foods and microbiai agents (30). Lo

deftning this group, there arose tenns such as environmental illness, 2 0 ~ Century disease,

environmentai hypersensitivity syndrome, total allergy syndrome, and chemical AlDS [reviewed

by Salvaggio el d (1996) (3 1) 1. Today, the t a m most curzentiy used is multiple chemical

sensitivity or MCS, although a newer term - idiopathic environmental intolerances -, which does

not imply causality, has recently been proposed (1).

The ongins of clinical ecology appeared in the 1950's when Randolph expanded the

concept of food dergy to include a causative role for it in chronic diseases of unknown etiology

such as rheurnatoid arthritis, ulcerative colitis, and migraine (30, 32). Randolph introduced the

concept that synthetic chernids in the environment were simiiarly responsible for a wide variety

of symptoms (33). The tenn MCS was coined by Raadolph in the early 1960's to describe a

syndrome that he hypothesized was caused by exposure to chexnicals and foods (33).

A theory that distinguishes clinical ecology fiom those of conventional allergy is that the

onset of iilness depends on the sum of the psychosocial physical, chemical, infective, and

antigenic stressors that impinge on an individual (34). Low doses of substances, which may be

harmless on their owq interact synergistically to produce iIlness (34). The diagnostic utility and

efficacy of tests and treatment modalities employed by clinical ecologists have been evaluated

through a number of investigations (32,35,36,37) and found to be methodologicaily flawed.

Some evidence even exists that patients worsen with such treatment regimens (32).

1.3 Case Definitions of MCS

To distinguish persons given a diagnosis of MCS fkom those reporting similar symptoms

but labeled with other diagnoses such as chronic fatigue syndrome, many attempts have been

made to define MCS in te- of attribution of symptoms to environinenta1 exponire (38).

Although no basis for a diagnostic case definition has been generaiiy accepted, several dennitions

have been proposed.

Randolph (33) was the fïrst to define what he termed as MCS. The features of his

defuiition are as foliows:

Acquued, offen d e r chronic insidious or acute exposure to a petrochemical Chemicd exposures c m trigger physical (artbritis' asthma, colitis, etc.) and mental

(depression, diniculty with concentration, mania, psychosis, etc.) symptoms, dependiag on individual susceptibility . Specific adaptation syndrome: Adaptation to specific chemicals with chronic

exposure is foilowed b y maladaptation and chronic iliness, withdrawal symptoms when removed f?om the chernical environment, and "shock readons" on re-exposure. Spreading phenomena: As an individual becomes maladapted to the chernical

environment, intolerance to increasing numbers of environmental chemicals develops. Avoidance: By avoiding the chemicai environment, chronic illnesses may resolve

(33)

Cullen's effort to define MCS, primarily for research aims, is now the most widely

accepted. He has defined MCS as follows:

The illness is acquired as a result of some environmental exposure, insult, or iiiness that c m be docwnented. Symptoms involve more than one organ. Symptoms r e m and abate in response to some predictable stimuli. Symptoms are elicited by exposures to chernids of diverse structural classes and toxicologicat modes of action.

Symptoms are eücited by demonstrable exposures. Expowes that eiicit symptoms must be very low -Many standard deviations below the "average" exposures known to cause adverse human responses. No single widely available test of organ system fùnction can explain the symptoms (8).

More recently, an operational definition by Ashford and Miller (39) has been proposed:

'The patient with multiple chemical sensitivities can be discovered by removal fiom the suspected offending agents and by re-challenge, d e r an appropriate interval, under stnctly controlied environmental conditions. Causality is inferred by the clearing of symptoms with removal from the offending environment and recurrence of symptoms with specific challenge." (3 9)

The most recent definition is that of Nethercott et al (40):

Symptoms are reproducible with exposure Condition is cbronic Low levels of exposure result in manifestations of the syndrome Symptoms resolve with removal of incitants Responses occur to multiple, chemicaily unrelated substances (40)

These defrnitions are problematic in that no specific chemical is mentioned nor is any

specific effect.

1.4 Alleged Etiological Agents -

The number of specific substances believed to cause multiple chemical sensitivity

symptoms is virtuaiiy limitless, although the emphasis generally focuses on synthetic produas.

Salvaggio and Terr (30) have reviewed a number of studies and found that the chernicals most

fiequently cited hcluded formaldehyde, phenol, ethanol ammonia, hydrocarbons, and

petrochemicals. The products most often reported by MCS sufferers as causing symptoms are

cleaning solvents, paints, perfùmes, synthetic clothing, pesticides, stmctural plastics, building

construction materials, new carpeting, srnoke, gasoline, ve hicle exhaust fumes, and fûmes from

office machines. Among MCS patients, current concerm over the environment, the ever-

increasing number of chemicals beiag synthesized, and the widespread publicity given to their

possible toxic effects all may serve to ampli@ their illness aîtribution (30).

1.5 Prevalence of MCS -

There are currently no validated published population estimates of the prevaleace of

MCS. However, a number of studies (Table 1-1) have found that approximately one third of the

population considers itself especiaiiy sensitive to certain odors (4 1). However, mon of the

participants in these s w e y s were aeither sick nor disabled, which is not the case for patients

presenting with multiple chemical sensitivities.

Table 1-1. Frequency of Chemical Sensitivity in Four Prevalence Studies

Population N Question Posed % Answenng AfEiativel y

EPA office workers (45)

Arizona elderly living in a planned retirement community (46)

University of Arizona students (47)

Rural North Carolinians (48)

3955 Do you consider yourseif especially 3 1% sensitive to . . . (various indoor air con tban t s ) ?

192 Do you consider yourself especially 34% sensitive to certain chemicals?

Do you consider yourseif especially 28% sensitive to certain chemicals?

Some people get sick d e r smelling 33% chemical odors like those of perfurne, pesticides, tiesh paint, cigarene smoke, new carpet, or car exhaust. Other people don't get sick after smelling odors Wre these. Do any chemical odors make you sick?

Source: Ashford and Miller (41)

There are a number of etiological theories postulatcd concemi~g MCS. hdeed, various

treatrnent modalities emp Io yed b y various clinicians ofien reflect individual bias towards a

particular etiological theory. The remainder of this introduction will dedicate itself to a dose

examination of three major theories of MCS: immunologie, neurobiologicd, and psychogenic.

1.6 Theories of MCS -

1.6.1 Immunologie Theories of MCS

Most investigations have found no evidence of dtered immune tUnction to explain MCS

symptoms. For example, Sparks et al (42) reported on a clinical evaluation of 53 composite-

materials workers that filed workers' compensation daims for work-reiated illness. These

workers were among over 100 employees who reported multiple symptoms including d i d e s q

nausea, headaches, fatigue, shortness of breath, palpitations, and cognitive impairment beginning

after the introduction of fibergiass cloth impregnated with phenoi-formddehyde resin at levels

weli below U.S. regdatory standards. Symptoms did not Vary ~ i ~ c a n t l y by duration of

exposure. Although most workers had histones of transient skin or respiratory tract irritation

consistent with the known potentiai toxicity of these materials, none of the workers had IgG or

IgE antibodies to human serum aibumin (HSAib) complexed to formaidehyde (form) when

compared to controls. Interestingiy, 74% of the subjects met DSM-III-R criteria for major

depression, panic disorder or both, comelating in time with the use of phenol- and fom-

impregnated composite material. The authon concludeci that psychosocial factors were Likely to

have been major contributors to this outbreak of ilhess (42).

In another study, Terr (3) performed cluiical reviews of 50 patients with a ciinicai ecology

diagnosis of environmentally induced illness or MCS. Physical findings were normal in 3 1

patients. The most fiequent pnor diagnoses were anxiety, depression, somatoform disorder, and

conversion disorder. Abnormalities in the other 19 patients were related to non-environmental

conditions such as obesity, eczema, cardiovaxular problems, etc. The distribution of total

lymphocytes and T cells corresponded to normal values. S e m IgE concentrations were

distributed as in the general population, with high levels found prllnarily in those with atopic

disease. Terr concluded that the concept of an environmentally induced itlness producing a

defined clinical picture caused by a toxic effect on the immune system could not be supported by

the data (3).

Simon et al (4) compared 41 patients with MCS and 34 control patients with chronic

musculoskeletal injuries. Immunologie testing (lymphocyte counts) did not differentiate between

the two groups. However, patients with MCS reported a greater prevdence of current amciety or

depressive disorder, dthough this difference did not appear to precede the onset of chemical

sensitivity. The authors concluded that the data do not suppott an immuoologic mechanism to

explain MCS symptoms (4).

Proponents of an immunological theory of MCS have ofken cited the presence of

xenobiotic-specific antibodies as evidence of an allergic reaction in MCS patients. The most

recently uivestigated chemical in an immunological context has been formaldehyde, a ubiquitous

airbome chemical. Many MCS subjects report symptoms which they attribute to formaldehyde.

Most studies support the role of formaldehyde as a respiratoiy irritant, rather than a respiratory

sensitizer. However, systemic exposure to si@cant levels of formaidehyde, such as via

hemodialysis, can result in sensitization Formaldehyde has been reported to cause irritant or

allergic contact dermatitis. The prevalence of aiiergic contact dermatitis has been estimated

between 3% - 6% of the population [as reviewed by Bardana and Montaaaro (43)].

Patterson et al. (44) reported on 61 serum samples fiom various groups exposed to

gaseous formaldehyde as weli as non-exposed controb. The analysis included assays for IgG

antibodies against foddehyde-HSAlb. In aU 6 1 sera, there was no correlation with either the

presence or absence of IgG antibodies and the presence or absence of presumed symptoms to

gaseous formaldehyde. The authors concluded that the data fail to demonstrate any correlation

between IgG antibody to fonnaldehyde-HSAlb and respiratory symptoms (44).

Grammer et ai. (45) in a case-control study, descrïbed 37 workers exposed to

formaldehyde (0.003 - 0.073 ppm) via inhalation and evaiuated them to determine whether any

of their respiratory or ocular symptoms were mediated by an immunologie response specific to

formaldehyde. In none of the 37 workers was IgG or IgE activity specifically directed against

formaldehyde conjugated with human semm albumin demonstrated. Further, none of the

workers had an immunologicaily mediated respiratory or ocular disease caused by formaldehyde.

The authors concluded that the respiratory and ocular symptoms of the workers were most Likely

caused by an irritant mechanism fiom formaldehyde or other exposures (45).

Kramps et al. (46) measured formaldehyde-specific IgE in four groups of exposed

individuals: 28 construction workers exposed to off-gassing building materials with cornplaints

including headache, ocuiar and respiratory symptonw. fatigue, etc, 18 industriaiiy exposed

subj ects, paramedical diaiysis workers and 28 hemodiaiysis patients. Formaldehyde-specific IgE

could be detected in oniy one of the 86 sera This sample was tiom a worker occupationaiiy

exposed to formaldehyde, but who did not show any work-related symptoms. In two pools of

control sera fiom unexposed subjects, no specinc IgE antibodies to formaldehyde were detected.

The authors concluded that exposure to formaldehyde, even at relatively high concentrations,

rarely evokes the production of specific IgE antibodies. Furthemore, the presence of

formaldehyde-specific IgE is not necessarily attendeci by ailergic symptoms (46).

Some authon have found evidence they interpret as uidicating that low-level exposure to

formaldehyde results in immediate and / or delayed-type hypersensitivity in individuais with

MCS. Thrasher et al. have investigated MCS patients with multiple subjective heaith cornplaints

following exposure via inhalation to formaldehyde, at Ievels below U.S. regdatory standards. In

severai of their studies, antibody titers (IgE, IgM, and IgG) to formaldehyde conjugated to human

semm albumin have been reported. The authors have concluded that immune activation,

autoantibodies, and anti- forrnaldehyde conjugated to human serum albumin antibodies are

associated with inhalation (47,48,49).

The criticisms of Thrasher el al's (47,48,49) work are that theù studies do not include any

correlations between reported symptoms and either specific chernical exposures or disease due to

such exposures. In addition, the authors have not used asymptomatic workers but instead used

healthy adults as controls (47). It is possible thst the immunologicai "abmrmalities" may have

been found in asymptomatic workers acposed to identical levels of formaldehyde. The authors

also have never mentioned the smoking status or atopic status of the controls in any study

(47,48,49). Cigarette smoke is a significant source of formaldehyde exponire. In fact, in one

study, two patients who evidenced the highest IgE adbody titers to formaldehyde-HSAib were

both smokers (47). Most importantly, the authors have never reported the degree of non-specitic

binding to HSAib (47,48,49). In studies that have reported non-specïfic binding to HSALb

(45,46), no significant ciifferences have been observed between the titers of IgE specific to

formaldehyde and specific to human senun albumin alone. Commenthg on one saidy by

Thraiher et al (48), Beaven (50) bas argued that if the subjects were selected for exposure and

the controls for lack of exposure, ". . .is there any reason to think the higher leveI of antibodies in

the study subjects is anything more than a marker for exposun?" (50).

To summarize, the results of Grammer et. al. (45) and that of Kramps et. al. (46) are in

apparent contradiction to the results of Thrasher et. al. (47,48,49). Following the editoriai by

Patterson et. d. (5 1). some facts are clear regardhg the role of formaldehyde in the etiology of

environmental illness. Irritant concentrations or formaldehyde ( 1-3 ppm or higher) will produce

mucous membrane (odar , nasal, and airway) symptoms. Formaldehyde - human serum

albumin complexes appear to be immunogenic. However, it has not been proven that inhded

formaldehyde results in the formation of these complexes that produce IgE antibody-mediated

reactions or IgG-mediated immune complex damage. It also rernains to be proven that inhaled

non-toxic levels of formaldehyde may cause end organ damage or dysfunction. Indeed, because

of the capability of formaldehyde to react with proteins, ceiis, and fluids on mucous membranes,

transport of significant concentrations of fke formaldehyde to remote tissues rnay be unlikely

(51)-

Taken together, Literature citing immune alteratioas does not show a consistent pattern of

test abnormalities or a consistent correlation of the reported 6ndings with either specific chemical

exposures or disease due to such exposues. To date, no controlled and blinded challenge studies

have emerged which demonstrate a consistent pattern of alteration in immune parameters in MCS

patients after chemical exposure with the patient senhg as their own control.

1.6.2 Neurobiological Theories of MCS

Direct neurotoxic damage, postulated to result fiom intermittent low-level chemical

exposures, is yet another theory being advanced to explain several symptorns of MCS. Bell et al.

(1 994) have proposed a the-dependent sensituation or TDS model to explain MCS. TDS is

defmed as the progressive increase in behavioral, neurochemical, endocrine, or immunologicai

responses to a foreign substance by the passage of t h e between successive exposwes. According

to this model, intermittent exposure to offending agents, provided the intervening periods are of

sufficiently long duration, generates what might be described as a cumulative increase in

responsiveness (52).

Beii et al. (52) hypothesize that MCS patients may be individuals who are susceptible to

sensitization, to the point of adverse symptomatology. To address the question of how low levels

ofxenobiotics could result in CNS effects, Beli et ai (52) cite evidence that since the olfactory

system has direct neuroanatomical and neurophysiological input to the amygdaia and eventudy

the hippocampus, it is conceivable that chemical stimuli at low levels could Vigger limbic

dysfunction in MCS patients (52). The amygdala is involved in emotional tone and regdation of

hypothalamic activity.

There are severai criticisrns of applying the TDS model to the etiology of MCS. if limbic

structures such as the amygdala or hippocampus were partially lcindled in chemical sensitivity,

then one might expect certain clinical symptoms nich as Iowa thresholds for emotional and/or

memory impairment (52). Standard neuropsychological tests includiag attention, verbal memory,

visuaf memo ry, visuo-motor speed, and mental fiexibiI ity (4) have no t revealed signi ficant case-

control differences (4). Support for the TDS model in MCS would require demonstrating

similarities in the underlying meîhanisms of both phenornena, namely olfactory-limbic

activation. Despite the paraliels between TDS and MCS, a specific mechanism of neurotoxicity

by low levels of chernicals in cacosmics has yet to be elucidated. Also, aithough TDS is a weU

characterized phenomenon in animals, it has yet to be consistently demonstrated in humans. The

application of this theory to explain MCS uftimately depends on consistent evidence that TDS is

a CNS phenomenon that also occurs in humans. Lastly, no investigations have reported the

results of repeated exposures to low-level chemicais over t h e , comparing MCS patients and

controls on sensitizability of autonomie, CNS, or immune responses.

Gots (53) has argued that although theories such as neural sensitization are interesting

exp f orations of neurophy siology, they fail to distinguish betwan classicai conditionhg and an

organic disease. He posits that individuals who are conditioned to respond to a stimulus will

have neurophysiological correlates of that response, EEG changes for example. The analogy

given by Gots (53) is that some people would vomit at the sight of blood but the smell does not

produce toxicity. h tead , it Leads to an emotional response with physical expressions.

1 .6.3 Overview of Anxiety and Mood D i r d e r s

According the Diagnostrc and Starisicaf M m d of MentaI Disoràèrs - IVN@SM-IV),

anxiety disorders include panic with and without agoraphobia, agoraphobia without paoic

disorder, specifk phobia, social phobia, obsessive-compulsive disorder, pst-traumatic stress

disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general

medical condition, substance-induced anxiety disorder, and anxiety disorder not otherwise

specified. The foiiowing characterizations of the disorders are taken fkom the DSM-IV (1 8).

A panic attack is a discrete penod in which there is a sudden omet of intense

apprehension, fearfblness, or terror, often associated with feelings of impending doom

Agoraphobia is anxiety about, or avoidance of; places or situations nom which escape might be

dificult (or ernbarrassing) or in

attack or panic-like symptoms.

which help may not be avaiiable in the event of having a panic

Specific p ho bia is characterized by clinically si@cant d e t y provoked by exposure to

a specific feared object or situation, oRen Ieading to avoidance behaviour. Social phobia is

characterized by clinicdy significant anxiety provoked by exposure to certain types of social or

performance situations, often leading to avoidance behaviour.

Obsessive-compulsive disorder is characterized by obsessions (which cause marked

anxiety or distress) and J or by compulsions (which serve to neutraiize anxiety). Post-traumatic

stress disorder (PTSD) is characterized by the re-experiencing of an extremely traumatic event

accompanied by symptoms of increased arousal and by avoidance of stimuli associated with the

trauma. Acute stress diroder is chcter ized by symptoms similar to those of PTSD that occur

immediately in the dermath of an extremely traumatic event.

Generalized anxiety disorder is characterkd by at least 6 months of persistent and

excessive aaxiety and worry. AnUety disorder due to a general medical condition is

characterized by prominent symptoms of an=-ety that are judged to be a direct physiological

consequence of a general medicd condition. Substanctinduced anxiety disorder is

characterized by prominent symptoms of aaxiety that are judged to be a direct physiologicai

consequence of dmg abuse, rnedicatjon, or toxin exposure. Ansiety disorder no< otherwise

specified is included for coding disorders with prominent anxiety or phobic avoidance that do not

meet criteria for any of the specific anxiety disorders defïned.

Other disorders not termed anxiety disorders include depression (an affective disorder),

somatoform disorders and psychosis. A major depressive episode is characterized by a time of

feeling depressed, down, or uninterested in almost aii one's unial activities for most of the day,

nearly everyday, for at least 2 weeks, accompanied by distress or hctional impairment.

Psychosis includes strange or unusuai experiences such as hearing voices or seeing

visions that others cannot hear or see. Alternatively, it includes holding unusual beliefs such as

one believing that othen are plothg against m e r or that one had special powers that others

did not have, or that one was receiving special messages fiom the TV, radio, newspaper, or

surrouadings.

Somato form disorders are characterized by persistent phy sicai symptoms together with

repeated requests for medicai investigations despite medical reassurance that the symptoms are

not the result of an organic pathology. There are many types of somatoform disorders. but ali

involve somatization, the process by which people with psychological disorders present in non-

mental health settings with somatic symptoms. Somatoform disorders include conversion

disorder, hypochondriasis, somatization disorder, and somatoform pain disorder (54).

Somatization disorder refers to a chronic iiiness in which one experiences recurrent,

multiple physical symptoms with an omet before age 30, and an apparent Link to psychosocial or

psychological distress. Conversion disorder is characterized by an alteration / loss of physical

functioning unconsciously produced and expressing a psychological conflict or need.

Hypochondriasis refers to the persistent pre-occupation with a fear of having, or believing that

one has, a serious disease despite medical reassurance. Somatoform pain disorder is

characterized by a pre-occupation with pain in absence of adequate physical flndings to account

for pain or its intensity.

1.6.4 Literature Supporthg the Psychogenic Theory of MCS

During the past decade, the central nervous system has supplanted the immune system as

the most fiequently investigated area to explore the etiology of multiple chernical sensitivity

(MCS). In particular, the psychiatrie status of MCS patients has been the subject of intense

study, debate and speculation (55).

The psychiatric disorders most prevalent among evaiuated MCS patients appear to be the

affective and amiety disorders (6). Schottenfield and Culien (56) reported on 12 patients

evduated by a psychiauist who were severel y disabled because of multiple or vague recurrent or

persistent somatic symptoms for which no organic etiology had been determined during the

course of an extensive diagnostic work-up. Patients were excluded if there was evidence of

physiologic impairment that muid account for persistence of symptoms or evidence of significant

exposure to any substance known to cause the symptoms. Six patients were diagnosed as

suffering major depressive episodes a d o r PTSD (56). The drawbacks of this study include the

lack of a control group, the s d sample size, and the non-blinded psychiatric assessment.

Stewart and Raskin (55) reported on 18 MCS patients referred to a university psychiatry

consultation liaison service. Psychiatric disorders were diagnosed in al1 18 patients. Specificaily,

7 patients exhibited somatoform disorders, 3 patients su ffered fiom a schizophrenic disorder, 3

patients suffered fiom a mood disorder, 4 patients suffered nom an anxiety disorder (this

included 2 patients with panic disorder), and one patient had a personality disorder, classined as

antisocial and malingering. The authors acknowledged that limiteci conclusions could be drawn

from the patients they assessed given their small sample size. However, they indicated that their

fiding s suggest that psychiatric diagnoses as well as non-ps ychiauic ones s hould be considered

when patients have multiple ili-defineci symptoms in the presence of normal clinical and

Iaboratory fmdings. Like those of Schottenfeld and Cullen (56), patients were referred for the

purpose of psycbiatnc assessment (55) which may have introduced a bias @ the diagnoses.

More recentiy, Fiedler et al (57) reported on eleven patients who had multiple

unexplained symptoms to low-IeveI chemicals. In addition to imrnunolog.ïc and

neuropsychologicai evaiuation, the Stnictured Clinicai Interview for the Diagnostic and

S~atisticuI M'al of Mental Disor&rs-version III-Revised (SCID-IiI-R, DSM-III-R) was

administered to quantitatively assess current and previous psychiaaic symptomatology and

diagnoses. The SCID-III42 interview was modined so that patients were specifically asked if

their symptoms had existed before the development of chemicd sensitivities. The Diagnostic

Interview Schedule-III-A (DIS-III-A) section for somatization disorder was separately

administered to assess lif'eiime prevalence of somatization disorder. The Minnesota Multiphasic

Personality Inventory (MMPI) was given to assess curent psychiatric sy mptoms (5 7)-

Subjects met Cullen's cnteria of MCS and had no physical and / or psychiatric history or

current diagnosis that couid explain the development, breadth, and severïty of their symptoms. In

addition, none experienced a particular episode associated with a medicaily treated acute

intoxication and none were under the treatment of a clinicd ecologist. According to the SCID-

m-q ody one of the subjects exhibited symptoms fùlfding cntena for a pre-morbid psychiatric

diagnosis. Four of the eleven subjects met diagnostic criteria for depression. No subjects met

criteria for any of the anxiety disorders. The MMPX findings indicated that on an individuai

basis, 6 of the 8 female subjects presented profiles characteristic of a somatoform disorder.

Another subject's profile was suggestive of a subject with a thought or affective disorder. Two of

the three male subjects had significant devations of MMPI scales indicative of depression, and

the third male had a profile similar to somatofonn disorder. The authors concluded that the

findings do not support the notion that premorbid psychiatric conditions or immune dysfunction

account for MCS (57). However, in retrosped, Fiedler et ai's study may not have adequately

tested for pre-MCS psychiatnc morbidity since the authors in their screening process excluded

abjects with premorbid psychiatric illness and therefore their study was not designed to assess

the prevalence of psychiatric morbidity prior to the omet of MCS.

Black et al (58) evaluated 26 patients who had been assigned a diagnosis of

environmental illness by a ciinid ecologia and compared them to 46 age- and sex-matched

controls. The DSM-III was used to assess lifetime prevdence of major mental disorders.

Compared to controls, MCS patients had a significantiy higher lifaime prevdences for major

depression, mood disorders, anxiety disorders, and somatization disorder. The authors reported

that many patients had a history of multiple somatic complaints but either had an age of onset

after 30 years of age or had too few symptoms to fiiffi the diagnostic criteria for somatization

disorder. The authors also conceded that the data do not address causality given that the

Diagnostic Interview Schedule (DIS) results indicated a Lifetime diagnosis but do not speciv

when the psychiatric disorder developed in relation to the diagnosis of environmentai iilness. Of

interest is rhat 35% of MCS patients had never experienced an anxiety, mood, or somatofom

disorder. The authors conciuded that patients receiving the diagnosis of MCS may have one or

more commonly recognized psychiatric disorders that could explain some or al1 of their

symptoms (58).

Simon et al (4) examined the role of immunologie, psychological, and

neuropsychological factors in MCS using 41 patients with chernical sensitivity and 34 age- and

sex-matched control patients with chronic musculoskeletal injury. Psychiatrie measures included

the Hopkins Symptoms Checklist-90 (SCL-90) and the Diagnostic Interview Schedule (DIS) for

the DSM-III-R The DIS was supplemented with questions to determine the age of onset for

individual somatization symptoms. Current psychological distress was higher among MCS

patients than controls. Howmr, this difference did not appear to pre-date the omet of chemical

sensitivity. Scores on the SCL-90 revealed more fkquem symptoms of anxiety and depression

and a greater tendency to report physical symptoms among patients with MCS. The DIS revealed

a higher prevalence of current diagnosis for panic disorder, generaiized anxiety, and major

depression among MCS patients compared to controls, respectively. When analysis was contined

to symptoms that predated the onset of MCS, the two groups showed similar prevalence of pre-

existing anxiety or depressive disorder. MCS patients, however, reported a markedly higher

number of unexplained physicai symptoms preceding the onset of MCS versus controls. When

ail symptoms beginning after the omet of MCS were eiimiaated, 9 of 34 MCS patients and no

controls satisfied DSM-III-R criteria for somntùation disorder. Interestingly, psychiatric

morbidity among p2tients with MCS was not universal. Twenty-three of 4 1 MCS cases had no

current psychiatric diagnosis. The authors concluded that psychologicai symptoms, although not

necessarily etiologic, are a central component of chemical sensitivity (4). Positive features of this

study included the use of a chronically il1 control group, in contrast to previous studies that used

community volunteers or mildly il1 controls who might be expected to report less psychological

distress. The authon acknowledged that these results do not necessarily demonstrate a

psychological cause for chemical sensitivity, but they suggested that psychological factors

associated with health beliefs rnay predispose some individuals to respond to precipitating events

b y d evelo p ing a g eneralized chemical sensitivity (4).

Staudenmayer and Selner (59) compared 58 MCS patients, 55 control subjects without

psychological symptoms and group of 89 outpatients fkom a psychology practice on

neuropsychologicd measures during relaxation. Measures included the electroencephalograph

(EEG), scalp electromyography (EMG), periphaai temperature, and s k h resistaace fevel. AU

MCS patients failed to show objective evidence of chemical sensitivity consistent with their

reported experiences when chaiienged under controiied conditions. Interestingîy, the distribution

of MCS patients across eight EEG spectral categories were not significantly different from that of

the psychology patients, both of which were significantly different from controls. In other words,

high levels of EEG beta activity, indicative of anxiety, were observed in more MCS patients and

psychology patients that in controls. The authors concluded that their results were evidence of

objective psychophysiologie stress (59).

Proponents of a neurobiologicai process at work in MCS have also found psychiatric

morbidity in patients with ~el~reported chemical intolerance. Beil et al (60) conducted a

questionnaire survey study in which they examined subjective characteristics of illness fiom

chemical odors, sensitivity to chemicals, psychological and stress profile, and medicaf,

psychiatric, and family health histones of 28 women with MCS, 17 wntrols with cacosmia in

good health, and 20 normal controls with neither cacosmia nor MCS (60). Cacosmia is loosely

defined as feeling il1 fkom odors (60). The t e m does not opeci@ a particular symptom complex

or characterize the offending odors. Cacosmia is thought to be a feature of MCS but not a

suficient condition given that MCS is ofien diagnosed if the- patient reports a variety of

unexplained physical symptoms to a many substances, not limited to odors (60). MCS ~ b j e d s

scored significantly higher than the other two groups on the revised Symptom Checklist-90

(SCL-90-R) measures of somatization, obsessive-compulsiveness, depression, anxiety, and

phobic anxiety. In assessing group differences on personal medical and psychiatric physician

diagnoses, the MCS group had a significmtly higher fkquency of diagnoses of depression,

anxiety, and panic disorder wmpared to the nomial group. The qudonaaires did not p e d t

discrimination of current versus past diagnoses. The authors Jso were not abb to validate the

reported medical and psychiatrie diagnoses with review of medicol records or structureci clinical

interviews. The authors concluded that the fïndings were consistent with somsitization disorder.

However, without direct clinid interviews, it is not certain what subset of subjects would meet

full DSM-II-R criteria for somatization disorder, major depression, anxiety or panic disorder (60).

Fiedler et al (1 5 ) conducted a cross-sectional cornparison of the foiiowing groups matched

for age, se& and education: 23 MCS patients whose symptoms began with a defïned exposure, 13

MCS patients without a clear date of onset, 18 patients meeting Centre for Disease Control

(CDC) cnteria for chronic fatigue syndrome (CFS), and 18 normal controls. To examhe current

and Lifetime Axis 1 psychiatric morbidity, the SCID for the DSM-DR was administered, dong

with the MMPI-2 (Minnesota Multiphasic Personality Inventory-2). The somatization section of

the Diagnostic Interview Survey-III-A was ais0 administered to ascertain the rate of medicaiiy

explained and unexplained symptoms (15). Seventeen percent of MCS patients with a dehed

exposure, 38% of MCS without a defined date of onset, and 22% of CFS patients qualified for a

current diagnosis of either dysthymia or a major depressive episode. None of the controls

qualified for these diagnoses. Chemically sensitive subjects without a dehed date of omet had

the highest rate of psychiatric morbidity (69%). On the MMPM, 44% of MCS subjects with an

exposure event, 42% of MCS without a date of omet, 53% of CFS patients, and noue of the

controls achieved clinically significant elevations on scales associated with somatolorm

disorders. The most fiequently diagnosed disorder among MCS and CFS patients was

de pression. Despite signifkant psychopat hology, 74% of MCS patients with a defineci exposure

and 6 1% of CFS patients did not meet criteria for any m e n t psychiatric disorder (1 5).

Staudenrnayer et al (6 1) investigated the addt sequeiae of childhood abuse presenting as

environmental illness. Sixty-three patients with polysomatic complaints attributed to

environmental chemicals had detailed clinicaf assessrnene and diagnostic psycho logic

evaiuations. Objective medical parameters f d e d to substantiate their beliefs that multiple

chemicals were the cause of their problems. A group of 64 patients with chronic medical

conditions and defined psychological disorders (anxiety or mood disorders) not attributed to

chemicai exposure served as controls. Approximately half of the patients in each group

undenvent long-term psychotherapy. In these patients, the prevalence of physical and senial

chitdhood abuse was significantly higher among the cohort of women who attributed the^

symptoms to environmentaliy related illness. There were no signiticant ciifferences between the

groups with respect to reporting of semal abuse by males. The authon concluded that

somatization rnay reflect sequelae of childhood abuse and may play an important role in the

illness experienced by women who believe they are sensitive to environmental chemicals (61).

Iiiness outbreaks among workers and recent life stressors have d o w e d the investigation

of psychiatrie factors in persons wîth unexplained multiple physical chronic complaints, which

they attribute to a chernical exposure event. In a recent study, 99 self-referred patients

complaining of multiple somatic and mental symptoms attributed to dental amalgam nIlings were

compared with patients with known chronic medical disorders seen in alternative (N=93) and

ordinary (N=99) medical family practices and control asymptomatic patients with dental

amaigams (N=80). Patients with exposure to merniry at work or a history niggesting that the

symptoms were Linked to psychological factors were excluded. Self-report questionnaires

suggested that 62% of ili dental arnalgam patients suffered fiom generalized d e t y disorder or

panic. Forty-seven percent of the patients suffered fiom major depression compared with 14% in

the two ciinical comparison groups and none in the dental control sample. Symptoms suggesting

somatization disorder were found in 29.h of the il1 dental amalgam group compared with only

one subject in the 272 comparison subjects (62). The authors found no significant cordations

between the total symptom load and the number of dental amalgam filiings in the two dentai

sarnples. However, it was not dehitively mled out that heavy metal exposure fiom the £illinas

might have played a role in the etiology of the symptoms for some patients (62).

An outbreak of chernical-induced ihess among aerospace workas faciiïtatod the study by

Simon et al (13) of psychoiogicd factors in environmentai ifiness. Thirty-seven symptomstic

plastics workers completed the Diagnostic Interview Schedule, administered by one of the

authors to assess current and past psychiatric disorders according to DSM-III-R criteria 'ïhirteen

of the 37 subjects were classified as having environmental iliness and they were compared to the

other 23 subjects. Among the cumnt DSM-III-R diagnoses assessed, depression and panic

disorder occurred Erequently but neither was significantly associated with the development of

MCS. A histoly of psychiatric morbidity predating exposure was a strong predictor of MCS.

Seven of the 13 MCS subjects met DSM-III-R criteria for prior anxiety or depression compared

to 1 of 23 patients without MCS. None of the subjects met critena for the diagnosis of

somatization disorder. The merence in the Whitley Index core between MCS patients and non-

MCS patients approached significance, with the MCS patients scoriag in the range as typical for

hypochondriasis. The MCS patients also scored significantly higher on both the Barsky

Amplification Scale and the SCL-90-R somatization scale suggestive of a tendency to amplify

bodiiy sensations and report physical symptoms. The authors concluded that the fhdings

suggested that the development of environmental illness is related more to an underhg trait of

symptom amplification and prior psychological distress than to m e n t psychiatnc symptoms or

diasnoses. They went on to postulate that such a trait muid ruult in the increased sensitivity to

many noxious ahdi that environmental iliners patients report (13).

Gupta et al (63) peflonned a retrospective analysis of 20 patients exposed to wood

preservative products. Thirteen patients attributed their symptoms to a wood preservative soon

after exposure (hunediate attribution group), and 7 patients developed the attribution at a later

date (late attribution group). Clinical fmdings suggested that the acute symptoms were consistent

with the expected toxic effécts of the pruuvative, however, the chronic unexpfained symptoms

were not. Ail but one of the 20 patients proceeded to develop persistent symptoms, which could

not be explained physicaliy. Ln each patient, one or more of the foilowing factors figured

prominently in their understandhg of being poisoned: exposure-related symptoms (only in the

immediate attribution group); unhelphil building contractors; media reports; pressure group

publications; misinterpretation of scientinc Literahire; and opinions expressed by medical /

alternative practitioners that their symptoms were of an allergic toxic etiology. The authors

concluded that patients' beliefs about chernical poisonhg could be underaood as arising in the

context of an attributional process, representing a sociopsychosomatic syndrome precipitated by

wood preservative exposure (63).

Dager et al (64) described 3 cases of a response to occupationai solvent exposure, with

symptoms characteristic of panic disorder. After each patient's idiosyncratic reaction to a

particu l ar solvent mixture* recurrent attacks were of abrupt omet, with symptorns consistent with

panic attacks as defined by the DSM-III. One of the patients had experienced attacks that were

similar to his post-exposure symptoms. The other 2 patients had no prior history of psychiatric

illness. Extensive medical evaiuation in al i 3 patients revealed no objective evidence of toxicity

or allergic reaction In aii three cases, antidepressant treatment without psycho therap y resolved

the attacks. Dager et al (64) suggested that organk solvent exposure could provoke recurrent

symptoms that are indistinguishable fiom panic attacks. Furthemore, nich solvent-provoked

panic attacks may subsequently occur with incnasing fiequency and without apparent

precipitants, thus fùlfiiling DSM-III criteria for panic disorder (64).

1.6.5 The Classical Conditioning Theory of MCS

Binkley and Kutcher (16) reantiy reported on the observation of a panïc response to

sodium lactate f i s i o n in 5 patients with MCS* AU patients were investigated to d e out

underlying medical conditions, including asthma, as a cause of their symptoms. Patients with a

present diagnosis of panic disorder were excluded. After a standardized psychiatric assessment,

patients underwent single blind htravenous infusions of n o r d saline solution (placebo) and

sodium lactate. Sodium lactate reproduces panic attack symptoms in individuals with underiying

panic disorder (16). Standard psychiatric assessment (Mini SCID-III-R) identified 4 of the 5

patients as meeting DSM-III-R diagnostic cnteria for panic disorder dong with other depressive

and/or anxiety-related disorders. AU 5 patients exhibited a positive syrnptomatic response to

sodium lactate compared with placebo infusion The self-report outcome was the Acute Panic

Inventory modified to reflect DSM-III-R panic attack critena. The authors concluded that the

result s suggest that MCS may have a neurobiological basis similar, if not identical, to that of

panic disorder (16). Binkiey and Kutcher (16) hypothesized that neutrai stimuli c m become

paired with panic symptoms, thus becoming conditioned stimuli, which may then be considered

by the patient to be causes of the attacks. These otherwise neutrai stimuli may then a a as

independent triggers of panic symptoms (16). The conceptuaüzation of MCS as a type of phobic

disturbance has support £tom the perspective of a classical conditionhg paradigrn.

In the classical conditioning paradigm, a person's symptoms are an unconditioned or

naturaliy occurring response (UR) to exposure to a neurotoxic substance, the unconditioned

stimulus (US). The association of the odor of the toxicant with the symptoms of exposure causes

classical conditioning whereby the strong odor done can serve as a conditioned stimulus (CS) in

the future, eliciting the same symptoms or conditioned response (CR) as the toxicant itself. The

development of symptoms in response to other strong odors such as car exhaust, etc., is an

example of stimulus generalization When generalization occurs, a different odor (CS) will elicit

the same response as the original stimulus. S yrnptoms are viewed as the result of unintentional

learning. Sorne, albeit anecdotal evidence exists to support this theory of MCS. Boila-Wilson et

al (65) descnbed 2 cases of patients who experienced re-occurrence of exposure-related

symptoms when exposed to a varïety of common environmental substances. They authors

employed a cognitive-behavioural therapy approach with one patient that focused on restnicturing

his maladaptive negative cognitions, which were related to the exposure. They also employed

systematic desensitization techniques. These procedures were effective in reducing bis symptoms

when he encountered wmmon environmental substances (65). The classical conditioning

hypothesis of MCS is plausible given the large amount of literature in many species (including

humans) on conditioning to aversive flavors (66). There is a smaller amount of literature on

olfactory aversion conditioning. Since many toxic chemicals have distinctive imitant propedes at

human olfactory detection thresholds, overexposure to these chemicals may involve the pairing of

a distinctive olfactory a ie with iiiness. This hypothesis h a corne under cnticism pnmarily

because many cases of MCS do not involve or arise from an acute exponire incident, hence, there

is no unconditioned stimulus on which to base the paradigm.

1.6.6 Evidence of Annety Reactions in MCS Patients Challenged with their Purponed Triggers -

A few studies have demonstrated that the responses of MCS patients to their purported

chernical triggers may be better characterized as an anxiety reaction rather than an aliergic one.

Doty et al (67) measured odor deiection thresholds to orgaaic solvents in 18 persons who

exhibited symptorns of MCS and 18 controls. Persons who had a history of psychiatric or other

medical problems that might explain their symptoms were excluded. Although olfactory

thresholds were equivalent in the two shidy groups, the MCS group evidenced significantly

higher nasal resistances (before and after test sessions), respiration rates and Beck Depression

Inventory scores. The authors wncluded that the resdts did not support the hypothesis that MCS

is associated with greater olfactoq threshold sensitivity, but instead suggested that MCS is

associated with depression, increased respiration rate, and decreased nasal W a y patency. The

authors noted that the increased nasal congestion and heightened respiratoxy rate suggested that

persons with MCS have labored breathing that may be associated with a number of their somatic

cornplaints (67).

Leznoff (24) chailenged 15 MCS patients with products they deemed to cause distresshg

symptoms. Pre-challenge and post-challenge pulmonary function tests and blood gases were

measured. In 1 1 of the 15 mes, the challenge reproduced the symptoms described by the patient

as being characteristic of his or her disease. In four patients, the challenge produced no

symptoms, and these patients showed no clinicai abnormalities and no objective evidence of

hyperventilation. However, in the 1 1 respondhg patients, the challenge resulted in

hyperventilation, which was observed clinically and c o a e d by the demonstration of a rapid

fa11 in the PCOt in blood or end-tidal gas. The author wncluded that hyperventilation is, at les t

in part, one of the mechaaisrns by which this group of patients develop their symptomatology.

Leznoff postulated that the logical explanation is that these patients respond to their putative

environmental iasults by experkncing an acute müety reaction (24).

Taken together, several studies show that MCS patients rnay have increased psychiatnc

morbidity, either before or after omet of chemical sensitivity. However, these studies seldom

provide data to assess whether or not psychiatric iiiness is a cause, effect or comlate of

environmental sensitivity. Bell (52) cnticized the psychogenic explanation of MCS, indicating

that the pattern of MCS af5ective symptoms is atypical for classical psychiatric disorders- MCS

sufferers become irritable, depressed, or confiised for a few minutes or hours, only during days

invo lving chemical exposures, but are asymptomatic thereafter (52). In contrast, DSM-IV cnteria

for depression stipulate being in a depressed mood for most ofthe day, neady every day, for at

least 2 weeks (1 8).

The same shortcoming holds tme of both somatization disorder and panic disorder. Many

symptoms experienced by patients in these studies may be considered to be a part of the panic

attack constellation. Panic attacks are, for the most part, symptomaticaily similar to acute

reactions to life-threatening emergencies. In the context of panic disorder, however, there are

qualitative differences, in that the individual with panic attacks expenences the symptoms out of

context, in situations where he or she did not acpect to have them. Individuais that expenence

situation-specific panic attacks rnay be more aptly characterized in the DSM-N in terms of

simple or social phobias. DSM-IV criteria for panic disorder require the occurrence of 4 attacks

during a one-month period or at least one expected attack foliowed by one month of persistent

fear of recurrence. The diagnosis of panic disorder also requins ruling out other conditions such

as hyperthyroidism, paroxysmal tachy cardia, and dnig effects (1 8.68). The panic attacks

documented in the rwiewed studies (in cases where patients did not fiIfdl DSM criteria for panic

disorder) may be more aptly characterized as "Limiteci-symptom panic attacks'' (68).

Sornatîzation disorder may ais0 have limited utiiity in MCS patients. Many studies have

failed to diagnose it in MCS patients because many report the o n e of the multiple unexplained

physical syrnptoms after age 30. Furthemore, many MCS patients have been treated by

alternative rnedicai practitioners and their symptoms are "validated" by a diagnosis. To

overcome these barrîers to diagnosis, many investigators have utilized modified labels such as

"atypicd post-traumatic stress disorder", "odor-triggered panic attacks", and 'cbehavioural

sensitization to odorants" (68).

Nevertheless, a consistent finding throughout many investigations of psychiatric

morbidity arnong MCS patients is that of elevated rates of somatization. Compared to

somatization disorder, somatization, is by contrast, not a specific disorder. Rather, it describes a

symptom complex arising fiom a wide variety of emotional factors. Somatization may be

rnanifested by depression, anxiety disorders, phobias or other Life stresses (53).

In conclusion, the chronicity of the symptoms of MCS, and the coexisting psychiatric

ilInesses that are clearly present in many of these patients should not obscure the observation that

exp osure to volatile c hemicals at su b-toxic levels, rnay precipitate psychophy siologic symptoms

consistent with panic attacks and depression (38). However, it has not yet been consistently

demonstrated that psychiatric illness predates the onset of chernical intolerance. Further, it has

been shown that large proportions of MCS patients do not filfil1 lifetime criteria for any

psychiatric iliness.

Chapter 2: Methods

A case-control study was designed to test the hypothesis that patients with symptoms to

suggest MCS exhibit features of PD in response to non-noxious environmental stimuli.

r

2.1 Subjects -

36 patients with symptoms to suggest multiple chernical sensitivity (MCS) were recruited

from: a) the praaices of the midy allergists b) a previous study of environmental illness and c) by

advertisement. Because stringent diagnostic criteria have not been developed for MCS, and

because the most widely cited Cullen's criteria (7) do not apply to al1 MCS patients, subjects

were screened using criteria obtained from Simon et. al. (4) who conducted a we-controiied

cornparison sîudy to examine the role of immunologie, psychological and neurophysiological

factors in MCS (4). Simon's cnteria was chosen mainiy due to its quantitative nature. inclusion

criteria were as foiiows: (i) duration of iilness of at least three months, (ii) symptoms reported in

at least three organ systems, including the central nervous system, and Qii) reported sensitivity to

at least four substances.

37 healthy control individuals without symptoms ~ ~ ' M C S were recruited by advertisement

in local hospitals. Although gender differences in panic outcome following carbon dioxide

inhalation haven't been reported, attempts were made to match the groups as weff as possible for

gender due to the relationships cited between gender and panic disorder, namely that PD patients

are predominantly female (15). It was felt that matching the groups for sex wouid remove bias

associated with a possible gender difference in panic symptomatology.

Exclusion criteria for aii subjects inc1ud.d: g r a t a than 60 or less than 18 years of age,

current or past migraine, seizures, uncontroîied hypertension, uncontrolied diabetes, heart disease,

thyroid disease, current pregaancy or lactation, current asthma or other respiratory problems.

Subjects who had already been given a diagnosis and were on medication for treatrnent of any

p s y c hiatric disorder were excluded.

2.2 Diagnostic Measures -

The Structured CLinical I n t e r v i ~ for DSM-MSCID-IV) (691 was used to assess current

and p s t psychiatric morbidity in MCS subjects. The SCID-N is a revision of the SCID for the

DSM-III-R which bas been shown to have adequate test-retest reliability, in agreement with

other diagnostic instruments (70). Williams et a1 (1992), found an overd weighted K of 0.6 1 for

current and 0.68 for liietime diagnoses in patient samples (70). The SCID-N was carried out by

a psychology research assistant trained and expenenced in its administration.

2.3 Self-Report Measures (please refer to Appendk 1) -

Ail subjects were read the recruitment information correspondhg to their subject group

over the telephone (Appendk 1). Subjects were d e d a questionnaire package and an informed

consent statement 5 - 10 business days prior to their visit. The questiomaire package included

the Health and Demographics Questionnaire, Depression Anxiety Stress Scales (DASS), Panic

Frequency Questionnaire (PFQ), Agoraphobie Cognitions Questiomaire (ACQ), Mobility

Inventory for Agoraphobia (MI), and the Anxiety Sensitivity index (MI), packaged in the above

order. These questionnaires were administered once. When the subjects arrived for theù visit,

the questionnaires were checked for completeness.

The selection of questionnaires reflected the participant recommendations of the Natioaal

Institutes of Health Consensus Development Conference on the Treatment of Panic Disorder

regarding standardized assessrnent for paaic disorder research The group recommended the

emp Io y ment of structured clinical interviews, measures of panic fiequency, anticipatory anxiety,

e-g. ACQ and ASI, phobic fear and avoidance, e.g. MI, symptoms, generalized anxiety and a

dimensionless rating of depression, cg. DASS (7 1).

The Aooravhobia Cosmitions Ouestionnaire (ACO). (Appendix 1) is a 14-item self-report

questionnaire designed to measure thoughts related to agoraphobia and the consequences of

panic. Each item is rated on a 5-point scale. The ACQ is reported to have adequate reliability,

(Pearson r = 0.86, n = 3 8) over a testgretest pretreatrnent median interval of 3 1 days (72).

The Anxiety Sensitivit~ Index (AS4 (73) (Appendix 1) is a 1Citem self-report

questionnaire in which individuals rate the extent to which each item applies to them using a 0 4 -

point scde. Items reflect an aversion to the expenences of anxiety and related symptoms (e-g. '2

is important for me not to appem nervous". "Il scares me when I feel fuint "). The AS1 was found

to have adequate test-retest reliability (Pearson r = 0.75, n = 127) (74) and intemal consistency (a

= 0.88, n = 122) (75).

The Deoression Anxietv Stress Scales IDASS) (Appendix 1) consin of a 42-item self-

report questionnaire of 3 subscales designed to me- dysphoric mood (depression subscaie),

symptoms of fear and autonornic arousd (anxiety subscale), and symptoms of general

nervousness and agitation (stress subscale). The DASS is reported to be a partiicularly good

measure for separating out depressed and anxious mood in non-clinical(76) and clinical

populations (77,78). Interna1 consistencies (a) for each scde in a normative sample were

Depression 0.9 1, Anxiety 0.84, and Stress 0.90 (76). In clinical samples (N = 43 7), interna1

consistencies (Cronbach's a) were favorable: Depression 0.96, Aiutiety 0.89, and Stress 0.93.

Test-retest correlations of aU 3 scales indicated fkvorable temporal stability (r = 0.71 - 0.8 1) (77).

The Mobilitv Inventoy for Agoraphobia &ïQ (Appendix 1) is a 26-item self-report

questionnaire which includes items to which inàividuals rate the extent to which they avoid 26

common agoraphobic situations on 5-point scales when they are done and when accompanied.

This measure has been found to have adequate reliability (median Pearson r = 0.76, n=159, over

3 1 days) and constnict vaiidity (79). The MI has been proven to be a sensitive rneasure of

agoraphobiaper se rather than a reflection of anxiety disorders in general(79).

Health and .Demofzra~hics Questionnaire @IDCI) (Appendix 1) is stmctured to obtain a

demographic and health profile and to provide a standardized information source for descriptive

features considered to be typical of MCS. It has been demonstrated to have adequate reiïability.

Over a test-retest interval of 40 days in 10 subjects, correlation coefficients for the sum of

s ymp t oms, sum of provohg environmental sources, and the limitations and dissatisfaction index

were 0.9 1, 0.93, and 0.88, respectively (80).

The Panic Freaue- Ouestionnaire PFO) (Appendix 1) was designed by one of the

authors (MA.) to assess the number of unexpected and expected panic attacks in the past month,

as well as the intensity of worry over possibly having a panic attack during the past month.

2.4 Measures of Response to the Challenges -

The Diamostic S-yn~tom Ouestionnaire (DSO) (Appendix 1) was the prixnary self-report

outcome variable. The DSQ asks subjects to rate the intensity on a O-8-point scale of each of the

DSM-IV panic attack symptoms experienced following inhalation. The DSQ also asks whether

or not a subject experienced a feeling of fear or panic and its intensity (O-8-point scale) as well as

the similarity of these feelings to their n a t d y occurring panic attacks or anxiety (0-%point

scale). Subjects also indicate which thoughts they had during the inhalation, from a List of six

catastrophic thoughts (e.g. "1 need help") and six non-catastrophic thoughts (e.g. "1 feel relaxer)

(2 1). The DSQ separates the DSM-IV symptom of dininess I faintness into two symptoms,

items 3 and 6 and also separates the DSM-N cognitive symptom fear of going c r a q / losing

control into two symptoms, items 14 and 15. Therefore, DSQ items 3 and 6 were wmbined into

one item for caiculations as were DSQ items 14 and 15. The DSQ aUowed for the determination

of whether or not each subject had a panic aîtack. For the purpose of this study, a panic attack

was defined as: (i) the presence of 4 or more of the 13 DSM-N p d c symptoms, at least 1 of

which m u t be a cognitive symptom and (il) a sensation of panic or fear. This definition is

similar to that used in previous studies (2 1,8 1).

The Subiective Units of Discornfort Scde (SUD) (81) is a 0-100 point Likert-type scale

on which subjects rate their level of discornfort at one-minute intervals. This messure has

commonly been used in CO2 inhalation challenge procedures (26,27,8 1,83).

Heart Rate and Minute Ventilation Heart rate was monitored using a Polar Vantage

W heart rate monitor. Minute ventilation was measured using an Interface Associates VMM-

40 i Ventilation Meanuement Module and was recordcd as an average over 30 seconds before

each challenge and at regular 30-second intenals during each recovery phase. MV indicates the

degree of hyperventilatioa This measure is important &n the similarity in MV responses

during panic attacks in PD patients (84) and after expowe to purported triggers in MCS patients

(24)-

Pulmonary Function Tests. Pulmonq fiinction tests were carried out using a MIR

SpirobankTM mode1 pneumotachograph in accordance with the Amencan Thoracic Society

Sfandcwdirmion of Spiromehy 1994 Opriate guidelines (85). Any subject with a % predicted

=VI of less than 75% was excluded.

2.5 Procedure -

The study was carried out at the Gage Occupational and Environmental Health Unit at

University of Toronto. At the outset of their visit, subjects were asked to present their

questionnaires. The questionnaires were then examined to ensure there were no blanks. If blanks

were found, they were brought to the subject's attention and addressed. The subject's height and

weight were then measured. They were then given instructions on the inhalation technique.

Baseline measures included pulmonary function tests, hart rate, minute ventilation (MV),

DSM-IV panic symptoms and SUD. They were informed over a tape recorder that the procedure

wouid involve one single breath inhalation of either air done or air which has a higher than

normal amount of carbon dioxide in it (Appendix 1). While they were also told that they might

experience temporary feelings ranging fiom nothhg at aU to some level of amiety during the

CO2 inhalation., the possibility of a panic attack was never mentioned.

Foliowing the 5-minute baseline period, each subject underwent one vital capacity

inhalation of compressed air thmugh a one-way demand valve in line with a pneumotachograph

and held hidher breath for 5 seconds. The inhalation was considered valid if the subject inhaled

at least 80% of hidher vital capacity or fuifUed DSM-IV criteria for a panic attack before doing

so. These criteria have been used in previous studies (2 lyZî,Z8,8 1) and are as follows: (0

reporting of at Ieast 4 of the 13 DSM-IV panic attack symptoms fiom the DSQ, at least one of

which must be a cognitive symptom (e.g. "feu of going cray / losing control" or "fear of dying")

and (11 reporthg of a sensation of panic or feu. Following the inhalation was a 10-minute resting

phase d u ~ g which breathing rate, M V at 5-minute intenals, hart rate at 10-minute intervals and

SUD at one-minute intervals were measured. Breathing rate and MV d u ~ g each 1 0-minute

resting phase were measured at t = 0,5 , and 9-minutes. Heart rate was measured at t = O and 9-

minutes during each resting phase. The subject was asked to fill out the DSQ at the end of the 10

minutes to report how they felt immediatety after the gas inhalation. Upon completion of the

DSQ, the inhalation procedure was repeated with a 35% C a in 65% O2 mixture, foiiowed by an

identical 10-minute resîhg phase and a second measure of the tests as performed at baseline.

Subjects were blind as to the order of air and carbon dioxide. Halfan hour afler the challenges, a

subset of MCS patients ( ~ 2 1 ) received the SCID for the DSM-IV.

In an additional 5 MCS subjects, the gas inhalations were carrïed out in the reverse order,

carbon dioxide first and air second. In addition to this, in 4 MCS subjects, the carbon dioxide

inhalation was replaced with an air inhalation such that two successive air inhalations were

carried out, 10 minutes apart.

2.6 Statistical Analysis -

Analyses were pefionned using a personal cornputer and the SAS statistical s o b a r e

package. Outcome variables included DSM-N panic symptoms, panic attack, questionnaire

scores, SUD, heart rate, and minute ventilation The groups were described and compared usîng

univariate statistics, chi-square, the Student's t test, and the Weich modified t test in the case of

unequal variances. Correlations were examined within the main dependent and independent

variables. Fisher's exact test (FET) was used to compare prcportions and logistic regression was

used to assess the joint effect of multiple variables on a binary response variable. The p k d t-

test was used for paired data A significance level of 5% was used.

2.7 Sample Sùe (Appendix 1) -

An estimate of sample size was detemiined fkom an assessrnent of previous reports of

carbon dioxide challenge in panic disorder (2 1,27,28,8 1,86,87,88), as weLi as questionnaires used

to assess the panic symptomatology including the Diagnostic Symptom Questionnaire (DSQ),

and Subjective Units of Discodort (SUD).

The sample-size caiculation is based largely on results from Rapee et al. ((8 1) in which

only the post-CO2 exponire measurements were in their analysis. The five variables used for the

analysis are: number of physical symptoms, number of cognitive symptoms, intensity of physical

symptoms, intensity of cognitive symptoms, Uitensity of reported fear, and number of

iAitastrophic thoughts. These variables were used because they corrwponded to the largest F

values associated with the analysis of variance used to compare the 7 diagnostic groups. The

intensity of physicd symptoms variable was not used.

The information nom Rapee el ai- (81) on means and standard deviations for the 7 groups

was extracted. With this information, a pooled variance for each of the variables was calculated.

It was assumed that MCS subjects would display more panic symptoms than a normal control

group. Therefore sample size was estimated under two dinerent assumptions. Fust, it was

calculated assuming that MCS subjects would have a mean respoase identical to the controls in

Rapee et al. (sample size N2). Secondly, the sample size N1 was calculated by assuming that the

mean response of the MCS subjects was identical to the social phobic group whose mean

response was approximately halfway between that of the controls and the patients with panic

disorder. The sample sue N2 ranged nom 13 to 21, while the sample size N1 ranged fkom 28 to

50. The highest sample size estimate is for the single variable, intensity of fear. A sample size of

30 MCS subjects and 30 controls was selected. This is slightly less than the number used by

Rapee et al. (8 l), taking advantage of their analysis to ident* which variables are most Likely to

vary the most across the diagnostic groups.

Cbapïer 3: Rcsults

3.1 Instrument Validation -

Validation of the accuracy of the pulmooa<y function instruments according to minimal

recommendations for diagnostic spirometry (85) is summarized in Table 3-1. The flow

spirometer was accurate in its messurement of IVC withïn 1%, W C , and FEVl within 3%, PEF

within 4% and FEFSo within 3%. These values were aii withia the accuracy guidelines outiined in

by the American Thoracic Society @), namely an accuracy in NC, FVC, and FEVi within 3%,

PEF within 10% and FEFso witbia 5%.

Table 3-1. Accuracy Validation of Flow Spirometer Over 8 Triais

FVca F-V Calib. 3.02 3.02 3.02 3.02 3-01 3.02 3.02 3.02 Spirometer 3.1 1 . 2.96 2.97 2.97 2.97 2.96 2.96 3.04 % Error 2.9 2 1.7 1 -7 1-3 2 2 0.7

FWlb F-V Calib. 3.02 3.02 3.02 3.02 3-01 3.02 3.02 1.73 Spirometer 3.1 1 2-96 2.97 2.97 2-97 2.96 2.96 1 .n % Error 2.9 2 1.7 1.7 1.3 2 2 2.3

PEP F-V Calib. 6.33 4.85 5.96 5.44 4.23 5.21 4.58 2.00 Spirometer 6.22 4.80 5.87 5.38 4.21 5.1 2 4.51 2.08 % Error 1.7 1 .O 1.5 1.1 0.3 1.7 1.5 3.8

FEFM* F-V Calib. 5.94 4.85 5.36 5.12 4.23 4.97 3.80 1 -78 Spirometer 5.97 4.74 5.27 5-06 4.20 4.87 3.73 1.79 % Error 0.5 2.3 1 -7 1 -2 0-7 2.0 1.8 0.6

MV VMM4 4.03 4.02 4.04 4.03 3.99 3.98 4.04 4.03 % Error 0.7 0.5 1 0.7 0.3 0.5 1 0.7

IVC~ Spirorneter 4.01 4.0 1 4.03 4.03 4.01 4.02 4.00 4.00 % Error 0.2 0.2 0.7 0.7 0.2 0.5 O O

a forced vital ca~acity. spimmeter value compated to flwvolume calibrator value for trials 14,7,8 (camed out on same day); ~ Z a l 5 carried out on a separate day; Tnal 6 canied out on a separate day; For trials 5 and 6, spirometer value as obtained by Ocean & Spirobankm PC software wmpared to flow-volume cati brator value b forced expiratory volume in one second, spirometer value compared to flow-volume calibrator value. Trials 1-4,7,8 carried out on same day; Tn'al 5 cam'ed out on a separate day; Tnal 6 camed out on a separate day; For trials 5 and 6, spirometer value as obtained by Ocean & Spirobanknr PC software compared to flow-volume calibrator value

Table 3-1 Cont'd.

peak expiratory fiow, spirometer value compared to flow-volume calibrator value. Trials 1-4,7,8 cam'ed out on same day; Trial 5 camed out on a separate day; Trial 6 canfed out on a separate day; For trials 5 and 6, spirometer value as obtained by Ocean & Spirobankm PC software compared to flow-volume calibrator value d forced expiratory flow at 50%. spirometer value compared to flow-volume calibrator value. Trials 1 -4,7,8 carried out on same day; Trial S cam'ed out on a separate day; Trial 6 cam'ed out on a sepamte day; For trials 5 and 6, spirometer value as obtained by Ocean & Spirobankm PC soihvare cornpared ta flow- volume calibrator value minute ventilation, VMM-401 Ventilation Measurement module^ value compared to volume of

standardized 4 L calibraüon synnge; Trials 1-3 canied out on same day; Trials 4-8 carried out on same day f slow inspiratory vital capacity, spitometer value compared to volume of standardized 4 L calibration synnge; Trials 1-5 carried out on same day; Trials 6-8 cam'ed out on same day

The percentage of carbon dioxide in the 3 5% carbon dioxide in oxygen tank was

rneanired in dupticate on two occasions. Before the start of the study, the percentage of carbon

dioxide was measured at 33.7% and 33.2%. Two-thirds through the study it was measured again

at 33.2% and 34.2%.

3 -2 Demographic Variables -

One hundred and five MCS subjects were contacted. Thirty-four did not meet our MCS

criteria. Of the remaining 71 candidate MCS subjects, 32 were d e d out for various reasoas.

Fourteen of the 32 subjects (45%) were mled out because they were currently in treatment for an

anxiety disorder; 5 (16%) reported suffering from migraines; 11 (35%) declined to participate; 1

(3 %) reported suRering fiom asthma; 1 (3%) muld not schedule an appropnate visit tirne. Of the

remaining 39 abjects were invited to participate, 3 subjects did not arrive for their visit, leaving

36 MCS subjects enroiied in the study.

Table 3-2 shows that the groups did not differ significantly in gender distribution.

However, MCS subjects (mean age 4 1.6 years) were signifcantly older than controls (mean age

34.6 years) by approximately 7 years. Contingency table Malysis indicated no significant overaii

differences in marital status, highest education levei, curent residence, or m e n t area of

residence. Most participants were single and achieved some level of post-secondary education.

Most subjects, in both groups, were urban apartment dweiîers. However, contingency table

anaiysis indicated signifcant overall differences in current ernployment status. A large

proportion of MCS abjects (53%) were employed in white-coiiar jobs while 46% of controls

were students.

Table 3-2. Health and Demographics Questionnaire: Demographic Variables

contro~ MCS x2 pvalue (no. of subjeds) (no. of subjeds)

Number of subjects

Mean age (s.d .)

Sex - Male Female

Marital status Single Mamed Separated Divorced Widowed

Current ern~lovment Student Home Blue collar White collar Retired Other

Hishest education level Public school High school University / College Other

Current residence Apartment House Other

Current area of residence

Rural (< 10 000) O 3 ' Analyzed using the Student's t test " Analyzed using Fisher's exact test - Analyzed using chbsquare analysis

3 -3 Illness History -

Table 3-3 summarizes ilines history in MCS aod control subjects. A significantly greater

proportion of MCS ~ b j e c t s compareci to controls reported having had either on a continuhg or

intermittent basis, health problerns in the foîiowiug areas: mai, eye, ear, throat, lung, stomach,

kidney, hormone, arthritic, blood supply, skin, allergies (exclusive of nasal, lung, or skin),

nervous system, and emotional or psychiatrie probIems. No sipifkant merences between

groups were observed in the foliowing illness categories: heart, menstrual, thyroid, blood

problems, or swoilen glands. MCS subjects (P-36) reported significantly more illnesses per

person, with a mean of 6.6 ilinesses, compared to controls (NL37), who reported a mean of 1.5

illnesses out of a possible 19.

Table 3-3. lllnesses Present on Either a Conünuing or Intemittent Basis and Medication Use

lllness MCS (no. otsubjeds) Coritrd (no. of subficts) p-value'

Number of subjech 36 37

Nasal problems 25 6 < -00001 Mebcation' 7 1 1 .O0

Eye problems 22 3 c .00001 Mescation 5 O 1 .O0

Ear or heanng problems I O 2 = .O1 Medication 1 O 1 .O0

Throat problems P 1 < .0000061 Medication 2 1 0.1 4

Lung or branchial problems 15 1 c .O001 Medication 6 O 1 .O0

Heart or blood pressure problems 2 3 1 .O0 Medication O O

Digestive. stomach. or bowel problerrts 20 5 c -001 Medication 5 3 0.29

Kidney. or bladder probiems 8 2

Menstmal problems, including cnrnps 11 12 0.79 Medication 3 6 0.40

Thyroid problerns 7 2 0.09 Medication 4 O 0.48

Other hormone problems 5 O .M5 Medication 4

Blood problems, or anemia 5 2 0.26 Medication 1 O 1-00

Arthriîic probtems 8 1 .O1 Medication 3 O 1 .O0

Blood supply, or vein problems in a m 1 legs 5 O .MS Medication O

Skin problems 20 5 < -001 Me dica bon 5 3 0.28

Swollen glands 9 3 -06 Medication O O

Allergies, exclusive of nasal, lung or rkin 23 6 c .O001 M edication 3 1 1 .O0

Nervous system problems 4 O .O5 Medication 1

Emotional or psychiatrie problem 6 O .O1 Medicalion O

Total nurnber of ilInesses p u prrton (s.dJ 6.6 (N = 36) (3.7) 1.5 (N t37 ) (1.1) t -7.52 (d = 49) P.' = .ml

Binary categorkal variables analyzeâ wing Fisher's mct tW " Anriyzod using MoBfied t test, ' Reportad if i l Inau was prescnt

3 -4 Medicatioa Use -

Table 3-4 shows that a significantly greater proportion of MCS subjects (69%) reported

taking medications on most days compared to controls (38%). For individuals who reported

taking medication on most days MCS subjects (N45) repocted taking ~ i g ~ c a n t l y more types

of medication per person, with a mean of 3.2 types, versus convols (N=16) who reported taking a

mean of 1.1 types of medication.

A significantly greater proportion of MCS subjects compared to controls respectively,

reported taking the foiiowing medications: vitamins (67% vs. 40%); herbal remedies (44% vs.

0%); inhalers (22% vs. û??); and ointments (22% vs. 0%). No signiticant Merences between

groups were observed for the use of antibiotics, antacids, laxatives, painkillers, sedatives, eye

drops, nose drops, or injections.

Table 3-4. Medication Use

MCS (N = 36) Control (N = 36) p-value* (number and % (number and % of subjeds) of su bjects)

Use of medication (s) on most days 25 (69%) 14 (38%) < .O1

Number of medicaüons used' 3.2 1.1 t = -3.89 (df= 25) (S. d.) (2 7) (O. 3) p" c .O01

Tvpes of Medications use@ fin number of subjects)

Vitamins 24 (67%) 12 (40%) .OS

Antibiotics O 2 (7%) 0.20

Antacids 4 (11%) 2 (7%) 0.68

Laxatives 1 (3%) O ? -00

Pain killers 4 (11%) 2 (7%) 0.68

Tranquilizers O O

Sedatives 2 (6%) O 0.5

An tidepressants O O

Herbal remedies 16 (44%) O < .O001

Drops for allergy, eyes, or nose 6 (1 7%) 1 (3%) 0.12

Injections 1 (3Oh) O 1 .O0

Ointments 8 (22%) O c -01 * Analyzed using Fisher's exact test unless othefwise stated " Analyzed using Welch's modifieci t test a lnciuded only if reported to use medications on most days b lnduded regardless if reported to use medications on most days

Refers to pm use of pagonists

3 -5 Heafth Care Needs -

Table 3-5 shows that no significant merences between groups were observed in the

number of times they had visited the foliowing health a r e professionds in the past two years:

family doctor; any M.D. specialist; ciinical ecologist; or acupuncturist. Also, no significant

dserences were observed ia the number of hospital admissions in the past two years. However,

MCS subjects reported more visits to diet therapists than controls. This difference bordered on

statist i d significance. MCS abjects reported signiticantiy more visits to chiropractors, with

mean number of visits of 7.1, compared to controls, who reported a mean number of visits of 1.2.

Similarly, in the category "other type of caregiver", MCS subjects reported significantly more

visits to this caregiver, with a mean number of visits of 2.0, versus controls, who reported a mean

number of visits of 0.6. The most common type of caregiver reported in the latter category was a

massage therapist.

Table 3-5. Heaith Care ütilization in the Past Two Years

MCS Control -t (dl) pvaIue' (mean no. of wsits, ( m n no. of wsits, N = 36) N =37)

Family doctor 6.5 (S. d.) (5.7)

M.D. specialista 2.3 (S. d.) (3.5)

Clinical ecologist 0.03 (S. d.) (0.2)

Acu pundurist 1-1 (S. d.) (3- 7)

Chiropractor 7.1 (S. d.) (12- 8.

Diet therapist 0.7 (S. d.) (2- 0)

Other caregiversb 2-0 (S. d.) (3- 3)

Been admitted to hospital 0.2 O. 1 -0.98 (58) 0.33 (S. d.) (O. 6) (0.4) * Analyzed using Welch's modified t test a except dinical ecologist b The most cornmon type of caregiver in this category was a massage therapist

3 -6 Effects of Environmental Exposures (MCS subjects) -

Al1 36 MCS subjects reported being adversely affected to a senous degree by

environmental factors. Table 3-6 shows that the duration of the environmental iiiness ranged

fro m one to 47 years but was on average 14 years. The average age of onset was 28 years, with a

range £iom birth to age 50. Approximately half (57%) could ideatm an omet event. The

circumstances of the omet were attributed to somethhg in the workplace in 47% of al1 those who

reported an omet event. An exposure m n t in the home or an illness was oRen jointly involved.

MCS subjects almost invariably reported that they were afkcted by environmental iIhess in

public places (97%), although the workplace (89.h), home (77%), and outside (90%) were dso a

problem for most subjects. Over half of the MCS subjects (56%) reported that they were

affected the worst in public places.

Table 3-6. Onset of Environmental Sensitivities in MCS Subjects (N = 36)

Mean duration of illness ()mars) (S. d.) Range in duration of illness (years)

Mean age of onset (pars) 27.6 (S. cf. f Range in age of onset vears)

w- 7) 0 - 50

Circumstances of onseta

% of subjects able to identify an onset event 57% % of subjects attributing onset to a workplace event 47% % of subjects attributing onset to something at home 47% % of subjects attributing onset to an illness 36%

a Some subjects reported that a woricplace exposure was either solely responsible for onset orjointly involved with an illness or home exposure event

As seen in table 3-7, most MCS subjects (97Y0) reported being adversely affected by

substances in the air. The mean number of airbome substances pet person was 6, with a range of

two to 20. The most cornmon substance in this category was diesel exhaust. Sixty-seven percent

of MCS subjects reported being affected by ingested substances. The mean number of ingested

substances was 5 per person, with a range of one to 15. In this category, wheat and dairy

produas were most often reported. Sm-one percent of MCS subjects reported being aEected by

substances touching the skin. The mean number of dermal substances was between one and six,

with a mean of three substances per person Cosmetic creams were the most fiequently reported

dermal agent.

Table 3-7. Locations of Environmental Exposures in MCS Subjeds (N = 36)

Locations where affededa

% of subjeds affeded at home % of subjecl affeded at work % su bjects affected in pubiic places % of subjects affeded when outside

Locations identified as beina the worst for svmdoms

% of subjects indicating that home was the worst 4% % of subjeds indicatirig that work was the wofsî 22% % of subjects indicating that puMc places wem the worst 56% % of subjects i~di~ating that outside as the worst t9%

Environmental triaqers

of subjects affeded by substances in the air 97% Mean no. of airbome substances 1 per person 6 Range in no. of airbome substances 2 - 2 0

~f subjects affeded by substances ingested Mean no. of ingested substances / petson Range in no. of ingested substances

% of subjects affeded by substances touching the skin 61% Mean no. of dermal substances 1 person 3 Range in no. of dennal substances 1-6

a Some subjects endorsed more than one location

As seen in table 3-8, most MCS subjects (79%) reported that a given substance usuaily

affects them in the same way. Almost two thirds of MCS subjects (63%) reported that a "minute"

or "small" amount of exposure was sufficient to elicit symptoms. Seventy-seven percent reported

that symptoms begin in minutes f i e r exposure. Many subjects reported that symptoms last hours

(42%). Symptoms were reported to 1 s t for days in 37% ofMCS subjects. Twenty-percent of

MCS subjects reported that they were afEected on a daily basis, 13% weekly, 27% monthly, and

40% reported that they experienced symptoms less than once a month. Approximately three

quarters of MCS subjects (76%) indicated that they were ' k e W when eqosure was avoided.

One convol abject reporteci being sensitive to one bnnd of hair care product and caffeine.

However, she did not meet the study criteria for MCS.

Table 3-8. Environmental Sensitivity Symptoms in MCS Subjects (N = 36)

% of subjects reporüng a minute amount 40% % of subjects repotting a srna// amount 23% % of subjects reporting a mod8fate amount 31 % % of subjects reporting a 1- amount 6%

Time interval between exoosure and svrnbtorns

% of subjects reporting minutes 77% % of subjects reporthg hows 17% % of subjects reporüng longer 6%

Ouration of svrnDtoms

% of subjects reporting minutes 15% % of subjects reportiflg hows 42% % of subjects reporthg days 37% % of subjects repotting more 6%

Frequencv of svmotoms

% of subjects reporting daily 20% % of subjects reporting weeWy 13% % of su bjects reporting monthly 27% % of subjects reporthg less 40%

Reaction if re-exoosed

% of subjects reporting the same 79% % of subjects reporting difBfe#t 21 %

Status when exposure is avoided

% of subjects reporting well 76% % of subjects reporting so-$0 21 % % of subjects reporting sr*& 3%

3.7 S ymp toms Experienced -

A signXcantly greater proportion of MCS subjects compared to controls, respectively,

reported that they experienced a number of symptoms on an ongohg basis (Table 3-9). For ail

the symptom variables, the proportion ofsubjects reporthg the symptorn was much higher

among MCS subjects than among controls and significant in all cases except decreased hearing,

burping, or sweliing of the arms or legs.

Table 3-9. Symptorns Experienced on an Ongoing Basis

Headache Fatigue Confusion Concentration Dizriness Lig htheadedness Pins and needles Poor cocrdination

Blurred vision Decreased hearing

Stuffy, mnny nose or hayfever Sore throat Hoarseness Swelling of throat

Cough Shortness of breath Wheezing, chest tightness CanY get air in

Palpitations

Nausea Abdominal bloating Burping Flatulence Abdominal pain

Swelling of amis or legs Itching, rash

MCS (N = 36) (% of subI'ecrs)

' Binary categorical variable analyzed using Fisher's exact test

pvalue*

Table 3 - 10 shows that MCS subj ects (Ab3 6) indicated experïencing signi ficantly more

symptoms per person, with a mean of 14.2 symptoms compared to controls (N=37), who reported

expenencing a mean of 3.1 symptoms out of a possible 26.

Table 3-1 0. Mean Num ber of Ongoing Symptoms

MCS (N = 36) Control (N = 37) t (m pvalue*

Mean no. ongoing syrnptoms 14.2 3.1 -8.91 (53) .O001 (6.6) (3- 5) (S. d.)

Wnalyzed using Welch's modified t test

Conthgency table anaiysis indicated no significant overd effects in frequency, duration,

or severïty in iiiness categories between MCS and control subjects groups with a few exceptions

(Appendix Il). There were significant overd differences in the fkequency and duration of heart

palpitations between groups although ody 5% of controls versus 44% of MCS subjects reported

experiencing heart palpitations (Appendix II).

3 -8 Tests for Symptoms -

A large majority of MCS subjects (83%) reported having tests for their symptoms (Table

3-1 1). A large proportion of those tested (82%) hdidicated that the test results were positive. The

moa common tests were ailergy skin tests for dergens such as pollen, d u s mite, animals, etc.

Table 3-1 1. Test (s) for Symptorns Listed in Table 3-9

MCS Control pvalue* (N=35) (N=31)

O h of subjects that had test (s) for symptoms 83 13 < .O000001

Oh of subjects with positive test fe~ultg 82 75 1 .O0

* Binary categorical variables analyzed using Fisher's exact test a Endorsed only if subjed reported having had test (s)

3.9 Lifestyle Activities

Table 3-12 shows that there were no significarit merences were found between MCS

subjects and controls, respectively, regardhg their involvement in hobbies, exercise programs or

spons, use of alcohoi, cigarettes, or recreational dnign However, a significantly greater

proportion of MCS subjects (64%) cornparrd to controls (19%) reported that they fcliowed

special diets and used dietary supplements (69.h vs. 41%, respectively). More than half the MCS

subjects (58%) indicated having to alter &eir home or work environment for health reasons.

Table 3-1 2. Lifestyle Activities

MCS Control t (do" pvalue (N = 36) (N = 37)

% of subjects engaged in hobbies 86 70 0.16'

% of subjects engaged in exercise programs or sports

% of subjects on special diets 64 19 < .001'

% of subjects using dietary supplements 69 41 -02' Mean no. of types of dietary supplementsa 7.0 2.3 -1.85 (20) .O8 (S. d.) (1 1.2) (f*%"

% of subjects consuming alcohol Mean number of drinks / weeka (S. d.)

% of subjects that are smoken 22 19 0.78' Mean number of cigarettes / day a 8.6 12.4 0.54 (9) 0.60 (S. d.) (7.9) (1 6.9)

% of subjects that use recreational drugs 3 O 0.49'

% of subjects that had to aiter their home or 58 O < .00000001* work environment for health reasons

Binary categorical variables analyzed using Fisher's exad test " Analyzed using WelM's modified t test a Reported only if subjed indicated invoivement in the corresponding adivity

3.10 Lifestyle Limitations - As shown in Table 3- 13, MCS subjects reported a significantly greater degree of

limitation in various lifestyle areas compareci to controls. Specifically, contingency table anaiysis

indicated significant overaii dflerences between groups in the degree of limitation with regard to

household activities, shopping, travel, school, work, recreation, famiiy or social relationships. No

significant overali difSerences were observcd between groups in the degree of iimitation with

respect to self-care

Table 3-1 3. Limitations in Lifestyle Capabilities

~ c t ivîîy 96 MCS % Control X' (dlj) pvalue* (N = 36) (N = 37)

Self care - unable - restnded - no problem (Mean)'

Household activities - unable - restrided - no problem (Mean)'

Shopping - unable - restricted - no problern (Mean)'

Travel - unable - restricted - no problem (Mean)'

School - unable - restrided - no problem (Mean)'

Work - unable - restrided - no problem (Mean)'

Recreation - unable - restrided - no problem (Mean)'

Family relationships - unable - restrided - no problem (Mean)'

Social relationships - unable - restricted - no problem

Analyzed using chi-square analysk Limitations are scored 1 = no pmblem; 2 = resîricted; 3 = unable

3. I I Life Circumstance Dissatisfaction

MCS subjects reported a significantly greater degree of dissatisfaction in certain aspects

of life compared to controls (Table 3-14). Specifically, contingency table anaiysis indicated

signifiant overaii dinerences between groups in the degree of dissatisfaction with regard to

home iife, and health status. No significant dinerences were observed in the degree of

dissatisfaction were found regarding work or school, hancial stahis or social relationships.

Table 3-14. Dissatisfaction in Life Circumstances

Circumstance % MCS % Controi $km pvalue* (N = 36) (N = 37)

Home life - Dissatisfied 14 3 5.24 (2) 0.07 - Neutral 28 - 16 - Content 58 8 1 (~ean) ' (1 -6) (1 .2)

Financial status - Dissatisfied 40 19 - Neutral 26 41 - Content 34 41 (Mean)a (2.1 (1.8)

Health status - Dissatisfied 44 O - Neutral 28 14 - Content 28 86 (~ean)' (2-2) (1 -1)

Work or school - Dissatisfied 13 14 - Neutral 45 11 - Content 42 76 (Mean)' (1 -7) (1 -4)

Social relationships - Dissatisfied 8 5 4.24 (2) 0.12 - Neutral 39 19 - Content 53 76 (Mean)" (1.6) (1.3)

' Analyzed using chi-square analysis " Dissatisfactions are score 1 = content; 2 = neutral; 3 = dissatisfied

3.12 Effect of Age and Gender -

Among the controls, there were no signifiant Merences between males and females in

the number of reported illness or the number of ongoing symptoms (Table 3-1 5). There were no

significant correlations between age and the number of reported iiinesses (p = -0.23, Pearson,

n.s.) or the number of ongoing symptoms (p= 0.08, Pearson, ns.). Similarly, in the MCS group,

there were no significant Merences between males and females in number of reported illness

(Table 3- 15) or the number of oagoing symptonu. There were no si#cmt correlations

between age and the number ofreporteci ilinesses (R'= -0.16, Pearson, m.) or the number of

ongoing symptorns (l? = -0.08, Pearson, as.).

pvalue 1 p-value

Table 3-1 5. lllness and Symptom History between Males and Females in MCS and Controls*

MCS

Males Females f (dl)

Controls

Males Fernales f (do

Mean no. of illnesses 5.5 7 -0.98 (34) (S. d.) (2.2) N = 8 (4.0) N = 28 0.33

Analyzed using the Student's t test

-

1.5 1 .S -0.03 (35) (1 -6) N = 10 (1 -8) N = 27 0.98

Mean no. of ongoing Symptoms 10.6 15.2 7 ( ) (S. d.) - (4.9) N = 8 (6.7) N = 28 0.08

3.13 Effect of Recruitment Source

1

3.8 2.9 0.70 (35) (3-4) N+iO (3.6) N t 2 7 0.49

As summarized in Table 3- 16, 18 MCS subjects were recruited by advertisement. No

attempt was made to ascertain whether or not these individuals had undergone a sufficient

previous medical evaluation to reasoaably exclude organic causes of their symptoms. The

remaining 18 subjects were recruited either from the study physicians or nom a participation List

of a previous study carried out at the University of Toronto. These individuals had undergone a

medical evaiuation and possible pathological causes of their symptoms were rded out.

MCS subjeas recruited by advertisement did not differ significantly from subjects

recruited from clinical practice with respect to the number of oogoing symptoms. However,

subjects recruitedJkom clinical practice were found to have a signifcantly greater number of

reported illnesses, with a mean of 8.1, compared to individuals recruited by advertisement, who

reported a mean of 5.5 illnesses.

MCS subjects from the two sources did not diffa significantly with respect to their

environmental sensitivities. The proportions of individuaïs being sensitive to substances in the

air, substances that touch the skin or substances that are ingested were not significantly different

between the two sources. There were dso no siWcant ciifferences in the number of

environmental triggers, neither ingested, touching the skin, nor inhaleci, between the two sources.

Table 3-16. IlIness History and Environmental Perceptions in MCS Subjects Recruited from Two Sources

Remited by Remited fiom t (do p-value advertisement clinical pradice (N= 18) (N= 18)

lllness history

Mean no. ilInesses 5.5 8.1 -2.31 (33) < -05' (S. d.) (3.4) (3-3) Mean no. of ongoing symptoms 13.3 15.1 -0.81 (34) 0.43' (S. d.) (7.0) (6.2)

Environmental oerce~tions

No. of subjects sensitive to airbome substances No. of subjects sensitive to substances touching the skin No. of subjects sensitive to ingested substances

Mean no. of airbome substances (S. d.) Mean no. of demal substances (S. d.) Mean no. of ingested substances

" Analyzed using Student's t test " Analyzed using Fisher's exact test " Analyzed using Welch's modified t test

3.14 Psychological Scores

Table 3-17 shows that MCS subjects scored significantly higher than controls on the total

number of panic attacks, the Mobility Inventory for Agoraphobia (MI), both done and

accompanied; the anxiety and stress subscaies of the Depression Anxieîy Stress Subscales

(DASS); the Agoraphobic Cognitions Questionnaire (ACQ); and the Anxiety Seasitivity Index

(ASI). MCS subjects scored higher than controls on the depression subscale of the DASS as

weU, a difference that was marginaliy significant.

Table 3-1 7. Mean Psychological Seif-Report Questionnaire Scores in MCS and Control Subjeds

MCS Controls t df Probe> 1 t 1 (n=36) (n=37)

Mobility lnventory (Accompanied) (S. d.)

Mobility lnventory (Alone) (S. d-)

DASS: Stress (S. d.)

DASS: Anxiety (S. d.)

DASS: Depression (S. d.)

Agoraphobic Cognitions Questionnaire (S. d.)

Anxiety Sensitivity Index (S. d.)

Mean no. panic attacksa (S. d.)

Mean no. expected panic attackeb (S. d.)

Mean no. unexpected panic attacksab (S. d.)

a Represents panic attacks in the month preceding the visit Unexpected and expeded no. panic attacks reporteci for subjects who reported having panic attacks, je., 6 MCS subjeds and 1 control subjed

* Analyzed using WeIch's modifiecl t test

Eight MCS and one control subject reported that they had experienced at least one panic

attack, either unexpectcd or expected in the month preceding theu visit.

3.1 5 Gas Inhalation Chaiienges -

3.1 5 (a) Baseline Measures

As shown in Table 3-18,3 1 controis (10 miles) and 3 1 MCS subjects (7 males) weat on

to successfully complete a compressecl air followed by a 35% carbon dioxide in oxygen

inhalation challenge. MCS subjects (mean age of 4 1.6 yean) were significantly older than

controls (mean age of 33.8 years).

Table 3-18. Demographic Parameters and Mean Psychological SesReport Questionnaire Scores in MCS and Control Subjects who Completed Gas Inhalations

MCS Controls f df pvalue' (N = 31) (N = 31)

Mean age (S. d.)

No. males 7 10 OS?* No. females 24 21

Mean no. of illnesses (S. d.)

Mean no. of ongoing symptoms 14.4 3.0 98-49 U .O001 (S. d.) (6.7) (3.4)

Mobility lnventory (Accompanied) (S. d.)

Mobility lnventory (Atone) (S. d,)

DASS: Stress (S. d.)

DASS: Anxiety (S. d.)

DASS: Depression (S. d.)

Agoraphobic Cognitions Questionnaire (S. d.)

Anxiety Sensitivity 1 ndex (S. d.)

Mean number of panic attacks' (S. d.) (4.8) (0.4)

a Represents panic attacks in the month preceding the visit, both expected and unexpected * Analyzed using Welch's modified t test unless othetwise stated " Analyzed using Fisher's exact test

Table 3 - 19 summarizes puhonary fùnction data. MCS subjects and controls,

respectively, did not di f fa sigdicantly in baseline peak expiratory flow rate (PEF), forced vital

capacity, forced expiratoiy volume in one second, vital capacity, percent predicted FVC or

percent predicted FEVl. MCS subjects however, h d a signincantly Iowa FEVI as a percentage

of the FVC, (mean of 80.1 %) wrnpared to controls (mean of 83 -6%). No su bject in either group

had a percent predicted FEVl less than 75%.

Table 3-1 9. Pulmonary Function Parameters in Challenged Subjects

Mean pulmonary fundion parameters MCS Control t (do p-value' (N = 31) (N = 31)

PEF (Usec) (S. d.)

FEVI / FVC (%) (S. d.)

% Predided R/C (%) (S. d.)

% Predided FEV, (%) (S. d.)

vc (1) (S. d,)

Volume (S. d.)

Volume (S. d.)

cornpressed air inhaled (L)

35% CO2 in oxygen inhaled (L)

Volume 35% COz in oxygen inhaled (L) as a percentage of VC (%) (S. d.) (20.78) (9.68)

' Analyzed using Welch's modified t test

Table 3-20 shows that no significant ciifferences between MCS subjects and controls,

respedvely, were observed in breathing rate, minute ventilation, subjective units of discornfort

(SUD) or heart rate preceding the g s challenges.

Table 3-20. Physiological and Subjective Parameters lmmediately Prior to Air Inhalation

MCS Control t (a pvalue" (N = 31) (N = 31)

Phvsiolo~ical parameters

Breathing rate (breaths 1 minute)' (S. d.)

Minute ventilation (L 1 rnin~te)~ (S. d.)

Heart rate (beats 1 minute)' (S. d.)

Subjective parameter

Su bjedive units of discomfortd 6.5 7.7 0.45 (53) 0.65" (S. d.) (1 2.6) (8 .S)

' Analyzed using Student's t test unless otheMlise stated " Analyzed using Welch's modified t test a.bTaken 5 minutes prior to compressed air inhalation. therefore not representative of pre-challenge values C.d Taken irnmediately pnor to compressed air inhalation

Table 3 -2 1 shows that no significant merences were found between groups with respect to

DSM-IV panic attack symptoms, the sensation of panic or feu, the degree of safety or control

felt, or the number of negative or positive thoughts during baseline.

Table 3-21. Baseline Self-Report DSMlV Panic Attaclr Symptom Ratings

DSM-IV panic attack symptonn~ MCS Coribol t m pvalue' (N = 31) (N= 31)

Numbness or tingling in face or extremitias (S. d.) Trembling or shaking (S. d.) Dizziness, Iightheadedness, unsterdines, or faintnars (S. d.) Pounding or racing heart (S. d.) Breathlessncss or srnothering senution (S. d.) Chest pain or tightncss 6-d-) Choking (s- d.) Sweating (S. d.) Hot flushes or cold chilis (S. d.) Feeling unreal or in a drearn (s-d.) Nausea or abdominal stress (S. d.)

Mean sum of DSM-IV physical symptom ratingsb (S. d.)

Fear of dying (S. d.) Fear of going crazy or l&ng control (S. d.)

Mean surn of DSM-IV cognitive symptarn nttngsb

Sensation of panic or fear 0.1 0.1 0.0 (43) 1 .OO" (S. d-) (0.3) (0.7)

Degree of salety felf (S. d.)

Degree of control'felt6 (S. d.)

Mean no. of non-catastrophic thoughts' (S. d.)

Mean no. of catastrophic thoughb 0.1 0.1 0.39 (25) 0.7 (s-d.) (0.4) (0.3)

Mean no. of DSM-IV panic rüack symptoms ( s d )

Mean sum, of DSM-IV pank 8-k symptom ntbigl' 1.3 1.1 -0.22 (60) 0.82 (s-d.) no) (1 -9)

Analyzed using Studsnt's t test unlm othenuk. rtdad; " Anatyzoâ uaing Wdchts modMed t test ' DSQ symptoms are rated O = not noticrd 8t dl; 1 ; 2 - SlbhUy felt; 3; 4 = rnodontrly fdt; 5; 6 = diongly fdt; 7; 8 = very strongly fdt lntensity ratings of DSM-IV prnic altrck rymptomr fiom the DSQ wdn summd ta give an wmfl index d symgtom severity Degree of safety felt k mted O = not 8t dl #h; 1 ; 2 + rfbhtfy d e ; 3; 4 = quka d o ; 5; 6 - mry ufe; 7; 8 = cornpietely uh

Table 3-21 Cont 'a

Degree of conbol b rated O = no tonbol; 1; 2 - di#~t conbol; 3; 4 = moderata conbol; S; 6 = much control; 7; 8 = total control ' Intensity ratings of DSM-IV panic attack syrnptomr fr0m the DSQ ur~. rummd to gwe an ovemll index of symptom severity ' Non-catastrophic and mtasbophic thoughb u e in rmpoma to DSM-IV p n k &hck symptorn8 expeffanchd and ther8fOn recordcd only if at least 1 DSM-IV panic 8 h c k symptom m s -ad

3.15 (b) Response to Air Inhalation

Table 3-22 summarizes responses to single-breath vital capacity inhalation of compressed

air. One MCS subject and no conîrols Mieci DSM-IV panic attack criteria after air inhalation.

No significant ciifFerences were observed between MCS abjects and controls, respectively, with

respect to breatbiog rate, minute ventilation, heart rate or subjective units of discodort measured

immediately after air inhalation.

Table 3-22. Absofute Physiological and Subjective Parameters after Compressed Air Inhalation

MCS Control t (do p-value* (N=31) (N=31)

Physioloaical aram met ers

Breathing rate (breaths 1 minute)' (S. d.)

Minute ventilation (L 1 minute)b (S. d.)

Heart rate (beats 1 minute)' (S. d.)

Su biective parameter

Subjective units of discomfortd 10-1 10.9 0.22 (60) 0.83 (S. d.) (1 5.9) (1 1.8)

* Analyzed using Student's t test unless otherwise stated " Analyzed using Welch's modified t test

a.b.c.d Taken immediately after compressed air inhalation

However, as summarized in Table 3-23, compared to immediately before inhalation, controls

demonstrated a signincant hcrease in heart rate following air inhalation. No simcant

differences were observed in the change in breathing rate, minute ventilation, or subjective units

of discomfort. MCS subjects demonstrated a signincaat increase in heart rate and SUD after air

inhalation. The changes in breathing rate, minute ventilation, or subjective units of discornfort

were not significantly different bbctween MCS subjects and controls. However, the increase in

heart rate of controls compared to MCS subjects following air inhalation border4 on statisticai

Table 3-23. Change in Physiological and Subjective Parameters after Air Inhalation (Post - Pre)

MCS Control t (Ut) pvalue* (N = 31) (N = 31)

Breathing rate (breaths / minute) (S. d.)

Minute ventilation (L / minute) (S. d.)

HeaR rate (beats / minute) (S. d.)

Subiective Dammeters ( ~ o s t - orel

Subjective units of discomfort +3.61" +3.16 -0.20 (60) 0.84 (S. d.) (7.5) (9.88)

' Analyzed using Student's t test unless othemise stated " Analyzed using Paired t test, significantly different fmm baseline or pre-challenge at p c .O5 " Analyzed using Welch's modified t test

As shown in Table 3-24, MCS subjects and wntrols did not ciiffer significantly in regards to the

number of DSM-N panic attack symptoms or the sum of cognitive or physicai symptom severity

ratings Listed on the Diagnostic S ymptom Questionnaire @SQ) following air inhalation Also,

the groups did not.difEer significantly in the degree of severïty reported with respect to any of the

DSM-IV panic atîack synptom, the exception being "hot flushes or cold chills". However, only

one MCS subject and no controls reported the fecling of hot flushes or cold chills. The groups

did not differ ~ i g ~ c a n t l y on the degree to which they identified theu symptorns and feelings as

similar to a typical panic attack. They alro did not Mer significantly regarding the degree of

safety they felt or how much control they felt duriag the inhalation There were no significant

differences between groups wirh respect to the number of non-catastrophic or atastrophic

thoughts they experienced when they k t noticed their symptoms after air inhalation.

Table 3-24. Self-Report Panic Symptom Raüngs after Compmssed Air Inhalation

No. of s u b i e fuffilling panic a h c k criteria 1 O

Mean intensihr of OSM-IV ~ a n k

Numbness or tingling in face or extremities (S. da) Trembling or shaidng (S. d.) Dininess. Iightheadedness, unsteadiness. or hintness (S. d.) Pounding or racing heart (S. d.) Breathlessness or smothefing s e m f ion (s-d.) Chest pain or tightness (S. d.) Choking (S. d.) Sweating (S. d.) Hot Rushes or cold chills (s- d.) Feeling unreal or in a dream (S. d.) Nausea or abdominal stress (S. d.) Mean sum of DSM-IV phpical symptom ratingsb (S. d.)

Mean Intensitv of DSM-IV Panic Attack Coaniüve SvmdOm

Fear of dying (S. d.) Fear of golng crazy or losing control (S. d.) Mean sum of DSM-IV cognitive syrnptam ntingsb (S. d.)

Sensation of panic or fear (S. d.) Degree of safety feltC (S. d.) Degree of control fend (s- d.) Mean no. of non-catastrophic thoughtso (S. d.) Mean no- of ~ata~trophic thouahk

Mean no. of DSM-IV panic attack symptoms (S. d.) Mean sum of DSM-IV panic ittack symptom müngSb - . (S. d.) (3.4) (281

' Analyzed using Student's t t i c t unlarr otherwise Md; " Aniiyzed using Wddr's modiied t test OSQ symptoms are rated O = not noticad 8t il; 1 ; 2 = SlïgMty k S 3; 4 - modmtely fait; 5; 6 = strongly f e

7; 8 = very strongly f a ; lntensity ratings of DSM-IV pi* 8-k symptomr frorn the DSQ m r e summed to givo an ovml l index of symplam severity Oegree of safety fclt is mted O - n d 8t rll u fe ; 1 ; 2 = dig)ay Uf8; 3; 4 = quite #f.; 5; 6 = vefy 88f8; f; 8 = campietely u f e

* Oegree of control b rated O = no control; 1; 2 = mt Corrbd; 3; 4 = moderato conbol; 5; 6 - much conbol; t; 8 -total controt ' Non-catastrophic and catasüophk thoughb are in -nu to DSM-IV prnic ilbdt syrn@om up«iericcrd and therofr. recordcd only if at least 1 OSM-IV panic W u k symptom m8 npodd

3.1 5 (cl Response to Carbon Dioxide Inhalation

Table 3-25 summarizes masures taken irnrnediately prcceding the carbon dioxide

challenge. MCS subjects and controls, respectively, did not M e r ~ i ~ c a n t l y with respect to

breathing rate, minute ventilation, or subjective uniîs of discornfort. MCS nibjects did however,

show a greater heart rate (mean of 78.77 beatdmin) compared to controls (mean of 73 -6 1

beatdmin), a result which bordered on staîistical significance.

Table 3-25. Absolute Physiotogicaf and Subjective Parsmeters before 35% CO& Oxygen Inhalation

MCS Control t (@ pvalue* (N = 31) (N = 31)

Breathing rate (breaths / minute)' (S. d.)

Minute ventilation (L / minutelb (S. d.)

Heart rate (beats 1 minute)' (S. d.)

Su biective ara me ter

Subjective units of discomfortd 7.3 7.5 0.09 (60) 0.93 (S. d.) (1 1.5) (8.2)

' Analyzed using Student's t test Taken immediately pnor to 35% C a in oxygen inhalation

Responses to single-breath vital capacity inhalation of 35% C a / 65% O2 among MCS subjects

and controls is surnmarized in Table 3-26. There were no signifiant differences between groups

in regards to breathing rate, minute ventilation, heart rate, or subjective units of discornfort

measured Wediately d e r carbon dioxide inhalation.

Table 3-26. Absolute Physiological and Subjedive Parameters after 35% C a in Oxygen Inhalation

MCS Control t (df) pvalue* (N = 31) (N = 31)

Phvsioloaical Parameters

Breathing rate (breaths f minute)' (S. d.)

Minute ventilation (L 1 rninutelb (S. d.)

Heart rate (beats / minute)' (S. d.)

Subiective s ara me ter

Subjective units of discornfort* 33.9 28.5 -0.71 (60) 0.48 (S. d.) (33.8) (25.5)

Analyzed using Student's t test unless otherwise stated * Analyzed using Welch's modified t test a.b Taken immediately after 35% CQ in oxygen inhalation Taken immediately affer 35% C Q in oxygen inhalation

d RepoRed immediately after 35% C a in oxygen inhalation

However, as shown in Table 3-27, MCS subjects showed a significant increase in breatbing rate,

minute ventilation, subjective units of discomfort, and heart rate foiiowing gas inhalation

compared to immediately preceding it. Controls experienced similar increases, but were

significant for minute ventilation, subjective units of discomfort and hem rate.

Table 3-27. Change in Physiological and Subjedive Parameters after 35% COz in Oxygen Inhalation

MCS Control t (d9 pvalue* (N=31) (N=3t )

Phvsioloaical aram met ers Wst - ~ r e )

Breathing rate (breaths / minute) (S. d.)

Minute ventilation (L / minute) (S. d.)

Heart rate (beats / minute) (S. d.)

Subiective parameters (mst - me) Subjective units of discornfort +26.61n +20.97" -0.84(60) 0-41 (S. d.) (30.31) (22.1 7)

Anaiyzed using Student's t test unless otkeninse stated " Analyzed using Welch's modifieci t test " Analyzed using Paired t test, significantly diflerent from baseline or prechallenge at p c -05

The increases in breathing rate, minute ventilation, and subjective units of discodort were not

significantly different between MCS abjects and controls. Controls, however, did demonstrate a

rnarginally greater increase in hart rate compared to MCS subjects. As shown in Table 3-28,

however, when the change in SUD and physiological parameters after carbon dioxide inhalation

was compared to the change after air inhalation, the groups did not M e r in heart rate, minute

ventilation, breathing rate, or SUD.

90

Table 3-28, Physiological Responses and SUD Before and M e r Gas Challenges in MCS Subjects and Controls

Breathing rate (breaths / minute) (S. d.)

Minute ventilation (L / min.) (S. d.)

Heart rate (beats / min.) (S. d.)

Su bjedive units of discornfort (S. d.)

MCS (N = 31)

Air C a t )+

(post-pre) @est-pre) pvalue

Controls (N = 31)

Air Co2 t" @est-pre) (post-pre) pvalue

-0.71 1.83 2.70 (2.76) (5.1 5) < 0.05

-

t (do - p-value

-1 -08 (47) 0.29

0.79 (51) 0.43

0.32 (54) 0.75

-0.85 (50) 0.4

Analyzed using Paired t test, post - pre significantly different from O at p < 0.05 " ~nalyzed using Paired t test. COz (post-pre) - Air (post-pre) sig nificanuy different from O at p < 0.05 " Welch's modified t test used to compare [COz Most-pre) - Air (post-pre)] variable across groups

As shown in Table 3-29, significantly more MCS subjects, 22 of 3 1 (71%) than controls,

8 of 3 1 (26%) fulfilled panic attack cntena foiiowing inhaiation of 35% CO2 / 65% O*. The

proportions of control subjects satisfLing panic cnteria f i e r air and carbon diolcide inhalation

were designated P l and P2, respectively. The proportions of MCS subjects satisfjhg panic

criteria after air and carbon dioxide inhalation were designated Q1 and 42, respectively. The

difference Q2-Q 1 was significantly greater than P2-P 1 (P < 0.00 1). As seea in Table 3 - 1 9, MCS

subjects inhaled ~ i g ~ c a n t l y less 35% CO2 165% O2 as a percentage of their vital capacity

(87.5%) than controls (97.4%).

MCS subjects reported a signficantiy greater numba of DSM-IV panic attack symptoms

than controls. They also showed p a t e r sum of physical and cognitive symptom severity ratings

than controls. More specincally, MCS subjects rated 3 of 1 1 DSM-IV panic attack physical

symptoms, both of the DSM-N panic attadc cognitive symptoms and the sensation of panic or

fear as significantly more severe thm controis. The groups did not differ significantly regarding

the degree of safety they felt or how much control they felt during the inhalation There were no

significant differences between groups with respect to the number of non-catastrophic thoughts

when they fust noticed their symptoms. Howmr, MCS subjects reported significantly more

catastrophic thoughts than controts.

Table 3-29. SeFReport Panic Symptom Ratings Mer 35% C& in Oxygen Inhalation

MCS Control t (m p-value* (N = 31) (N * 31)

No. of subjects fuMlling panic a(trck critaria P(71Q) 8 (26%) < -001"

Mean intensitv of DSM-IV ~anic

Numbness or tingting in face or extremities (S. d.) Trembling or shaking (S. d.) Dininess. fightheadedness. unsterdiness, or faintness (S.d.1 Pounding or racing heart (S. d.) Breathlessness or smothering sensation (s-4 Chest pain or tlghtness (S. d.) Choking (S. d.) Sweating (s.d.) Hot flushes or cold chilh (s-d.) Feeling unreal or in a dream (S. d.) Nausea or abdominal stress (S. d.) Mean surn of DSM-IV physical symptom ratings' ( S d )

Mean intensity of DSM-IV ~ a n k attack coanitive

Fear of dying (S. d.) Fear of going crazy or losing control (S. d.) Mean sum of DSM-IV cognitive symptom ntingsb (S. d.)

Sensation of panic or fear (S. d.) Degree of safety kite (S. d.) Degree of conbol feltd (S. d.) Mean no. of non-catastrophii thought,' (S. d.) Mean no. of catastrophic thouphts - - . (S. d.) (21 ) (1 .T)

Mean no. of DSM-IV panic atbck symptoms (S. d.) Mean surn of DSM-IV panic attack m d o m n t i m d

7.1 9 4.81 3.31 (ôû) < 0.01 (298) 328 19.6 -3.1 5 (601 0.01 - . - . .

(s.d.) (1 8.6) (1 3.9) ' Analyzed using Student's t test un las otharvvise i8ted " Analyzed using Fisher's exact t e "' Analyzed using Wekh's modiiied t t r d

DSQ symptoms are nteâ O = not no- r t ail; 1 ; 2 = digMly feR 3; 4 = modentely falt; 5; 6 = strongly fdt; 7; 8 = very rtrongly feiî; lntensity ratings of DSM-IV p rnk albck symptoms from th. DSQ m r e summed to give an overall index of symptom sevtrity ' Degree of safety feit k nted O = not rt rII ufe; 1; 2 - rlbhtty 881.; 3; 4 - qua8 me; 5; 6 = vrry d e ; 7; 8 = compietely sale ' Degree of contralis ratad O = no control; 1; 2 - sll@t conW: 3; 4 = modmto conbol; 5; 6 = much tontrol; 7; 6 = total controt

Non-catastrophic and catastrophit thoughts u e in rrrponu to DSMlV prnic atbck symptomr experienced and tharefor. ruorded only if at lcast 1 DSM-IV pank lttrck rymptom w88 r.poR.d

Table 3-30 shows subjective responses to carbon diofide inhalation compared to those of air

inhalation. The increase in the number of DSM-IV panic symptoms after C a inhalation

compared to air was greater for MCS subjects than for controls. The increase in the surn of

physical and cognitive DSM-N symptom severity ratbgs after C a inhalation compared to air

was also greater for MCS subjects than for controls. The increase in the sensation of panic was

greater among MCS subjects than controls. There were no significant differences between

groups regarding changes in the degree of safety or wntrol felt during the inhalation. There were

aiso no signifïcant differences between groups regarding changes in the number of non-

catastrophic thoughts when they fist noticed their panic symptoms. However, among MCS

subjects, the increase in the number of caîastrophic thougbts upon notice of their panic symptoms

during CO2 inhalation compared to air was significantly greater than controls.

Table 3-30. Subjective Responses Comparing 35% Carbon Dioxide to Air Inhalation Between MCS and Control Subjeds

MCS Control - P-valuea &I = 31) (n = 31)

CO3 - Air

Mean Subjective Units of Oiscomfoft raüng ( s d ) 23.00 (28.86)

Mean sum of DSM-IV physical symptom ratingc 26.7 (1 5.9) (S. d.) Mean sum of DSM-IV cognitive syrnptom ratingC 3.4 (3.5) (S. d.)

Mean no. of DSM-IV panic attacic symptorns (sd.) 5.7 (3.0)

Mean sensation of panic or fear (s.d.) Mean degree of safety feItQ (s-d.) Mean degree of control felte (SA)

Mean no. of non-catastrophic thoughtsr (s-d.) -1.9 (1.6) - -

Mean no. of catastrophic thoughts -(s.d.) 3.7 (118) - 2.1 (1 .7 j < 0.05

a Analyzed using Student's f test unless otherwise stated Analyzed using Welch's modifia f test DSM-IV symptoms were rated O = not noticed at all; 1; 2 = slightly felt: 3; 4 = moderately felt; 5; 6 =

strongly felt; 7; 8 = very strongly feft; Intensity ratings of DSM-IV panic attack symptoms from the DSQ were summed to give an overall index of symptom sevefity;

Table 3-30 ICont'd)

' Degree of safety felt was mted O = not a l a l safe; 1 ; 2 = sliihüy safe: 3; 4 = quite safe; 5; 6 = very safe; 7; 8 = completely safe; data not obtained from al1 participants Degree of control was rated O = no control; 1; 2 = sJiiM control; 3; 4 = moderate control; 5; 6 = rnuch

control; 7; 8 = total control; data not obtained from al1 participants I Non-catastrophic and catastmphic thoughts were in respnse to DSM-IV panic attack symptorns experienced and therefore recorded only if at least 1 DSM-IV panic attack symptom was reportecl

3.18 Effect of Age, Gender, Employrnent Staîus, and Psychological Questiomaire Scores

Among controls, there were no signifiant dierences in any pre-visit self-report

psychoio~cai questionnaire scores, illness or symptom history amoag those who fbWied paaic

attack cntena foliowing 35% C G 1 65% OZ inhalation and those who did not (Table 3-3 1).

Table 3-31. Effect of Self-Report Psychological Symptom Scores and Gender on Panic Outcome after 35% C a Inhalation in Controls

Panic No Panic t @O pvalue* (N = 8) (N = 23)

Mean age 42.6 30.7 -2.38 (29) 0.02

Mobiiity lnventory (Accompanied) (S. d.) Mo bility lnventory (Alone) (S. d.) DASS: Stress (S. d.) DASS: Anxiety (S. d.) DASS: Depression (S. d.) Mean no. panic attacksa (S. d.) Agoraphobie Cognitions Questionnaire (S. d.) Anxiety Sensitivity Index (S. d.)

No. males (%) No. females (016)

Mean no. of illnessesb (S. d.) Mean no. ongoing symptoms

Table 3-31 Gont 'a

' Analyzed using Student's t test unless othefwise stated " Analyzed using Welch's modified t test " Analyzed using Fisher's exad test a Represents the number of unexpected or expeded panic attadrs in the month preceding the visit

Nurnber of illnesses in the past two years from the Heaith and Demographics Questionnaire

However, among MCS subjeds (Table 3-32), those who fùllilled panic attack criteria foliowing

35% CO2 / 65% OZ inhalation scored significantly higher on the ASI, DASS depression scale, and

MI - AIone than those who did not. Furthemore those who tiillifled panic attack cnteria

following 35% COz / 65% 02 inhalation reported significantly more unexpected or expected

panic attacks in the month preceding their visit than those who did not. MCS subjects who

filfilied and did not fÙKi panic criteria foiiowing carbon dioxide inhalation did not differ

signi ficantly in illness or symptom history, or environmental sensitivities.

Among controls, 5 of 10 males and 3 of 21 fernales fblffled panic attack critena afker

3 5% CO2 / 65% O2 inhalation. Among MCS subjects, 5 of7 males and 17 of 24 females fûlfded

panic attack criteria There were no significant differences in the proportion of males and

femaies that tùlfilled panic attack criteria after carbon dioxide inhalation in either the MCS or

control group.

MCS subjects and controls that completed the gas inhalations were of comparable age

ranges, 18-56 years in controls and 21-58 yean in MCS subjects. Among MCS subjects, there

was no significant differences in age between those who niifilled paaic attack criteria after 35%

CO2 / 65% O2 inhalation and those who did not (Table 3-32). However, among controls (Table

3-3 1), those who fûlfiiied panic attack cnteria afker 35% C a / 65% 0 2 inhalation were

significantly older (mean age 42.6 years) vernis those who did not fuüiii panic attack cnteria

(mean age 30.7 years). Logistic regression indicated no significant efféct of age @=0.29),

ernployment status (@.21), or panic history (p4.38) on panic outcome with group in the model.

Excluding individuais with a panic history d resulted in signifïcant Merences between MCS

and controls in panic outcome foiiowing C a @<0.01, ET).

Table 3-32. Differences in Self-Report Psychological Symplom Scores and Gender in MCS Subjeds Fulfilling and not Fulfilling Panic Criteria after C a Inhalation

Panic No Panic t (dl) pvalue* (hi = 22) (N = 9)

Mean age 40.4 44.8 1.1 1 (29) 0.28 (S. d.) (9.9) (1 0.4)

Mobility lnventory (Accompanied) (S. d.) Mo bitity lnventory (Alone) (S. d.) DASS: Stress (S. d.) DASS: Anxiety (S. d.) DASS: Depression (S. d.) Mean no. panic attacks' (S. d.) Agoraphobic Cognitions Questionnaire (S. d.) Anxiety Sensitivity Index (S. d.)

No. males (%) No. females (%)

Mean no. of illnessesb (S. d.) Mean no. ongoing symptoms (S. d.)

Mean duration of MCS (years) (S. d.)

% reporting sensitivity to airborne substances % re po rting sensitivity to ingested substances % reporting sensith& to tadile substances S.6 66.7 0.70-

* Analyzed using Student's t test unless otherwis8 stated " Analyzed using Welch's modified t test, " Analyzed using Fisher's exad test

*

Represents the number of unexpeded or expeded panic attacks in the month precedirig the visit Number of illnesses in the past two yeaan from the Maith and Demographia Questionnaire

3.19 Differences in Panic Symptomatology, Physiologie Responses, and MCS Symptomatology -

Between Panickers and Non-Panickers

Table 3-33 shows physiological responses and pank symptomatology in MCS subjects

who fulfilled panic criteria foiiowing C a (panickers) as compared to those who did not (non-

panickers). MCS panickers and non-panickers did not ciiffer signifiicantiy with respect to changes

in breathing rate, M V or HR- However, MCS panickers reported a significant decrease in the

degree of safety felt during C a inhalation compared to non-panickers (Student's t, p e 0.0 1).

There were no significant dserences between panickers and non-panickers regardhg changes in

the degree of control they felt or the number of non-catastrophic thoughts they had when they

noticed their inhalation-provoked symptoms. ' However, MCS panickers subjects reported a

significantly greater increase in the number of catastrophic thoughts they had when they noticed

their symptoms compared to non-panickers (Student's t, p < 0.00 1).

Table 3-33. Physiological and Subjective Parameten between MCS Panickers and Non-Panickers

Phvsioloaical Resoonses (AC07 - bAir) Breathing rate (breaths / minute) (S. d.) Minute ventilation (L / min.) (S. d.) Heart rate (beats / min.) (S. d.)

Subiective Resoonses (AC09 - Mi0 Subjective units of discornfort (S. d.) Mean degree of safety felt8 (S. d.) Mean degree of control feltb (S. d.) Mean no. of non-catastrophic thoughtsC (S. d.) Mean no. of catastrophic thoughts

Non- Panickers (N = 9)

2.78 (9 -38) 5.80 (9.1 2) 1 . la (1 0.27)

6 . S (1 2.82) -1 -3 (1 -8) -2.2 (1.8) -2.0 (1 -1) 1.7 (0.81

pvalue'

Table 3-33 (Cont'a

' Analyzed using Student's t tesi unlm olherwb. -ad " Analyzed using Wdth's modMmd t ted

Degree of safety hlt was rated O = not at 811 d e ; 1 ; 2 = dgMy We; 3; 4 = quite d.; 5; 6 - very d e ; R 8 = compfoteiy rrfe Degree of controt was rated O = no conbol; 1; 2 Gslighî control; 3; 4 = modemte conbd; 5; 6 = much conbol; 7; 8 = tdal control Non-catastrophic and catastrophk thoughb nnre in nrponw to DSM-N prnic atWk 8ymptom expefienced and therefore

recorded only if at least 1 DSM-iV plnk dtdt symptom nnr nported

Table 3-34 shows physiological responses and panic symtomatology in controls who

hl filled panic cnteria foliowing C a compared to non-panickers. There were no significant

differences in the change in any physiological parameter between controls who panicked and

those who did not Patiickers and non-panickers did not differ significantly with respect to

changes in the degree of safety or control felt during C a inhalation There were also no

significant differences between panickers and non-panickers regarding changes in the number of

non-catastrophic thoughts they had when they noticed theu inhalation-provoked syrnptoms.

However, panickers reported a significantly greater hcrease in the number of catastrophic

thoughts they had when they noticed their symptoms compared to non-panickers (Student's t, p <

Table 3-34. Physiological and Subjective Parameters between Coritrol Panickers and Non-Panickers

Phvsioloaical Res~onses (AC& - Mir') Breathing rate (breaths / minute) (S. d.) Minute ventilation (L / min,) (S. d.) Heart rate (beats 1 min,) (S. d.)

Subiective Res~onses (ACO:, - bAir) Subjective units of discornfort (S. d.) Mean degree of safety fe(ta (S. d.) Mean degree of control feltb (S. d.) Mean no. of non-catastrophic thoughtst (S. d.) Mean no. of catastrophic thoughts

Panickers

(N = 8)

2.25 (3.37) 5.63 (6.60) 2.57 (5.26)

23.1 3 (1 8.63) -3.4 (2.7) -4.0 (2.1) -2.3 (1 -8) 3.2 (1 -9)

Non- Panicken (N = 23)

3.21 (6.4) 7.42 (8-67) 6.33 (1 3.43)

15.96 - (1 7.67) -2.0 (2) -2.9 (2-3) -1.6 (1 -4) 1 -4 (1 -1)

pvalue*

Analyzed &ng Student's t test unlwf othemise stateâ " Anatyzed using Wekh's rnodiied t test

~ e ~ r e e cf safeG hft was mted O = not at dl safe; 1; 2 = 85gMly mk; 3; 4 = quite safe; 5; 6 = very sale; 7; 8 = completely sale ' Degree of conbol was rated O = no conbol; 1; 2 = süght control; 3; 4 = moderato conbol; 5; 6 = much control; 7; 8 = total control ' Noncatastrophic and cahdrophic thoughts were in raponre to DSM-N pin& att8ck symptoms experienced and therefore recorded only if at least 1 DSM-IV pank attlck symptom was reportai

3.20 Effect of Recruitment Source on Responses to 35% COt in Oxygen -

As shown in Table 3-35, there were no significant differences between MCS abjects

recruited fiom clinical practice and those recniited by advertisement in the proportion fblfdling

panic attack critena aAer 35% carbon dioxide inhalation Similarly, there were no significant

differences between these sources in the change in breathing rate, minute ventilation, heart rate or

subjective units of discomfort foilowing carbon dioxide inhalation There were no significant

differences in reporting of DSM-IV panic attack Jymptoms, degree of safety or control felt,

sensation of panic, or number of non-catastrophic or catastrophic thoughts between the two

sources.

Table 3-35-3556 Carbon Dioxide Challenge Parameten in MCS Subjeds Recruited from Two Sources

Reçniited by Recntited fiom t (dl) pvalue* WueRisement dinical pmctice ( N t 17) (N = 14)

No. of subjeds fulfilling panic attack 12 (70.6%) 1 O (71.4%) 1 .OO" criteria after 35% C a inhalation

Phvsioloaical aram met ers (oost - ~ r e )

Breathirig rate (breaths / minute) 4.04 2.92 0.52 (24) 0.61 (S. d.) (9.82) (6.27)

Minute ventilation (L / minute) 6.06 3.80 0.96 (16) 0.35" (s- d.) (3.63) (7-37)

Heart rate (beats / minute) 9.31 6.1 5 0.91 (27) 0.39 (S. d.) (1 0.92) (7.81)

Subjective uni& of discornfort 24.41 29.29 -0.44 (27) 0.66 (S. d.) (29.75) (31 3)

Mean sum of DSM-IV physical symptom 26.71 32.71 -1 .O4 (29) 0.31 ratings (1 8.28) (1 2.64) (S. d.)

Mean sum of DSM-IV cognitive 2.65 4.32 -1.28(20) 0.21- symptom ratings (2.48) (4.34) (S. d.)

Mean no. of DSM-IV panic attack 6.82 7.64 -0.76(29) 0.46 symptoms (3.54) (2- 1 7) (S. ci.)

Sensation of panic or fear 3.41 4.64 -1 -1 4 (29) 0.27 (S. d.) (3.12) (2.84)

Degree of safety felt (S. d.)

Degree of control felt (S. d.)

Mean no. of non-catastrophic thoughts 1 .O6 1 .O0 0.14 (29) 0.89 (S. d.) (1 -34) (0.88)

Mean no. of catastrophic thoughts 3.41 3.93 -0.68 (29) 0.50 (S. d.) (2.29) (1 -86)

' Analyzed using Student's t test unless othenMse stated " Anal yzed using Fisher's exact test; -Analyzed using Welch's modifieci f test

3.2 1 Results fiom Five MCS Patients who received the Challenges in the Reverse Order -

Five additional MCS subjects receivd the gases in the gases in the reverse order, namely,

35% carbon dioxide in oxygen fira and compressed air second. No subject filfilied panic attack

cnteria after a i . inhalation Three of the five subjects (60%) fuEiIed panic attack critena in

response to 35% carbon dioxide in oxygen inhalation

3 -22 Resuits f?om Four MCS Patients who received an Air / Air Sequence

A fùrther four MCS subjects received cornpresseci air foiiowed by another M a t i o n of

compressed air, rather than 35% carbon dioxide in oxygen None of the four subjects fiilfüled

panic attack criteria d e r either inhalation of compressed air.

3.23 Structured Clinical Interviews for Major DSM-N Disorders

Twelve of 21 MCS subjects who received the SCID for the DSM-N tiilfiiied critena for

one or more of the foliowing disorders: specific or social phobia, panic disorder, major depressive

disorder, generalued anxiety disorder, past major depressive episode, or pst-traumatic stress

disorder. In an additional three subjects, the interviewhg clinician suggested a diagnosis of

undifferentiated somatoform disorder if the participant's environmental sensitivities are not

accounted for by a recognized condition or if the impairment is found to be in excess of what

would be expected. Six subjects did not fulfill DSM-N critena for any principal or additional

clinical diagnoses. Results of the SCID-IV are summarized in Table 3-36.

Seventeen of the 21 MCS subjects who underwent the SCID-IV were among those who

completed the gas inhalations (air fkst, carbon dioxide second). AU except one Mfdied criteria

for a panic attack foiiowing 3 5% C a in 65% oxygen M a t i o n This individual did not meet

DSM-N cnteria for any cumnt or past diagnoses Ofthe 16 individuals who W e d panic

attack criteria, 12 met either current or past DSM-IV criteria for one or more of the disorders

listed in Table 3-36. The remaining four subjects did not meet criteria for any current or past

DSM-lV diagnoses.

Table 3-36. Current end Past Psychiabic Findings in 21 MCS Subjects

DSM-IV Diagnosis Number of diagnoses made

Cunent

Specific phobia 4 Social phobia 3 Panic disorder 2 Post-traumatic stress disorder Generalized anxiety disorder 2 Major depressive disorder 2 Possible undifferentiated sornatoform disorder 3

Past - Major depressive episode 6

* Some subjects were diagnosed with more that one disorder

Chapter 4: Discussion

Multiple chemical sensitivity (MCS) is the subject of intense speculation and controversy

with regards to its etiology, diagnosis, and treatment. Many MCS patients are active in seeking

compensation for what they believe to be a work-relateci illness. The regance of many patients on

alternative health care practitioners who often employ unconventional and unproven diagnostic

and treatment techniques has often lefi sufferers isolated h m fiends and farnily.

The overlap in symptoms between MCS and panic disorder (PD) patients prornpted us to

shidy of the responses of MCS patients to carbon dioxide inhalation. We postulated that some

MCS patients might exhibit features of pauic disorder, which has become paired with non-

noxious environmental stimuli. MCS and PD patients may respond similarly to a panic induction

challenge.

Single-breath 35% carbon dioxide inhalation has beni shown to be a safe, nominvasive

trigger of laboratory-induced panic (27). The 35% C a induced state of panic has been

descnbed to be similar to spontaneous panic attack by PD patients (26). indicating good symptom

convergence. 35% CO2 has adequate specificity and there appean to be a specific vulnerability

of PD patients (89) and social phobics with a history of panic attacks (90) to 35% CO2. Single

breath 35% COz inhalation üas been shown to elicit a panic attack in 48%-92% of individuals

diagnosed with PD and 14% of controls (26,2728.29). Akhough the carbon dioxide inhalation

test is not necessarily diagnostic of panic disorder, a panic response may be indicative of an

underlying diathesis consistent with panic disorder.

Anticipatory anxiety or the worry about having a panic cpide, and anxiety seasitivity

are considered key features of panic disorder (71). Panic disorder is o h linked to .agoraphobia

which is the fear of being in places or situations h m which escape rnight be dficult (or

embarrassing) or in which help might not be available in the event of a panic attack (18).

The analysis of demographic variables in this study dernonstrate tbat MCS patients are

generally, wetl-educated women in their forties, consistent with previous reports (4,6,14). The

overall significant differences in curent employment status were most likely due to the large

proportion of students that comprised the control group. Therefore, any conclusions made with

regards to the employment status of MCS patients m u t be made with caution given that an age-

matched control group was not used in this study.

MCS patients reported more health problems and ongoing symptoms compared to

controls. Medication use was more prevalent among MCS patients, specificaily with respect to

over-the-counter medications nich as vitamins and herbal remedies. MCS patients also utilized

chiropractors and massage therapists to a greater degret than controls. In addition, the majority

reported following special diets. These results may reflect an increased tendency to subscribe to

alternative forms of health care arnong MCS patients and possibly a shift in health care utilization

away korn conventionai medicine among MCS patients.

Approximately half of MCS patients identified a precipitating event responsible for their

symptoms. A workplace exposure was most ofien impücatd The rest indicated that theu

symptoms developed graduaily over tirne. The latter hding militates against the use of Cullen's

cntena (8) to diagnose MCS because in the case of some patients, a precipitating exposure event

could not be identified. For the most part, MCS patients reported îhat enviro~mental triggers

were almost ubiquitous, appearing in public places, the workplace, outside, and even at home.

AImost al1 MCS patients reporteci aversions to substances detected in the air, particularly

automotive exhaust and perfùmes. Sensitivity to a heterogeneous gmup of airborne substances is

consistent with prevïous descriptions of this patient group (3.8).

It is likely that the MCS study subjects were not representative of the more severe cases of

this condition since such patients may be unlikely to venture into urban centers. Although more

MCS patients than controls reported some degree of impairment or dissatisfaction in various

aspects of life, the inclusion criteria, outlined by Simon et al. (4), are somewhat liberal.

Specifically, MCS patients were not screened accordhg to the degree of liféstyle impainnent, a

construct that may be important in differentiating MCS SUfferers fiom people who are merely

environmentally intolerant Nevertheless, the heterogeneous nature of environmental triggen and

reported symptoms in the MCS subjects in this study are consistent with previous descriptions

(3), suggesting that the MCS patients investigated in this study were symptomatologically similar

to patients previously charactenzed as having MCS (3) rather than individuals who are merely

offended by noxious odors. The fact that controls were recruited exclusively h m a similar

setting (area hospitals) to MCS subjects suggests that the two groups arose from a similar base

population.

Eighteen of the MCS subjects were recniited by advertisement. No attempt was made to

ascertain whether or not these individuals had undergone a sufticient previous medical evaluation

to reasonably exclude organic c a w s of their symptoms. The remaining 18 subjects were

recruited either from the study physicians or fkom a participation List of a previous study carried

out at the University of Toronto. These individuals had undergone a medical evaluation and

possible pathological causes of their ~ymptoms were d e d out.

MCS subjects recruited by advertisement did not di& significantly fiom subjects

recniited fiom c l in id practice with respect to the number of reported illnesses. However,

subjects recruited fiom clinical practice were found to have a significantly greater number of

ongoing symptoms experienced compared to individuals recniited by advertisement. MCS

subjects fÎom the two sources dso did not dBér significantiy with respect to the number or type

of environmentaktriggers. Psychologicai scores between MCS subjects recruited h m clinical

practice and subjects recruited by advertisement did not dina significantly. Twelve of the 17

MCS subjects recruited fkom advertisement and 10 of the 14 MCS subjects recruited fiom clinical

practice fulfilled panic attack criteria after 35% CO2 / 65% Oz inhalation. The groups did not

differ significantly with respect to the proportions fulnlling panic attack criteria, number of

DSM-IV panic attack symptoms or sum of syrnptom seventy ratings. In Light of these kdings,

recruitment source is unlikely to have introduced a bias.

MCS patients scored signincantly higher than controls on standard self-report

questionnaires measuring anxiety, stress, agoraphobia, anxiety sensitivity, and marginally h i e

on a measure of depression. MCS subject score on the Depression, Anxiety, and Stress sections

of the DASS were lower than those previously reportcd for panic disorder patients but were

consistent with those reported in patients with simple phobias (77).

107

The finding that MCS patients scored significantly h i g k than wntrols on the Mobility

hventory (MI) for Agoraphobia suggests increased avoidance of common agoraphobic situations

in these individuals. However, MCS scores on the MI wcre lower than those report4 elsewhere

for agoraphobic outpatients (91).

Elevated scores on the Anxiety Sensitivïty Index (MI) among MCS patients compared to

controls suggest an increased tendency to fear anxiety-related physical sensations. Although AS1

scores in MCS patients as a group were consistent with those reported for a non-dinical

population (92,93), the mean AS1 score of MCS panickers was consistent with those previously

reported in social phobics (81). Elevated scores on the AS1 among MCS patients who fulnlled

panic critena after C G inhalation suggest an increased tendency to fear anxiety-related physical

sensations (74) in this subset of MCS patients. The mean AS1 score in controls who M i l e d

panic cntena aAer COz was sub-clinical(93). This suggests that high aflxiety sensitivity is

associated with laboratory-provoked panic in MCS subjects. In a number of studies, high anxiety

sensitivity has been found to be a predictor of subjective reporting of physical symptoms in

response to hyperventilation (94,95,96,97) even in the absence of a history of panic (94). An

interesting theoretical speculation concerning anxiety sensitivity is that it may be a predisposing

factor in the development of anxiety disorders (74). Anxiety sensitivity has been found to be a

predictor of hypochondriacal concems ranging fiom disease phobias to bodily preoccupations in

patients with panic disorder (98) and major depression (99). Anxiety sensitivity is considered to

be a central feature of PD (72) and has been shown to distinguish individuals with PD h m other

clinical and non-chical groups (94). The hding of high anxiety sensitivity among MCS

subjects who fulfilled panic criteria following the carbon dioxide challenge lends support to the

hypothesis that PD is a feature in at least some individuals with MCS.

Significantly higher scores on the Agoraphobic Cognitions Questiomaire &O aggest an

increased tendency to fear anxiety-refated bodily sensations amon8 MCS subjects compared to

controls. Again, the scores were Lower than those reported for a clinical sampfe of agoraphobies

(72). Although MCS patients appeared to differ nom othecwise healthy controh on a number of

psychological measures, it must be emphasized that these scores were al1 below what would be

expected for a clinical psychiatrie population. These findings may be interpreted in one of two

ways. On measures of agoraphobia, depression, stress and atlxiety, MCS patients may represent a

group with morbidity significantly higher than a non-clinical population but less than what would

be expected for a clinical population. Altematively, the control abjects participating in this

study may have understated their psychological morbidity, leading to self-report scores at the

lower end of the normal range.

Their appeared to be no differences in illness history or MCS symptomatology between

MCS subjects who fùlfüled panic cnteria following carbon dioxide inhalation and those who did

not. However, the number of panic attacks reported by MCS panickers was significantly greater

than non-panickers. This suggests that the response to carbon dioxide inhalation was independent

of illness history and environmental sensitivities but related to a history of panic attacks.

Other potential confounding sources include age, given that panickers were significantly

older than non-panickers in the control group and MCS subjects were significantly older than

controls. In addition, employment status might have influenceci panic outcorne, gïven that most

controls were students and most MCS subjects were employed. However, the fact that neither

employment status nor age explahed a significant amount of the variance in panic outcome over

and above that of group on regression analyses suggests that these parameters were not actual -

confounding variables.

No controis and one MCS subject fùifïlled criteria for a panic attack following air

inhalation. This subject also fultilled plaic criteria foUowing 35% carbon dioxide inhalation.

This individual was later found to meet criteria for a past diagnosis of panic disorder. In response

to 35% CO2 in oxygen, almost three tiines as many MCS patients fulfilled criteria for a panic

attack than controls, despite the fact that controls, on average, inhaled more 3 5% CO2 as a

percentage of theû vital capacity. Physiological responses to 35% COÎ in oxygen challenge

between MCS patients and controls were not significantly dflerent when compared to air

inhalation Moreover, within a group, physiological responses between panickers and non-

panickers were not significantly different. However, in both MCS subjects and controls,

panickers exhib ited a greater degree of subjective panic sy mptomatology than non-panickers.

The finding that significantly more MCS patients fiilfilled panic attack criteria suggests that a

greater proportion of them interpreted their physical symptoms as more catastrophic, a finding

consistent with the increased number of catastrophic thoughts reported after CO2 inhalation

among panickers. A similar phenornenon was observed by Margraf et al. (100) in which

physiological responses of pmic patients and normal controls were similar in response to lactate

infusion, however, the groups differed in terms of their seWreported fear responses (100).

The high rate of panic ammg controis in this study (26%) contrasts with that of 14% in

previous reports (27.29). This might be explainad by out novel use of a mouthpiece and noseclip

directly in line with the demand valve compared to otha studies (27,89) which have used a mask.

It is possible that by using a mouthpiece, the C a may have haâ more direct contact with the

airways, and the elevated rate of panic may have been partiy owing to a mild imtant effect of the

gas over and above that of hypercarbia One option to overcome this shortcoming was to use the

lactate infusion to provoke panic, however aven that invasiveness of the procedure, it was felt

that few MCS patients would consent. Our relatively high rate of panic among controls might

also be explained by our use of less conservative panic attack cnteria compared to other studies

(29) which have used a visual analogue scale where the abject gave a rating of his/her global

feeling of anxiety in addition to the criteria used in our study.

From the results of the SCID-IV, over half of the MCS patients W l l e d cumnt or past

DSM-IV criteria for an anxiety or mood disorder. This is especiay noteworthy since none had

received a psychiatric diagnosis in the past. The most fiequent cumnt diagnoses were specific or

social phobias. Counterintuitive to the hypothesis that PD is a feature of MCS, few MCS patients

filfilled criteria for panic disorder. This hding is consistent with the sub-clinical scores on

psychological questiomaires but inconsistent with results of the 35% C a challenge. Many

symptoms reported by MCS patients in response to purporteci environmental triggers are similar

to those reported by PD patients. It is possible that some MCS patients may exhibit features of

PD but the expected nature of their attacks, being temporally related to environmental triggers

such as odors, precludes a formal clinical diagnosis of PD (18).

Limitations of this work include its single-blinded nature and non-randomization of the

order of gases. Although several a u t h have performed similv challenges in a random order

(27,89,101), others contend that when Ca was administercd first, subjects are on occasion,

reluctant to undergo another inhalation (8 1). This study was unable to corroborate this fhding in

that a11 five of the additional MCS patients who received the 35% carbon dioxide first were

willing to comply with the study protocol. This suggests that it would be feasible to randomize

the order of gases in future work using 35% carbon dioxide as a pauic provoking agent. The fact

that CO2 was aiways given second may have introduced a bias if MCS subjects were more likely

than controls to react to a second challenge irrespective of its nature. However, the finding that

none of the four MCS subjects reacted on the second challenge of the &/air sequence suggats

that an order effect was unlikely to have inîroduced bias.

Carbon dioxide mixtures often have a marked taste and it can be argued that the response

of MCS patients was merely consistent with their envim~mentai sensitivities to odors/tastes,

rather than to inhaled carbon dioxide. However, unlike their symptoms triggered by chemicais

foreign to the body, the carbon dioxide inhalation represented a high level of a normal

physiological constituent. If the subjects were, in fact, suspected to be "chernically sensitive" to

carbon dioxide, it can be argueci that their response to an inhaled chernical trigger, Le. carbon

dioxide, was consistent with that of a panic attack. A lower concentration of carbon dioxide, for

example, 5.5% has not been reporteci to have a taste. Howcver, protocols using this concentration

involved the subject breathing the mixture for at least fifieen minutes (8 l), and would requin

using an odorous disiriratant, which may not have been tolerated by MCS patients. A usefbl

strategy in friture studies would be to mask the taste of the 35% C a challenge, however, this

112

masker would necessitate ruiing out MCS subjects with a seasitivity to it. Moreover, a masker

may not be able to overcome the imitant effects of the &onic acid which is produced on the

mucus membrane by inhded carbon dioxide. Another caution in interpreting the results of the

35% carbon dioxide inhalation is that the amount of inhaled carbon dioxide was not actually

measured but rather estimated fiom the inspiratory vital capacity. Using this estimate, the

exposure to carbon dioxide was on average less in the MCS group than in the controls. In other

words, MCS subjects on average, Mfrlled panic criteria in response to less inhaled carbon

dioxide than controls, suggestive of a tendency to be overly sensitive to the effects of carbon

dioxide inhalation among these patients compared to controls.

Although much of the questionnaire data used ordinal scales, which could have warranted

the use of non-pararneuic tests of significance, previous studies have treated this data as

continuous in their analyses and for that reason, parametric tests were employed in this study

(8 1,92).

Future research directions stemming from this work depend largely on being able to

replicate these fmdings in a randomized fashion, with a patient's provocative agent possibly

supplanting carbon dioxide gas. The finding that MCS patients respond similarly to a 35%

carbon dioxide inhalation indicate a rationale for intervention studies to assess components of

panic disorder management in patients with symptoms suggestive of MCS with feahires of panic

disorder.

In conclusion, this study has s h o w tbat MCS patients reported a p a t e r number of heaith

problems and ongoing symptoms than otherwise heaithy control abjects. MCS patients scored

higher on self-report measures of agoraphobic avoidance, anxiety, stress, and anxiety sensitivity

than do otherwise healthy controls. However, these scores were iower than those reported in

clinical samples. Among MCS subjects who fiifiiled panic criteria but not controls, high anxiety

sensitivity, consistent with that of anxiety disorder patients, appears to be a feature. MCS

patients fuifïlled panic attack cnteria more fiequentiy than did controls in response to a carbon

dioxide inhalation challenge. The response to carbon dioxide inhalation is suggestive of a

tendency to over-report and possibly catastrophicaiiy misinterpret physical symptoms among

patients with MCS, the latter has been a consistent fhding among patients with PD (72,74).

Findings of high anxiety sensitivity and a panic response to carbon dioxide inhalation are

consistent with the hypothesis that MCS shares an underlyïng diathesis similar with ifnot

identical to PD.

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65. Bolla-Wilson K., Wilson R and M. Bleecker (1988) Conditionin? of Phvsical Sym~toms After Neurotoxic Emosure. J. Occup. Med. 30:684

66. Braveman N. et al (1985) Eds. Furperimentul Assesmerats und Clinical Appiicatiom of Condirioned Food Aversions. New York: NYAS

67. Doty R., Deems D., Frye R, Pelberg R and A. Shapiro (1988) Qlfactorv Sensitivitv. Nasal ic Function in Patients ~ i t h Multide C Resistance. and Autonom hemical Sensivitiq. Arch.

Otolaryngol. Head Neck Surg. 1 14: 1422

68. Shusterman D. and S. Dager (1 99 1) nevention of Psvcholonical Disabilitv After Occu~ational Remiratorv E x m s m . Occupational Md.: State of the Art Reviews 6: 1 1

69. First M., Spitzer R, Gibbon M. and J. Williams. Stnictured Clinical h t e ~ e w for DSM-N . . Axis 1 Disorders-Patient FditlgD (SCID-VP Vers. 2.0). (1 996) New York: Biometrics Research Dept., New York State Psychiatric k t .

70. Williams J., Gibbon M., First M., Spitzer R, Davies M., Bonis J., Howes M., Kane J., Pope . . H., Rounsaville B. and H. Wittchen. The Structured C b c a l Intedew for DSM - IïI - R (SCID): II. Multisite test-retest reliability. Arch. Gen. Psychiatry (1992) 49:630

7 1. Shear M. and J. Maser. -dard A s s w e n t for Panic Disorder Research: A Conference Reoort. Arch. Gen. Psychiatry (1 994) 5 1 :346

72. Chambless D., Caputo G., Bright P. and R Gdagher. -t of 66 fem off eaf' in A e o r a ~ g e m h o b i c qOPEaphobicoenihoi\~ . . Ouestionnaire. J. Consult, Clin. Psychol. (1984) 52:1090

73. Peterson R and S. Reiss. Test for the &&$v Sensibvitv Inda .. . . (1987) Orland Park, IL: International Diagnostic Systems.

74. Reiss, S., Peterson, R, Gursky, D. and R. McNally (1986) hx ie tv Sens - . itivitv. Anxietv Freauencv and the Predicbon of Fcarfiilnq. Behav. R a . Ther. 24: 1

75. Peterson R. (1987) Th .. vi tu l n b Fact r Analvtic e Anie& Sensitt Structure. J. Anxieîy Dis. 1 : 1 17

76. Lovibond P. and S. Lovibond. me Stmchuc ofNeggjîive Emotional States: Cornnarison of

~nventones. Behav. Res. Ther. (1995) 33:335

77. Brown T., Chorpita B., Korotitsch W. and D. Barlow. P j p. Behav. Res. Ther. (1 997) 3579

78. Antony, M., Bieling, P., Cox, B., Enns, M. and R Swinson (1998) P p the 42-item and 21-item Versions of the Deoression - m e t v Stress Scales (DASSI in Clinical Grou~s and a Communitv Samie. Psychological Assesment. 10: 176

79. Charnbless D., Caputo G., Jasin S., Gracely E. and C. Williams. The Mobilitv Inventorv for Aeora~hobia. Behav. Res. Ther. (1985) 23:35

80. Broder, I., Tarlo, S., Binkley, S. and P. Corey (1994) 331 . . . -e Dia-mosis of Environmental H-mersensitwty. Contract reported to the Ontario Ministry of Health, Canada. Contract No. H4078-2-C646/Ol -SS

8 1 . Rapee R., Brown T., Antony M. and D. Barlow. ft . . eswnse to H y y n of 5.5% Carbon Dioxide - Enrïched Air across the DSM - III - R 'etv Disordm J. Abnormal Psychol. (1992) 101538

82. Wolpe J. The Practice of Behaviour Therapy, 3rd ed. (1982) Pergamon Press Inc.: New York. pp. 141

. . 83. Griez E. and M. van den Hout. Effects of Carbon n i o x r d e - u u e

Anxiee and Some Newove~ative P-etm. J. Behav. Ther. & Exp. Psychiat. (1982) 13(1):27

. . 84. Ley R. Anora~hobia. the Panic Attack m d the Hy~eivenhlation Svndrome. Behav. Res.

Ther. (1985) 23:79

85. Amencan 'ïhoracic Society Standardkation of Spiitorne.~ 1994 Updute. Am J Respir Crit Care Med. 152:1107-1136 (1995)

86. G r i a E., Zanbergm S., Pols H. and C. de Loof. mnsc to 35 O /i CQ as a Marker of Paniç in Severe Anxietv. Am. J. Psychiatry (1990) 147:796

87. van den Hout M. and E. Griez. Panic S m ~ t o m s d e r Inhalation of Carbon Dioxida . . Br. J. Psychiatry. (1984) 144:504

88. van den Burgh O., Vandendriessche F., de Broeck K. and K. van de Woestuie. wd - . * icatbilitv

O/ and Perceiveci Control dming 5.5 O Ca-enricheci Air hhalabon in Hiph and Low Anxioug Subiects. J. Anxiety Disorders. (1 993) 7:6 1

89. Gnez, E., de Loo& C., Pols. H., Zandbergen, J. and H. Lousberg (1990) .. - . .

of Patients with Panic Attacks to Carbon Dioxtde Inhalatioq. Psychiat- Res. 3 1 : 193

90. Caldirola, D., Perna, G., Arancio, C., Bertani, A. and L. Bellodi (1997) The 35% CC& % ig, Psychiat. Res. 71:41

9 1. Cox, B., Swinson, R., Kuch, K. and J. Reichman (1993) Dimensions of Agoraphobi% Assessed bv the Mobilitv Inventory. Behav. Res. Ther. 31:427

92. Taylor, S., Koch, W. and R McNally (1 992) fI H e w Anxiety Disorders? J. Anxiety Dis, 6:249

93. P eterson, R. and S. Reiss (1983) Anxietv Sensitivity Index Revised Test Manual. Worthington, OH: IDS Publishing Corporation

94. Domeil, C. and R. McNally (1989) Anxietv Sensitivitv and Historv of Panic as Predictors of Response to Hmerventilation. Behav. Res. Ther. 27:325

95. Sturges, L., Goetsch, V., Ridley, J. and M. Whitîal(1998) *etv Sens . S .

itrvitv and Remonse to ~herventilation Challenge: Phvsiolopic Distress. J. Anxiety Dis. 12: 103

96. Holloway, W. and R McNally (1 987) Effects of Anxiety Sensitivitv on the Remonse to Hnerventilation. J. Abnormal Psychol. 96:330

97. Asmundson, G., Norton, G., Wilson, K. and L. Sandler (1994) s s d . . - . . t Cardiac Reactiitv to Bnef Hybewenblatton in b d b 'tivitv. Behav. Res. Ther. 32: 237

98. Otto, M., Pollack, M., Sachs, G. and J. Rosenbaum (1992) &mchondriacal Concms, &aand J. Anxiety Dis. 6:93

99. Otto, M., Dernopulos, C.. McL- N., PoUack, M. and M. Fava (1998) w t i o n a l Findi- . . . - .. .

an the Association Retween &pie* ~ i h w t v and H-ai Co-inahon . . of Patients with Maior Deptessioq.

100. Mar@¶ J., Ehlers, A. and W. Roth (1986) S o d i ~ ~ o ~ d Panic Attacks: . . Review and CnQauç. Psychosomatic Med. 48:23

101. Goman J., Papp L., Martinez J., Goetz R, Hollander E.. Liebowitz M. and F. Jordan. 0 . Hieh-Dose Carbon Dioxide Challenne Test in Anxiety Disorder Patients. Biol. Psychiat,

(1990) 8:743

re 2-1. Subject Recruitment (healthy controis)

We am condudini a study to leam more about the relaüonship betw~en anxriev and environmental sensiWÎ. The study wiH be perforrned at the Gage Occupationai & Environmental Health Unit at College 8 Ross.

a

It will indude two tests that e a ~ h involve taking a deep breath through a paper mouthpiece. One of these breaths will be nomial rmm air and the other will contain a higher than nomial amount of carbon dioxide, a natural substance nomally produced by your body that is present naturally in the air. Afterwards, we ask that you fiIl out some questionnaires about your feelings and responses-

You will have your heart rate measureâ by a smafl instrument wom on your wrist and chest Your breathing rate wilt be rneasured by breathing into a paper mouthpiece. These tests have been used for many years and are ail safe. They will be performed by qualified techniàans and the entire procedure will take less than 2 hours of your time,

The information collected will be kept confidential. Your participation is voluntary and you have the option at any time of not finishing if you wish.

t have some questions that I need to ask you:

1 ) Are you behveen 18-60 years of age? 2) Have you been taking any medication? 3) Are you currenffy pregnant or lacfating? 4) Are you an asthmatic? 5) Have you ever been diagnosed as having heart problems, migraine. uncontrolled diabetes. uncontrolled hypertension, respiratory problerns or thyroid problems? 6) Do you have wrrent or past seuures? 7) Have you ever been to a psychologist or psychiatrist to help deal with an emotional problem?

8) Do you exparience allergic nose or eye syrnptoms or hayfever?

I now have some questions regarding environmental sensitMty 9) Do you identify yourself as being sensitive to substances in the environment? 1 O) If you have syrnptoms to substances in the environment, what are some of thern? 1 1) How long have you had these symptoms? 12) What things bring about these spptoms? Rule out if l&i2 an, positive

You will receive $30 as compensation for your time and travel costs. 1s there anything you would like to ask me? Can we set up a meeting or would you like some time to think about it?

Please spell your name and give me your address and a telephone number where you can be reached. Please also give me your date of birth. You w l receive a package of questionnaires in the mail and we ask that you fil1 it out and bring it to your visit

W. Patient Recruitment (MCS subjects)

We are mducting a study to kam more about the problem of envimnmental sensiüvity. The information obtained will enhance ouf understanding of why it occurs and h o w !O help people who have it, The study will be performed at the Gage Occupational 8 Environmental Health Unit at College 8 Ross.

It will include two tests that each invdve taking a deep breath through a paper mouthpiece. One of these breaths wil be normal r w m air and the other will contain a higher than normal amount of carbon dioxide. a natural substance n m a l t y produced by your body that is present naturally in the air. Afterwards, we ask that you fiIl out some questionnaires about your feelings and responses.

You will have your heart rate measured by a srnall instrument worn on your wrist and chest, Your breathing rate will be measured by breathing into a paper mouthpiece. These tests have been used for many years and are al1 safe. They will be performed by qualified technicians and the entire procedure wiIl take less than a few hours of your time.

The information collected will be kept confidential. Your participation is voluntary and you have the option at any time of not finishing if you wish-

I have some questions that I need to ask you:

1 ) Are you between Y 8-60 years of age? 2) Have you been taking any medication? 3) Are you cunently pregnant or lactating? 4) Are you an asthmatic? 5) Have you ever been diagnosed as having heart problems, migraine, uncontrolled diabetes. uncontrolled hypertension, respiratory problems. thyroid problems? 6) Have you ever been to a psychologist or psychiatrist to help deal with an emotional problem? 7) Do you have cuvent or past seizures?

l now have some questions regarding environmental sensitivity 8) How long have you had environmental sensiüvity symptoms? 9) Please tell me what some of those symptoms are? 10) What things bring about these symptorns? 11) Can you give me any information about the onset of your symptoms. eg. Can you remember a specific exposure event or did they develop gradually over time?

You wifl receive $100 as compensation for your time and travel costs. Is there anything you would like to ask me? Can we set up a meeting or would you like some time to think about it?

You will also need to participate in an interview to nile out any psychological factors. Please spell your name and give me your address and a telephone number Mere you can be reached. Please also give me your date of bifth. You will receive a package of questionnaires in the mail that we ask that you fil1 out and bring ta your visit

F i p e 2-3. Agoraphobie Cognitions Questionnaire -- -------- ACQ

Below a& some thouets or ideas thït may pass through your mind when you arc nervous or aightened. Plcase indicate how ofien each thoughr occun when you arc nervous uring any of the numbers h m 1 to 5 on the s d e below. For exampie, if a particuiar thought aiways occurs when you are navous, a 5 h n t of the thoughc if a thought unially occurs (but not always), mite a 4 in &ont of the statement; and-= on Please nite all items in that rnarmer.

1 = nougbt 2 = Thought 3 = nought 4 = Thought 5 = ThoLlght

never occurs rardy occun occurs during half the times 1 am nervous uSually o c m aiways occurs when 1 am nemous

1. Iamgoingto throwup.

2. 1 am going to pass out

6. I& going to act foolish.

8. 1 will not bc able to control ayseif.

1 wiiI hurt someone.

10. I am going to have a moke.

13.1 am going to babblc or talk h y .

15. Other ideas (dcsmibe on the Iine bdow and rate with a numbcr).

Now that you have wrinen a numba in h n t of ach t h o ~ & ~ put a circie around the thrte ideas that occur most oAcn whcn you arc &ightcncd or anxiow.

F i p r e 2-4. Anxiety Sensivity Index -- ----*--- AS1

INSTRUCTIONS: Please rate each item by sdccring on; of the five phrases below for each of the following sixteen questions.

C L 1 2 3 - A . . Vcry Little A Linle Some Mwh Vcry Much

œ

It is i m p o ~ n t for me not to Wear nemous.

m e n 1 carmot keep m y mind on a îz& 1 wony that 1 mi@ be going cny.

It scares me when I fet1 m. It scares me whcn 1 fetl fain't,

Ir is important for me to stay in conml ofmy emotions-

It scarcs me when my-kart b- rapidly.-

It embarrassts me whcn m y stomach growls.

It scares me when 1 am nauscous.

When I notice my heart is bcating rapidly, 1 worry that I might have a h m attack.

10. It scarcs me when 1-become short of brcath, -

11. When my nomach is upset. 1 wony rhat 1 mi@ be seriously ill.

12. It scares me when 1 am unable to ketp my mind on a task

13. Other people notice whcn 1 feel shsky.

14. Ununial body sensations scarc me. -

15. When 1 am nervous, I worry that 1 might be mentally ilL

16. It scars me whcn 1 am nemous.

Figure 2-5. Depression Anxiety Stress Scales ---------_- DASS (1 of 2)

-.. - INSTRUCTIONS: PIease rcad each stament and choose the answer w&ich indicates how much the statcmmt applicd.to you over the There m no right or m g answers. Do not spcnd too much rime on my statcment Please use the foiiowing ratmg d e :

O = Did not apply to me at aiI 1 = AppIied to me to some de-, or some of the Mie 2 = Appiied to me to a considerable degrce, or a good part of the tmie. 3 = Applied ta me very much, or mon of the timc

1 fond myseLf gcthg upset by quite trivial thmgs.

I just couldn't scem to get gomg.

I exp&tnced brwthing Wdty (e.g., excessively rapid breathing, brcathicssncss in the absence of physical cxt.on)=

1 feIt sad and dcpressed. .

1 found it bard to- calm down..afk sornething .upsec me. - 1 penpired noticcabiy (e.g.,.hands swcaty)-in the absence ofhigh tcmperaturcs or physical exenion.

I found myself getting impatient - whcn 1 was delaycd in any way (eg, e lwato~ , t~affÏc lights, being kept waiting).

1 found myself m situations which made me so anxious 1 was most nlievcd wtien thcy endcd

1 tendcd to over-rat to situations.

1 found mysclf gettmg upset ratha easily.

1 felt that 1 had notbmg to look forward to.

1 couldn't seem to urpcrÎence any positive feeling at di.

1 found that 1 was very irritable.

1 was awaft of m e s s of my rnoutb.

1 felt that 1 had Iost interest in just about evcxything.

1 couid sec nothhg m the future to be hopcful aboirt

I was awarc of the action of my h m in the absence of physicd cxcrtion (e-g., sense of hean rate mcrease, kart missing a kat).

I felt scared without q good rcason.

1 felt that Me wasn't wmhwhile.

1 felt that I was rathcr toucfiy.

22. 1 felt that 1 was using a lot of nentous mergy.

O = Did not apply to me at di 1 = Applied to me to somt degrtt, or somc of the time 2 = Appiitd to me to a considerable degrce, or a good part of the time. 3 = Appiied to me v a y much, or most of the tÏme

--

- 23. 1 couldnt scem to gct any eajoymeat out of the t h g s 1 d i b

- 24. I had a fetimg of shahess {e-g, legs goiag to give away).

- 25. 1 felt dom-hcaned and biut.

- 26. 1 fomd it difncuit ta work up the initiative to do things.

- 27. 1 found it hard to wind down.

- 28. I.was intolerant of anything that kcpt me h m gctting on witb what 1 was domg.

- 29. 1 haddifficuitymswallowing. - 30. 1 feartd îhat 1 would-be."tixownn by somt aivia1 but damiliar task

- 3 1. 1 felt 1 was preq worthless.

- 32. 1 was unabic to become enthusiastic about mything,

- 33. 1 was worricd about situations m which 1 might panic and makt a fool of myself. - 34. I was m a state of ncrvous &on-

- 35. 1 felt 1 was close to panic.

36. 1 felt 1 wasn't worth much as a pason.

- 37. 1 found it difficult to relax.

- 38. 1 feltttmfied. - 39. 1 experienced ~ e n r b h g (e-g., in the b d s ) .

- 40. 1 found rnyself gcrting agitaud.

- 41. 1 felt that WC was meaningless.

- 42- 1 found it drffIcult to tolerate intarupuons to what 1 was doing.

Figure 2-6. Mobility l[nventory f o r Agoraphobia ----------*

F i . e 2-7. Health and Demograpliics -- ------- Questionnaire

THE GAGE RESEARCB INSTITUTE

QUESTIONNAIRE

B . DEMOG=EIIC

WHAT IS YOUR:

AGE

GENDER (l=rnaie; 2=f emal e)

EDUCATION (highsk I v l : 1 s ; 2=h.s: .3=univ/coll; 4=other) [ 1 ---

W.?LOoPiENT ( 1 - s t d n t ; 2=home; 3 = b l c l ; 4=whcl; 5=ret: 6~0th) [ 1 $ years LI3

FMPLOYHENT 3 t " O R E TRIS (samc categories) aP years

EMILOYMLNT BEFOEZt LATTER (same cat ego ries ) B years

E S I D E N C E (Papartment ; 2=house; 3tother) area (l=urban >10,000; 2=ruraL <10,000)

r 1

3 years m . .- RESIDENCE ZEFORE THIS (same categor ie s )

area (l=urban >10,000; 2=rural <10,000) C 1

+ years d IISSIDENCE 3SFORE LATTER (same c a t egori es )

area (I=urban >10,000; 2=rural <10,000) C 1

d years d DRINKING KATER SOURCE (l=municipal; 2=uell; 3=bottle)

% years

?REV DRINnZNG WATER SOURCE (same c a t e g o r i e s ) $ p a r s

B. ILLNESS BISTORY

=VE YOU D ! (on either a continuing or intermittent basis) :

NASAL PROBLEMS (l=no; 2 = y e s ) if yes spec i fy

c 1

is this onçoing (l=no; 2-yes) c 1 ào you take meàs for this ( l = n o ; 2 - y e s ) [ ]

if yes specify - _ -. --Cs this ongoing- Cl=rio; 2-yesj--- - - c 1 do you toke me&. for this (l=ao; 2 = y e s ) [: 1

-. . EAX OR FEARZNG PROBLLNS (L=no; 2=yes. )

if y e s specify C I

is t h i s o n g a b g (I=no;. 2 = y e s ) c 1 do y o u t a k e meds for this (l=no; 2 = y e s ) [

i f y e s s p e c i f y . is t.his -ongoing (l=ao; 2;yes) C 1 do you take meds for this (l=no; 2 = y e s ) [ ]

LUNG OR BRONCHIAL PRORLEMS (l=no; 2 = y e s ) c -1 if yes s p e c i f y

is this ongoing ( l = n o ; 2 = y e s ) C 1 do you take -meds for t h i s ( I=no ; 2=yes) [ 1

E Z M T , O 2 BLOOD PRFSSURE PROBLEXS ( l = n o ; 2 = y e s ) if yes s p e c i f y

C 1

is this ongoing (l=no; 2 = y e s ) C 1 do y o u take m e c s for t h i s (l=no; 2 = y e s ) C j

DIGESTIVE, STOMACII, OR 3OWEL PROBLEHS (I=no; 2 ;yes ) C 1 if yes s p e c i f y

is this ongoing (I=no; 2 = y e s ) [ 3 do you take meds for this (I=no; 2 = y e s ) [ 1

KZDNEY, OR BLADDER PROBLEMS ( I=no ; 2 = y e s ) C 1 if yes spec i fy

is t h i s ongoing (l=no; 2=yes) C 1 ào you take meds for t h i s (l=no; 2 = y e s ) [ 7

if fernale, YSNSTRUAL PROBLEHS incl cramps (l=no; 2 = y e s ) if yes specify

C 3 is tnis ongoing (l=no; 2 = y e s ) C 1 do you take meds f o r this (l=no; 2 = y e s ) [ f

TETROID PROBLZHS (l=no; 2=yes) - if y e s s p e c i f y

C 1 is this ongoing (l=no; 2=yes) c 1 do yo u take meds for this (I=no; 2 = y e s ) [ 3

OTEÈR HORMONE ?ROBLEMS (i=no; 2=yes) if yes specify

C 1

is this ongcing (l=no; 2=yes) C 1 do y o u t a k e meds for tnis ( l = n o ; 2=7es) [ ]

3LOOD PROBLEMS, OR ANEMIA (I=no; 2 = y e s ) if yes s p e c i f y

C 1

. is --this. ongoing (I=no; 2 = y e s ) . . - C I 60 you take meds for t h i s ( I = a o ; 2 = y e s ) [: ]

AXTERITIC PROaLEMS -(1=n0; 2=yes) if yes s p e c i f y

C 1

is this ongoing (l=no; Z=yes) c I do you take me& for :thi-s (I=no; 2 = y e s ) [ ]

aLOOD SUPPLY, OR VEIN PROHLEMS . IN -:AMSI/'LEGÇ (IL:=no; 2=yes ) [ 1 if ?es s p e c i f y _--

is t h i s ongoing -(l=no; 2=yes) C 1 ào you take me& for t h i s (l=ao; 2=?es) [ ]

S K I N PROBLEMS (l=no; 2 = y e s ) C 1 if y e s s p e c i f y

is t h i s ongoing (I=no; 2 = y e s ) C 1 60 you take meds for this (l=no; 2 = y e s ) [

SWOLLEN GLANDS (l=no; 2 = y e s ) C 1 if yes specify

is this ongoing ( I=no ; 2 = y e s ) c 1 - do y o u take meds for this (I=no; 2 = y e s ) [ 1

ALLEIZGILS e x d u s i v e of nasal , lung or s k i n (I=no; 2 = y e s ) [ if pes s p e c i f y

is t h i s ongaing (l=no; 2=yes) C 1 ~o you take meds for t h i s (l=no; Z=yes) [ 1

NZXVOUS SYSTEM PROBS eg para ly s i s or numbness(l=no; l = y e s ) [ ] if y e s s p e c i f y

is this ongoing ( l = n o ; 2 = y e s ) C 1 do y o u take meds f o r th i s (I=no; 2 = y e s ) [ 1

cMOTIONiIL OR PSYCHIATRIC PROBLZMS (l=no; 2 = y e s ) C 3 if yes s p e c i f y

is t h i s ongoing (ltno; 2 = y e s ) C 1 90 you take meds for this (I=no; 2=?es) C 1

OTHER E ~ A L T S P R O B L M S (I=no; 2=yes) r f - - - if yes s p e c i f y

are these ongoino ( l = n o ; 2 = y e s ) E 1 do y o u t a k e me& for these (I=no; 2=yes) C

DO PO0 ? P X MEDICATIONS ON MOST DAYS (1=n0; 2=yes) if yes hou many kinds of medication

INDICATE TYPES OP MEDICATIONS : . . v i t a m i n s (T=na; 2 = y e s ) -

antibiotics (I=no; 2 = y e s ) antacids - ( l=no; 2 = y e s ) laxat ives (l=no; 2 = y e s ) pain killers (l=no; 2=yes) tranquilizers (l=no; 2 = y e s ) sedat ives (l=no; 2 = y e s ) antiàepressants ( l =no ; 2 = y e s ) herbal remedies (l=no; 2=yes) ürogs eg f o r allergy, e y e s or inhal ers (l=no; 2yes) injections ( l = n o ; 2 = y e s ) ointments (I=no; 2 = y e s ) others (l=no; 2 = y e s )

if y e s s p e c t f y

IN TEE PAST TWO UEARS, BOW MANP T I Z S KAVE Y0U: seea pour family doctor . . En- seen an MD specialist (except clin e c o l o g i s t ) 1 7 1

s p e c i f y t y p e s

seen a clinical ccologist [ I f seen an acupuncturist m

seen a c h i r o p r a c t o r seen a àiet therapist

m seen other care givers

specif y t y p e s

been aomitted t o hospital ri7

7 - L El. ENVIRONHENTAL PERCEPTIONS

DO ENVIRONYZNTAL THINGS THAT !COU BRSATSE, EiIT, DRINK OR TOUCH SZRïOUStY 1NTERr"E:EZ WITB YOUR KAY Or" LIIE ( L = n o ; 2 = y e s ) c 1

IF NOT ADVERSELP AFE'ECTED, GO TO SECTION F.

IF ADVERSELP AFFECTED .....

CAN YOU IDENTIZY HOW TEIS STAXTED (l=no; 2 = y e s ) if yes s p e c i f y

C 3 - .- . .

was it due to something at uork:(l=no; t = y e s ) [ ] . . something-at home~!l=no; 2 = y e s ) C ]

an il h e s s , ( I = s o : - 2 = y e s ) C 1

AXE Y00 XZFECTED 1. .AT H O P i . (l=no; 2=yes ) 2. AT WORK (l=no; 2=yes) 3. IN PUBLIC ?LACES .(.k=no.z:2=yes) 4. E E N OUTSIDE (1-0; - 2 = y e s ) which location is the .worst

W"dT TEiINGS IN TEE ENVIIZOtWENT AEœFSCT POU:

TEZNGS IN TEE A I R (l=no; 2 = y e s ) 1 -1 if yes s p e c i f y

. - hou many things in. the air botner y o u

T E I N G S TIIAT YGU EZT (I=no; 2 = y e s ) if y e s s g e c i f y

C I

hou many things that ycu eat bother you 1 7 4 TUINGS THAT TOUCB YOUR SICIN (l=no; 2=yes)

if y e s s p e c i f p C 1

hou rnany things of thas type bother you [(J

OTSSR TEZNGS (I=no; 2=ftes) if yes s p e c i f y

I l

hou many things of this t y p e bother pou 1 7 EOW MUCE SXIOSURE fS NEZDED (l=minute;2=sml;3=mod;4=ige) C 1 FZTER XOW LONG DO SY=TOMS 3 2 G M (I=min; Z=hrs; 3=1onger) [ ]

ZOW LONG DO SYMPTOMS LAST ( l=min; - 2 = h r s ; 3-days; osmore) C 1

BOW OFTfN DO YOU GET IT (4=daily;3=ueekly;2=monthly;l=less)[:

DO ANY OF TEE FOLLOWING SUHPTOYS OCCUR ON AN ONGO-ING SASIS :

. .. . . - -

for frequeacy : 4=daily; 3 = v e e k l y ; 2=monthl y ; * l=less f o r duration: 4=weeks; - f = d a y s ; Z=hours; l=less f o r s e v e r i t y : 4=ubearable; 3:severe; Z=mild; .l=minimal

FATIGUE, WEAiWESS (l'no ; 2-yes ) if yes frequeacx

duration severitp

CONFUSION (Inno; 2 = y e s ) if y e s frequency

duration sever i ty

I N A B I L I m TO CONCENTRATE (l 'no; Z = y e s ) if yes frequency

duration s e v e t i t y

DIZZINZSS (I=no; 2 = y e s ) if yes frequency

duratian s e v e r i ty

GIGXTEIADSDNESS (l=no; 2 = y e s ) if yes f requencr

auration severi ty

X N S ?.ND NBEDLKS ( O 2 = y e s ) if yes frequtncy

duration s e v e r i tf

for f requency : 4=dail y; 3=ueekly; 2trnonthly; l=less for 6 u r a i i o n : 4=ueeks : 3=àays ; 2=hours ; l=l ess f o r s e v e r i t y : o=unbearable; 3zsevere; 2=mild; I=minimal

POOR COORDINATION (l=no; 2=yes) if y e s frequency

duration s e v e r i ty

BLURREI) VISION (l=no; 2 = y e s ) if y e s fre~uency

duration severi ty

. DECREASED EEARING (l=no; 2 = y e s ) i f y e s frequency

àuration severi ty

STUIFY; RUNNY..NOSE, 'OR ZAY 'FEVCX ( I=no ; 2=yes ) if y e s frequency

- duration s e v e r i ty

SOIE TXXOAT (l=no; 2=yes) if y e s frequency

duration s e v e r i t y

EOAXSZNESS (l=no; 2 = y e s ) - C rl yes frequency duration severi ty

SWELLING OP TEROAT (l=no; 2 = y e s ) if yes frequency

duration severi ty

COUGZ ( l=no ; 2 = y e s ) if yes f requency

duration severi t y

SZORTNZSS OF BRZATX ( l = a o ; 2 = y e s ) if yes frequency

duration severi t y

for frecuency: 4=daily; 3=weekly; 2=monthly; l=less f o r duration: 4=weeks; 3=days; 2=hours; I=less for severity : 4=unbearable; 3=severe; 2=mi ld; I=micimaI

WHEEZING, CSEST TIGBTNESS (T=no; 2=?es) if y e s frequency

durat ion severi t y

CANT GST &IR I N (I=no; 2=yes) if yes frequency

duration s e v e r i ty

if yes frequency d u r a t i o n s e v e r i ty

NXJSEP, (l=no;. 2 = y e s ) if y e s frequency

duration severi ty

ABDOHINX, aLOATING ('l=no; 2 = y e s ) if yes frequeacy

duration s e v e r i t y

8UXFZNG (I=no; 2=yes) if y e s frequency

durat ion severi ty

FLATULc'NCE ( l = n o ; 2=yes ) i f y e s frequency

a u r a t i o n severi ty

A3DOMIh'?L P A I N (l=no; 2=yes ) if p s frequency

duration s e v e r i t y

=ZLLfNG O F ARMS OR LEGS (I=no; 2 = y e s ) i f yes frequency

dura t i on severi t y

for frequency: 4=daily; 3=weekly; 2=monthly; l=less for duration: 4=uceks ; 3 = d a y s ; 2=hours ; 1-less for severity: 4=unbearabh; 3=severe; 2=mild; l=minimal

ZTCSING, RASH (I=~o; 2 = ~ e s ) if y e s frequency

duration s e v e r i t y

OTRER (l=no; 2 = y e s ) C 1 if y e s s p e c i f y

f requency C 1 duration c 1 s e v e r i t y - f 1

EAVE YOU EAD TESTS FOR ANY OF THESE SYMITOMSS(l=no; 2=yes) [ if yes specify which symptoms-

- .. . spe-cif y, which tests

if tested were resui ts neçative(1) positive(2) C 1 if p o s i t i v e s p e c i f y which t e s t s

G- LIFE STPLE

DO YOU USE, OR ENGAGE

EOBBIZS (l=no; 2=pes

IN (ON FAIRLY REGULAR SASS'S ) :

. -

if yes specify

LXZrZCISt PROGRAMMES OR SZORTS (l=no; 2 = y e s ) - - - - - . - C 1 - if yes s p e c i f y hr/wk

if yes do you avoid sorne foods (l=no; 2=2es) hou many fooas do you a v o i d

s p e c i f y other s p e c i a l d i e t a r f f eatures m SUPILEMENTS (l=no; 2 = y c s )

if y e s , hou many ( c g vitamins, h e r b s , etc) s p e c i f ,v

OTHZR SPECfAL DSETAR!? FEATURES (%=no;. 2 = y e s ) . i f yes specif y

c 1

i f y e s , how many dr5&;si . p e r week .

-. CLG-TTES (I=no; 2 = y e s ) - .

if yes hou many per day

RZCREATIONAL DRUGS (L=no ; 2 = y e s ) if yes hou many tirnes

EAVE YOU iIAD TO ALTER YOUR EOME OR IIZALTE REASONS ( I = n o ; 2=yes' )

p e r day

FOR

if yes s p e c i f y

DO TOU FAVE LIMITATIONS K I T H ANY OF THE FOLLOGIING ACTIV-ITIES: for each item s p e c i f y : l=no problem; 2=restrictet i ; 3=unable

SZLE' CEIIIE EZOUS-dOLD ACT1 VITTES SHOPPING TRAVEL SCHOOL (if -re levent) WOLS (if re.levent) .XEC=ATION FAMILY RELATIONSHIPS SOCIAL =LAT1 O N S E 1 PS

ZOW SATISFIED ARE POU WITH YOUR LIIE CIXCUMSTANCES for each item s p e c i f y : l=content; 2zneutral; 3 = d i s s a t i s f i o d

E 0 Y i LXIE FINAHCIAL STATUS EEALTE STATUS IJ'ORX OR SCEOOL

- SOCIAL IZELBTIONSEf3S

F i ~ e 2-8. Panic Frequency Questiomaire -- -------*

A panic a w k as a period of in- fear or discomfon tfiit kgbs nrddmly and peak in 10 minutes or Iess. Panic attacks must be accompanied by at leas 4 of thc foiiowing symptoms:

1. racing or pounding hept 2- sweaang 3. trtmbling/shaLing 4. shortncss of breath 5. chest pddiscodort 6. choking fceimg 7. nausdabdominal discornfort

8. m, imsttady, lightheadtd, faintntss 9. feeling umtal or dctached 10. numbndtingiing sensations 11. c m o t flashes 12- fearof dymg 13. fem of gomg -nosmg C O ~ ~ I

2 .

2.

3 -

the

4.

In the hast approximately how many panic aaacks (set above definition) have you had of or whtn youdidnot cxpect to have a panic attack?

in the approximaîdy how many attacks did you have in .situaîïonsiwhcre you m - t o have a panic a---&?- - - anacks

What whae these situations or places?

During the m. how w e e d or concemcd wtrc you about havulg more panic anacks. Estimate your level of concern by circling a nrrmber on the scaie beiow h m O to 8, wbcrc O = no wony or conccm about panicking and 8 = canstantly worried about having a panic atrack over p s t month.

O- 1 2 3-5-7 8 not at ail mildy modcrattiy VerY corutantly

worried about panic worried worried womcd worricd about panic . ..

During a panic attack m the pas month, how intmsciy do you ftci each of the following synrptoxns? Writc a numk to the Icft of each -rom, using the following d e : O = not at ail; 1 = mil& 2 = moderaie; 3 = sevtrt; 4 = very scvcrt.

- racing or pounding hcart - sweating - trtmblingldsaking - shormess of breath - ches paiddiscomfort - choking feeling - nausea/abdominaI discornfikt

F i p e 2-9. Diagnostic Symptom Questionnaire -- -------*

Diagnostic Symptom Quemoimam - Page 1

Name: Date:

DlS?RUCliiONS: Bciow is a lin of syrnptoms which &us people have noticeci duxhs tbe gas inhalation which you'just und-mt These expoiams arc very individuai; some people notic atmoa aiï thc symptoms, 0th- notice hardly any. For each symptom lined below incikate ifyou qerienc:d it jus %w by Girclbg "yesn or "non. lfyou did qcricnce a symptom, rate how -@y you felt the symotom using the scrle below.

1 f I t

I 1 t I I t 1

f I I I

O i i 3 - 4 i 6 7 8 Not at di SLightIy Modcareiy S~=@Y Very Swngly Notic td Felt Felt Feit Feit

5. Breathlcsslcss or srnoth- sensation

6. F&mess

12. Kausta or abdominal

m g -

1 I

O 1 Not at all S i d a r

Plcve rate how SAFE you feit throu@out the proctdurc. (Circle one numbu)

Plrzse rate now much CONTROL you felt you had over the smsations diiring the pmce&re. (Circie one numbcr)

I 1 1 1

t I t t 1

1 I I t 1

1 I 1

O I LI 7 3 4 5 g 7 8 No SE@ Moderare Much - Total

ConmZ Conpol Contr~i Control Control

Whcn you Lrst noriceci the symptoms which you Zisted on the prwious page, did you have any of the following though~: ( C k k TES" or "NO")

p E u e 7-1 Q. Taped prclimiaPsy instructions

The assessmcn~involves 3 main phues and will take approximately 2 houn.

The h t phase is simply a reJting phare. AU you have to do is sit quietly for 5 minutes while we take normai, resting measures.

The next phase will involve two single breath inhalations of either air donc or air which has a higher than n o d amount of carbon dioxide in it Carbon dioxide is a h a r d e s gas, which is nomially prcsent in the air we breathc. Research aromd the world has suggested that carbon diolade levcls and breathing might bc involved in somc typa of anxiety so we are conducting this study to mcasure people's physical response to carbon dioxide. DBerent people seem to experiencc diffmnt effects h m carbon dioxide. These experiences range fiom ftfling nothing at al1 to feeling somc anxiety. Any feelings you expcrinicc wiU be temporaxy. It is important that you hy and sit through the entire procedure, but if you feel that you absolutely must stop at any point, simply let me know. M e r the first inhalation, you will have a 1 0 minute r h g perïod d u k g which we will again take normal, resting measures. Mer the resting period will be your second inhalation, which wiil again be followed by a 10 minute resting period.

The third phase will be another resting phase during which we will take the last set of normal, resting masures. During each resting phase, you will be asked to n1l out 1 or more questiomahs.

Throughout the procedure you will also hear a number of beeps. Please try not to be alarmed by them. They givc us an indication that our instruments are working propcrly.

T a b l e 1 I values for the coaparison of the 7 diagnostic w o u p

V a r i a b l e E'(6,212) P Value

Number of Physical Symptoms 4-61 < 0.001 N d e r of Cognitive Symptoms . 5 -60 < 0.001- Intensi ty of Physical, Symptoms 2-39 < 0-05 Intensity- of Cognitive Symotoms 5-69 < 0,001 Intensity of Repor~ed F e u 4 - 85 < 0,001 Number of Cat~s~rophic Thoughts 5-04 < 0,001

T a b l e 2 Means and Standard Deviations for the 7 Croups

PDA PD GAD SOC SP OCD CONTROL N = 40 35 33 38 27 25 2 5

No. Physical Mean 5.6 5.9 4 . 8 4.2 4.2 3.9 2.6 S y q t o m s SD 3.2 2.7 2.9 2.7 2 - 4 2.6 2.3 (n=12)

Iatensity Mean 3.6- 4.3 2.9 2.2 3.1 2.9 1.1 of T e x SD 2 . 8 2.7 2.4 2.3 2 . 7 2.3 2.0

No* Cognitive Mean 1.0 1.0 0.6 0.4 0.3 - 0.7 0.1

In tens i ty Cogitive

No. C z t z s t rophic SD 1-9 1.9 1.9 1 - 2 1.2 1.7 1.1 Thoughts

T a b l e 3 Sample Size of ES and P a n i c Disorder Patients Needed to Detect a Moderate ( H Z ) or Large (NI) E f f e c t Size w i t h 80 Percent Power at the 5 Percent Signifieance Level

S M L Z SIZE -

I n t e n s i t y of Fe=

N u m h e r of C o g a i t i v e S p p t o m s

Zntonsity of 2 - 5 Cognitive Sy-toms

C N u m h e r of 2 - 2 b; CztzstropMc thoughts

Table 1 . Symptoms Experienced on an Ongoing Basis

MCS (N = 37) Cwibol (N = 36) xz (m- p-value (% of subjects) (% of SU~JJWS)

Headache 81 35 c ,001'

dail y weeWy monthly less

weeks days hours less

unbearable severe mild

Fatisue 75 16 < .000001*

Frequency - - -

Duration - - - -

Severity -

daily weekl y mon thly less

weeks days hours less

unbearable severe mild

- minimal 11 17 " Binary categoflcal variable analyzed using Fisher's exact test " Categorical variables anal& using aii%quare analysis a Subject gave details of fraguency. duration. and severity given that the conesponding symptom was reported

Table 1 (cont'd). Symptoms Experienced on an O f ~ o i r i ~ B ~ s ~ s

MCS (N = 37) Control (N 36) Xz (MW p-value (% of subl'ecfs) (% of su^)

Confusion 46 O

Frequency - daily 19 - weekiy 44 - monthly 6 - less 31

Duration - weeks 13 - days 13 - hou= 25 - less 50

Severity - unbearable 13 - severe O - mild 50 - minimal 37

Concentration 64 16

Frequency - daiiy 22 - weekly 35 - rnonthly 26 - less 17

Duration - weeks 9 O - days 13 33 - hou= 48 33 - less 30 33

Severi ty - unbearable 4 - severe 13 O - mild 65 83 - minimal 17 17

Table 1 (cont'd). Symptoms Experienced on an Ongoing Basis

MCS (N = 37) ConW (N = 36) xz (@* pvalue (% of subjects) (% of slîbiects]

Dininess

Frequency - - -

Duration - - - -

Severity - - -

daily weekly monthly less

weeks days hours less

unbearable severe mild

- minimal 35 50

Liahtheadedness 72 14 < .OOOOOi*

Frequency - daily 7 20 2.7 (3) 0.44 - weekiy 23 O - monthly 50 40 - l a s 19 40

Duration - weeks O O 5.13 (2) 0.08 - days 8 4 0 - ~ O U ~ S 35 O - I ~ S S 58 60

Severity - unbearable O O 1.89 (2) 0.39 - severe 27 O - mild 50 60 - . minimal 23 4 0

Table i (cont'd). Symptoms Experienced on an Ongohg Basis

MCS (N = 37) Caitrol (N = 36) $ (dl)- p-value (% of subjecfs) (% of suWeds)

Pins and needle~ 39 16 -04'

Frequency - daily 14 O 1 .19 (3) 0.76 - weekly 21 17 - monthly 21 33 - Iess 43 50

Duration - weeks 7 O 1.54 (3) 0.67 - days 7 O - hours 29 17 - less 57 83

Severity - unbearable 7 O 3.93 (3) 0.27 - severe 7 O - rnild 50 17 - minimal 36 83

Poor coordination 36 3

Frequency - daily 7 O - weekly 43 O - monthly 21 O - less 29 100

Duration - weeks O O 0.71 (2) 0.70 - days 7 O - hours 36 O - less 57 100

Severity - unbearable 7 0 2.14 (2) 0.34 - severe O O - mild 64 O - minimal 29 100

Table 1 (cont'd). Symptorns Experienced on an Ongoing Basis

MCS (N = 37) Controi (N = 36) Xz (dow pvalue (% of subi8C1s) (% of subiects)

Blu rred vision 42 O < .OO001*

Frequency

- Du ration

- *

- -

Severity

daily weekly rnonthly less

weeks days hours less

un bearable severe mild

- minimal 20

Decreased hearinq 25 8 .06*

Frequency

- Duration -

daily weekly rnonthly less

weeks days hours less

unbearable severe mild

- minimal 67 67

Table 1 tcant'dl. Symptoms Expedenced ori an Ongohg b i s

MCS (N 37) Contrd (N = 36) $ (doH p-value (% of subjècts) (% of su61'acfs)

Stuffv. runnv nose or havfever 81 32 < .OOOl'

Frequency - daily 31 17 8.02 (3) 0.05 - weekly 38 8 - rnonthly 21 33 - less 10 42

Duration - weeks 21 25 - days 31 33 - ~ O W S 41 33 - less 7 8

Severity - unbearable 7 8 4.66 (3) 0 1 - severe 38 25 - mild 52 42 - minimal 3 25

Sore throat 78 19 < .000001'

Frequency - daily 4 O 6.17 (3) 0.10 - weeWy 15 14 - monthiy 44 O - less 37 86

Duration - weeks 4 O 1.96 (3) 0.58 - days 44 71 - hours 37 14 - less 15 14

Severity - unbearable O O 4.80 (2) 0.09 - severe 14 14 - mild 68 29 - minimal 38 57

Table 1 fcont'd). Symptoms Eicperienced on an Ongaing Beris

MCS (N = 37) Contrd (N = 36) fi (dow p-val ue (% of subl'ecls) (96 ofsubj8C1s)

Hoarseness 56 8 < .OOO1*

Frequency - daify 10 O 0.76 (3) 0.86 - weekly 19 33 - monthly 24 33 - less 48 33

Du ration - weeks 10 O - days 24 33 - hou= 52 67 - less 14 O

Severity - unbearable O O 0.91 (2) 0.64 - severe 24 O - mild 52 67 - minimal 24 33

Swellina of throat 44 O < .00001*

Frequency - daily O - weekly 27 - monthly 20 - less 53

Duration - weeks 7 - days 33 - hou= 40 - less 20

Severity - unbearable 7 - severe 33 - mild 53 - minimal 7

Table 1 (cont'd). Symptoms Experienced on an Ongoing Basis

MCS (N = 37) Conol (N = 36) f (MW p-value (% of subjeds) (% of suW8ds)

Frequency -

- Duration

- Severity

daily weekly monthly less

weeks days hours less

un bearable severe mild

Shortness of breath 61 14 c .0001'

Frequency - daily 9 O 1.60 (3) 0.66 - weekly 32 20 - monthly 27 20 - less 32 60

Duration - weeks 5 O 2.62 (3) 0.45 - days 9 O - ~OUIS 45 20 - less 41 80

Severity - unbearable O O 1.79 (2) 0.41 - severe 18 O - mild 64 60 - minimal 18 40

Table 1 Icont'ql. Syrnptoms Experienced on an OnWw 6rwL

MCS (N = 37) Conbol (N = 36) xz (dl)- p-value (% of subjects) (96 of s u b j " )

Wheezina. chest tiahtnes~ 50 O < .000001'

Frequency -

- Duration

-

- Severity

*

daily weekl y monthly l a s

weeis da y s hours less

unbearable severe mild

- minimal 32

Can't aet air in 31 3

Frequency - daily 8 100 - weekly 8 O - monthly 33 O - I ~ S S 50 O

Duration - weeks 8 O 0.93 (2) 0.63 - days O O - hours 42 O - less 50 100

Severity - unbearable O O 1.26 (2) 0.53 - severe 42 100 - mild 42 O - minimal 17 O

Table 1 (cont'dl. Symptorns Experienced on an Ongoing Basis

MCS (N = 37) Contrai (N = 36) xz (dl)" p-value (% ofsubieczs) (% of su~BcfS)

Frequency - daily O 50 9.W (3) 0.02 - wee kly 31 50 - monthly 19 O - less 50 O

Duration - weeks O O - days O 50 - ~ O W S 13 50 - less 87 O

Severiîy - unbearable O O 1.43 (2) 0.49. - severe 13 O - mild 56 100 - minimal 3 1 O

Nausea 53 8 < .O001'

Frequency

- Severity

daily weekl y monthly less

weeüs days hours less

unbearable severe mild

- minimal 16 33

Table 1 (cont'd). Symptoms Experienced on an OnMrIg Bais

MCS (N = 37) ConW (N = 36) (m- pvalue (% of subiects) (% of subv'eds)

Abdominal bloatinq

daily weeùiy monthly less

weeks days hours l e s

unbearable severe mild

- minimal 8 O

Frequency - daily 38 29 1.63 (3) 0.65 - wee kly 23 14 - monthly 31 29 - less 8 29

Ouration - weeks 23 O 2.50 (2) O 2 9 - days O O - hours 23 14 - less 54 86

Severity - unbearable O O 4.1 7 (2) 0.13 - severe 8 O - mild 54 14 - -minimal 38 86

Table 1 (cont'd). Symptoms Experienced ari an Ongoing Basis

MCS (N = 37) Conbol (N = 36) $ (aL p-value (% of subjects) (% of subi8C1S)

Flatulence

Frequency - - - -

Duration - - - -

Severity - - -

daily weekl y monthly less

weeks days hours less

unbearable severe mild

- minimal 25 50

Abdominal ~ a i n 67 14 < .00001'

Frequency - daily 21 O 5.01 (3) 0.1 7 - weeùiy 50 20 - monthly 25 60 - less 4 20

Ouration - weeks 4 O 1.67 (3) 0.64 - days 2 1 O - ~ O W S 50 60 - less 25 40

Severity - unbearable O O 3.07 (2) 0.22 - severe 29 O - mild 67 80 - minimal 4 20

Table 1 (cont'd). Symptoms Experienced on an Ongoing Basis

MCS (N = 37) Contrd (N = 36) f (@" pvalue (% of subjects) (% of suf$ects)

Swellina of arms or leqg 22 8 0.11'

Frequency - - daily

weekly monthly less -

Duration - weeks

da y s hours less

un bearable severe mild

- minimal 33 67

Itchina. rash

Frequency daily weekl y monthly less -

Duration weeks days hours less -

Severity - un bearable

severe mild minimal