BRIEF CLINICAL UPDATE

Idiopathic Environmental Intolerance: A Review of the Literature, with a Therapeutic Approach in Two Cases


William B. Klaustermeyer, M.D. and Pravin Muniyappa, M. D.

We present two patients with idiopathic environ-mental intolerance (IEI) and describe their subsequent
management. One patient had a severe systemic illness and the other did not. The first patient had an
imminent need to start D-Penicillamine (DPA) for treatment of systemic sclerosis (scleroderma). She
had symptoms of headache, fatigue, alleged facial swelling and was subsequently non-compliant with
DPA. She identified the medication as a trigger for her various symptoms. The second patient had previ-ously
seen multiple physicians for intolerances to a wide variety of foods and fabrics. Her symptoms
consisted of headaches, non-specific rash, fevers and fatigue. Both patients were diagnosed with IEI and
treated as described below.

Overview

Formerly known as multiple sensitivities syndrome,
IEI refers to a subjective condition in patients who typically describe multiple symptoms which they
attribute to numerous and varied environmental chemical exposures. These symptoms occur in the
absence of diagnostic, physical, or laboratory findings. 1 The term \"idiopathic environmental intol-erance\"
may be preferable to \"multiple chemical sensitivities syndrome,\" as the latter implies a
biochemical or immunologic mechanism for the patient\'s symptoms. 1,2

The symptoms associated with IEI include, but are not limited to, headache, visual changes, non-urticarial
rash, swelling, unspecified pruritis, and gastrointestinal distress. None of the physical
symptoms are observed on exam, and the subjective symptoms are not those typically associated with IgE-mediated
reactions. The complaints associated with IEI can be worsened by stress and the introduction of
new medications. This constellation of symptoms may occur in patients with an underlying serious
medical illness, but this is not necessary. 1-3

The list of triggers involved in IEI is unlimited and can often be identified by odor and taste. 1,2 Triggers
most often include fabrics, food, chemicals, and various patient-suspected molds. It is important to
note that symptoms bear no relationship to established toxic effects of the specific chemicals and occur at
concentrations far below toxic levels. Also patients with IEI are usually adult women. 1 The latency
period, the length of time from exposure to symptom development, is important in allergic disorders. This
latency period varies considerably in IEI patients, and is not predictable. The lack of a consistent latency
period, wide variety of triggers and symptoms is common. In addition, a double-blind, placebo-controlled
challenge with suspected triggers fail to reproduce the patients symptoms. 2,4

Patients with IEI will often take extreme measures to avoid perceived triggers. Measures observed include
the use of gloves and facemasks, changing geographic location, and changing employment. The degree of
avoidance is patient-dependent.

Over the past 50 years, a number of theories have surfaced addressing the etiology of IEI. None of these
theories has been validated by scientific inquiry. 1,2

Recently there have been several studies suggesting that IEI has a psychiatric basis. That is, the constella-tion
of symptoms generally regarded as IEI is an atypical manifestation of anxiety or panic
disorder. 3,5-7 Supporters of this theory suggest treat-ment of an underlying anxiety disorder may help
some of these patients. Often, however, these patients are reluctant to accept a psychiatric diagnosis or
psychiatric referral. Others believe the symptoms are amplified by the underlying social isolation IEI
creates. That is, patients with IEI may have baseline symptoms and take extreme measures to avoid
triggers such as wearing facemasks, which may lead to social isolation. Binkley et al revealed a 41%
prevalence of panic disorder-associated CCK-B receptor allele 7 in patients with IEI, providing
possible preliminary evidence that IEI and panic disorder share a common neurogenetic basis. 8

Case One

A 46-year-old white female, non-smoker, was diag-nosed
with systemic sclerosis with progressive dermatologic involvement. She was referred by her
rheumatologist because of intolerance to DPA.

The patient noted a two-decade intolerance to wool, all perfumes, papers, paints, detergents, and plastics.
She experienced headaches, facial tingling, gastroin-testinal distress and nasal congestion with exposure.
She had taken extreme measures toward avoidance, including wearing gloves and face masks when
touching paper. She even changed her residence, in an effort at avoidance.

Her past medical history was also significant for CREST syndrome (calcinosis cutis, Raynaud\'s
phenomenon, esophageal dysmotility, scleroderma, and telangiectasias) and Hashimoto\'s thyroiditis. She
had a history of well-controlled moderate asthma.

She had never used tobacco, alcohol, or illicit drugs. She was a trained clinical psychologist who focused
on family counseling. Two months prior to allergy evaluation, she had given up her clinical practice
secondary to her scleroderma.

She denied any allergies to medications, but noted nausea and fatigue with various proton-pump
inhibitors and montelukast. She was taking zafir-lukast 20 mg twice daily, levothyroxine 0.125 mg
daily, fluticasone MDI 100 mcg 3 puffs twice daily, ipratropium MDI 3 puffs thrice daily, fexofenadine
180 mg daily in the winter alternating with cetirizine 10 mg daily in the summer. She was also taking pred-nisone
5 mg daily.

Her scleroderma was progressing and DPA was deemed necessary by her rheumatologist. The patient
experienced diffuse non-urticarial rash, peri-oral and peri-orbital tingling, fatigue and chest tightness
approximately 30 minutes after ingesting a 250 mg capsule of DPA. She was started on 10 mg of pred-nisone
daily and experienced similar reactions with a 125 mg capsule of DPA. Her goal dose was 750 mg
daily.

Furthermore, laboratory data revealed normal chemistries, electrolytes, hemoglobin, and
eospinophil count. Also, quantitative immunoglobu-lins were within normal limits.

A direct oral challenge was done with a DPA 125 mg capsule. After administration, she was closely
observed. Within several minutes she complained of tongue swelling and a rash on her face and arms. This
was not objectively evident and vital signs taken every 15 minutes remained unchanged. She was
observed for 4 hours, without a change in vital signs or physical exam, and her subjective complaints of
rash and swelling dissipated with reassurance. Based on her extensive history, physical exam, and negative
challenge, she was diagnosed with IEI.

She was started on a desensitization protocol of DPA: 125 mg daily for one week, then 250 mg daily for one
week, then 500 mg daily for one week, then 750 mg daily. She also was to continue prednisone 5 mg
daily. After 3 days, she discontinued the protocol secondary to subjective peri-oral tingling and
headaches. She was then started on paroxetene 10 mg daily for 2 weeks, followed by paroxetene 20 mg
daily. Paroxetene (Paxil?) is a selective serotonin re-uptake inhibitor. After approximately 3 weeks on
paroxetene, she was able to tolerate the DPA desensi-tization protocol. She was able to maintain DPA 750
mg daily for several months without incident. She also noted improvement in symptoms associated with
other triggers, including paper and fabrics.

Case Two

A 65-year-old African-American woman was referred
from her primary care physician because of an \"allergy to everything\" for approximately 10 years.
She reported reactions to foods including seafood, rice, beans, all fruits, legumes, a variety of meats, and
most fabrics. She has been carefully avoiding these foods and had lost weight as a result.

On careful history, she notes that her symptoms include headaches, visual changes, indigestion, and
non-urticarial rash. She notes that the same food can induce a variety of symptoms. She denied exercise
intolerance, rhinitis symptoms, and night symptoms. She further denied urticaria, angioedema, heat, or
cold intolerance. She denied any anxiety or insomnia. Her depression screen was negative as well.

For her multiple symptoms, she had seen 4 allergists and a dermatologist in the past without success. Five
years ago she was admitted for one month of inpatient treatment, which included sub-lingual desensitization
and strict avoidance. These records were not available; however, she noted no improvement in her symptoms after this in-patient treatment.

On further detailed history, she notes that all of her symptoms started 6 months after the death of her
husband and son. She had no significant past medical history and her family history was unremarkable. She
had never undergone surgery and was not taking medications. She denied any history of tobacco use
and was still working as a public school teacher.

Her physical exam and spirometry were within normal limits. Skin testing done to 40 suspected
foods and aeroallergens showed no reaction. Also, complete blood count, chemistry panels, and thyroid
panels were unremarkable.

Her symptoms were consistent with IEI. The patient refused psychiatric referral, stating, \"I am not crazy.\"
She was started on paroxetene (Paxil?) 10 mg daily, which was titrated to 20 mg daily after two weeks.
She was unable to tolerate 20 mg daily, secondary to \"shaking,\" but was able to maintain a dose of 15 mg
daily. Six weeks after starting paroxetene, she noted that she was \"50% better\" and she could tolerate more
foods. She then accepted psychiatric referral, and after extensive counseling and paroxetene titration,
she was completely symptom-free.

Conclusion

Idiopathic environmental intolerance is a poorly
defined condition in which patients have a wide variety of complaints with a perceived association to
a wide variety of triggers.

There is a known overlap among patient with IEI, fibromyalgia, and chronic fatigue syndrome. Jason et
al 9 found that 40.6% of patients with chronic fatigue syndrome also had symptoms characteristic of IEI.
Furthermore, patients who had symptoms of IEI and either chronic fatigue syndrome or fibromyalgia
reported more physical and mental stress. Those patients also reported greater disability than those
with one diagnosis. 9 There is a known similarity in demographic characteristics and specific symptoms
among patients with chronic fatigue syndrome, fibromyalgia, and IEI. Buchwald et al also found that
patients with IEI had an average of 23.3 provider visits per year. 10

Two key principles in allergy are that the symptoms of
an allergic reaction are consistent with an immuno-logic mechanism, and that the symptoms are repro-ducible,
with challenge to the antigen. The symptoms experienced by both patients reported are not consis-tent
with an immunologic mechanism. We would expect classic atopic symptoms of urticaria,
angioedema, asthma exacerbation, gastrointestinal distress, or rhinitis. In Case One, the patient had
symptoms of headache, visual changes, non-urticarial rash, swelling, and pruritis. Because these symptoms
were based on patient history, and because there is a possible immunologic mechanism associated with
\"rash, swelling, and gastrointestinal distress,\" the decision was made to challenge the patient.
Interestingly, the patient did complain of similar symptoms during the challenge, which were not
evident on direct observation. In Case Two, the patient reported symptoms of \"headache, indiges-tion,\"
and non-urticarial rash. Her complaints were inconsistent with an immunologic mechanism. We
did test her to suspected food and aeroallergens, and all were negative.

The second principle described is that symptoms should be reproducible, and to an extent predictable.
In Case One, the patient failed to show objective findings with direct challenge. In both reported cases,
patients had varying complaints associated with the same alleged allergen. For example, in the second
case reported, the patient would experience visual changes associated with chocolate ingestion on one
occasion and malaise on another occasion.

There are many challenges in dealing with patients with IEI. Patients are often reluctant to accept psychi-atric
referral or may have an underlying medical illness. In the two cases presented above, both
patients refused initial psychiatric referral. Both patients had testing done which demonstrated no
immunologic component involved in their symptom complex.

In both cases presented here, an extensive history and in vivo testing ruled out allergic disease. The thera-peutic
focus shifted to treating an underlying psychi-atric illness. It is important to note that resolution of
symptoms with treatment is not equivalent to a psychiatric diagnosis, and every effort should be
made toward psychiatric referral. Paroxetene (Paxil?) was chosen because it is selective for sera-tonin
with very little effect on dopamine and norepi

nepherine.

In these cases, the primary care physician or specialist evaluating the patient might consider initial psychi-atric
pharmacotherapy. As the patient\'s symptoms improve, they may be then willing to accept psychi-atric
evaluation and further treatment.

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