Neural Autoantibodies and Neurophysiologic Abnormalities

in Patients Exposed to Molds in Water-Damaged Buildings

ANDREW W. CAMPBELLMedical Center for Immune and Toxic DisordersSpring, TexasJACK D. THRASHERSam-1 TrustAlto, New MexicoROBERTA A. MADISONDepartment of Health SciencesCalifornia State UniversityNorthridge, California

ARISTO VOJDANIImmunosciences Lab., Inc.Beverly Hills, CaliforniaMICHAEL R. GRAYProgressive Healthcare GroupBenson, ArizonaAL JOHNSONintegrative NeurologyRichardson, Texas

ABSTRACT. Adverse health effects of fungal bioaerosols on occupants of water-damagedhomes and other buildings have been reported. Recently, it has been suggested that moldexposure causes neurological injury. The authors investigated neurological antibodies andneurophysiological abnormalities in patients exposed to molds at home who developedsymptoms of peripheral neuropathy (i.e., numbness, tingling, tremors, and muscle weaknessin the extremities). Serum samples were collected and analyzed with the enzyme-linked im-munosorbent assay (ELISA) technique for antibodies to myelin basic protein, myelin-associ-ated glycoprotein, ganglioside GMi, sulfatide, myelin oligodendrocyte glycoprotein, CC-B-crystallin, chondroitin sulfate, tubulin, and neurofilament. Antibodies to molds andmycotoxins were also determined with ELISA, as reported previously. Neurophysiologicevaluations for latency, amplitude, and velocity were performed on 4 motor nerves (medi-an, ulnar, peroneal, and tibial), and for latency and amplitude on 3 sensory nerves (median,ulnar, and sural). Patients with documented, measured exposure to molds had elevated tilersof antibodies (immunoglobulin [lg)A, IgM, and IgC) to neural-specific antigens. Nerve con-duction studies revealed 4 patient groupings: (1) mixed sensory-motor polyneuropathy (n =55, abnormal), (2) motor neuropathy (n = 17, abnormal), (3) sensory neuropathy (n = 27,abnormal), and (4) those with symptoms but no neurophysiological abnormalities (n = 20,normal controls). All groups showed significantly increased autoantibody liters for all iso-types (IgA, IgM, and IgG) of antibodies to neural antigens when compared with 500 healthycontrols. Croups 1 through 3 also exhibited abnormal neurophysiologic findings. The au-thors concluded that exposure to molds in water-damaged buildings increased the risk fordevelopment of neural autoantibodies, peripheral neuropathy, and neurophysiologic abnor-malities in exposed individuals.<Key words: mold exposure, mycotoxins, neural antibodies, neuropathy, neurophysiology>

WATER INTRUSION into houses and office buildingsleads to the growth of molds and bacteria, which areknown to produce toxic byproducts that include endo-toxins (lipopolysaccharides), |3-D-glucans, and myco-toxins (e.g., trichothecenes, ochratoxins, and aflatoxins,tremorgens), as well as volatile organic compounds.1-8These compounds have been found in water-damagedbuildings and homes, and in artificially infested build-ing materials.7"11 Indoor air can be contaminated withmold spores and hyphae fragments.12 In addition, my-

cotoxins have been identified in ventilation duct partic-ulate matter or dust, and in the air of buildings in whichoccupants and pets have experienced adverse health ef-fects related to mold exposure.13"23

Molds and mycotoxins affect the respiratory tract,kidneys, liver, and skin, as well as the immune and ner-vous systems.24""45 Neurotoxic mycotoxins include ergotalkaloids, trichothecenes, citreovirdin, patulin, fumon-isins, and tremorgens.46"54 Tremorgens affect the brain-stem46 and stellate ganglion, and the basket and Pur-

464 Archives of Environmental Health

kinje cells of the cerebellum/7 Mycotoxins affect neu-roreceptor sites (e.g., gam ma-am inobutyric acid[GABA] receptor site48 and inositol 1,4,5-trisphophatereceptor49), inhibit acetylcholinesterase,50 release exci-tatory neuretransmitters (e.g., glutamate, aspartate,GABA, and serotonin),51-52 and block biosynthesis ofcomplex sphingolipids through inhibition of ceramidesynthase.53-54 They are also mitochondrial toxins andapoptotic agents.43-44-53

The symptoms and health problems associated withmold-infested, water-damaged buildings involve multi-ple organs, including the upper and lower respiratorytracts, gastrointestinal tract, circulatory system, and thecentral nervous system (CNS) and peripheral nervoussystem (PNS).2-5-24"37 Recent studies have shown thatmold exposure has adverse effects on the nervous sys-tem. Some mycotoxins have been shown to be tremor-genie and are suspected as causative agents in wood-trimmer's disease20 and tremorgenic encephalopathy;21

mycotoxins present in household environments havebeen found to affect dogs.22'23

Two patterns of neurobehavioral impairment attribut-able to mold exposure have been described. Kilburn26

reported on 10 individuals who had impaired balance,reaction time, color discrimination, visual fields, cogni-tion, verbal recall, and trail making. A different group of10 subjects exhibited impairments in all but measuresof color discrimination and visual fields. Abnormalitiesin electroencephalograph (EEC) theta and delta activity,visual evoked potentials, and brainstem evoked poten-tials have been reported in children exposed to molds.27

The EEC changes in the children were specific to thefrontotemporal area of the brain, suggesting a metabol-ic encephalopathy. Six individuals had abnormal nerveconduction. In addition, abnormal brainstem auditoryevoked potentials have been described in 4 childrenwith suspected mycotic neuromas who were exposedto mixed molds, including Stachybotrys chartarum andAspergillus species.57 Moreover, both neurobehav-ioral3''57 and correlated quantitative EEC31 changes in-dicative of right frontal lobe involvement have been re-ported in patients with chronic exposure to mold inwater-damaged buildings. Mold exposure has also beenimplicated in optic neuritis57 and multifocal choroidi-tis.58 Finally, demyelination of the CNS has been re-ported following exposure to ibotenic acid,59 abuse of"magic mushrooms" (Psilocybe),60 and gliotoxin.61 Be-cause stachylysin has been found in human serum fol-lowing exposure to 5. chartarum,62 and mycotoxins arepresent in indoor air and bioaerosols,13"19 it is impera-tive that health complaints of occupants exposed tomolds in water-damaged buildings be taken seriouslyand be investigated with appropriate diagnostic testing.

This communication describes 119 mold-exposedpatients who had multiorgan symptoms and peripheralneuropathy. Complaints included severe fatigue, de-

creased muscle strength, sleep disturbances, numbnessand tingling of extremities (with and without tremors ofthe fingers and hands), and severe headache. Patientshad abnormal neurological examinations. Ninety-nineof these individuals had abnormal nerve conduction ve-locities (NCVs) in association with autoantibodiesagainst 9 neural antigens, whereas 20 had normal testresults. We present data on motor neuropathy, sensoryneuropathy, and mixed sensory-motor polyneuropathy,as well as increased antibodies to neural antigens.

Materials and Method

Patients. The study population consisted of 119 pa-tients (79 females and 40 males; mean age ± standarddeviation [SD] = 41.3 ± 12.9 yr). The patients hadhealth complaints and proven environmental exposureto molds in their homes and/or workplaces. Mold ex-posure was documented by Aerotech Laboratories(Phoenix, Arizona). All patients were interviewed one-on-one by the principal author (AWC) regarding expo-sure history, as well as health problems and symptomsfor each organ system (e.g., CNS, PNS, respiratory, skin,musculoskeletal). Mold-specific serum antibody testsfor S. chartarum, Penidllium, Aspergillus, Cladospori-um, Alternaria, and Chaetomium, performed on eachpatient by Immunosciences Lab., Inc. (Beverly Hills,California), verified exposure to molds. Some of thesedata have been reported previously.63-65

We studied patients who had symptoms of peripher-al neuropathy (e.g., tingling, tremors, loss of sensationin extremities). Blood was drawn for serology testing forneural antigens. NCV tests were performed at or nearthe time of initial presentation as follows: all 119 pa-tients were tested at 10.8 ± 41 days; patients with ab-normal NCVs (n = 99) were tested at 11.5 ± 44 days;and patients with normal NCVs (n = 20, controls) weretested at 7.5 ± 18 days.

Blood samples. Peripheral venous blood was collect-ed and shipped at ambient temperature to Immuno-sciences Lab., Inc. (Beverly Hills, California). Autoanti-bodies (immunoglobulin IgG, IgM, and IgA) against 9neural antigens were assessed for each patient.

Neural antigens. Myelin basic protein (MBP), myelin-associated glycoprotein (MAG), ganglioside (CM,),chondroitin sulfate (CONSO4), a-B-crystallin (crys-tallin), and tubulin were purchased from Sigma-Aldrich(St. Louis, Missouri). Neurofilament antigen (NAF) waspurchased from Boehringer Mannheim Roche (Indi-anapolis, Indiana). MBP peptides 87-206 and myelinoligodendroctye glycoprotein (MOG) peptides 21-4-,61-80 were synthesized by Research Genetics(Huntsville, Alabama).

Controls for neural antigens. The controls for deter-mination of the mean ± 5D and 95% confidence inter-vals (CIs) for the neural antigens consisted of 500

August 2003 [Vol. 58 (No. 8)] 465

healthy adult blood donor volunteers. The controlswere of similar age and sex distribution as the 119 pa-tients.

ELISA testing. We used enzyme-linked immunosor-bent assay (ELISA) to test for antibodies against 9 differ-ent neural-specific antigens, as reported previously.66"68

Briefly, antigens were dissolved in methanol at a con-centration of 1.0 mg/ml and then diluted 1:100 in 0.1M carbonate-bicarbonate buffer (pH 9.5). Then, 50 pi ofthe mixture was added to each well of a polystyreneflat-bottom ELISA plate. Plates were incubated over-night at 4 °C and then washed 3 times with 20 mM Tris-buffered saline (TBS) containing 0.05% Tween 20 (pH7.4). The nonspecific binding of immunoglobulins wasprevented by adding a mixture of 1.5% bovine serumalbumin (BSA) and 1.5% gelatin in TBS and then incu-bating for 2 hr at room temperature, followed by incu-bation overnight at 4 °C. Plates were washed as de-scribed above, and serum samples diluted 1:100 in 1%BSA-TBS were added to duplicate wells and incubatedfor 2 hr at room temperature. Sera from patients withmultiple sclerosis (MS), polyneuropathies, and otherneurological disorders with known high tilers of IgG,IgM, and IgA against different neurological antigenswere used to rule out nonspecific antibody activities ofinter-assay and intra-assay variability. Plates werewashed, and peroxidase-conjugated goat antihumanIgG, IgM, or IgA antiserum (KPI [Gaithersburg, Mary-land)), diluted 1:400 in 1% BSA-TBS, was added toeach well. The plates were incubated for an additional2 hr at room temperature. After washing 5 times withTBS-Tween buffer, the enzyme reaction was started bythe addition of 100 u I of o-phenylenediamine in citrate-phosphate buffer containing hydrogen peroxide dilutedto 1:10,000 (pH 5.0). After 45 min, the reaction wasstopped with 50 ul of 2N sulfuric acid. The optical den-sity was read at 492 nm with a microtiter reader (DynexLaboratories [Chantilly, Virginia]). Several control wellscontaining all reagents except human serum were usedto detect nonspecific binding.

We calculated coefficients of intra-assay variation byrunning 5 samples 8 times in 1 assay. Coefficients ofinter-assay variation were determined by measuring thesame samples in 6 consecutive assays. This replicatetesting established the validity of the ELISAs, deter-mined the appropriate dilutions with minimal back-ground, and detected IgG, IgM, and IgA against differ-ent antigens. Sera from 500 asymptomatic blood donorsin southern California were used to calculate expectedranges at 95% Cl.

Neurophysiological tests. Bilateral peripheral nervestudies involving nerve conduction and central re-sponse (F wave) were performed on the 119 patients inaccordance with accepted techniques of the AmericanSociety of Electroneurodiagnostic Technologists (KansasCity, Missouri) and the American Neurological Associa-

tion (Minneapolis, Minnesota).69-71 The testing was per-formed under the direct supervision of, and interpretedby, a board-certified neurologist. Onset latency (ms),amplitude (uV), and velocity (m/sec) were recorded for4 motor nerves (median, ulnar, peroneal, and tibial).The peak latency (ms) and amplitude (|jV) were record-ed for 3 sensory nerves (median, ulnar, and sural). Fwave and H reflex were recorded for the median, ulnar,peroneal, and tibial nerves. The studies were conduct-ed with a TECA Synergy Multimedia Electromyographwith multisync color SVGA monitor and Delux stimula-tor probe (TECASyngery, Synergy Version 8.2 (OxfordInstruments ISurry, U.K.1]). The motor axons of periph-eral nerves that innervate somatic muscle were evaluat-ed by recording the response following electrical stim-ulation.

Statistical analysis. We performed critical 2-tailed ftests on neural autoantibodies. Odds ratios (ORs) werecalculated for the data to determine the percentage of in-dividuals with antibody liters that exceeded the maxi-mum expected laboratory range (95% Cl) for each neur-al autoantibody. For this calculation, data for patientswith abnormal and normal NCVs were combined.

Results

Neural autoantibodies. The mean ± SD of autoanti-bodies for each isotype (IgA, IgM, and IgC) against eachneural antigen for patients with abnormal NCVs (n =99), normal NCVs (n = 20), and asymptomatic blooddonor controls (n = 500) are given in Table 1. Ratherthan repeating the data for each antineural antigen iso-type, the salient features will be outlined briefly. In gen-eral, the highest isotype liters detected were MBP,MAG, tubulin, and NAF. These were followed by theother 5 neural antigens: CM,, sulfatide, MOG, crystal-lin, and CONSO4.

We performed crilical 2-tailed r tests for each isotypeliter against neural antigens, comparing abnormal vs.normal patienls, abnormal patients vs. controls, andnormal patients vs. controls for each isotype (statislicaldala nol shown). With respect to IgG liters, the only sig-nificant difference between abnormal and normal pa-tients was NAF (p < 0.01). IgG tilers for all isotypes forabnormal and normal patients differed significantlyfrom controls (p < 0.001). IgM tilers for neural antigenswere significantly different between abnormal and nor-mal palienls for glulamate receptor (p < 0.01), tubulin(p < 0.01), NAF (p < 0.01), and CONSO4 (p < 0.05).IgM liters againsl each neural antigen for abnormal pa-tients vs. controls (p < 0.001) and for normal patienlsvs. controls (p < 0.001) were significantly different. Theonly significant difference between patients with abnor-mal vs. normal IgA tilers was NAF (p < 0.05). Compar-ison of abnormal and normal patients vs. controls re-vealed IgA liters for each neural antigen which were

466 Archives of Environmental Health

significantly different (p < 0.01), except for normal crys-tallin liters (p < 0.05).

The percentages of individuals with autoantibodiesfor each isotype that exceeded the laboratory expectedrange at 95% Cl against the neural antigens are pre-sented in Table 2. IgG tilers for abnormal patients ex-ceeded the 95% Cl for sulfatide (17.2%), MOG(10.1%), crystallin (10.1%), glutamate receptor (11.1%),tubulin (57.6%), CONSCX, (27.3%), and NAF (6.1%);MBP (4%), MAC (4%), and CM, (0%) did not exceedtheir expected ranges. Similar observations for normalpalients were made for sulfatide (20%), MOC (20%),crystallin (20%), tubulin (30%), and CONSO4 (20%),except for MBP (0%), CM, (0%), glutamate receptor(0%), and NAF (0%). IgM tilers for abnormal patienlsexceeded those of controls for all neural antigens (range= 17.2%-42.4%) except CM, (0%). In normal patients,

IgM tilers did not exceed control values for CM, (0%),sulfatide (5%), MOG (5%), glutamate receptor (0%),and tubulin (5%), whereas MBP (20%), MAG (30%),crystallin (25%), CONSO4 (20%), and NAF (20%) ex-ceeded control values. IgA autoantibodies in abnormalpatients for each neural antigen exceeded control val-ues for MBP (20.3%), MAG (23.2%), crystallin (8.1%),glutamate receptor (7.1%), tubulin (8.1%), CONSO4

(10.5%), and NAF (10%). With respect to normal pa-tients, only MAG (15%), tubulin (10%), and NAF (10%)exceeded values for controls.

The percentage of patients who had ORs that ex-ceeded the 95% Cl are given in Table 3. The ORs forIgG were not significant for MBP (0.66) and MAG(1.05), whereas those for all other neural autoantibod-ies were significanl as follows: sulfatide (3.36), crys-tallin (6.53), glutamate receptor (10.08), tubulin (55.1),

Table 1.—Autoantibody liters against 9 Neural Antigens in Patients with Abnormal Nerve Conduction Velocities (NCVs) (a = 119) andThose with Normal NCVs (n = 20), vs. Asymptomatic Controls (N = 500), for Each Isotype

IgG IgAAbnormal Normal Controls Abnormal Normal Controls Abnormal Normal Controls

Neural autoantibody x SO x SO SO SD SD SD SD SD

MBPMACGMiSulfatideMOGCrystallinGlutamateTubulinCONSO«NAF

63.363.615.816.715.916.110.264.111.561.6

21.61B.86.76.25.95.83.4

16.84.7

23.9

54.769.016.417.517.516.59.2

58.710.253.3

18.318.27.06.76.66.71.5

11.92.1

10.7

27.026.011.112.28.9

11.97.0

23.77.7

26.4

12.27.32.83.45.52.52.89.22.2

11.3

50.851.016.417.218.218.710.641.911.853.1

24.316.16.36.36.36.93.7

18.54.9

20.7

47.048.115.615.116.819.09.3

33.010.444.1

9.212.44.54.34.78.21.27.82.0

12.0

25.124.510.411.38.4

12.17.6

18.15.6

24.7

13.28.13.33.75.52.92.07.92.1

10.3

18.519.412.313.312.013.69.5

17.911.018.2

6.07.66.29.13.57.53.7

16.17.78.2

16.817.512.612.411.413.28.5

14.79.2

16.4

4.77.44.44.02.34.72.13.71.45.4

7.28.3

11.59.47.9

11.18.19.87.08.7

3.72.41 6T 14.64.32.12.62.73.4

Notes: Ig = immunoglobulin, x = mean, SD = standard deviation, MBP = myelin basic protein, MAG = myelin-associated glycoprotein,GMi = ganglioside, MOG = myelin oligodendroctye glycoprotein, CONSO* = chondroitin sulfate, and NAF = neurofilament antigen.

Table 2. — Percentages of Individuals with Autoantibody Tilers that Exceeded Expected Ranges (95% Confidence Intervals), for Patientswith Abnormal Nerve Conduction Velocities (NCVs) and Those with Normal NCVs, vs. Asymptomatic Controls, for Each Isotype

AbnormalNeural autoantibody (%)

MBPMAGGM,SulfatideMOGCrystallinGlutamateTubulinCONSO«NAF

4.04.00.0

17.210.110.111.157.627.3

6.1

IgG

Normal(%)

050

2020200

3020

0

Controls(%)

5426521223

Abnormal(%)

34.342.40.0

17.225.327.315.239.433.341.4

IgM

Normal(%)

2030055

2505

2020

Controls(%)

2345440212

Notes: Ig = immunoglobulin, MBP = myelin basic protein, MAG = myelin-associated glycoprotein,oligodendroctye glycoprotein, CONSO4 = chondroitin sulfate, and NAF = neurofilament antigen.

IgA

Abnormal Normal(%) (%)

20.223.24.03.01,08.17.18.1

10.518.2

GM, =

51555050

105

10

ganglioside, MOG

Controls(%)

1252332121

= myelin

August 2003 [Vol. 58 (No. 8)] 467

CONSO4 (17.26), and NAF (5.15). The OR for CM,could not be calculated because of the 0 value for thepatients. The ORs for IgM neural autoantibodies weresignificant for all antigens, and ranged from 3.39 to44.6. The ORs for CM, and glutamate receptor werenot calculated because of 0 values for the controls.With respect to IgA autoantibodies, the ORs for sul-fatide (1.7) and MOG (0.82) were not significant,whereas those for the other neural antigens were signif-icant as follows: MBP (21.2), MAG (13.7), crystallin(2.65), glutamate receptor (3.03), tubulin (9.08),CONSO< (4.99), and NAF (2). CM, could not be calcu-

lated because of 0 values; the 95% Cl for MOG was notcalculated because of the value of 1 in controls.

The percentages of individuals with autoantibodyliters that exceeded the maximum 95% Cl for expectedlaboratory ranges, along with ORs, are presented inTable 4. We calculated these data for abnormal, nor-mal, and control patients as follows: If an individualhad only 1 isotype against a neural antigen (i.e., IgG),that person was given the same score as an individualwith 2 or more isotypes (i.e., IgG + IgM + IgA). The per-centages of individuals with autoantibodies againsteach neural antigen were highest among the abnormal

Table 3. — Odds Ratios (ORs) and 95% Confidence Intervals (CIs) for Autoantibodies for Each Isotype Presentedin Table 1

IgC

Neural autoantibody OR 95% Cl

MBP 0.66 1.92,0.22MAC 1.05 3.86,0.39CM, — *Sulfatide 3.36 6.1,1.84MOC 2.53 4.95,1.25Crystallin 6.53 15.2,2.83Glutamate 10.08 29.4,3.3Tubulin 55.1 112.4,27.1CONSO4 17.26 36.6,8.2NAF 5.15 13.06,1.88

OR

22.9821.86

*3.396.78.83

, *

24.844.629.8

Notes: Ig = immunoglobulin, MBP = myelin basic protein, MAC =glioside, MOG = myelin oligodendroctye glycoprotein, CONSO« =antigen. For these calculations, patients with abnormalthose with normal NCVs and compared vs. controls.•Not calculated because of zero values (refer to Table 2)

IgM

95% Cl

47.9, 11.040.9,11.59

5.6, 2.0512.2,3.516.4,4.9

50.9, 11.8116.7, 16.462.2, 14.9

myelin-associatedchondroitin sulfate.

OR

21.213.7

*1.70.822.653.069.084.99

20.0

glycoproteinand NAF =

nerve conduction velocities (NCVs) were

IgA

95% Cl

57.4, 7.86.2,28.8

0.52, 5.5— t

1.13,6.178.17, 1.14

38.02,26.82.05, 11 .97.26, 54.6

, GMi = gan-neurofilamentgrouped with

tNot calculated because of the value of 1 in a cell (refer to Table 2).

Table 4.—Percentages of Individuals with 1 or More Isotypes for Each Neural Antigen thatExceeded the Maximum 95% Confidence Interval (Cl) Tiler

Neural autoantibody

Abnormal(n=119)

Normal(n = 20)

Controls(n = 500)

OR 95% Cl .

MBPMAGCM,SulfatideMOGCrystallinGlutamateTubulinCONSO.,NAF

47.554.54.0

30.332.335.426.369.746.550.5

20455

2525350353025

8911131293555

8.6311.40.912.83.35.59.0

33.5814.7516.3

11.5,6.416.4,7.81.7,0.484.4,1.7

4.85,2.28.0,2.717.6,4.6

56.8,19.125.3,8.5816.3,12.4

Notes; MBP = myelin basic protein, MAG = myelin-associated glycoprotein, GMi = ganglioside,MOC = myelin oligodendroctye glycoprotein, CONSO4 = chondroitin sulfate, and NAF = neu-rofi lament antigen. The percentages were determined as follows: If a patient had 1 isotype (e.g.,immunoglobulin llglC, IgM, or IgA), that patient was given the same score as a patient with 2 ormore isotypes. Thus, the total percentages for patients with abnormal nerve conduction velocities(NCVs), normal NCVs, and controls were less than the totals for each isotype as presented inTable 1. For simplicity, the data for patients with abnormal and normal NCVs were combined toobtain the odds ratios (ORs).

468 Archives of Environmental Health

patients (range = 26.3%-69.0%) when compared withcontrols (range = 3%-13%), with the exception of CM,(4%). Similarly, the normal patients had an increasedpercentage of individuals with higher tilers (range =20%-45%) when compared with the controls, with theexception of CMi (5%) and glutamate receptor (0%).The ORs were significant (95% CD for all neural anti-gens, except for CM, (0.91). The ORs were highest fortubulin (33.58) and decreased, in descending order, forNAF (16.3), CONSCX, (14.75), MAG (11.4), glutamatereceptor (9.0), MBP (8.63), crystallin (5.5), MOG (3.3),and sulfatide (3.3).

NCV testing. No changes or abnormalities were ob-served for F and H waves in the abnormal or normal pa-tients (data not shown).

The data obtained from the NCV studies for motornerves and sensory nerves are summarized in Tables 5and 6. Patients with abnormal findings comprised 3groups, as follows: (1) mixed sensory-motor polyneu-ropathy (n = 55), (2) motor neuropathy (n = 17), and (3)sensory neuropathy (n = 27). There were 20 patientswith no abnormalities (controls). We compared the dataobtained for the 20 controls with data for the 3 groupsof abnormal patients (mixed, motor, and sensory neu-ropathies), for statistical purposes.

Results for the mixed poly neuropathy group differedsignificantly from controls. Latencies for the median(4.2 ± 1.2 ms, p < 0.001), ulnar (3.13 ±1.1 ms, p <0.05), peroneal (5.1 ± 1.4 ms, p < 0.001), and tibia!motor nerves (5.5 ± 2.9 ms, p < 0.001) were signifi-

Table 5.—Neuropathies Experienced by Patients with Abnormal Nerve Conduction Velocity(NCV) Measurements (n = 119), vs. Controls with Normal Values (n = 20), by NCV ParameterTested

Neuropathy with abnormal NCV

NCV parameter

Mixed(n = 55)

x SO

Motor

SO

Sensory(n = 27)

x SD

Controls(n = 20)

x SD

Median latency (ms)Median amplitude (uV)Median velocity (m/sec)Ulnar latency (ms)Ulnar amplitude (uV)Ulnar velocity (m/sec)Peroneal latency (ms)

Peroneal amplitude (uV)

Peroneal velocity (m/sec)

Tibial latency (ms)

Tibial amplitude (uV)

Tibial velocity (m/sec)

Median latency (ms)

Median amplitude (uV)

Ulnar latency (ms)

Ulnar amplitude (uV)

Sural latency (ms)

Sural amplitude (m/sec)

4.29.5

56.53.139.9

60.95.1

(n5.6

(n52.5

(n5.5

(n9.8

(n46.6

(n4.2

(n27.1

(n3.7

(n27

(n4.9

(r)11(n

1.2*4.37.8*Lit3.79.9§1.4*

= 54)3.2

= 54)12.7

= 54)2.9*

= 53)6

= 53)11. 3t

= 53)1.3*

= 54)15.9

= 54)1.41*

= 54)18.5t

= 54)3.2*

= 44)8.4t

= 44)

3.67.6

55.93.79.9

60.45.5

4.2

47.5

6.3

8.1

47.3

3(n =

40.3(n =

2.7(n =

31.9(n =

3.8(n =

14.2(n.

1.13.3t5.3*2.05*27.4*1.2*

1.9§

. 13.3t

3§

4.8t

s.st

0.1616)15.2

16)0.2

16)14.9

16)0.28

11)5.9

11)

3.410.858.12.79.9

65.14.7

(n6.05

(n52.2

(n4.2

13.6

46.6

4.2

32.4

4.6

28.1

4.4(n

11.2(n

0.362.67.40.381.86.60.52*

= 26)2.2

= 26)5.8

= 26)0.55

4.8

4.4§

1.5*

20.5

2.3*

18.6

1.4t= 24)

10.5t= 24)

3.310

61.52.56

1066.23.9

6.6

58.2

4

12.7

52.3

3.08

35.1

2.54

35

3.8(n =

21.7

("~

0.43.37.10.533.135.40.86

3

13.8

1

6.8

8.3

0.17

15.6

0.25

15.3

0.3217)19.2

17)

Notes: With respect to the 20 normal patients, no abnormal values were observed for each mea-surement except for the tibial motor nerve measurements, in which the velocity was slightly re-duced (41 ms), with the cutoff for normal being > 41 ms. For cases in which the number of pa-tients was not the same as that shown in the column heading, the actual number (n) is givenwithin the table.*p< 0.001.tp < 0.05.tp < 0.02.§p < 0.01.

August 2003 [Vol. 58 (No. 8)] 469

Table 6.—Percentages of Individuals with Various Numbers(0-7) of Nerves Showing Abnormal Nerve ConductionMeasurements (Latency Onset, Amplitude, or Velocity),for Mixed (Motor and Sensory), Motor, and SensoryNeuropathies

Neuropathy

No. of nerves withabnormal measurements

Mixed(n = 55)

Motor Sensory(n=17) (n = 27)

0.01.8

38.223.621.810.9

1.81.8

0.041.247.15.95.9

11.133.333.718.5

Notes: Among the 20 controls, 1 individual had an abnormalmeasurement for the tibial motor nerve (velocity = 41 ms), re-sulting in an abnormal rate of 0.4% for all motor nerve mea-surements. No abnormalities were seen among the controls forthe other 4 motor nerves or the 3 sensory nerves.

cantly increased vs. controls. Amplitudes for all motornerves were not significantly different from controls.Velocities for the median (56.5 ± 7.8 m/sec, p < 0.02),ulnar (60.9 ± 9.9 m/sec, p < 0.01), and tibial (46.6 ±11.3 m/sec, p < 0.05) motor nerves were significantlydecreased vs. controls. Latencies for the median (4.2 ±1.3 ms, p < 0.001), ulnar (3.7 ± 1.41 ms, p < 0.02), andsural (4.9 ±3.2 ms, p < 0.02) sensory nerves were sig-nificantly increased vs. controls. Amplitudes for theulnar (27 ± 18.5 uV, p < 0.05) and sural (11 ± 8.4 uV, p< 0.5) sensory nerves were significantly decreased com-pared with controls.

In patients with only motor nerve neuropathy, laten-cies for ulnar (3.7 ± 2.05 ms, p < 0.02), peroneal (5.5 ±1.2 ms, p < 0.001), and tibial (6.2 ± 3 ms, p < 0.01)nerves were significantly increased; amplitudes for themedian (7.6 ± 3.3 uV, p< 0.05), peroneal (4.2 ± 1.9 uV,p < 0.01), and tibial (8.1 ± 4.8 uV, p < 0.5) nerves weresignificantly decreased; and velocities for the median(55.9 ± 5.3 m/sec, p < 0.01), ulnar (60.4 ± 7.4 m/sec, p< 0.02), peroneal (47.5 ± 13.3 m/sec, p< 0.05), and tib-ial (47.3 ± 5.5 m/sec, p < 0.05) nerves were significant-ly slower than the controls. Latencies and amplitudesfor the sensory nerves (median, ulnar, and tibial) werenot significantly different from control values.

In patients with only sensory neuropathy, latenciesfor the median (4.2 ± 1.5 ms, p < 0.001), ulnar (4.6 ±2.3 ms, p < 0.001), and sural (4.4 ± 1.4 ms, p < 0.05)nerves were significantly increased vs. controls; ampli-tudes of the sural nerve (11.2 ± 10.5 uV, p < 0.05) weresignificantly decreased; and all neurophysiologicalmeasurements tended to differ from the control values.None of the measurements for motor nerves in this

group—except for peroneal latency (p< 0.001) and am-plitude (p < 0.01)—were different from the controls.

Table 6 summarizes the data for the percentages of pa-tients with various numbers of nerves that demonstratedabnormal conduction. In those patients with mixed neu-ropathy, all nerves had abnormal measurements with adistribution as follows: 1 involved nerve (5.5%), 2 in-volved nerves (38.2%), 3 involved nerves (23.6%), 4 in-volved nerves (21.8%), and 5 or more involved nerves(14.5%). Of those patients who exhibited motor neu-ropathy, 41,2% had only 1 involved nerve, whereas58.9% had 2 or more involved nerves. Patients with sen-sory neuropathy had the following distribution: 11.1%had nerves with no abnormal findings, 33.3% had only1 nerve with abnormal measurements, and 52.2% had 2or more nerves with abnormal measurements.

Discussion

All patients in this study had documented exposure tomolds in their homes and/or workplaces. They also hadsignificantly elevated antibodies to molds and to myco-toxins, which confirmed exposure.63"55 In addition,multiple organ symptoms were present, as reported pre-viously.63 In this particular group of patients, additionalhealth complaints consisted of symptoms of peripheralneuropathy (i.e., tingling, numbness, tremors, and mus-cle weakness in the extremities). Thus, we evaluatedthese patients for the presence of antibodies to 9 neur-al antigens, as well as for evidence of abnormalities inperipheral nerve conduction. All patients had signifi-cant increases in autoantibodies against neural antigens(Tables 1-4). Abnormalities in latencies, amplitudes,and velocities of selected peripheral nerves (Tables 5and 6), and peripheral neuropathy, were observed in 99patients, whereas 20 symptomatic patients had normalNCV measurements.

Examination of the patients' antibody liters revealedthat IgG antibody tilers to the neural antigens betweenpatients with abnormal vs. normal NCVs were not sig-nificantly different, with the exception of NAF (p <0.01). However, when compared with healthy controls,the difference between IgG tilers for abnormal vs. nor-mal patients was highly significant (p < 0.001). In con-trast, IgM tilers in abnormal patients were consistentlyelevated when compared with normal patients, withsignificant differences for CONSO4 (p < 0.05), gluta-mate receptor (p < 0.01), tubulin (p < 0.01), and NAF (p< 0.01). Autoantibodies in both abnormal and normalpatients showed significant elevations compared withcontrols (p < 0.001). With respect to IgA antibodies,NAF liters were significantly elevated in abnormal vs.normal patients. The liters for both abnormal and nor-mal patients were significantly elevated compared withcontrols, with the exception of CMi and glutamate re-ceptor. Thus, we concluded that exposure to molds,

470 Archives of Environmental Health

and symptoms of peripheral neuropathy, are associatedwith autoantibodies to 9 different neural antigens.These data support and extend the observations of Grayet al.,30 who demonstrated increased antibodies tomyelin and NAF in mold-exposed individuals.

Autoantibodies to neural antigens have been report-ed for several neurological conditions.66'72 Pestronk etal.66 confirmed that elevated tilers of MAG antibodies inpatients are relatively specific for sensory and motorpoly neuropathy syndromes with demyelination. NCVswere used to confirm the demyelinating changes inthese patients. Of the patients studied, 92% with IgMantibodies to MAG had physiologic evidence of de-myelination.66 MS patients have shown antibodies tomyelin, MOG, MBP, a-B-crystallin, and complement-mediated demyelination.6873 Anti-ganglioside, anti-gly-colipid, anti-sulfatide, anti-MAG, anti-tubulin, and anti-CONSO4 antibodies have been demonstrated in motor,sensory, and polyneuropathies with demyelination.72"66

IgM isotypes to sulfatide,74'73'77 ganglioside,78 andMAG83 are correlated with electrophysiological periph-eral nerve abnormalities. Moreover, antigangliosidesand galactocerebroside antibodies are associated withinfections from Campylobacter jejuni and Mycoplasmapneumonias in patients with Guillain-Barre syndrome.81

In addition, IgM, anti-MAG, anti-glycolipids, and anti-NAF antibodies are present in individuals with chronicdemyelinating conditions of the nervous system.67'73'83-86

Thus, we suggest that the presence of autoantibodies toneural antigens in our patients is the result of exposureto toxic metabolites'3-2m61 of molds, or may resultfrom an infectious process. The presence of abnormal Tand B cell function of the immune system30 in nasal,41

pulmonary,39'40 and neurologic87'88 infections by moldssupports this conclusion. Finally, we have observed in-creased T cell activation; C3 and C4 complements; andIgA, IgM, and IgG immune complexes in 33 patientswho had chronic exposure to molds in a water-dam-aged building, which suggests an inflammatory process(manuscript forthcoming).

The ORs in Table 3 are also revealing. IgM isotypesagainst the neural antigens had ORs consistently greater(range = 3.39-44.6) than those for IgG isotypes (range= 0.66-17.26), with the exception of antitubulin (55.1vs. 24.8). The ORs indicate an increased risk of devel-oping antineural antibodies, but also may suggest thatIgM isotypes are more consistent with symptomatic ac-tive or progressive neuropathy than are IgG isotypes,and may represent an ongoing acute or subacuteprocess. As mentioned earlier, IgM antibodies to variousneural antigens have been associated with neurophysi-ological and pathological changes characteristic of var-ious neuropathies. Finally, the ORs in Table 4 for thepercentages of individuals with 1 or more isotypesagainst the neural antigens show a relative increasedrisk (range = 2.8-33.58) of developing autoantibodies.

The only exception was GM, autoantibodies (OR =0.91). Thus, we concluded that individuals exposed tomolds in a water-damaged building have an increasedrisk of developing antineural antibodies. Additionalwork is needed to determine at what point theseprocesses become irreversible.

Our neurophysiological data revealed 3 differenttypes of peripheral neuropathies: mixed sensory-motorpolyneuropathy (55 abnormal patients), motor neuropa-thy (17 abnormal patients), and sensory neuropathy (27abnormal patients), as well as patients who exhibitedsymptoms but had no abnormal electrophysiologicalfindings (20 normal controls) (Table 5). The differencesbetween the 20 normal patients and the 99 abnormalpatients are likely attributable to the significant increasein IgG and IgM autoantibodies to NAF, tubulin, gluta-mate receptor, and CONSO4 observed in the abnormalpatients. The role that IgA antibodies play is unclear atthis time. Additional observations are needed to clarifythe role of each isotype (IgA, IgM, and IgG) and to de-termine which neural autoantibodies contribute to theobserved neuropathies.

The increased latencies for motor and sensory nervesobserved in the 55 patients with mixed neuropathy sug-gest a demyelinating process.83 The increased latencieswere accompanied by a decrease in velocities for themedian, ulnar, peroneal, and tibial nerves. All threesensory nerves (median, ulnar, and sural) exhibited in-creased latencies and decreased amplitudes. Thus, thepolyneuropathy observed in these patients appears tobe a demyelinating process with decreased number andsize of fibers (decreased amplitudes) and chronic in-volvement of the nerve (decreased velocities).72'83

Those with motor neuropathies (17 patients) had de-creases in latencies (ulnar, peroneal, and tibial nerves),decreased amplitudes (median, peroneal, and tibialnerves), and decreased velocities (median, ulnar, per-oneal, and tibial nerves). This appears to be a diffuseneuropathy and may involve some demyelination.89 Fi-nally, those with sensory neuropathies (27 patients) hadincreased latencies for all 3 nerves, whereas the suralnerve had a decreased amplitude. The increased laten-cies and decreased amplitude of the these nerves sug-gest that demyelination is occurring.90

The severity of the neuropathies experienced by thepatients in our study is implicit as a result of the in-volvement of several nerves (Table 6). With respect tothe mixed-neuropathy patients, only 1.8% had abnor-malities in only 1 nerve, whereas 38.2% had at least 2nerves involved. The remaining patients (59.5%) had 3or more nerves with abnormal neurophysiologicalrecordings. Impairments in the patients with motor neu-ropathy were slightly less dramatic, with 41.2% havinga single nerve involvement, and the remainder having 2or more nerves involved. Finally, in those patients withsensory neuropathy, 33.3% had 1 nerve and 52.2% had

August 2003 [Vol. 58 (No. 8)] 471

2 or more nerves involved. Thus, we concluded that theneuropathies in these patients were severe and in manycases involved several nerves.

In summary, 119 individuals exposed to mold col-onies in water-damaged buildings were found to haveautoantibodies directed against 9 different neural anti-gens. Neurophysiological recordings for latencies, am-plitudes, and velocities on 4 motor nerves and 3 senso-ry nerves revealed peripheral neuropathies in 99patients (83%). Three abnormal conditions were found:mixed sensory-motor polyneuropathy, motor neuropa-thy, and sensory neuropathy. We recommend thatmold-exposed individuals with symptoms of neuropa-thy be evaluated for antibodies against neural antigensand for neurophysiological abnormalities. Additionalwork is needed to correlate and clarify the extent of theperipheral nerve pathology and demyelination, as wellas the role of neural autoantibodies in this process.

The authors thank Nina Immers for her kind technical sup-port during the data gathering and tabulation for this study.

Submitted for publication April 5, 2004; revised; acceptedfor publication May 14, 2004.

Requests for reprints should be sent to Andrew M. Camp-bell, M.D., Medical Center for Immune and Toxic Disorders,25010 Oakhurst, #200, Spring, TX 77386.

E-mail: md@immunotoxicology.com

* * * * * * * * * *

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