Indian J Physiol Pharmacol 2000; 44 (3) : 297-303

BRAINSTEM AUDITORY EVOKED POTENTIAL RESPONSESIN IRON-DEFICIENT ANEMIC CHILDREN

N. SHANKARt, o. P. TANDON, R. BANDHU,N. MADAN* AND S. GOMBER**

Departments of Physiology, *Pathology and **Paediatrics,University College of Medical Sciences and G. T.R. Hospital,Dilshad Garden, Delhi - 110 095

( Received on February 23, 2000 )

Abstract: Iron deficiency is a major health problem in developing countriesmanifesting not only as overt anemia but also involving the eNS resultingin cognitive and behavioral deficits. Iron is an important nutrient andessential element involved in myelin formation and neurotransmittersynthesis and thus contributes to normal neurological activity.Hypomyelination has been reported in iron deficient states with possibleneural conduction defects. The brainstem auditory evoked potentialresponse is used extensively to identify lesions associated with variousdemyelinating diseases and hence has been used in the present study toobserve the effect of iron deficiency on sensory brain function. A trend ofincreased absolute and interpeak latencies and reduced amplitudes of thewaves leading to a definite linear correlation between the severity ofanemia and the degree of neurophysiological deficit suggests a subclinicalinvolvement of the auditory pathway in the brainstem of iron deficientchildren.

Key words: iron deficiency brainstem auditory evoked potentialsmean corpuscular volume absolute peak latenciesneurophysiological deficit

INTRODUCTION

Iron deficiency (ID) is the most commonsingle nutrient deficiency in the world. Ithas ben described as a major health problemin developing countries including India (1).Several reviews of ID (2, 3) have noted thatthe documentation of prevalence by virtueof measurement of anemia dramaticallyunderestimates the prevalence of tissue ID.As in other tissues, iron is an essentialelement and an important nutrient of the

brain. Specific to neurological activity, ironhas a major role in myelin formation (4)besides Its involvement in the synthesis andfunction of various neurotransmittersnamely dopamine, serotonin, catecholaminesand possibly GABA (5, 6). There are datathat indicate that iron uptake into the brainis maximal during the period of rapid braingrowth (7) which conincides with the peakof myelinogenesis (8) and that perinatal irondeficiency significantly alters myelination ofthe spinal cord and white matter of

tCorresponding Author

298 Shankar et al

cerebellar folds (9). However, iron uptakeinto the brain continues throughout life (10).In general, the existing data stronglysuggest that the majority of iron, in thenormal brain, is related to oligodendrocyteswhere it is directly involved in myelinproduction as a required co-factor forcholesterol and lipid biosynthesis andindirectly because of its requirement foroxidative metabolism (11). Oligodendrocytesparticipate in iron homeostasis throughthe synthesis and secretion of transferrinwhich is essential for their maturationand function (12). Conditions such asID may reduce iron acquisition by oligoden-drocytes and in this regard the observationthat ID rats are hypomyelinated is highlyrelevant (13). Since myelination isconcerned with the conduction in nervefibers and brainstem auditory evokedpotential (BAEP) recordings have been usedextensively to identify subclinical lesionsassociated with various demyelinatingdiseases (14) we undertook the presentstudy to see if there was any effect of ID inthe BAEP recordings of anemic children.

METHODS

Subjects: 36 children, of both sexes,from _a low socioeconomic group, wereselected for the study after a thoroughclinical assessment to exclude any otherpathological disorder besides anemia. On thebasis of their hemoglobin content they weredivided into a control group (Group I, n = 17,Hb>12 g/dl) and an anemic group (Group II,n = 19, Hb<12 g/dl). The mean age of thecontrol group was 8.65 ± 3.28 y while thatof the anemic group was 7.53 ± 4.29 y. Theparents were informed about the nature ofthe study and following their written

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consent all the investigations wereperformed in their presence.

Recording of hematological parameters:A number of hemotological parameters wereinvestigated to evaluate the iron-deficientanemic (IDA) status of the subjects. Hb,MCV'and MCHC were detected by electricalimpedence method using CoulterHematological Particle Counter Model T-890, Coulter Electronics, UK. Serum iron(S1) and total iron binding capacity (TIBC)were measured by spectrophotometry.

Recording of BAEPs: The subjects werebriefed about the test procedure. They wereseated comfortably in a chair in a standardaudiometric, sound proof and air-conditionedroom. The recording was done using theNeuropack II Evoked Potential RecorderMEB-5200, Nihon Kohden (Japan). TheBAEPs were obtained from scalp electrodes(Ag/AgCI disc electrodes) anchored on thevertex with collodian. The active electrodewas placed at CZ with reference electrodeson the mastoid at M1 & M2 and the groundelectrode at FZ. Both ears were testedindividually using shielded headphones. Thestimulus consisted of 0.1 ms square wavesof an intensity of 70 dB nHL. On an average2048 of such stimuli were given. Recordingsconsisted of the absolute peak latencies (ms)of waves I, II, III, IV and V together withinterpeak latencies (ms) of I-III, III-V & I-V and the amplitudes (J.1v)of wave I and V.The methods used are similar to thosereported in earlier studies (15).

Statistical analysis: Unpaired Student"t" test was done to find out the statisticalsignificance of changes in the BAEP wavesin the anemic children as compared to the

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controls. ANOVA test was performed to findthe correlation between differentparameters. Regression studies were alsodone between the various BAEP recordingsand the hematological parameters.

RESULTS

1. Mean age of both groups: Statisticalanalysis showed no significant differencebetween the mean ages of the anemics andcontrols (Table I).

BAEP in Iron Deficiency 299

2. Comparison of the hematologicaland BAEP values of both groups:

(a) Hematological values: There weresignificantly lower values of Hb, MCV,MCHC and SI in the anemic group ascompared to the control group thuscorroborating their IDA status. The TIBCof the anemic group was found to be morethan that of the controls though thisdifference was not statistically significant(Table I).

Parameter

TABLE I: Age and hematological parameters of control (Group 1) and anemic (Group II) children.

Group I (n = 17)mean ±SD

Group II (n. = 19)mean ±SD

Age (y)Rb (g/dL)MCV (fL)MCRC (g/dL)SI (mg/L)TIBC (mg/L)

8.65±3.2812.88±0.6784.84±7.4634.62±1.760.80±0.353.50±0.59

7.53±4.299.39±2.63**

72.51±11.09**30.22±3.17*0.51±0.23*3.77±0.83

Significance: **P<O.OOl, *P<O.Ol

TABLE II: BAEP parameters (average value both ears) of control(Group I) and anemic (Group II) children.

Parameter Group I (n = 17)mean ±SD

Group II (n = 19)mean ±SD

Peak latencies (ms)

III

IIIIVV

1.63±0.232.61±0.233.70±0.254.77±0.255.56±0.23

Interpeak latencies (ms)

I-VIII-VI-III

3.94±0.161.86±0.152.08±0.13

Amplitue (pv)I

V0.38±0.210.39±0.22

0.36±0.140.37±0.11

Significance: *P<0.05

1.71±0.242.66±0.243.81±0.274.96±0.27*5.67±0.30

3.98±0.221.90±0.202.09±0.15

300 Shankar et al

(b) BAEP values: The absolute peaklatencies of all the waves (I to V) were morein the case of anemic children though thevalue was significantly different from thecontrols only in the case of wave IV. Theinterpeak latencies of the waves as well astheir amplitudes were not significantlydifferent between the two groups eventhough the anemic group showed increasedlatencies and lower amplitudes as comparedto the controls (Table II).

(c) Correlation between hematologicalparameters and the BAEP recordings in theanemic group by Regression studies: Asignificant correlation was found betweenMCV values and the waves III to V with

7.0r-----------------"'9

6.5

6.0. .

5.5

••E::;- 5.0Q.ct

4.5 IV'"D

4.0

3.5 III

3.0-I-----~--~-....--~-___._-_r_--i40 50 60 70 80 90 100 110 120

MCV(fl)

1·11\ D IV. viFig. 1: Scatter diagram showing a significant

correlation between MeV values (fL) and theabsolute peak latencies (APL ms) of BAEPwaves III, IV and V. (The r values for wavesIII, IV and V are 0.372, 0.432 and 0.382respectively).

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lower values of MCV corresponding withlonger absolute peak latencies of the waves(Fig. 1). The significance was maximallyseen with wave IV. The other hematologicalvalues though correlating with the latenciesof the BAEP waves did not show statisticallysignificant results.

DISCUSSION

The brainstem auditory evokedpotentials have been found to be a usefultool in investigating neurologic disordersthat may involve the brainstem auditorypathway (14). On the basis of several studiesit appears that waves I, III and V primarilyrepresent volume-conducted electricalactivity from the acoustic nerve, superiorolivary and inferior olivary nuclei while IIand IV represent the acitivity from cochlearnucleus and lateral laminiscus respectively.The interpeak latencies between the wavesindirectly reflect neural conduction in thecorresponding segments of the centralauditory pathway. Another basic BAEPparameter of central auditory conduction isbased on the relative amplitudes of the wave(16). BAEP has been used extensively toidentify subclinical lesions associated withvarious pathological disorders includingdemyelinating diseases (17, 18). Thelatencies have been shown to increase inthese disorders as has been seen in ourstudy. Several studies have shown thedisruption of iron homeostasis indemyelinating diseases (13, 14) and insensorimotor deficit seen in ID children (19).

This study reveals that a correlationexists between the hematological parametersand the BAEP recordings of IDA children

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suggesting a subclinical involvement ofauditory pathway in the brainstem asindicated by the increased absolute andinterpeak latencies of the waves. Thesefindings suggest that the functionalintegrity of this pathway is perhapsdependent upon the normal hematologicalprofile of the individual and that theunfavorable environment of ID could leadto structural or functional damage of thepathway resulting in the BAEPabnormalities. A definite correlation is alsoseen between the severity of anemia andthe degree of neuro-physiological deficits.A Chinese study also showed a directrelationship between the severity of IDA andthe degree of abnormality of the auditorybrainstem responses in infants (20).

The mechanisms for this alterationIn the conductive process may bemultifactorial involving a number ofbiochemical pathways in which iron isessential. These include mitochondrialenzymes, various neurotransmitters andlaying down of myelin sheath. The alteredlevels of these may explain decreasedconduction and some of the behavioral anddevelopmental changes that occur. Moore etal (21) have shown that myelinationaccounts for the onset of acoustimotorreflexes and BAEPs, processes which dependon rapid synchronized conduction ofauditory impulses in the cochlear nerve andbrainstem. Animal models of nutritional IDhave demonstrated a reduction of the brainnonheme iron (22, 23) with a mostsignificant and selective diminution ofcentral dopaminergic neurotransmissionresulting from decreased number of the

BAEP in Iron Deficiency 301

dopamine D2 receptors in various regions ofCNS including frontal cortex (24, 25). Theconsequences of diminished dopaminergicneurotransmission is modification of thedopamine dependent sensory and cognitivemechanisms of behavior and biochemicalreactions, the most important of which isthe learning process (26). Erikson et al (27)showed a heterogenous decrease in regionalbrain iron due to ID in rats, with significantamounts of iron lost from the hippocampusand the cortex as compared to other regionsof the brain.

The ability to detect ID has improvedvastly over the past several decades (28). Ameasure of the hemoglobin concentration is .often preferred over hematocrit or thenumber of red cells to establish the presenceof anemia. In children anemia is defined ashemoglobin values less than 12 g/dl (29).Functional iron exists mainly as hemoglobinin circulating red cells and in lesseramounts in myoglobin and various tissueenzymes. Laboratory measurements of IDAhave been taken.as Hb < 12 g/dl,MCHC < 34 g/dl, MCV < 80 fL, ferritin< 12 ug/L and transferrin saturation < 16%(30). In case of popu l at.i on s with highprevalence of IDA, red cell measure andserum iron measures (serum iron andtransferrin saturation) are more preferablefor diagnosis (31). Serum transferrin or totaliron binding capacity (TIBC) is inverselyrelated to serum ferritin in otherwisenormal subjects and hence it also providesan indirect measure of storage iron (32). Inthe present study the various hematologicalparameters measured were indicative of IDin the anemic children.

302 Shankar et al

Regression studies revealed a relation-ship between the various hematologicalparameters in the anemic children and thedefects in the BAEP waves which wassignificant between MCV and the absolutepeak latencies of waves III, IV and V. Theseverity of the defect correlated with theabnormal hematological finding in that

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increasing microcytosis produced longerlatencies of the waves. Thus thefindings are indicative of a neurologicalinvolvement consequent to IDA though,perhaps, the significance could not berevealed in all the groups because thechildren showed only mild anemia and maybe larger numbers have to be studied.

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