Saccade Dysfunction Associated with Chronic Petrol Sniffing and Lead Encephalopathy S Cairney, P Maruff, C B Burns, J Currie, B J Currie

472 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2003.019406 on 13 February 2004. Downloaded from

PAPER Saccade dysfunction associated with chronic petrol sniffing and lead encephalopathy S Cairney, P Maruff, C B Burns, J Currie, B J Currie ......

J Neurol Neurosurg Psychiatry 2004;75:472–476. doi: 10.1136/jnnp.2003.019406

Background: In chronic petrol sniffers, recent exposure to high levels of leaded petrol may give rise to a lead encephalopathy characterised by tremor, chorea, ataxia, hyperreflexia, convulsive seizures, and death. Neurological abnormalities associated with lead encephalopathy involve the cortex, basal ganglia, cerebellum, and brain stem. Objective: To use saccadic eye movement tasks as an experimental tool to determine which CNS changes See end of article for are associated with chronic petrol sniffing and which with a history of lead encephalopathy, and to what authors’ affiliations ...... extent these changes are reversible. Methods: Saccade function was assessed in chronic petrol sniffers with a history of lead encephalopathy Correspondence to: (encephalopathic sniffers), chronic petrol sniffers who had never suffered lead encephalopathy (chronic Dr Sheree Cairney, Menzies School of Health sniffers), individuals who had sniffed petrol in the past but had not done so for more than six months (ex- Research, PO Box 41096, sniffers), and individuals who had never sniffed petrol (non-sniffers). Casuarina, NT 0811, Results: Chronic sniffers showed increased latency of visually guided saccades and antisaccades and Australia; Sheree.Cairney@ increased antisaccade errors which suggested cortical and basal ganglia dysfunction. These abnormalities menzies.edu.au returned to normal in ex-sniffers. Encephalopathic sniffers showed the same abnormalities as chronic sniffers but with greater severity and additional saccadic signs including dysmetria, gaze evoked Received 24 May 2003 nystagmus, and saccade slowing which usually indicate cerebellar and brain stem dysfunction. In revised form 4 August 2003 Conclusions: Chronic petrol abuse is associated with cortical and basal ganglia abnormalities that are at Accepted 23 August 2003 least partially recoverable with abstinence. Additional long term cerebellar and brain stem abnormalities ...... are associated with lead encephalopathy. copyright.

s with other types of inhalant abuse, the acute effects Because saccades can be controlled, recorded, and quanti- of inhaling or ‘‘sniffing’’ petrol (gasoline) include fied with much greater precision than most other interactive Aeuphoria, relaxation, ataxia, diplopia, and slurred physiological variables, they have proven to be an excellent speech which reflect the neurotoxic effects of aromatic tool for detecting early and subtle changes in brain function hydrocarbons such as toluene, xylene, and benzene.12 related to neurodegenerative or neuropsychiatric disease. Intoxication from sniffing petrol containing tetraethyl lead Different classes of saccadic eye movements can be distin- may be associated with additional visual hallucinations, guished, each of which has a certain function and a distinct visual distortions, and psychosis.3 High levels of exposure to anatomical substrate and physiological organisation.10 11 To leaded petrol may also give rise to a lead encephalopathy, determine the extent of saccade abnormalities that may be which extends beyond any acute intoxication and is

associated with chronic petrol sniffing or lead encephalo- http://jnnp.bmj.com/ characterised by decreased conscious state, tremor, myoclo- pathy, we assessed groups of chronic recreational petrol nus or chorea, limb and gait ataxia, hyperreflexia, motor sniffers with and without a history of hospital admission for impairment, nystagmus, and convulsive seizures. Death can lead encephalopathy on a battery of saccadic function tests. also occur4–6 (reviewed by Cairney et al1). Lead encephalo- To investigate whether any abnormal saccadic functions pathy requires emergency admission to an intensive care unit normalise with abstinence from petrol sniffing, we also with intubation and sedation. A long period of inpatient studied individuals who had been chronic petrol sniffers in treatment usually follows admission, although full recovery the past but had since abstained. 78

of cognitive, motor, and emotional function may not occur. on September 26, 2021 by guest. Protected Clinical, radiological, and necropsy studies on patients admitted to hospital with lead encephalopathy show METHODS abnormalities involving the cortex, basal ganglia, cerebellum, Participants and brain stem.4–6 8 These patients almost always have a long The study was set in two remote Aboriginal communities in history of chronic recreational petrol abuse,4–6 8 so it is Arnhem Land in northern Australia, where petrol sniffing difficult to determine whether the neurological impairments had been prevalent for many years. From these communities, and brain abnormalities are related to the chronic petrol 112 male volunteers agreed to participate in a prospective sniffing, the lead encephalopathy, or both. In recreational research trial to investigate health and social outcomes of petrol sniffers who had not suffered lead encephalopathy, we petrol abuse.912We present data on a subgroup of 96 subjects recently showed impairments in memory and attentional (age range, 13 to 35 years) for whom saccade assessments functions as well as neurological impairments that suggested were obtained at baseline. Participants were classified into abnormalities of the frontocerebellar brain regions.9 How- groups according to their history of petrol sniffing, using the ever, the cognitive and neurological tasks were unable to consensual methodology used in our earlier studies involving dissociate performance measures that suggested cortical the same participants912(see Clough et al13). impairment from those arising from cerebellar or brain stem Participants who had never sniffed petrol were classified as dysfunction. non-sniffers or controls.

www.jnnp.com Saccade effects of petrol sniffing 473 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2003.019406 on 13 February 2004. Downloaded from

Participants who had sniffed petrol in the past for at least Saccade accuracy (gain) was calculated as the displacement six months but, at the time of the study, had not sniffed of the final eye position with respect to the target position. petrol for the last six months were classified as ex-sniffers. The percentage of hypometric saccades (,85% of target), On average, ex-sniffers had abstained from sniffing petrol for hypermetric saccades (.15% of target), and anticipatory 2.6 (SD 3.3) years. saccades (,70 ms from target onset)19 was calculated for Participants who were currently and actively sniffing petrol each participant. Duration and peak velocity for visually and had done so for a period of at least six months were guided saccades were plotted against saccade amplitude. classified as chronic sniffers. No participant from the ex- Saccade recordings were examined by visual inspection for sniffer or chronic sniffer groups had ever been admitted to the following abnormalities: post-saccadic drift reflecting hospital for lead encephalopathy from sniffing petrol. pulse–step mismatch; saccadic intrusions that are inappropri- Chronic sniffers who were currently living in the commu- ate saccades taking the eye away from the target during nity but who had been admitted to hospital previously for attempted fixation; and gaze evoked nystagmus, which lead encephalopathy from petrol sniffing were classified as shows difficulty maintaining eccentric fixation of the target encephalopathic sniffers. These individuals had required (¡10˚ and ¡15˚) characterised by an alternation between emergency hospital admission and ongoing intensive care slow drift and corrective quick movements of the eye.20 For treatment for lead encephalopathy on a median of 1.0 the antisaccade task, a central fixation point was offset previous occasions (range one to six), confirmed by records simultaneously with the onset of a peripheral target. A at the Royal Darwin Hospital (RDH). Before testing for this correct antisaccade was a deliberate eye movement to the study, the most recent admission for lead encephalopathy location in the opposite visual field of the target and among these individuals was a median of 3.5 (range 1 to 7) equidistant from the centre. Any initial reflexive eye move- years earlier, when they were admitted for a median of 25 ment towards the target was scored as an error, even if a days (5 to 118) and had a median blood lead of 4.6 mmol/l subsequent correction to the opposite side was made. The (1.69 to 7.25) on admission. Blood lead concentrations higher latency for the onset of correct antisaccades was recorded and than 0.48 mmol/l are above Australian recommended safe a percentage error calculated. limits, and concentrations above 3.85 mmol/l indicate lead poisoning.14 All of the encephalopathic sniffers, chronic sniffers, and ex-sniffers (using a retrospective rating) met Data analysis the criteria for inhalant abuse from the Diagnostic and Before analysis, the distributions of data for each perfor- Statistical Manual of Mental Disorders, fourth edition.15 These mance measure were inspected for normality and hetero- individuals had inhaled a combination of leaded and geneity of variance. Demographic, behavioural, and unleaded petrol. biochemical indices of petrol abuse, neurological, and saccade Study exclusion criteria included a history of head injury variables were compared between groups using analysis of with loss of consciousness, known epilepsy, dependence on variance (ANOVA), with post-hoc comparison between each or abuse of alcohol or cannabis, and psychiatric disorders of the petrol sniffer groups and the non-sniffer group using copyright. other than petrol abuse. Participants who had been sniffing Dunnett’s test. Where no control data were available—such petrol for less than 12 hours before testing were also as for measures of the age when sniffing began, the volume excluded. of petrol sniffed each week, or the number of years spent The final study sample consisted of 34 non-sniffers, 24 ex- sniffing petrol—data for each of the ex-sniffer and encepha- sniffers, 22 chronic sniffers, and 16 encephalopathic sniffers. lopathic sniffer groups were compared with those of the chronic sniffer group. Where data were not normally distributed or were categorical, comparisons were done using Procedures Mann–Whitney U non-parametric analysis or Fischer’s exact Ethical approval for the project was obtained from the test. Previously, we computed a global neurological abnorm- institutional ethics committees, an independent Aboriginal ethics committee, and the town councils from the commu- ality score for each individual by summing the number of abnormal neurological assessments using only those symp- nities involved. Informed written consent was given by all http://jnnp.bmj.com/ toms that were identified as being related to petrol sniffing participants before testing. Blood samples were taken from 9 each participant and analysed to determine the concentration (maximum score, 8). These symptoms were postural tremor, of lead and the hydrocarbons toluene and benzene.16 A tandem gait, finger to nose movements (dominant and non- standardised neurological examination was done by a dominant hands), rapid alternating hand movements (domi- physician, based on the ataxia staging and scoring system.17 nant and non-dominant hands), deep reflexes, and palmo- This system rated ataxia and pyramidal and deep tendon mental reflexes. This neurological abnormality score was reflexes. The physician who did the examination was blind to recruited for the present study and used to represent neurological performance in comparison with saccade data. each participants’ petrol sniffing classification. on September 26, 2021 by guest. Protected Eye movement (saccade) recordings were undertaken in a The amplitude range for saccades across all participants darkened room with the head stabilised, using a high was 0.3˚ to 40.9˚. In this amplitude range, the saccade resolution infrared scleral reflectance technique (IRIS, duration–amplitude relation is best represented using a linear Skalar; bandwidth, dc to 100 Hz (23 dB)). Participants were function,21 and the saccade peak velocity–amplitude relation seated one metre from a horizontal display of light emitting is best represented using a square root function.22 From these diode (LED; 16.9 cd/m2; rise time 3 ms) visual targets, with functions, a duration gradient and a velocity coefficient were computer controlled illumination timing. Eye and target derived for each participant and used as the dependent position signals were digitised at 1 kHz and scored for off-line variables representing saccade duration and saccade peak computer analysis. Eye velocity was calculated as the first velocity for analysis between the groups. Dose–response differential of eye position with respect to time. The saccade relations were investigated using Pearson’s product–moment tasks used in this study have been described in detail correlation between measures of the severity of petrol abuse previously.18 Briefly, participants performed visually guided (age started sniffing, volume petrol sniffed each week, saccades to fixate random targets. Saccade latency was number of years sniffing) and biochemical measures (blood calculated as the time from the onset of the target to the lead and blood toluene concentrations) compared with the onset of the saccade. A velocity detection threshold of ¡20˚/s neurological abnormality score and performance on saccade was used to define the saccade onset and saccade end. tasks. The level of significance for comparisons within each of

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Table 1 Paired comparisons between each of the ex-sniffer, chronic sniffer, and encephalopathic sniffer groups and the non-sniffer group for demographic, behavioural, and biochemical data

Non-sniffer Ex-sniffer Chronic sniffer Encephalopathic (n = 34) (n = 24) (n = 22) sniffer (n = 16) F statistic

Age (years) 20.0 (4.0) 22.7 (5.4) 20.8 (5.4) 18.7 (3.9) 7.0 Age range (years) 14 to 32 15 to 35 13 to 31 13 to 27 Age petrol sniffing began (years)a – 13.1 (3.0) 12.5 (3.3) 12.7 (3.4) 0.3 Volume/week (No of 373 ml cans)a – 4.1 (3.7) 3.2 (1.8) 6.6 (2.8)*** 4.2 Duration sniffing (years)a – 6.0 (4.7) 7.4 (3.9) 10.6 (5.7) 2.9 Blood lead (mmol/l) 0.3 (0.1) 1.2 (0.6)*** 1.6 (0.7)*** 2.3 (1.1)*** 44.2 Detectible toluene (%) 0 0 50.0* 66.7* Blood toluene (mmol/l)a – – 0.10 (0.16) 0.27 (0.16)** 6.0 Detectible benzene (%) 0 0 36.4 42.9 Blood benzene (mmol/l)a – – 0.03 (0.04) 0.08 (0.08)* 3.2

Unless otherwise stated, data are presented as group mean (SD). *p,0.05; **p,0.01; ***p,0.001; comparisons made between non-sniffer group and all other groups, except variables flagged with superscript a, where comparisons are with the chronic sniffer group. the domains assessed (demographic, behavioural, biochem- Relations between petrol sniffing severity and ical, neurological, and saccade) was set at 0.05. biochemical measures and neurological and saccadic measures RESULTS Age was not correlated with any measure of neurological or Demographic, behavioural, and biochemical saccade performance for all four groups combined. For the measures ex-sniffer group, the number of years of abstinence from Demographic, behavioural, and biochemical data are given petrol sniffing correlated negatively with the percentage of in table 1. For the ex-sniffer, chronic sniffer, and ence- hypometric saccades (r = 20.44, p = 0.04) and positively with phalopathic sniffer groups combined, the duration of saccade accuracy (r = 0.473, p = 0.03). For the encephalo- sniffing in years correlated positively with blood lead level pathic sniffer group, the number of years since the most (r = 0.472, p,0.001) and the volume of petrol sniffed recent hospital admission for lead encephalopathy did not

per week (r = 0.409, p = 0.002), and negatively with the correlate with the neurological abnormality score or any copyright. age petrol sniffing began (r = 20.610, p,0.001). For the saccade measure. Combining data for the ex-sniffer, chronic ex-sniffer group, the number of years abstinence from sniffer, and encephalopathic sniffer groups, the length of petrol sniffing correlated negatively with blood lead con- time petrol sniffing correlated positively with the neurologi- centration (r = 20.475, p = 0.03). Blood hydrocarbon level cal abnormality score (r = 0.44; p,0.01), the percentage of did not correlate with any measure of petrol sniffing hypometric saccades (r = 0.37; p,0.01), saccade latency behaviour. (r = 0.33; p,0.05), antisaccade latency (r = 0.43; p,0.01), and antisaccade error rate (r = 0.30; p,0.05), and negatively Neurological assessment with saccade accuracy (r = 20.32; p,0.05). Blood lead Group means, standard deviations, and statistical variables correlated positively with the neurological abnormality score for each of the neurological and saccade measures are shown (r = 0.58; p,0.001) and antisaccade latency (r = 0.51; in table 2. In comparison with non-sniffers, the neurological p,0.001). Blood toluene (r = 0.67; p,0.001) and blood benzene (r = 0.63; p,0.01) correlated with the proportion

abnormality score was increased in ex-sniffers, and increased http://jnnp.bmj.com/ to a greater extent in both chronic sniffers and encephalo- of hypermetric saccades but with no other neurological or pathic sniffers. saccade variables.

Saccade assessment DISCUSSION Visually guided saccades These data showed that chronic petrol sniffing is associated In comparison with non-sniffers, ex-sniffers showed no with raised blood lead and hydrocarbon levels, and with saccadic abnormalities. Compared with non-sniffers, chronic neurological and saccade impairments consistent with

sniffers had a significant increase in saccade latency but no dysfunction of cortical and basal ganglia brain regions. on September 26, 2021 by guest. Protected further abnormalities for visually guided saccades. Compared These are at least partially recoverable with abstinence. with non-sniffers, the performance of encephalopathic Importantly, chronic petrol sniffers with a history of lead sniffers on the visually guided saccade task was characterised encephalopathy from petrol sniffing (hereafter called by increased rates of saccadic intrusions, post-saccadic drift, encephalopathic sniffers) showed additional saccade gaze evoked nystagmus, hypometric and hypermetric sac- impairments that suggested cerebellar and brain stem cades, anticipatory saccades, increased saccade latency, and abnormalities. Their saccadic abnormalities were charac- reduced peak velocity. terised by increased saccadic and antisaccadic latency, increased antisaccade error rates, saccadic intrusions, post- Antisaccades saccadic drift, gaze evoked nystagmus, increased anticipa- Performance of ex-sniffers was the same as for non-sniffers. tions, dysmetria, and a reduction in the peak velocity of Antisaccade error rate was increased significantly in both the visually guided saccades. For encephalopathic sniffers, strong chronic sniffer and encephalopathic sniffer groups compared evidence for a petrol related disruption to cerebellar and with the non-sniffer group. Compared with non-sniffers, brain stem ocular motor areas was suggested by the antisaccade latency was also increased in the chronic sniffer dysmetria, gaze evoked nystagmus, and saccadic slowing. group and to a greater extent in the encephalopathic sniffer For example, a strong association between cerebellar group. abnormalities and saccadic dysmetria is shown in studies of

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Table 2 Paired comparisons between each of the ex-sniffer, chronic sniffer, and encephalopathic sniffer groups and the non-sniffer group for neurological and saccade data

Non-sniffer Ex-sniffer Chronic sniffer Encephalopathic (n = 34) (n = 24) (n = 22) sniffer (n = 16) F statistic

Neurological abnormality score (max = 8) 0.5 (1.1) 1.3 (1.5)* 3.1 (1.8)*** 5.9 (2.5)*** 42.4

Visually guided saccades Saccadic intrusionsÀ 10 4 9 12** Post-saccadic driftÀ 44212*** Gaze evoked nystagmusÀ 0103* Hypometric (%) 19.4 (5 to 53) 22.3 (4 to 59) 23.2 (2 to 67) 29.5 (4 to 70)* 1.5 Hypermetric (%) 7.7 (0 to 28) 7.0 (0 to 35) 6.3 (0 to 18) 14.0 (0 to 47)* 2.8 Anticipations (%) 10.0 (0 to 47) 8.5 (0 to 51) 13.2 (0 to 42) 18.6 (3 to 74)* 2.4 Latency (ms) 170.2 (22.7) 175.5 (25.2) 185.2 (27.2)* 205.1 (32.1)*** 7.0 Accuracy (%) 98.8 (12.6) 95.2 (6.6) 94.3 (7.0) 93.8 (11.8) 1.3 Peak velocity` Coefficient 133.7 (20.5) 131.7 (19.1) 129.3 (23.6) 119.4 (23.6)* 1.7 For 10˚ saccades ( ˚/s) 423 416 409 378 For 20˚ saccades ( ˚/s) 598 589 578 534 Duration` Amplitude gradient 2.2 (0.5) 2.2 (0.7) 2.3 (0.8) 2.4 (0.6) 1.0 For 10˚ saccades (ms) 39 39 40 41 For 20˚ saccades (ms) 61 61 63 65

Antisaccades Latency (ms) 261.4 (38.4) 280.3 (65.0) 300.8 (62.8)** 406.1 (99.2)*** 15.4 Error rate (%) 16.3 (12.0) 26.0 (27.4) 40.7 (33.6)*** 52.3 (37.4)*** 7.1

Values are median (range) or mean (SD). ÀScored as the number of participants from each group who show these saccade characteristics. `To give meaningful examples of the data, measures of peak velocity and saccade duration were derived from the coefficient and gradient scores, respectively, for saccade amplitudes of10˚ and 20˚. *p,0.05; **p,0.01; ***p,0.001; comparisons made between the non-sniffer group and all other groups.

23–25 humans with degenerative cerebellar disorders and than six months showed mild neurological abnormalities and copyright. generalised cerebellar brain lesions in both primates26 and no saccadic abnormalities. This reduction in the extent and humans.27 Individuals with cerebellar abnormalities also severity of neurobehavioural impairment with abstinence show gaze evoked nystagmus23 25 28 and saccade slowing is from petrol sniffing is consistent with our previous cognitive commonly reported in individuals with lesions affecting both data that showed only subtle memory and attentional cerebellar and pontine brain regions.23–25 28 dysfunction in ex-sniffers.9 These data suggest that at least Chronic petrol sniffers with no history of hospital admis- some of the neurological deficits associated with recreational sion for lead encephalopathy (hereafter called non-encepha- petrol abuse may be ameliorated by abstinence. Importantly, lopathic sniffers) began sniffing petrol at the same age and none of the ex-sniffers had a history of lead encephalopathy had sniffed for the same number of years as the encephalo- from petrol sniffing and all the participants from our study pathic sniffers. However, in comparison with the encephalo- who had been admitted to hospital with lead encephalopathy pathic sniffers, they had a lower exposure to petrol as they continued to sniff petrol upon discharge. Consequently, we

sniffed less petrol each week and consequently had lower were not able to determine the nature or magnitude of http://jnnp.bmj.com/ blood lead and hydrocarbon concentrations. More impor- improvement in neurological and saccade function that is tantly, and despite showing neurological abnormalities, the possible with abstinence from petrol sniffing after lead non-encephalopathic sniffers did not have any dysmetria, encephalopathy has occurred. gaze evoked nystagmus, or saccadic slowing. Instead their These results showed that blood lead and blood hydro- saccadic abnormalities were limited to increased saccadic and carbon levels, as well as the length of time spent petrol antisaccadic latency and an increased antisaccade error rate. sniffing, correlated with the magnitude of neurological and Thus saccade abnormalities in non-encephalopathic sniffers saccade impairment. As in our previous study, this suggested

were less severe and less extensive than those observed in the that the extent of brain dysfunction among petrol sniffers is on September 26, 2021 by guest. Protected encephalopathic sniffers. determined by the severity of their past exposure to petrol.9 Importantly, the abnormalities observed in non-encepha- Many studies have reported positive relations between blood lopathic sniffers included no evidence of any disruption to lead levels and cognitive performance.93334 When inhaled, the cerebellar and brain stem areas associated with saccadic lead is stored by bone and fat for many years and slowly control. Instead the pattern of impairment was consistent released into the circulation; consequently there is a with disruption to cortical and basal ganglia saccadic areas. continued decline of cognitive function for up to 16 years For example, increased latency of visually guided saccades after the most recent exposure to lead.35 Thus, although and antisaccades in combination with increased antisaccade leaded petrol has not been available in Australia since 2002, errors is observed following focal cortical lesions, in past exposure may continue to have a detrimental impact on neurodegenerative diseases with a cortical focus such as brain function even years after petrol sniffing has stopped. Alzheimer’s disease, and in neurodegenerative disease that The neurological and saccade impairments observed here disrupt frontal and basal ganglia pathways (for example, in petrol sniffers are qualitatively similar to those found in Parkinson’s disease).29–32 Abnormal neurological signs are chronic sniffers of hydrocarbon solvents.36–38 However, also common in these patient groups. whereas those inhalant abusers were exposed only to Compared with healthy controls, participants who had hydrocarbons, the current group of petrol sniffers had abused sniffed petrol in the past but who had abstained for longer both leaded and unleaded varieties of petrol, and were

www.jnnp.com 476 Cairney,Maruff,Burns,etal J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2003.019406 on 13 February 2004. Downloaded from therefore inhaling organic lead as well as the hydrocarbons 8 Goodheart RS, Dunne JW. Petrol sniffer’s encephalopathy. Med J Aust 1994;160:178–81. toluene, xylene, and benzene. These data suggest that the 9 Maruff P, Burns CB, Tyler P, et al. Neurological and cognitive abnormalities toxicity of both lead and hydrocarbons contributes to the associated with chronic petrol sniffing. Brain 1998;121:1903–17. decline in neurobehavioural function that occurs in petrol 10 Schall JD, Thompson KG. Neural selection and control of visually guided eye sniffers, although the specific toxic effects of each of these movements. Annu Rev Neurosci 1999;22:241–59. 11 Gaymard B, Ploner CJ, Rivaud S, et al. Cortical control of saccades. Exp Brain chemicals could not be isolated. Res 1998;123:159–63. The abuse of petrol and other inhalants is often prevalent 12 Burns CB, D’Abbs P, Currie BJ. Patterns of petrol sniffing and other drug use in among indigenous groups who have limited English lan- young men from an Australian aboriginal community in Arnhem Land, Northern Territory. Drug Alcohol Rev 1995;14:159–69. guage skills, limited experience with cognitive or neurological 13 Clough AR, Baillie R, Burns CB, et al. Validity and utility of community health testing, and live in remote isolated areas where there is no workers’ estimation of kava use. Aust NZ J Public Health 2002;26:52–7. access to modern medical technologies such as brain 14 National Health and Medical Research Council. Lead in Australians. Report 18 of the 115th session. Canberra: NHMRC, 1993. imaging. In addition, given the recent finding that 15 American Psychiatric Association. Diagnostic and statistical manual of mental neuropsychological tests were not a good indicator of brain disorders, 4th ed. 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