Chronic fatigue syndrome as a delayed reaction to chronic...

In the early 1960s, researchers noted persistent central nervous system effects in workers who had been chronically exposed to organophosphate (OP) insecticides. A large number of anecdotal reports of neurobehavioural abnormalities in agricultural workers exposed to insecticides and OPs have accumulated since then. In the last few years in Great Britain, there has been increasing interest in farmers who develop neurobehavioural abnormalities. These farmers are identical clinically to patients with typical chronic fatigue syndrome (CFS). The mode of onset, clinical symptoms and results of detailed neuroendocrine studies are identical in both groups. This paper compares and contrasts patients with classical CFS to those with the neurobehavioural syndrome that occurs following delayed chronic exposure to OPs.

Keywords: chronic fatigue syndrome, organophosphates, neurobehavioural syndrome, hypothalamus, buspirone, 5-hydroxytryptamine, dexamethasone, pyridostigmine, growth hormone, brain steroid receptors.

INTRODUCTION
Chronic fatigue syndrome (CFS) is a clinical disorder that is increasingly recognized in most countries as a major health hazard. It is a relapsing illness which may occur in epidemics or as sporadic cases, the majority of cases now being sporadic. Its predominant feature is fatigue, so severe that it reduces the patient's pre-morbid level of activity by 50% or more and is often accompanied by myalgia. The diagnosis until now has been made on the basis of certain symptoms with the exclusion of other causes of fatigue [ 1]. This working definition which has recently been proposed will suffice until more is known about the illness.

In CFS, the patients complain of a bewildering variety of psychiatric and autonomic symptoms: confusion, atypical depression, poor memory and lack of concentration, mild anomia, attacks of nocturnal sweating and changes in the pattern of their sleep often associated with the initial stages of excessive sleep. Other non-specific symptoms may include a recurrent sore throat, other infections, mild fever, painful lymph nodes, irritable bowel syndrome (IBS) and chronic dysequilibrium. At times the symptoms include changes in appetite, body weight, fluid retention and irregular menstruation, symptoms that are strongly suggestive of hypothalamic dysfunction [ 2]. Indeed, we have demonstrated in a number of studies of patients with CFS that there is abnormal hypothalamic function including upregulation of hypothalamic 5-hydroxytryptamine ( 5-HT) receptors [ 3] and abnormal arginine/vasopressin responses to water loading and deprivation tests [ 2].

It has long been recognized that a neurobehavioural syndrome can occur in workers who have been chronically exposed to organophosphates (OPs)[ 4-6]. In an initial report, we have confirmed that this occurs in farmers and others exposed to OPs, mainly as insecticides and after sheep dipping [ 7]. The neurobehavioural syndrome in these patients is clinically identical to that found in patients with CFS. We therefore carried out a number of tests aimed at demonstrating abnormalities of neurotransmitter and neuroendocrine receptor function in a well-defined group of such patients with the neurobehavioural syndrome following OP exposure, and in age- and sex-matched healthy controls. Data on similar studies in patients with CFS are known [ 3]. This paper reports our preliminary observations.

PATIENTS
Ten patients were seen over a year with neurobehavioural symptoms and well-documented chronic exposure to OPs. These patients had been referred to us by their general practitioners and some by consultant physicians who had noted in their history a welldocumented exposure to OPs. Two of the patients were admitted acutely with OP exposure in the past and these two had subsequently developed non-Hodgkin's lymphoma (NHL). This drew our attention to the possible association of exposure to OPs and the subsequent development of neurobehavioural syndrome. Indeed, this alertness allowed us to select out patients readily with a similar neurobehavioural syndrome who had clear-cut, documented evidence of exposure to OPs (Table 1). They were all male whose ages varied from 31 to 60 years with a mean age of 42.3 years. Their clinical details are given in Tables 1-3. The onset of their symptoms was preceded by a definite influenza-type reaction in all cases except one which began after cholecystitis. They had each developed acute, severe, incapacitating fatigue, made worse by exercise and associated with myalgia, excessive sleep, attacks of night sweats, symptoms of IBS and mental changes of atypical depression with conspicuous emotional lability. They all complained of forgetfulness and poor concentration, often with anomic aphasia. None of these patients had a past history or family history of psychiatric illness (Table 3), all had been extensively studied as in-patients and all had had known causes of fatigue eliminated.

The control subjects consisted of ten healthy, male subjects with no known exposure to any OPs. They had no history of psychiatric illness or of fatigue and all were in excellent health. Their ages varied from 29 to 58 years with a mean age of 41.9 years.

The patients had all been exposed to a variety of OP toxins including malathion (Table 1). It was impossible to obtain specific details of precise exposure but, as seen from Table 1, all the patients gave a history of chronic exposure over years to the putative OP.

METHODS
Buspirone Studies
The patients and controls fasted overnight. At 8 a.m., a cannula was inserted into the antecubital vein and a blood sample for baseline prolactin estimation taken 15 min later. Both the subjects and controls were then given 60 mg of buspirone orally at 9 a.m. Serial blood samples were collected. The prolactin concentrations were measured, blind to diagnosis, by immunometric assay. Assays were standardized against the National Institutes for Biological Standards and Controls, Third International Standard, 84/500. The withinand between-batch coefficients of variation (CVs) were 3 and 6%, respectively, over the concentration range 200-3000 mU 1[-1]. The response to buspirone was determined by subtracting the baseline from the peak prolactin concentrations and the latter value expressed as a percentage of the baseline. The data were analyzed by one-way analysis of variance.

Pyridostigmine-induced Growth Hormone Test
All the patients and controls were hospitalized the night before the test. The test commenced the next morning following an overnight fast. An intravenous cannula was inserted into a forearm vein at 8 a.m. and the patient allowed to relax for 30 min. The baseline blood for growth hormone estimations was drawn at 9 a.m. The cannula was kept patent by flushing it with heparin (0.5 ml, 50 units) after samples of blood were taken. The first 2 ml extracted at each time point were discarded. Pyridostigmine, 120 mg orally, was administered at 0 min, i.e. at 9 a.m., and further blood for growth hormone estimation then drawn at 1, 2 and 3 h. The subjects remained in a supine position throughout the procedure. The samples were centrifuged immediately and stored at -80 degrees C until analysis. Analysis was carried out in batches that were blind to the subject status.

Growth hormone was measured in the Department of Biochemistry, Royal Infirmary, Glasgow, using an 'in-house' immunoradiometric assay employing UK9 as the primary working human growth hormone (HGH) standard. The sensitivity of the method is 0.2 mU 1[-1] (CV < 22%) with a between-batch variation of 5% over the working range 5-40 mU 1[-1]

Dexamethasone-induced Growth Hormone Studies
This test was also carried out at 9 a.m., following an overnight fast. The patients relaxed for 15 min following the insertion of a cannula and heparin bung into a forearm vein. In the first phase of the test, 4 mg of dexamethasone was given orally at 0 min and blood samples then drawn at 0, 1, 2, 3 and 4 h for growth hormone estimation. Growth hormone was measured as described for pyridostigmine test.

RESULTS
Routine Laboratory Studies
Routine laboratory studies, including urinalysis, haematological evaluation, urea and electrolytes, sedimentation rate and thyroid function, were all normal. Five of the patients, however, had significant increased transaminases of ALT 54-113 (normal range < 40 IU 1[-1]). There were no increased antibrucella antibody titres. The cerebrospinal fluid of three of the patients contained feint but definite oligoclonal bands (patients 2, 6 and 8). Viral antibody titres, brucella serology, and tests for toxoplasma and leptospira were all negative.

Buspirone Study
Buspirone produced a modest increase in plasma prolactin in the controls. However, a significant increase in prolactin was observed in the patients. These differences were significant. The values shown are the median and standard error of the mean (SEM) (Fig. 1).

Pyridostigmine Study
The response to 120 mg of pyridostigmine taken orally is shown in Fig. 2. There was a significant increase in the growth hormone response at 1 h in the patients as opposed to the controls. The values given are the median and SEM values.

Dexamethasone Study
The baseline growth hormone levels were essentially the same in the two groups but there were impaired depressed responses of growth hormone to dexamethasone in the patients as compared to the controls at 1, 2 and 3 h. These values were significant. Figure 3 shows the response with the control mean values and SEM.

DISCUSSION
All the patients studied had enjoyed excellent health before the onset of their symptoms and none had any previous psychiatric history. They each presented with an acute influenza-like illness, followed by incapacitating fatigue plus a variety of other symptoms as outlined. This influenza-like illness was never confirmed microbiologically but interestingly has been commented on in other studies of similar patients who developed a similar syndrome [ 8]. The majority were farmers and most had been exposed to OPs as sheep dip insecticides (Table 1). The duration of exposure varied from 2 to 5 years (Table 1). Symptoms of CFS and neurobehavioural symptoms had been present from 18 months to 7 years in the group.

These patients were selected because there was definite long-term exposure in all. Two of the patients had developed NHL, a well-recognized complication of such chronic exposure [ 9-11]. Ideally, one of the control group might have been a patient chronically exposed to OPs who has not developed the neurobehavioural syndrome. Such patients were not readily available at the time of this study but it is planned to incorporate them in further studies of this type. The symptoms of fatigue and other complaints did not arise until some time after the patients had been exposed. Why there should be this delay between exposure and the development of the syndrome is unknown, but it suggests that the OP exposure in some way prepared the patient for the later development of CFS. This may well be similar to our observations on patients who developed CFS but who had aseptic meningitis or poliomyelitis in youth. There is evidence that OPs may have deleterious actions on the human organism [ 6, 9]. Newcombe, in particular, showed that patients exposed to OPs developed a number of abnormalities, including an increased incidence of lymphoproliferative disorders in workers associated with impaired natural killer cell and cytotoxic T-cell function [ 9]. He suggested that the patients may be prone to persistent viral infections including Epstein-Barr virus and human herpes virus type 6.

There are many descriptions of similar immunological abnormalities in patients with CFS [ 12-15] as well as circumstantial evidence to implicate the involvement of human herpes virus type 6 [ 16]. Recently, in a small group of patients with CFS, evidence of persistent Borna virus has also been found [ 17, 18].

It appears that the clinical features of the neurobehavioural syndrome occurring after chronic exposure to OPs are identical to those described in patients with CFS [ 19]. The laboratory data of our neuroendocrine studies reported here indicate that such features are identical in both conditions.

Bakheit et al. [ 3], using the buspirone-induced prolactin release test, showed that patients with CFS could be differentiated from patients with depression and normal controls. The results found in patients with the neurobehavioural syndrome as a delayed reaction to chronic exposure to OPs are identical to those in CFS. In both conditions, there is a definite augmentation of prolactin release in response to buspirone. The rates of the different 5-HT receptor subtypes in stimulating the secretion of prolactin are still not clear. Some studies indicate that the prolactin response to 5-HT stimulation is mediated predominantly by 5-HT[ 1] rather than 5-HT[ 2] receptors [ 20]. While the exact mechanism of buspirone-induced prolactin release in humans and animals is unknown, the majority of evidence suggests that prolactin release is mediated by 5-HT[ 1] receptors. In the case of CFS, an increased sensitivity of central 5-HT receptors has also been found using the 5-HT-releasing agent D-fenfluramine [ 21]. The available evidence therefore strongly suggests an increased sensitivity of central 5-HT receptors in patients exposed to OPs with neurobehavioural syndrome and those with CFS.

Further similarity between the two groups of patients was shown by the results of the pyridostigmine study. OP insecticides are cholinesterase inhibitors which prolong and intensify the effect of acetylcholine. There is convincing evidence for the role of acetylcholine in the regulation of mood, psychomotor activity and sleep [ 22]. This arm of the study was to show that, by giving pyridostigmine to increase brain acetylcholine, its neuroendocrine response would be measured. Acetylcholine activates central muscarinic receptors and acts on those receptors rather than on nicotinic receptors. Acetylcholine therefore promotes growth hormone secretion by activating central muscarinic receptors, rather than acting on nicotinic receptors since the stimulation of nicotinic receptors by nicotine failed to alter the growth hormone-releasing ability of the potent cholinergic agonist eserine [ 23]. Acetylcholine may also act at the median eminence of the pituitary.

In this study, we found an augmented growth hormone response to pyridostigmine in patients with the neurobehavioural syndrome after OP exposure. The difference was statistically significant when compared to that found in healthy controls. Indeed, the data were comparable to what has previously been found in patients with CFS [ 24]. Why increased sensitivity to acetylcholine occurs is unknown, but there are a number of factors that may explain it:

( 1) Increased sensitivity of the somatotrophs to growth hormone-releasing hormone (GHRH) in that pyridostigmine involves intermediate stimulation of GHRH.

( 2) Hyper-responsivity of cholinergic receptors at the hypothalamic level resulting in a greater decrease in somatostatin tone and a bigger surge in growth hormone release from the anterior pituitary. It is unlikely that the sensitivity of somatotroph is affected in CFS as found in two preliminary studies where the administration of GHRH produced normal responses in growth hormone release. Acetylcholine hyperresponsivity at the hypothalamic level is the most likely explanation for the increased growth hormone secretion and could be caused by presynaptic autoreceptor subsensitivity: upregulation or hyper-responsivity of the prosynaptic receptor or abnormalities in the intracellular second messenger systems coupled to the acetylcholine receptor.

The important feature is that these abnormalities in acetylcholine hyper-responsivity in patients with CFS and or a neurobehavioural syndrome in this study may be partly responsible for the sleep disturbances and the neurobehavioural symptoms found, and directly in keeping with the clinical observation that anticholinesterase administration may produce behavioural changes similar to those found in both CFS and the delayed syndrome of OP exposure [ 25].

Lastly, we found impaired growth hormone release after exposure to dexamethasone. Growth hormone is secreted by specific anterior pituitary cells, the somatotrophs, which in themselves are influenced by a number of factors. The main positive factor is GHRH and the negative inhibiting factor is somatostatin. A number of diverse factors act on the release of GHRH and on somatostatin. Exercise and stress together with beta-adrenergic stimuli reduce growth hormone secretion by increasing somatostatin tone. The exact role of glucocorticoids in the regulation of growth hormone is unclear but researchers [ 23, 26] have been able to demonstrate that dexamethasone administered acutely stimulates the production of growth hormone. This is thought to act through an alteration in somatostatinergic tone at the level of the hypothalamus [ 27]. In our study, we made use of the fact that dexamethasone, the synthetic glucocorticoid, when administered acutely, stimulates the type II steroid receptor in the brain and promotes growth hormone release [ 26]. In the present study, we demonstrated clear-cut differences in the growth hormone response in patients with the neurobehavioural syndrome after OP exposure and in healthy controls. Furthermore, the effects of the acute administration of dexamethasone on growth hormone release was markedly reduced in patients with this syndrome. This abnormality is compatible with a decreased responsivity of CNS type II glucocorticoid receptors and is similar to what has been previously reported in patients with CFS [ 27]. These findings therefore confirm the hypothesis of brain steroid receptor resistance in patients with the delayed response to OPs and in CFS.

Finally, it should be noted that some patients with the neurobehavioural syndrome after OP exposure had oligoclonal bands in their cerebrospinal fluid. This observation may have relevance in that exposure to OPs has been implicated in the pathogenesis of multiple sclerosis [ 28]. Fatigue is also a chronic feature of this disease and its mechanisms are not understood [ 29, 30].

In summary, therefore, we have shown that patients can develop a neurobehavioural syndrome following exposure to OPs. The clinical features of this syndrome are identical to those of CFS. Indeed, when the subjects with this neurobehavioural syndrome are subjected to detailed neuroendocrine studies, similar results are found in CFS and in the OP-delayed syndrome, suggesting that both entities share a common pathogenesis.

ACKNOWLEDGEMENT
Supported by The Barclay Research Trust, Glasgow University.

TABLE 1

Clinical details

Patient Age Sex Occupation

1 33 M Farmer
2 56 M Farmer/lecturer
3 35 M Farmer
4 51 M Agricultural research adviser
5 31 M Gardener
6 45 M Lorry driver
7 32 M Farmer
8 60 M Agricultural worker
9 41 M Agricultural research worker
10 39 M Farmer

Duration of
Exposure CFS-like
Patient OP duration illness

1 Sheep dip 4 years 7 years
2 Sheep Cypor Spot On > 3 years 5 years
3 Sheep dip Yaltox Durshan > 5 years 5 years
4 Sheep dip pesticides > 3 years 3 years
5 Pesticides malathion Acutely 3 years (NHL)
6 Insecticides/explosives > 2 years 2 years (NHL)
7 Sheep dip insecticides > 3 years 3 years
8 Insecticides > 3 years 5 years
9 Insecticides 4 years 18 months
10 Insecticides and sheep dip 5 years 2 years

TABLE 2

Symptoms

Precipitating Sleep
Patient agent Fatigue Myalgia disturbance

1 Flu-like illness 4 + 4 + +
2 Flu-like illness
and twitching 4 + 4 + +
3 Vital upper
respiratory
tract infection 4 + 4 + Hypersomnia
4 Influenza 4 + 4 + 2 +
5 Influenza 4 + 4 + 4 +
6 Cholecystitis 4 + 4 + 3 +
7 Acute loss of
consciousness 4 + 4 + 4 +
influenza (Arthralgia)
8 Influenza 4 + 4 + 2 +
9 Influenza 4 + 4 + --
10 Influenza 4 + 3 + --

Attacks
Precipitating of Emotional
Patient agent sweating Depression lability

1 Flu-like illness 2 + 2 + 2 +
2 Flu-like illness
and twitching 4 + 3 + 2 +
3 Viral upper
respiratory
tract infection 4 + 3 + 3 +
4 Influenza 4 + 4 + 4 +
5 Influenza 4 + -- 4 +
6 Cholecystitis 4 + -- --
7 Acute loss of
consciousness
influenza 4 + 4 + --
8 Influenza 2 + 2 + 2 +
9 Influenza 3 + 4 + --
10 Influenza 3 + 2 + --

Precipitating Poor Poor
Patient agent Pruritis concentration memory

1 Flu-like illness -- 2 + 2 +
2 Flu-like illness
and twitching -- + +
3 Vital upper
respiratory
tract infection -- 2 + 2 +
4 Influenza 4 + + +
5 Influenza 2 + 2 + 2 +
6 Cholecystitis -- + +
7 Acute loss of
consciousness
influenza -- + +
8 Influenza 4 + 2 + 2 +
9 Influenza -- + +
10 Influenza 2 + + +

Attacks
Precipitating of
Patient agent dizziness IBS Palpitations

1 Flu-like illness 3 + 3 + --
2 Flu-like illness
and twitching -- -- --
3 Vital upper
respiratory
tract infection 3 + -- --
4 Influenza 3 + -- --
5 Influenza 4 + -- --
6 Cholecystitis -- 4 + --
7 Acute loss of
consciousness
influenza -- -- 4 +
8 Influenza 2 + 4 + 2 +
9 Influenza -- -- --
10 Influenza -- 3 + 2 +

TABLE 3

Previous medical history

Medical Drug
Patient history treatment

1 Good Clomipramine (4 years ago
four 1 year)
2 Asthma Nifedipine and Atrovent
3 NC Antidepressants
4 NC Antidepressants
5 NHL None
6 NHL Ranitidine
7 Brucellosis aged 11 None
8 NC None
9 NC None
10 NC None

NC, non-contributory.
GRAPH: FIG. 1. Buspirone-induced prolactin release.

0h 1h 2h 3h 4h

Control 362.93 666.47 714.77 641.77 457.33
Patients 213.90 1005.80 1040.80 330.40 189.20

C-SEM 23.86 48.61 48.54 40.35 20.81
P-SEM 31.48 249.09 228.71 39.29 14.00
GRAPH: FIG. 2. Pyridostigmine-induced growth hormone release.

0h 1h 2h 3h

Control 0.71 2.23 5.71 5.09
Patients 0.50 9.07 3.32 1.73

C-SEM 0.11 0.89 1.27 1.21
P-SEM 0.16 3.76 1.16 0.71
GRAPH: FIG. 3. Dexamethasone-induced growth hormone release.

0h 1h 2h 3h 4h

Mean Control 1.48 6.53 14.49 12.23 2.73
Mean Patients 0.90 0.43 0.44 3.33 9.22

SEM Control 0.31 3.27 3.29 2.09 0.99
SEM Patients 0.57 0.11 0.13 1.22 3.78
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By PETER O. BEHAN MD DSc FACP FRCP (GLAS) (LOND) (IRE) University Department of Neurology, Institute of Neurological Sciences, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TF, UK

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