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Organophosphate induced delayed polyneuropathy in man: An overview
Clinical Neurology and Neurosurgery 113 (2011) 7–10
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Review
Organophosphate induced delayed polyneuropathy in man: An overview Milan Jokanovic´ a,b,∗ , Melita Kosanovic´ c , Dejan Brkic´ a , Predrag Vukomanovic´ a a
Faculty of Medicine, University of Nish, Nish, Serbia Academy of Sciences and Arts of Republic Srpska, Banja Luka, Bosnia and Herzegovina c Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates b
a r t i c l e
i n f o
Article history: Received 9 September 2009 Received in revised form 22 August 2010 Accepted 28 August 2010 Available online 28 September 2010 Keywords: Organophosphorus Organophosphate induced delayed polyneuropathy Neuropathy target esterase
a b s t r a c t About 80 years have passed since the first cases of organophosphate induced delayed polyneuropathy (OPIDP), as the consequence of human poisoning with certain organophosphorus compounds, were described in the literature. OPIDP is a relatively rare neurodegenerative disorder in humans characterized by loss of function, ataxia and paralysis of distal parts of sensory and motor axons in peripheral nerves and ascending and descending tracts of spinal cord appearing 2–3 weeks after exposure or later. The molecular target for OPIDP is considered to be an enzyme in the nervous system known as neuropathy target esterase (NTE). This review discusses OPIDP in man with emphasis on clinical presentation, pathogenesis, molecular mechanisms, and possibilities for prevention/therapy. © 2010 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical presentation of OPIDP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neuropathy target esterase (NTE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis of OPIDP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The possibilities of medical treatment of OPIDP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Organophosphorus (OP) compounds cause three main toxic effects. The first is well-known cholinergic syndrome, initiated by inhibition of acetylcholinesterase with subsequent accumulation of acetylcholine at nerve endings, which occurs within minutes or hours after exposure. The symptoms of cholinergic crisis include miosis (unreactive to light); sweating, rhinorrhea, lacrimation, and salivation; abdominal cramps and other gastrointestinal symptoms; cough and respiratory difficulties; dyspnea, constriction sensation in the chest, wheezing; tremors and fasciculations; bradycardia and ECG changes, pallor, and cyanosis; anorexia, nausea, vomiting, diarrhea, and involuntary urination and defecation.
∗ Corresponding author at: Nehruova 57, 11070 Belgrade, Serbia. ´ E-mail address: [email protected] (M. Jokanovic). 0303-8467/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2010.08.015
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These signs and symptoms are accompanied by central effects such as dizziness, tremulousness, and confusion; ataxia; headache, fatigability, and paresthesia. Finally, seizures, convulsions, twitching, coma, and respiratory failure may also occur. Death usually occurs due to respiratory failure resulting from a combination of central and peripheral effects, paralysis of the respiratory muscles, and depression of the brain respiratory center [1–3]. Medical treatment of OP poisoning has been recently discussed by Jokanovic´ [4]. The second effect is described as intermediate syndrome, occurring 24–96 h after exposure, characterized by acute ventilatory insufficiency due to paralysis of respiratory muscles. Intermediate syndrome was interpreted as a neuromuscular junction dysfunction probably related to prolonged overstimulation of cholinergic receptors with acetylcholine. The third effect is organophosphate induced delayed polyneuropathy (OPIDP) which represents a rare form of toxicity caused by certain OP. It is characterized by degeneration of long axons in the central and peripheral nervous system
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and consequent ataxia and paralysis that appear about 2–3 weeks after exposure or later [5]. It is important to understand that OPIDP is different from both anticholinesterase effects and intermediate syndrome. OPIDP has attracted scientists because of wide use of OP in agriculture, community hygiene and industry. OPIDP is unique in that it is caused by a single exposure to certain OP with effects appearing after 7–21 days or later. In addition, the important reasons for interest in OPIDP were thousands of cases of poisoning with triorthocresyl phosphate (TOCP) that occurred mainly due to beverage and food contamination in USA in 1930 [6] and Morocco in 1959 [7]. By the end of twentieth century there were many cases of OPIDP due to TOCP poisoning in Italy [8], Romania [9], Sri Lanka [10], Yugoslavia [11] and China [12]. In addition to TOCP, certain OP pesticides (leptophos, dichlorvos, fenthion, isofenphos, trichloronate, trichlorfon, merphos, methamidophos, chlorpyrifos) have caused OPIDP but only individual cases have been reported [1,13,14]. This issue was also reviewed by Lotti and Moretto [15]. In most cases these poisonings were well described clinically. However, toxicological data regarding the amount of OP taken, purity of OP formulation and eventual presence of OP impurities and isomers, that may have high neurotoxic potential, are lacking. Many OP were also able to cause OPIDP in domestic and experimental animals. The adult hen is the animal of choice for OPIDP studies and OP are routinely tested in this species for OPIDP potential.
2. Clinical presentation of OPIDP OPIDP is relatively rare neurodegenerative disorder in humans that is characterized by loss of function and ataxia of distal parts of sensory and motor axons in peripheral nerves and ascending and descending tracts of spinal cord. The early neurological symptoms usually are sharp, cramp-like pains in the calves, tingling in the feet followed by distal numbness and paresthesia [16,17]. Progressive weakness then occurs, together with depression of patellar and achilles reflexes. Pain and weakness in muscles spread rapidly and patients become unsteady and unable to keep their balance. Symptoms may also appear in the arms and forearms. Sensory loss may be mild and is usually less severe or absent. Muscle tonus of the limbs gradually increase and spasticity might later appear in the lower limbs mainly in severe cases. Physical examination reveals distal symmetrical mainly motor polyneuropathy, with wasting and flaccid weakness of distal limb muscles, especially in the lower limbs. Signs include a characteristic high-stepping gait associated with bilateral foot drop. In severe OPIDP quadriplegia with foot and wrist drop were observed as well as mild pyramidal signs. Central nervous system (CNS) dysfunction is usually inapparent early in the neuropathy as signs of peripheral nerve damage predominate. As time passes and peripheral nerves recover, signs of CNS dysfunction may emerge, including hyperreflexia, increased motor tone, and spastic gait. In most severe cases, OPIDP manifests upper and lower motor neuron involvement. A common physical finding in a 50-year follow-up study of individuals with TOCP poisoning was the combination of spastic paraparesis and distal leg atrophy [8]. Evidence of corticospinal tract dysfunction is a feature that may distinguish OPIDP from most other distal axonopathies. There may be some functional recovery, but pyramidal and other signs of central neurological involvement may become more evident with time. The recovery affects only sensory nerves when spinal tracts were not affected, while motor neurons may permanently lose its function as indicated by Morgan and Penovich [17] who described the lack of improvement during 47 years in 11 patients poisoned with TOCP. Tosi et al. [8] also noted the absence of any improvement after 50 years in 7 patients poisoned with TOCP in Verona, Italy. However, a recent study from China conducted 13
years after TOCP poisoning of 74 patients revealed that of 61 survivors, 35 patients almost regained normal function of limbs and work outside; 23 patients walked with bilateral support and could perform housework; and 3 patients could not self-care. Neurophysiological investigations showed normal electroencephalogram and visual, brainstem auditory and somatosensory evoked potentials. Motor evoked potential obtained from the upper limbs had normal central motor conduction time, but it was delayed or absent in bilateral lower limbs. Motor and sensory nerve conduction velocity and electromyography studies were normal except for two severely affected patients [18]. The prognosis for functional recovery depends on the degree of pyramidal involvement with ataxia and paralysis representing a permanent outcome of severe OPIDP. In mildly affected individuals the prognosis is usually good with most making nearly a complete recovery. Others with a more severe initial deficit are left with varying degrees of morbidity, which include sequelae of both peripheral (atrophy, claw hands, footdrop) and central (spasticity, ataxia) nervous system damage. In many cases the ultimate prognosis depends more on the degree of CNS than of peripheral nerve dysfunction. It appears that clinical signs of OPIDP in young individuals are considerably milder than in adults and that they recover completely, even from severe lowerand upper-limb involvement [13]. Electrophysiological evaluation revealed acute denervation of affected muscles with abnormal spontaneous activity (fibrillation potentials, positive sharp waves), increased insertional activity, reduced interference pattern and large polyphasic motor unit potentials. The muscle action potentials are reduced in amplitude, terminal motor latencies are delayed and with motor conduction velocity slightly reduced or normal [13,16–19]. Neurogenic abnormalities are usually limited to distal limb muscles in mild instances, but may be found in more proximal leg muscles in severe cases. The progression of the disease, usually over a few days, may lead to non-excitability of the nerve. These findings are in accordance with the results of pathological investigations that show than in OPIDP peripheral nerves are affected with the main pathological feature being axonal degeneration. Histopathological studies performed postmortem after the massive TOCP exposure in USA described Wallerian degeneration affecting myelin sheaths of peripheral nerves and involvement of central nervous system with changes in fasciculus gracilis at cervical level and on the corticospinal tracts at lumbar levels [20]. Experimental animal studies have conclusively demonstrated that TOCP induces a distal axonopathy in several species particularly in hen. Degeneration of the long ascending and descending fiber tracts within the spinal cord and the ends of the dorsal spinocerebellar tracts in the medulla oblongata and cerebellum are present in pathologic specimens from OP exposed experimental animals. Axonal degeneration initially involves focal but nonterminal areas of the axon and spreads in a somatofugal direction to involve the entire distal axon. Before the onset of OPIDP aggregation, accumulation and partial condensation of neurofilaments in peripheral nerves were described. After appearance of OPIDP changes in mitochondria and their accumulation was observed. In the central nervous system there was degeneration of myelin sheets and axons in cerebrospinal system involving “swelling” of axons. In humans, after the onset of paralysis, the disappearance of muscular tissue and its replacement with connective and lipid tissue was evident [13,21,22].
3. Neuropathy target esterase (NTE) Martin Johnson first indicated NTE as the molecular target for OPIDP in 1969 [23]. Most of his reviews describe his discoveries in detail [24,25]. He operationally defined NTE as esteratic activity
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towards phenyl phenylacetate, phenylvalerate, or closely related esters, which is resistant to paraoxon or tetraethyl pyrophosphate and sensitive to DFP and mipafox. The methods of assay of NTE activity in brain and spinal cord [26] and peripheral nerves [27] are well established. In these methods NTE activity is measured using a differential assay. Paraoxon (40 M), that does not cause OPIDP, inhibits about 85% of PV-esterases in hen brain, and about 80% of paraoxon-resistant PV-esterases are sensitive to mipafox (50 M), a compound that causes OPIDP. Further studies revealed that NTE is not a homogenous protein and that NTE exists in two forms. Distribution of these two forms of NTE in tissues was different: while in brain there was 90% of NTE activity in microsomes and about 10% in cytosol, in sciatic nerve there was about 45% activity in microsomes and 55% in cytosol. These two forms of NTE have shown different sensitivity towards mipafox and microsomal form had an I50 of 7 M and cytosol form of about 43 M. The importance of these two forms was discussed by Jokanovic´ et al. [5]. The physiological substrate for NTE is considered to be lysolecithin [28]. NTE can hydrolyse many esters of carboxylic acids and in reaction with OP it is progressively inhibited in a time- and temperature-dependent reaction. In that reaction phosphorylated NTE may lose one alkyl group bound to phosphorus (“aging” reaction) that is probably transferred to one (Asp1044 ) or more aspartate residues at/or near the active site [29]. The active site of NTE contains Ser966 and two aspartates Asp960 and Asp1086 that appear essential for enzymatic activity. Molecular cloning and sequencing have revealed that NTE is a member of a protein family with a domain conserved through evolution [30]. NTE comprises an N-terminal regulatory domain, containing three cyclic nucleotide binding domains, and a C-terminal effector domain which contains the esterase activity. NTE effector domain contains three predicted transmembrane segments, and the active site serine residue is placed at the center of one of these segments. NTE is an integral membrane protein in vertebrate neurons and its activity depends on lipid content. It is present in endoplasmatic reticulum of the neurons, but is absent from glia [31,32]. NTE regulates phospholipid metabolism and is known to be a phospholipase B [33,34]. There is evidence that inactivation of NTE may reduce the degradation of phosphatidylcholine to glycerophosphocholine. The deficiency of the NTE activity may lead to abnormal accumulation of phosphatidylcholine-containing membranes in cells, which may interfere with normal membrane lipid homeostasis and fluidity affecting the initiation of neurites. Since NTE has been shown to hydrolyze lysolecithin [28,35,36], the delay in initiation of neurites may also be caused by an abnormal accumulation of lysolecithin in NTE-deficient cells [37]. NTE is involved in intracellular membrane trafficking and cellsignaling pathway between neurons and glial cells [29,38,39]. There is a relationship between NTE activity and the axonal maintenance since it facilitates the transport of macromolecules from the neuron to the distal ends of long axons. In mice with genetic deletion of NTE from neuronal tissue (known as nestin-cre:NTEfl/fl mice) long spinal degeneration has not been observed [33,40]. NTE has important roles in mammalian development. NTE is essential for embryonic survival, since its deletion in mice caused embryonic death attributable to failed formation both of the placenta and vasculature [34,41]. Neuronal specific NTE knockout mice survive to adulthood, but show vacuolation and neuronal loss characteristic of neurodegenerative diseases [34]. In nestin-cre:NTEfl/fl mice, deletion of NTE is restricted to neural tissue and occurs at embryonic day 11 [40]. The hippocampal lesions might reflect abnormal neural development rather than lack of maintenance in the adult. It was recently suggested that NTE may be involved in the regulation of calcium entrance into cells being responsible for the maintenance of normal function of calcium channels, and that
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increasing calcium activated neutral protease activity is responsible for triggering OPIDP [42]. Genetic studies on two families of patients with progressive spastic paraplegia found an association of the disease with mutations of NTE gene encoding the catalytic domain of the enzyme. Disease-specific, nonconserved NTE mutations in unrelated motor neuron disease patients indicated the importance of NTE in maintaining axonal integrity, raised the possibility that NTE pathway disturbances contribute to other motor neuron diseases including amyotrophic lateral sclerosis, and supported the role of NTE abnormalities in axonopathy produced by neuropathic OP compounds [43]. 4. Pathogenesis of OPIDP The initial biochemical event in the development of OPIDP involves inhibition of NTE by phosphorylation. Phosphorylation of NTE is a rapid event, probably occurring within minutes or hours of exposure. A sufficient amount of NTE must be inhibited for OPIDP to develop (e.g., in the hen, about 70–80% of brain NTE must be inhibited) [24]. The amount of inhibited human NTE that is required before OPIDP occurs is not yet known, but appears to be less than required in the hen. The degree of NTE inhibition varies according to the OP and the source of NTE. Inhibition of peripheral nerve NTE is required to develop OPIDP and no clinical deficits appear if only brain NTE is inhibited. Inhibition of spinal cord, but not nerve, NTE results in a spastic spinal syndrome, without peripheral neuropathy. The ability of neuropathic OP to inhibit NTE from different tissues underlies the rationale for assaying lymphocyte NTE as an industrial screening procedure to predict the likelihood for developing OPIDP in individuals exposed to neurotoxic OP [44], but this approach is not widely used. Although inhibited NTE is required to develop OPIDP, its presence alone is insufficient for the development of neuropathy. The development of OPIDP requires, in most cases, “aging” of the inhibited NTE enzyme [24]. The exact mechanism by which aged inhibited NTE causes OPIDP is unclear. It is proposed that negatively charged phosphoryl residue at NTE induce a toxic gain of function in NTE since it engenders a “chemical transection of the axon”. This leads to calcium entry, elevation of axonal calpain activity and Wallerian-type degeneration [30]. Animal studies have correlated the presence of aged inhibited NTE with impaired retrograde transport within the sciatic nerve. Maximum reduction in axonal transport occurs 7 days after exposure, prior to morphologic evidence of axonal degeneration. Retrograde transport fails to show progressive deterioration once axonal degeneration occurs, suggesting that transport dysfunction does not result from the axonal degeneration itself. Anterograde slow and rapid transport systems remain intact. Animals with insufficient NTE inhibition do not develop abnormalities of retrograde transport or clinical evidence of OPIDP. There has been some evidence suggesting that aging of NTE is not invariably necessary to develop OPIDP. Some OP that inhibit NTE without aging have been shown to cause neuropathy when given at extremely high doses, with almost complete inhibition of NTE. The severity of neuropathy in these cases is mild, despite the great amount of inhibited NTE. Severity of the OPIDP does not appear to correlate with the amount of aged NTE [45]. Other mechanisms may also be involved in pathogenesis of OPIDP and those are discussed in the above section on NTE. 5. The possibilities of medical treatment of OPIDP Medical treatment of OPIDP in humans is symptomatic. Standard treatment of OP poisoned patients comprising atropine,
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pyridinium oxime and diazepam was not effective in treatment of OPIDP. However, there were several reports in the literature describing attempts of treatment of OPIDP in animals and these studies were reviewed by Lotti [13] and Jokanovic´ et al. [5]. Calcium channel blocker verapamil and certain gangliosides were able to reduce the symptoms of OPIDP without effects on NTE, but there is no evidence regarding possible effects of these drugs in humans with developed clinical signs of OPIDP [46,47]. High doses of methylprednisolone and repeated doses of triamcinolone were able to reduce histopathological effects of OPIDP in cats caused by diisopropylfluorophosphate (DFP), probably due to their antiinflammatory and immunosuppressive action. Corticosterone did not show any effects on OPIDP induced with DFP in hens. However, it was possible to prevent development of OPIDP induced with DFP in hens when atropine, trimedoxime (TMB-4) and methylprednisolone were given before DFP. This combination of drugs, already used in human medicine, was also effective in reducing symptoms of OPIDP when given after exposure to DFP indicating a possibility of treatment of OPIDP after its initiation [48]. Conflict of interest None. Funding None. Acknowledgement The research of M.J. was supported by grants from the Serbian Ministry of Science (Projects 145030 and 145035). References [1] Jokanovic´ M, Kosanovic´ M. Neurotoxic effects in patients poisoned with organophosphorus pesticides. Environ Toxicol Pharmacol 2010;29:195–201. [2] Karchmar AG. Anticholinesterases and war gases. In: Karchmar AG, editor. Exploring the vertebrate central cholinergic nervous system. Springer; 2007. p. 237–310. [3] World Health Organization. Organophosphorus insecticides: a general introduction, vol. 63. Geneva: Environmental Health Criteria; 1986. [4] Jokanovic´ M. Medical treatment of acute poisoning with organophosphorus and carbamate pesticides. Toxicol Lett 2009;190:107–15. [5] Jokanovic´ M, Kosanovic´ M, Stukalov PV. Organophosphate induced delayed polyneuropathy. Med Chem Rev Online 2004;1:123–31. [6] Smith MI, Elvove E, Valaer PJ, Frazier WH, Mallory EE. Pharmacological and chemical studies of the cause of so called Ginger paralysis. US Pub Health Rep 1930;45:1703. [7] Smith HV, Spalding JMK. Outbreak of paralysis in Morocco due to orthocresylphosphate poisoning. Lancet 1959;2:1019–21. [8] Tosi L, Righetti C, Adami L, Zanette G. October 1942: a strange epidemic paralysis in Saval, Verona, Italy. Revision and diagnosis 50 years later of tri-ortho-cresyl phosphate poisoning. J Neurol Neurosurg Psychiatry 1994;57:810–3. [9] Vasilescu C, Florescu A. Clinical and electrophysiological study of neuropathy after organophosphorus compounds poisoning. Arch Toxicol 1980;43:305–15. [10] Senanayake N. Tricresyl phosphate neuropathy in Sri Lanka: a clinical and neurophysiological study with a three year follow up. J Neurol Neurosurg Psychiatry 1981;44:775–80. [11] Todorovic´ S, Djordjevic´ S. Late neurological sequelae of poisoning with triorthocresyl phosphate (TOCP) (in Serbian language). Vojnosanit Pregl 1986;43:124–7. [12] He F, Lu X, Zhang S. An outbreak of triorthocresylphosphate (TOCP) induced polyneuropathy. Int Toxicologist 1995;7:22–38. [13] Lotti M. The pathogenesis of organophosphate polyneuropathy. CRC Crit Rev Toxicol 1992;21:465–87. [14] Jokanovic´ M, Stukalov PV, Kosanovic´ M. Organophosphate induced delayed polyneuropathy. Curr Drug Targets Central Nervous Syst Neurol Disorders 2002;1:591–600. [15] Lotti M, Moretto A. Organophosphate-induced delayed polyneuropathy. Toxicol Rev 2005;24:37–49. [16] Lotti M, Becker CE, Aminoff MJ. Organophosphate polyneuropathy: pathogenesis and prevention. Neurology 1984;34:658–62.
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Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Review
Organophosphate induced delayed polyneuropathy in man: An overview Milan Jokanovic´ a,b,∗ , Melita Kosanovic´ c , Dejan Brkic´ a , Predrag Vukomanovic´ a a
Faculty of Medicine, University of Nish, Nish, Serbia Academy of Sciences and Arts of Republic Srpska, Banja Luka, Bosnia and Herzegovina c Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates b
a r t i c l e
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Article history: Received 9 September 2009 Received in revised form 22 August 2010 Accepted 28 August 2010 Available online 28 September 2010 Keywords: Organophosphorus Organophosphate induced delayed polyneuropathy Neuropathy target esterase
a b s t r a c t About 80 years have passed since the first cases of organophosphate induced delayed polyneuropathy (OPIDP), as the consequence of human poisoning with certain organophosphorus compounds, were described in the literature. OPIDP is a relatively rare neurodegenerative disorder in humans characterized by loss of function, ataxia and paralysis of distal parts of sensory and motor axons in peripheral nerves and ascending and descending tracts of spinal cord appearing 2–3 weeks after exposure or later. The molecular target for OPIDP is considered to be an enzyme in the nervous system known as neuropathy target esterase (NTE). This review discusses OPIDP in man with emphasis on clinical presentation, pathogenesis, molecular mechanisms, and possibilities for prevention/therapy. © 2010 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical presentation of OPIDP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neuropathy target esterase (NTE) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pathogenesis of OPIDP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The possibilities of medical treatment of OPIDP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Organophosphorus (OP) compounds cause three main toxic effects. The first is well-known cholinergic syndrome, initiated by inhibition of acetylcholinesterase with subsequent accumulation of acetylcholine at nerve endings, which occurs within minutes or hours after exposure. The symptoms of cholinergic crisis include miosis (unreactive to light); sweating, rhinorrhea, lacrimation, and salivation; abdominal cramps and other gastrointestinal symptoms; cough and respiratory difficulties; dyspnea, constriction sensation in the chest, wheezing; tremors and fasciculations; bradycardia and ECG changes, pallor, and cyanosis; anorexia, nausea, vomiting, diarrhea, and involuntary urination and defecation.
∗ Corresponding author at: Nehruova 57, 11070 Belgrade, Serbia. ´ E-mail address: [email protected] (M. Jokanovic). 0303-8467/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2010.08.015
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These signs and symptoms are accompanied by central effects such as dizziness, tremulousness, and confusion; ataxia; headache, fatigability, and paresthesia. Finally, seizures, convulsions, twitching, coma, and respiratory failure may also occur. Death usually occurs due to respiratory failure resulting from a combination of central and peripheral effects, paralysis of the respiratory muscles, and depression of the brain respiratory center [1–3]. Medical treatment of OP poisoning has been recently discussed by Jokanovic´ [4]. The second effect is described as intermediate syndrome, occurring 24–96 h after exposure, characterized by acute ventilatory insufficiency due to paralysis of respiratory muscles. Intermediate syndrome was interpreted as a neuromuscular junction dysfunction probably related to prolonged overstimulation of cholinergic receptors with acetylcholine. The third effect is organophosphate induced delayed polyneuropathy (OPIDP) which represents a rare form of toxicity caused by certain OP. It is characterized by degeneration of long axons in the central and peripheral nervous system
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and consequent ataxia and paralysis that appear about 2–3 weeks after exposure or later [5]. It is important to understand that OPIDP is different from both anticholinesterase effects and intermediate syndrome. OPIDP has attracted scientists because of wide use of OP in agriculture, community hygiene and industry. OPIDP is unique in that it is caused by a single exposure to certain OP with effects appearing after 7–21 days or later. In addition, the important reasons for interest in OPIDP were thousands of cases of poisoning with triorthocresyl phosphate (TOCP) that occurred mainly due to beverage and food contamination in USA in 1930 [6] and Morocco in 1959 [7]. By the end of twentieth century there were many cases of OPIDP due to TOCP poisoning in Italy [8], Romania [9], Sri Lanka [10], Yugoslavia [11] and China [12]. In addition to TOCP, certain OP pesticides (leptophos, dichlorvos, fenthion, isofenphos, trichloronate, trichlorfon, merphos, methamidophos, chlorpyrifos) have caused OPIDP but only individual cases have been reported [1,13,14]. This issue was also reviewed by Lotti and Moretto [15]. In most cases these poisonings were well described clinically. However, toxicological data regarding the amount of OP taken, purity of OP formulation and eventual presence of OP impurities and isomers, that may have high neurotoxic potential, are lacking. Many OP were also able to cause OPIDP in domestic and experimental animals. The adult hen is the animal of choice for OPIDP studies and OP are routinely tested in this species for OPIDP potential.
2. Clinical presentation of OPIDP OPIDP is relatively rare neurodegenerative disorder in humans that is characterized by loss of function and ataxia of distal parts of sensory and motor axons in peripheral nerves and ascending and descending tracts of spinal cord. The early neurological symptoms usually are sharp, cramp-like pains in the calves, tingling in the feet followed by distal numbness and paresthesia [16,17]. Progressive weakness then occurs, together with depression of patellar and achilles reflexes. Pain and weakness in muscles spread rapidly and patients become unsteady and unable to keep their balance. Symptoms may also appear in the arms and forearms. Sensory loss may be mild and is usually less severe or absent. Muscle tonus of the limbs gradually increase and spasticity might later appear in the lower limbs mainly in severe cases. Physical examination reveals distal symmetrical mainly motor polyneuropathy, with wasting and flaccid weakness of distal limb muscles, especially in the lower limbs. Signs include a characteristic high-stepping gait associated with bilateral foot drop. In severe OPIDP quadriplegia with foot and wrist drop were observed as well as mild pyramidal signs. Central nervous system (CNS) dysfunction is usually inapparent early in the neuropathy as signs of peripheral nerve damage predominate. As time passes and peripheral nerves recover, signs of CNS dysfunction may emerge, including hyperreflexia, increased motor tone, and spastic gait. In most severe cases, OPIDP manifests upper and lower motor neuron involvement. A common physical finding in a 50-year follow-up study of individuals with TOCP poisoning was the combination of spastic paraparesis and distal leg atrophy [8]. Evidence of corticospinal tract dysfunction is a feature that may distinguish OPIDP from most other distal axonopathies. There may be some functional recovery, but pyramidal and other signs of central neurological involvement may become more evident with time. The recovery affects only sensory nerves when spinal tracts were not affected, while motor neurons may permanently lose its function as indicated by Morgan and Penovich [17] who described the lack of improvement during 47 years in 11 patients poisoned with TOCP. Tosi et al. [8] also noted the absence of any improvement after 50 years in 7 patients poisoned with TOCP in Verona, Italy. However, a recent study from China conducted 13
years after TOCP poisoning of 74 patients revealed that of 61 survivors, 35 patients almost regained normal function of limbs and work outside; 23 patients walked with bilateral support and could perform housework; and 3 patients could not self-care. Neurophysiological investigations showed normal electroencephalogram and visual, brainstem auditory and somatosensory evoked potentials. Motor evoked potential obtained from the upper limbs had normal central motor conduction time, but it was delayed or absent in bilateral lower limbs. Motor and sensory nerve conduction velocity and electromyography studies were normal except for two severely affected patients [18]. The prognosis for functional recovery depends on the degree of pyramidal involvement with ataxia and paralysis representing a permanent outcome of severe OPIDP. In mildly affected individuals the prognosis is usually good with most making nearly a complete recovery. Others with a more severe initial deficit are left with varying degrees of morbidity, which include sequelae of both peripheral (atrophy, claw hands, footdrop) and central (spasticity, ataxia) nervous system damage. In many cases the ultimate prognosis depends more on the degree of CNS than of peripheral nerve dysfunction. It appears that clinical signs of OPIDP in young individuals are considerably milder than in adults and that they recover completely, even from severe lowerand upper-limb involvement [13]. Electrophysiological evaluation revealed acute denervation of affected muscles with abnormal spontaneous activity (fibrillation potentials, positive sharp waves), increased insertional activity, reduced interference pattern and large polyphasic motor unit potentials. The muscle action potentials are reduced in amplitude, terminal motor latencies are delayed and with motor conduction velocity slightly reduced or normal [13,16–19]. Neurogenic abnormalities are usually limited to distal limb muscles in mild instances, but may be found in more proximal leg muscles in severe cases. The progression of the disease, usually over a few days, may lead to non-excitability of the nerve. These findings are in accordance with the results of pathological investigations that show than in OPIDP peripheral nerves are affected with the main pathological feature being axonal degeneration. Histopathological studies performed postmortem after the massive TOCP exposure in USA described Wallerian degeneration affecting myelin sheaths of peripheral nerves and involvement of central nervous system with changes in fasciculus gracilis at cervical level and on the corticospinal tracts at lumbar levels [20]. Experimental animal studies have conclusively demonstrated that TOCP induces a distal axonopathy in several species particularly in hen. Degeneration of the long ascending and descending fiber tracts within the spinal cord and the ends of the dorsal spinocerebellar tracts in the medulla oblongata and cerebellum are present in pathologic specimens from OP exposed experimental animals. Axonal degeneration initially involves focal but nonterminal areas of the axon and spreads in a somatofugal direction to involve the entire distal axon. Before the onset of OPIDP aggregation, accumulation and partial condensation of neurofilaments in peripheral nerves were described. After appearance of OPIDP changes in mitochondria and their accumulation was observed. In the central nervous system there was degeneration of myelin sheets and axons in cerebrospinal system involving “swelling” of axons. In humans, after the onset of paralysis, the disappearance of muscular tissue and its replacement with connective and lipid tissue was evident [13,21,22].
3. Neuropathy target esterase (NTE) Martin Johnson first indicated NTE as the molecular target for OPIDP in 1969 [23]. Most of his reviews describe his discoveries in detail [24,25]. He operationally defined NTE as esteratic activity
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towards phenyl phenylacetate, phenylvalerate, or closely related esters, which is resistant to paraoxon or tetraethyl pyrophosphate and sensitive to DFP and mipafox. The methods of assay of NTE activity in brain and spinal cord [26] and peripheral nerves [27] are well established. In these methods NTE activity is measured using a differential assay. Paraoxon (40 M), that does not cause OPIDP, inhibits about 85% of PV-esterases in hen brain, and about 80% of paraoxon-resistant PV-esterases are sensitive to mipafox (50 M), a compound that causes OPIDP. Further studies revealed that NTE is not a homogenous protein and that NTE exists in two forms. Distribution of these two forms of NTE in tissues was different: while in brain there was 90% of NTE activity in microsomes and about 10% in cytosol, in sciatic nerve there was about 45% activity in microsomes and 55% in cytosol. These two forms of NTE have shown different sensitivity towards mipafox and microsomal form had an I50 of 7 M and cytosol form of about 43 M. The importance of these two forms was discussed by Jokanovic´ et al. [5]. The physiological substrate for NTE is considered to be lysolecithin [28]. NTE can hydrolyse many esters of carboxylic acids and in reaction with OP it is progressively inhibited in a time- and temperature-dependent reaction. In that reaction phosphorylated NTE may lose one alkyl group bound to phosphorus (“aging” reaction) that is probably transferred to one (Asp1044 ) or more aspartate residues at/or near the active site [29]. The active site of NTE contains Ser966 and two aspartates Asp960 and Asp1086 that appear essential for enzymatic activity. Molecular cloning and sequencing have revealed that NTE is a member of a protein family with a domain conserved through evolution [30]. NTE comprises an N-terminal regulatory domain, containing three cyclic nucleotide binding domains, and a C-terminal effector domain which contains the esterase activity. NTE effector domain contains three predicted transmembrane segments, and the active site serine residue is placed at the center of one of these segments. NTE is an integral membrane protein in vertebrate neurons and its activity depends on lipid content. It is present in endoplasmatic reticulum of the neurons, but is absent from glia [31,32]. NTE regulates phospholipid metabolism and is known to be a phospholipase B [33,34]. There is evidence that inactivation of NTE may reduce the degradation of phosphatidylcholine to glycerophosphocholine. The deficiency of the NTE activity may lead to abnormal accumulation of phosphatidylcholine-containing membranes in cells, which may interfere with normal membrane lipid homeostasis and fluidity affecting the initiation of neurites. Since NTE has been shown to hydrolyze lysolecithin [28,35,36], the delay in initiation of neurites may also be caused by an abnormal accumulation of lysolecithin in NTE-deficient cells [37]. NTE is involved in intracellular membrane trafficking and cellsignaling pathway between neurons and glial cells [29,38,39]. There is a relationship between NTE activity and the axonal maintenance since it facilitates the transport of macromolecules from the neuron to the distal ends of long axons. In mice with genetic deletion of NTE from neuronal tissue (known as nestin-cre:NTEfl/fl mice) long spinal degeneration has not been observed [33,40]. NTE has important roles in mammalian development. NTE is essential for embryonic survival, since its deletion in mice caused embryonic death attributable to failed formation both of the placenta and vasculature [34,41]. Neuronal specific NTE knockout mice survive to adulthood, but show vacuolation and neuronal loss characteristic of neurodegenerative diseases [34]. In nestin-cre:NTEfl/fl mice, deletion of NTE is restricted to neural tissue and occurs at embryonic day 11 [40]. The hippocampal lesions might reflect abnormal neural development rather than lack of maintenance in the adult. It was recently suggested that NTE may be involved in the regulation of calcium entrance into cells being responsible for the maintenance of normal function of calcium channels, and that
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increasing calcium activated neutral protease activity is responsible for triggering OPIDP [42]. Genetic studies on two families of patients with progressive spastic paraplegia found an association of the disease with mutations of NTE gene encoding the catalytic domain of the enzyme. Disease-specific, nonconserved NTE mutations in unrelated motor neuron disease patients indicated the importance of NTE in maintaining axonal integrity, raised the possibility that NTE pathway disturbances contribute to other motor neuron diseases including amyotrophic lateral sclerosis, and supported the role of NTE abnormalities in axonopathy produced by neuropathic OP compounds [43]. 4. Pathogenesis of OPIDP The initial biochemical event in the development of OPIDP involves inhibition of NTE by phosphorylation. Phosphorylation of NTE is a rapid event, probably occurring within minutes or hours of exposure. A sufficient amount of NTE must be inhibited for OPIDP to develop (e.g., in the hen, about 70–80% of brain NTE must be inhibited) [24]. The amount of inhibited human NTE that is required before OPIDP occurs is not yet known, but appears to be less than required in the hen. The degree of NTE inhibition varies according to the OP and the source of NTE. Inhibition of peripheral nerve NTE is required to develop OPIDP and no clinical deficits appear if only brain NTE is inhibited. Inhibition of spinal cord, but not nerve, NTE results in a spastic spinal syndrome, without peripheral neuropathy. The ability of neuropathic OP to inhibit NTE from different tissues underlies the rationale for assaying lymphocyte NTE as an industrial screening procedure to predict the likelihood for developing OPIDP in individuals exposed to neurotoxic OP [44], but this approach is not widely used. Although inhibited NTE is required to develop OPIDP, its presence alone is insufficient for the development of neuropathy. The development of OPIDP requires, in most cases, “aging” of the inhibited NTE enzyme [24]. The exact mechanism by which aged inhibited NTE causes OPIDP is unclear. It is proposed that negatively charged phosphoryl residue at NTE induce a toxic gain of function in NTE since it engenders a “chemical transection of the axon”. This leads to calcium entry, elevation of axonal calpain activity and Wallerian-type degeneration [30]. Animal studies have correlated the presence of aged inhibited NTE with impaired retrograde transport within the sciatic nerve. Maximum reduction in axonal transport occurs 7 days after exposure, prior to morphologic evidence of axonal degeneration. Retrograde transport fails to show progressive deterioration once axonal degeneration occurs, suggesting that transport dysfunction does not result from the axonal degeneration itself. Anterograde slow and rapid transport systems remain intact. Animals with insufficient NTE inhibition do not develop abnormalities of retrograde transport or clinical evidence of OPIDP. There has been some evidence suggesting that aging of NTE is not invariably necessary to develop OPIDP. Some OP that inhibit NTE without aging have been shown to cause neuropathy when given at extremely high doses, with almost complete inhibition of NTE. The severity of neuropathy in these cases is mild, despite the great amount of inhibited NTE. Severity of the OPIDP does not appear to correlate with the amount of aged NTE [45]. Other mechanisms may also be involved in pathogenesis of OPIDP and those are discussed in the above section on NTE. 5. The possibilities of medical treatment of OPIDP Medical treatment of OPIDP in humans is symptomatic. Standard treatment of OP poisoned patients comprising atropine,
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pyridinium oxime and diazepam was not effective in treatment of OPIDP. However, there were several reports in the literature describing attempts of treatment of OPIDP in animals and these studies were reviewed by Lotti [13] and Jokanovic´ et al. [5]. Calcium channel blocker verapamil and certain gangliosides were able to reduce the symptoms of OPIDP without effects on NTE, but there is no evidence regarding possible effects of these drugs in humans with developed clinical signs of OPIDP [46,47]. High doses of methylprednisolone and repeated doses of triamcinolone were able to reduce histopathological effects of OPIDP in cats caused by diisopropylfluorophosphate (DFP), probably due to their antiinflammatory and immunosuppressive action. Corticosterone did not show any effects on OPIDP induced with DFP in hens. However, it was possible to prevent development of OPIDP induced with DFP in hens when atropine, trimedoxime (TMB-4) and methylprednisolone were given before DFP. This combination of drugs, already used in human medicine, was also effective in reducing symptoms of OPIDP when given after exposure to DFP indicating a possibility of treatment of OPIDP after its initiation [48]. Conflict of interest None. Funding None. Acknowledgement The research of M.J. was supported by grants from the Serbian Ministry of Science (Projects 145030 and 145035). References [1] Jokanovic´ M, Kosanovic´ M. Neurotoxic effects in patients poisoned with organophosphorus pesticides. Environ Toxicol Pharmacol 2010;29:195–201. [2] Karchmar AG. Anticholinesterases and war gases. In: Karchmar AG, editor. Exploring the vertebrate central cholinergic nervous system. Springer; 2007. p. 237–310. [3] World Health Organization. Organophosphorus insecticides: a general introduction, vol. 63. Geneva: Environmental Health Criteria; 1986. [4] Jokanovic´ M. Medical treatment of acute poisoning with organophosphorus and carbamate pesticides. Toxicol Lett 2009;190:107–15. [5] Jokanovic´ M, Kosanovic´ M, Stukalov PV. Organophosphate induced delayed polyneuropathy. Med Chem Rev Online 2004;1:123–31. [6] Smith MI, Elvove E, Valaer PJ, Frazier WH, Mallory EE. Pharmacological and chemical studies of the cause of so called Ginger paralysis. US Pub Health Rep 1930;45:1703. [7] Smith HV, Spalding JMK. Outbreak of paralysis in Morocco due to orthocresylphosphate poisoning. Lancet 1959;2:1019–21. [8] Tosi L, Righetti C, Adami L, Zanette G. October 1942: a strange epidemic paralysis in Saval, Verona, Italy. Revision and diagnosis 50 years later of tri-ortho-cresyl phosphate poisoning. J Neurol Neurosurg Psychiatry 1994;57:810–3. [9] Vasilescu C, Florescu A. Clinical and electrophysiological study of neuropathy after organophosphorus compounds poisoning. Arch Toxicol 1980;43:305–15. [10] Senanayake N. Tricresyl phosphate neuropathy in Sri Lanka: a clinical and neurophysiological study with a three year follow up. J Neurol Neurosurg Psychiatry 1981;44:775–80. [11] Todorovic´ S, Djordjevic´ S. Late neurological sequelae of poisoning with triorthocresyl phosphate (TOCP) (in Serbian language). Vojnosanit Pregl 1986;43:124–7. [12] He F, Lu X, Zhang S. An outbreak of triorthocresylphosphate (TOCP) induced polyneuropathy. Int Toxicologist 1995;7:22–38. [13] Lotti M. The pathogenesis of organophosphate polyneuropathy. CRC Crit Rev Toxicol 1992;21:465–87. [14] Jokanovic´ M, Stukalov PV, Kosanovic´ M. Organophosphate induced delayed polyneuropathy. Curr Drug Targets Central Nervous Syst Neurol Disorders 2002;1:591–600. [15] Lotti M, Moretto A. Organophosphate-induced delayed polyneuropathy. Toxicol Rev 2005;24:37–49. [16] Lotti M, Becker CE, Aminoff MJ. Organophosphate polyneuropathy: pathogenesis and prevention. Neurology 1984;34:658–62.
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