SAKU DISEASE - a review.

Saku disease is referred to as Optico-autonomic-peripheral neuropathy and as a visual disease syndrome related to use of agricultural Organophosphorus (OP) pesticides.
Japanese studies from 1965 involved Ethylthiometon, Fenthion, Fenitrothion, Malathion, Parathions, Dipterex, Vamidothrin and Diazinon.
Symptoms were dose dependant and range from lenticular changes to serious histopathalogical changes in tissues of e.g. ciliary body and retina. Little study has been done other than in Japan (and perhaps some in Italy) and results are inconclusive, but the association with OPs is probable and studies conclusively reveal the effects of OPs on the visual system e.g -
Myopia -short sightedness
Narrowing of the Visual Fields
Astigmatism - due to refractive errors from distorted cornea
Reduced vision
Histipathological Evidence of degeneration - of extra occular muscle, Ciliary Muscle, Retina and other tissues.
Certain Visual parameters e.g. Pupillary responses and electroretinographs (ERG)
All show effects from OPs at levels BELOW those that inhibit the blood cholinesterases and therefore such effects would go unrecognized with current test procedures.

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The incidence of Saku disease is only in the agricultural areas of Japan and increased from 1965.
Usual problems were linked to increased use of OPs with symptoms similar to those found in cholinesterase inhibition by OP medicines used in Ophthalmology.
Reduction in Erythrocyte anticholinesterase (AChe) responded to treatment with OP antidote 2PAM.
The use of Malathion and Ethyl and Methyl Parathions and subsequently Fenthion, Dipterox,Fenitrothion and Diazinon corresponded with increased Myopia in the population. The usual problems were linked to helicopter applications of Malathion, Vamidothrin and 2 carbamates Hopcide and BPMC (Hopcin) but mainly involved OPs. Parathion was also used on the ground. Saku children showed signs of reduced visual acuity with high vertical astigmatism, refractive abnormalities, narrowing of visual field, abnormal eye movements, abnormal pupillory response, optic nerve abnormality - including optic neuritis, pallor of the optic disc, and or optic atrophy. Some had lowered serum cholinesterase and one or more non-visual system problems such as sensorial neuropathy, dysmetria, abnormal electroencephalogram (EEG) and OPs in the blood plus mild clinical complications of central, peripheral and automotive nervous systems. (Typical nicotonic & muscarinic reactions of intoxification were not observed) Pseudo-cholinesterase (pseudo-CHe) levels recovered within days of spraying. Plasma pseudo-CHe reduced by 22% of normal and erythrocyte ACHe by 24% - both significant. Cholinesterase in lateral rectus muscles was totally inhibited indicating that they may be more affected by OPs. Plasma pseudo-CHe reduction was linked to the narrowing of the visual fields. Patients displayed Retinochoroidal atrophy and abnormal retinal pigment. The highest OP levels in the blood was linked to the worst problems.
Vision usually improved some months after therapy as cholinesterase activity normalized but refractive changes were not improved with treatment.
Strong myopic astigmatism was common but occular symptoms were not necessarily neurological.
In all cases the Optic nerve was swollen.
Chronic intoxication produced a fading optic nerve and finally atrophy. Strong OPs such as Parathion produced external congestion of the optic nerve. A considerable amount of time is required for improvement of optic nerve symptoms. Retinal disease halts with 2PAM and Atropine treatment.
The disease progresses with worsening optic disc, retina, retinal vasculature and ERG response. Macular changes in workers exposed to Fenthion for 8.6 years include; Perifoveal areas of hypopigmentation of 1/8 to 1/3 of disc diameter, irregular background pigmentation and dull foveal reflex, reduced visual acuity, abnormal colour vision and constriction of visual fields. Corneal opacity and lenticular change was found with direct contact of eye and the OP pesticide.
Workers exposed to Fenitrothion and Dichlorovos (DDVP) also suffered with:- Forgetfulness, heavy head feeling, headache, pressure feeling in chest, sweating in sleep, nausea, dry throat, twinkling in eyes, eye trembling, easy tiring etc.
Hematology and urinalysis assays were normal. Opthalmological study showed nothing.
Animal studies reveal adverse effects on the visual system caused by OPs.
Dogs given 5mg+ / day Ethylthiometon all developed myopia in 1 year.
Electron Microscope examination showed abnormal mitochondria (swollen, huge and degenerated huge).
Damage was not limited to cholinesterase inhibition. Extraocular muscle changes were found in the nerves at Neuromuscular junctions and in muscle fibres as a state of neuromyopathy.
Retina degeneration was evident in the pigment epithelial cell layer near the papilla with myelin like structure in the cells of the retina.
Some demyelinated nerves of extraocular muscles, small sparse functional folds in the motor end plate and optic nerves decreased in number and there was increased septal tissue (Astrocytes and their processes), and peripheral neuropathy in sciatic and sural nerves.
Miosis was found in rat studies as was general muscle tremor, exophthalmus and conjunctival discharge. Animals dosed with Fenthion showed signs of toxicity; Exophthalmus, shivering, diarrhoea etc, and Fenthion has the potential to cause retinal degeneration.
Myopia was induced in dogs by Fenitrothion and it persisted for a year after last exposure. It produced swollen muscle fibres in the ciliary muscle and thickening of the lens.
The retinal physiology is sensitive to OPs at dosage levels far lower than detectable by cholinesterase assays.

Cholinesterases in the Occular Tissues.
Lateral rectus muscle has highest total cholinesterase of all extraoccular muscles. High levels are also found in the Retina, Choroid and Ciliary body. Cholinesterase, Choline acetyltransferase and acetylcholine activity is found in the corneal epithelium which contains the highest concentration of acetylcholine of any animal tissue.
Organophosphate cholinesterase inhibitors cross the anterior chamber and enter the lens and iris. The Retina is an extracranial extrusion, part of the Central Nervous System, and contains 6 types of neuron:- Photoreceptor Cells -rods and cones, Horizontal Cells, Interplexiform Cells, Bipolar Cells, Amacrine Cells and Ganglion Cells (located in Retina but axons from them form the optic nerve)
All synapses between these cells are affected by chemical mediation and employ neuro-transmitter substances including Gamma-Aminobutyric Acid (GABA), Glycine, Doxamine, Idolamine,and Acetycholine (the latter is essential to the visual system) Cholinergic drugs affect the horizontal cells, ganglion cells etc.
This system is vulnerable to a host of visual anomalies as a consequence of cholinesterase inhibition.


Sources: Eye Injury by Organic Phosphorus Insecticides, Japanese Journal of Ophthalmology, Vol.15 (1)
60-67,(1971) by Satoshi Ishikawa, and the Journal of Applied Toxicology, Vol.14 (2), 119-129 (1994).

Dated 16/9/2000

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