Studies in demyelinating diseases of sheep associated with copper deficiency. I. "Lamkruis," a demyelinating disease of lambs occurring in South Africa. II. A biochemical investigation on the incidence of " Lamkruis " in lambs in the Saldanha Bay, Vredenburg, and St. Helena Bay environs. III. Experimental studies, treatment and control measures

Abstract

It cannot be claimed that the observations recorded have led to specific information as to the cause of the disease known as "lamkruis", yet valuable information has been obtained which makes it clear that the factors originally suspected, i.e. phosphorus and copper deficiency, can now be disregarded as the primary aetiologic factors. An ataxia of lambs called "lamkruis" or "litsiekte" was found to occur on the south and west coast of South Africa, mostly on the calcareous soils of recent origin but also on soils of partly granitic origin. Clinically it is a non-febrile disease characterized by a swaying gait in the hindquarters. When the lambs are driven they stumble easily and fall on to their sides. The striking pathologic feature is destruction of the myelin in the nervous system, and, in extreme cases, symmetrical areas of softening or cavity formation occur in both cerebral hemispheres. The white brain substance is principally affected. Cavity formation is extremely rare in the spinal cord. Lamkruis is probably identical with other demyelinating diseases affecting lambs in various parts of the world, for instance, enzootic ataxia or ataxia of young lambs in Australia and New Zealand, " swayback" or "singback", or "warfa" in England and Scotland, and "renguera" in Peru, Patagonia and the Argentine. "Lamkruis" as we know it in this country only develops in the progeny of ewes subjected to a pasture of a "low" copper content. Without a single exception the liver copper value of both ewes and their Jambs was of a low order. There is evidence, however, that a low copper content of the liver is not pathognomonic for Lamkruis. Presumably, therefore, the ataxia is not necessarily caused primarily by a copper deficiency. The ataxia is, therefore, probably not due to a copper deficiency alone. In this respect it differs from enzootic ataxia or ataxia of young lambs and is similar to swayback and renguera. It is assumed that copper may only be a link of a chain of contributory causes. The process of demyelination cannot be ascribed to a single factor such as a copper deficiency. It has been shown that, although the common lesion-demyelination is an anatomical entity, its aetiology need not necessarily be identical in each case. The view is expressed that in the case of " lamkruis" the lesions must be correlated with a circulatory disturbance and / or a possible defective tissue anabolism brought about by a deficiency of circulating copper. The bilateral symmetry of the lesions suggests a systemic involvement. The beneficial effect of administering copper salts to pregnant ewes in reducing or preventing the appearance of "lamkruis" in their progeny has been demonstrated. In this respect our findings are in close agreement with those of the other demyelinating diseases of lambs. l\It cannot be claimed, however, that the administration of copper salt has a curative effect on diseased lambs. The administration of copper salts to affected lambs may seem to have a curative effect in some cases. It should be remembered however that a number of animals may recover without any treatment at all. Apparent or total recovery, probably depends on the extent and degree of the lesion and the affected structure. Presumably in "lamkruis" the demyelination is due to a patho-physiologic process and the beneficial effects of copper may be ascribed to its physiologic or therapeutic properties rather than to its direct association with myelination. The ataxia seen in "lamkruis" is presumably not associated with the lesions in the cerebral hemispheres, since there was no relationship between the severity of the clinical symptoms and the extent of the lesions. The possibility that the ataxia is associated with alterations in the cerebellum or brain-stem or both, must be considered. The high concentration of iron and the low copper level in the livers of adult sheep and lambs on "affected" properties indicate a disturbance in the iron metabolism and may possibly be due to the absence from the food supply of some factor (cobalt) necessary for its utilization as is the case in enzootic marasmus. Presumably most of this iron is immobilized and stored in the organs, since only a very small amount is demonstrable in sections stained with •Berliner Blue and this does not occur principally in the form of haemosiderin. The haemoglobin values for both ewes and lambs may reasonably be considered to be of a low order. However, the magnitude of the values obtained is not such that one is justified in stating that haemoglobin synthesis and haemopoiesis have seriously been affected, since a very low blood copper level (less than 0•1 p.p.m.) apparently does not interfere with normal haemopoiesis. Evidence has been produced suggesting that a gradual rehabilitation to a normal iron-copper metabolism may take place but that the intra-uterine injury to the central nervous system may be permanent. It seems that the biochemical processes concerned in the copper and iron metabolism of the body may proceed normally, in spite of a marked depletion of the copper stores of the ewes and the developing lamb, and the condition may further be complicated by a significant deviation of the iron stores of the body from the normal. Based on the present evidence we wish to emphasise a post-natal as well as a pre-natal onset for " lamkruis" and related diseases. Possibly all cases developing within three months after birth may be looked upon as "delayed" pre-natal cases, whereas those occurring later are most likely post-natal. Although the end results may be identical, the pathogenesis in the various forms may differ in several respects. A reduced phosphorus content was demonstrated in the soil the vegetation, the blood and tissues of stock grazing on the " Strandveld" (Bredasdorp, Riversdale and Swellendam areas) and this was reflected in softness and fragility of the bones of the animals concerned, whereas no evidence of an apparent phosphorus deficiency was obtained in the vicinity of Saldanha Bay and Vredenburg. Phosphorus deficiency is probably a contributory factor of the disease called "heupsiekte" in cattle and that which was mistakenly termed " lamkruis " in older sheep by former investigators. The disease described by us has nothing in common with the previously mentioned condition. In some of these coastal areas several diseases, such as "duinesiekte" of sheep and young cattle, paratyphoid of calves, and " broken wind" in draught animals (called “ruksiekte" or "benoudebors") or "bighead" (osteofibrosis) in horses, may be very prevalent. The possibility of greater susceptibility of animals to diseases under conditions prevailing in these coastal regions is a problem that requires further investigation. Other diseases, for instance "slapsiekte" of lambs and donkeys, affections of lambs and goats due to Coenurus cerebralis, and "Malkop" occurring more inland and characterized by nervous symptoms, have been described. In addition some demyelinating diseases affecting man and presumably not associated with a copper deficiency have been mentioned. Evidence has been thereby produced indicating that diseases with similar clinical symptoms and morbid changes need not necessarily have the same aetiology. However, there may be some common factor responsible for their similarity. " Lamkruis " is not related to imperfect osteogenesis nor to a degeneration of the musculature as that seen in " white muscle" disease. The alterations in the central nervous system are not those of aplasia of the white substance of the brain nor of an inflammatory nature, but must be ascribed to an encephalomyelopathy or a diffuse leucoencephalopathy without sclerosis. The process in cavity formation appears to be that of autolysis occurring intra vitam. It is characterized by a scarcity of fat and "gitter cells". In this respect "lamkruis" differs significantly from Schilder's Disease, but is in close agreement with diffuse leucoencephalopathy of man (Josephy and Lichtenstein, 1943). Post mortem changes can be eliminated since the specimens were placed into formalin within a few minutes after slaughtering of the animals. Deficiencies of copper, phosphorus and vitamins may be excluded as primary causes, but they probably act as contributory factors. Apparently poisonous plants and fungi do not play a role in the aetiology of this disease. As the disease may occur intra-uterine it is essential that the placental circulation (maternal and foetal) and the chemical changes occurring in the foetal brain should receive more attention than in the past. Progress in elucidating the pathogenesis of "Jamkruis " and other related diseases may be expected, if the significance of these two factors will be fully appreciated. It is well-known that several demyelinating diseases occur in man and that demyelination can be produced experimentally by a number of variable factors and not necessarily by a copper deficiency. Our cases, as well as those mentioned in the literature, point to the necessity for careful neurologic study in all cases of "lamkruis " and similar conditions. The distribution and character of cerebral lesions in " lamkruis " are indicative of circulatory disturbances and the resultant alterations in the affected localities. More attention should be given to less pronounced changes, especially in the cerebellum, brain-stem and other organs, for instance the adrenal.