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Gardner, A. F., and N. Sakieuncz: Exp. Med. Surg. 21, 164191, 1963.
A Review of Neurolathyrism Including the Russian and Polish Literature
165
A Review of Neurolathyrism Including the Russian and Polish Literature*

By ALVIN F. GARDNER**, D.D.S., M.S., Ph.D., and NICOLAUS SAKIEWICZ, D.D.S.
Lathyrism is a disease caused by certain types of vetch when it is used excessively, i. e., 50 % of the diet of humans or animals. Seeds of some species of sweet peas which are used as fodder for 7 cattle and feed for the population in India, Iran, Southern Europe, and Northern Africa resulted in poisoning which mainly appeared as de-, generation, of somefibertracts in the spinal cord. The oldHindu literature mentioned cases of certain disturbances of the lower extremities upon consumption of some types of siliquose plants. Paralysis of the lower extremities resulting from vetch poisoning was known in the times of Hippocrates who noticed it among $he population of Ainos1. Pliny (2379 A.D.) 2 described |he poisonous qualities of lathyriis; Galen. {130-210 A.D.) 3 deducted the ill effects contained in this food'; and the effects are also mentioned by 'Avicenna (980-1037 ) 4 . Later this phenomenon was: reported during epidemics in the 17th, 18th and 19th centuries in South Europe and Africa, and in India in the 19th and 20th centuries. There are three types of lathyrus which are considered poisonous for man and animals: 1. Lathyrus satirjins, cultivated in India and growing
* This investigations was supported by U.S.P.H.S. research grant D-1156, D-1156 (SI) and D-1156 (Cl) from/the National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland. ** Alvin F. Gardner, D.D.S., M.S., Ph'D., Department of General and Oral Pathology, School of Dentistry, Baltimore College of Dental Surgery, University of Maryland, Baltimbre, Maryland. 1 Hippocrates, On Epidemics, Book II, Sec. IV, p. 3. 2 Pliny the Elder, Quoted by Semidalov (see 45), p. 734. 3 Ibid. 4 Ibid.
wild in the Tian Shian mountains; 2. L. cicera, which serves as fodder for cattle in France, Italy, and Algiers, and is also used in the production of flour when grain is difficult to obtain; and 3. L. clymenum, grownig in Spain, North Africa and in the Orient. Ramarzini (1691 ) 5 found many individuals with weakness of the legs in the principality of Modeh caused by the use of legume and especially ervo. In France from 17001701, there was a severe endemic of lathyrism, as a result of which it was illegal to plant lathyrus in certain provinces. Duvernoy (1770)6 reported that men eating Lathyrus cicera suffered from rigidity of the lower extremities and lameness. Hirzel (1780)7 described paralysis of knees and soles as a result of consuming the seeds of L. cicera. George Puihn (1785)8 emphasized that after eating lathyrus the knees became straight and bent inwards, and the feet became weak. There were no pains. Lathyrus affects only the human male. Tozzetti (1784)9 ascribed the endemic "storpio delle gambe" to the ingestion of L. sativus in the year of the failing harvest in Tuscany. Lathyrus, rye and barley were unquestionably of good quality. The population ate bread consisting of 2/3 lathyrus and 1lz barley or rye for a period of three months. The symptoms of. the disease included weakness in the lower extremities and loss of movement; however, pain was absent. Vilmorin (1819-).10 reported that a young man developed paralysis of the legs and required the aid of crutches. For several weeks before the paralysis he had eaten bread containing a large amount.of lathyrus. All the members of his family (6 or 7) suffered the same symptoms, and one of them died. Many of the poor population ate similar bread and became ill with lathyrism. Desparanches (1829)11 reported to the Paris Medical Academy the endemic which was spreading in many localities of the province of Loire at Cher, He reported that the disease spread as a result of eating bread
5
Ramarzini, "Lathyrism in Italy." Constituto Epidem. Anni., Modena,
1691.
6 G. D. Duvernoy, "Dissertazione de Lathyri Quadau Venenata Specie in Comitatu Montbelgardensi Cults." Basilliae, 1770. 7 F. von Hirzel, "Uber das Getreide und Bred." Zurich: Linguet und Tissot, Vol. 8, 1780. 8 G. Puihn, Quoted by Semidalov (see 45), p. 734. 9 Ibid. 10 Ibid. 11 Desparanches, "Le Lathyrisme." Bull. Scient. Med. XVIII, 1829, p. 433.
166
Gardner/Sakiewicz
167
containing 50 per cent L. sativus. All the ill individuals had the samesymptoms indicating damage to the spinal cord. Early in the disease there were spasmodic movements in the muscles of the hips and knees, weakness of the lower extremities, and inability to walk; the feet dragged and we're bent inwards. Sometimes the disease began with minor pains in the pelvis. Finally an incomplete paralysis resulted, with severe weakness of the lower extremities and often overwhelming sleepiness. The upper extremities were not affected, and paralysis of the lower extremities was never accompanied by pain. Sleeman (1829)12 reported that in one part of the Sangor territory of India, a poor harvest of wheat but a good harvest of L. sativus resulted in the latter being used for food. As a result many cases of paralysis occurred, usually of an insidious nature. The toxic effect of bread containing certain quantities of L. cicera was acknowledged by a court in Niorta. In the ancient scientific syllabi of 17th and 18th centuries, there is a case history of a perfectly healthy woman who developed paralysis of the lower extremities as a result of eating L. cicera for weeks. George Don (18341838)13 reported that in several countries there were so many cases of serious illnesses as a result of eating bread containing L. sativus that in 1671 prince George of Wiirtemberg forbade the use of Lathyrus bread in his principality. Teilleuse (1840)14 extracted tar substance from L. cicera and gave a few grams to healthy rabbits. Thip resulted in loss of motion in the hind limbs and tetanic contractions; ^n four days death occurred. Tenore and Pelliccioti (1847 ) 15 observed thirty cases of poisoning by L. sativus, with paralysis of the, lower extremities. When they discovered the etiology of the disease^ the use of the lathyrus flour was stopped and no new cases were reported. Irving reported that in Alia Habod, India, a severe endemic of lathyrism occurred in 185616. There Were 2,028 sick, or 1 out of every 31 inhabitants. As a result of the marshy ground in this region, there is
12 W. H. Sleeman, Rambles g/nd Recollections of an Indian Official. London: Hatchard and Sons, Vol. / / 1 8 4 4 . 13 G. Don, General System of Gardening and Botany. London: 1831-38, Vol. 4. 14 Teilleuse, Quoted by Semidalov (see 45), p, 739. 15 Ibid., p. 735. 19 / . Irving, "Notice of a Form of Paralysis of the Lower Extremities, Extensively Prevailing in Part of the District of All Habod, Produced by Use of Lathyrus sativus as an Article of Food." Indian Ann. M. S c , 1859, VI, 1859, p. 424. , . '
little cultivation of food; therefore, the population was forced to eat lathyrus. Some individuals became so ill that they could barely stand, while others were affected less severely. Without exception all affected individuals reported that they became paralyzed during the rainy season, and in a sudden manner during the night. They retired at night in a healthy condition and awakened With rigid legs, weakness in midsection, and inability to walk. At first there had been a slight lameness and a barely noticeable rigidity of the knees. As time progressed the calves became painful and the weakness increased. However, the arms of the affected remained healthy. The weakness of the legs became so severe that the ill could not walk. All ascribed their illness to the use of lathyrus as food. Irving (1859) reported that that lathyrus plant is less harmful when it is grown on dry ground. The ingestion of the lathyrus seeds in minimal quantities upsets only normal digestion. Dufour (I860)17 observed a chronic poisoning by L. cicera in Algiers. After prior convulsions and contractions an individual lost several phalanges of the right foot and the metatarsus of the left foot, apparently from gangrene. Both arms were bent, the flexors were shortened, and the tensors and opponens digiti minimi, as well as musculi interossei and the shoulder muscles, were atrophied. All symptoms appeared at once without any apparent cause. Sue (1861)18 described an Arab who lost both legs from gangrene. This man had anemia and syphilis, damaged adventitia of large vessels, and .hunger prostration. The gangrene was ascribed to the eating of lathyrus seeds. Bertrand (1867)19 described a case of gangrene in an eight-year-old boy who lost both legs. Hattute (1867 ) 20 reported that gangrene occurred in six individuals which he ascribed to malnutrition and to L. cicera. He believed that lathyrus, ergot, and spur of rye act upon the sympathetic nervous system producing irritation of the vasomotor nerves which results in a severe contraction arid toxic paralysis of arteries with stasis of the circulation. Verrier (1867)21 reported that because of the high price of oats, a large omnibus company replaced it by L. cicera. Fifty-five horses were fed on L. cicera for two months. Each horse received three kilograms of Lathyrus cicera for each thirteen kilograms of oats. Twentynine horses became paralyzed in the waist or in the throat muscles. Nine
17 Dufour, Recueil de Memoires de Medicine Militaire. Vol.3, 1860. Sue; Quoted by Semidalov (see 45), p. 736. 19 Ibid. 20 Ibid. 21 Ibid.
Gardner, A. F., and N. Sakiewicz: Exp. Med. Surg. 21, 164191, 1963.
165
A Review of Neurolathyrism Including the Russian and Polish Literature*

By ALVIN F. GARDNER**, D.D.S., M.S., Ph.D., and NIGOLAUS SAKIEWICZ, D.D.S.
Lathyrism is a disease caused by certain types, of vetch when it is used excessively, i. e., 50 % of the diet of humans or animals. Seeds of some species of sweet peas which are used as fodder for cattle and feed for the population in India, Iran, Southern Europe, and Northern Africa resulted in poisoning which mainly appeared as degeneration of some fiber tracts in the spinal cord. The old Hindu literature mentioned cases of certain disturbances of the lower extretnities upon consumption of some types of siliquose plants. Paralysis of the lower extremities resulting from vetch poisoning was known in the times of Hippocrates who noticed it among the population of Ainos 1 . Pliny (2379 A. D. ) 2 described the poisonous qualities of lathyrus; Galen (130-210 A. D . ) 3 deducted the ill effects contained in this food"; and the effects are also mentioned by 'Avicenna (980-1037) 4 . Later this phenomenon was reported during epidemics in the 17th, 18th and 19th centuries in South Europe and Africa, and in India in the 19th and 20th centuries. There are three types of lathyrus which are considered poisonous for man and animals: 1. Lathyrus sativws, cultivated in India and growing
* This investigations was supported by U.S.P.H.S. research grant D-1156, D-1156 (SI) and D-1156 (Cl) from the National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland. ** Alvin F. Gardner, D.D.S., M.S., Ph.D., Department of General and Oral Pathology, School of Dentistry, Baltimore College of Dental Surgery, University of Maryland, Baltimore, Maryland. 1 Hippocrates, On Epidemics, Book II, Sec. IV, p. 3. 2 Pliny the Elder, Quoted by Semidalov (see 45), p. 734. 3 Ibid. 4 Ibid.
wild in the Tian Shian mountains; 2. L. cicera, which serves as fodder for cattle in France, Italy, and Algiers, and is also used in the production of flour when grain is difficult to obtain; and 3. L. clymenum, g-rownig in Spain, North Africa and in the Orient. Ramarzini (1691) 5 found many individuals with weakness of the legs in the principality of Moden caused by the use of legume and especially ervo. In France from 17001701, there was a severe endemic of lathyrism, as a result of which it was illegal to plant lathyrus in certain provinces. Duvernoy (1770) 6 reported that men eating Lathyrus cicera suffered from rigidity of the lower extremities and lameness. Hirzel (1780) 7 described paralysis of knees and soles as a result of consuming the seeds of L. cicera. George Puihn (1785) 8 emphasized that after eating lathyrus the knees became straight and bent inwards, and the feet became weak. There were no pains. Lathyrus affects only the human male. Tozzetti (1784) 9 ascribed the endemic "storpio delle gambe" to the ingestion of L. sativus in the year of the failing harvest in Tuscany. Lathyrus, rye and barley were unquestionably of good quality. The population ate1 bread consisting of 2/3 lathyrus and V3 barley or rye for a period of three months. The symptoms of the disease included weakness in the lower extremities and loss of movement; however, pain was absent. Vilmorin (1819) 10 reported that a young man developed paralysis of the legs and required the aid of crutches. For several weeks before the paralysis he had eaten bread containing a large amount of lathyrus. All the members of his family (6 or 7) suffered the same symptoms, and one of them died. Many of the poor population ate similar bread and became ill with lathyrism. Desparanches (1829) 11 reported to the Paris Medical Academy the endemic which was spreading in many localities of the province of Loire at Cher, He reported that the disease spread as a result of eating bread
5
Ramarzini, "Lathyrism in Italy." Constituto Epidem. Anni., Modena,
6 G. D. Duvernoy, "Dissertazione de Lathyri Quadau Venenata Specie in Comitatu Montbelgardensi Cults." Basilliae, 1770. 7 F. von Hirzel, "Ober das Getreide und Bred." Zurich: Linguet und Tissot, Vol.8, 1780. 8 G. Puihn, Quoted by Semidalov (see 45), p. 734. 9 Ibid. 10 Ibid. 11 Desparanches, "Le Lathyrisme." Bull. Scient. Med. XVIII, 1829, p. 433.
1691.
166
Gardner/Sakiewicz
167
containing 50 per cent L. sativus. All the ill individuals had the samesymptoms indicating damage to the spinal cord. Early in the disease there were spasmodic movements in the muscles of the hips and knees, weakness of the lower extremities, and inability to walk; the feet dragged and we're bent inwards. Sometimes the disease began with minor pains in the pelvis. Finally an incomplete paralysis resulted, with severe' weakness of the lower extremities and often overwhelming sleepiness. T h e upper extremities were not affected, and paralysis of the lower extremities was never accompanied by pain. Sleeman (1829) 12 reported that in one part of the Sangor territory of India, a poor harvest of wheat but a good harvest of L. sativus resulted in the latter being used for food. As a result many cases of paralysis occurred, usually of an insidious nature. The toxic effect of bread containing certain quantities of L. cicera was acknowledged by a court in Niorta. In the ancient scientific syllabi of 17th and 18th centuries, there is a case history of a perfectly healthy woman who developed paralysis of the lower extremities as a result of eating L. cicera for weeks. George Don (18341838)13 reported that in several countries there were so many cases of serious illnesses as a result of eating bread containing L. sativus that in 1671 prince George of Wiirtemberg forbade the use of Lathyrus bread in his principality. Teilleuse (1840) 14 extracted tar substance from L. cicera and gave a few grams to healthy rabbits. This resulted in loss of motion in the hind limbs and tetanic contractions; in four days death occurred. Tenore and Pelliccioti (1847) 15 observed thirty cases of poisoning by L. sativus, with paralysis of the lower extremities. When they discovered the etiology of the disease, the use of the lathyrus flour was stopped and no new cases were reported. Irving reported that in Alia Habod, India, a severe endemic of lathyrism occurred in 185616. There were' 2,028 sick, or 1 out of every 31 inhabitants. As a result of the marshy ground in this region, there is
12 W. H. Sleeman, Rambles and Recollections of an Indian Official. London: Hatchard and Sons, Vol./ r '1844. 13 G. Don, General System of Gardening and Botany. London: 1831-38, Vol.4. 14 Teilleuse, Quoted by Semidalov (see 45), p. 739. 15 Ibid., p. 735. 16 / . Irving, "Notice of a Form of Paralysis of the Lower Extremities, Extensively Prevailing in Part of the District of All Habod, Produced by Use of Lathyrus sativus as an Article of Food." Indian Ann. M. S c , 1859, VI, 1859, p. 424.
little cultivation of food; therefore, the population was forced to eat lathyrus. Some individuals became so ill that they could barely stand, while others were affected less severely. Without exception all affected individuals reported that they became paralyzed during the' rainy season, and in a sudden manner during the night. They retired at night in a healthy condition and awakened with rigid legs, weakness in midsection, and inability to walk. At first there had been a slight lameness and a barely noticeable rigidity of the knees. As time progressed the calves became painful and the weakness increased. However, the arms of the affected remained healthy. The weakness of the legs became so severe that the ill could not walk. All ascribed their illness to the use of lathyrus as food. Irving (1859) reported that that lathyrus plant is less harmful when it is grown on dry ground. The ingestion of the lathyrus seeds in minimal quantities upsets only normal digestion. Dufour (I860) 17 observed a chronic poisoning by L. cicera in Algiers. After prior convulsions and contractions an individual lost several phalanges of the right foot and the metatarsus of the left foot, apparently from gangrene. Both arms were bent, the flexors were shortened, and the tensors and opponens digiti minimi, as well as musculi interossei and the shoulder muscles, were atrophied. All symptoms appeared at once' without any apparent cause. Sue (1861) 18 described an Arab who lost both legs from gangrene. This man had anemia and syphilis, damaged adventitia of large vessels, and hunger prostration. The gangrene was ascribed to the eating of lathyrus seeds. Bertrand (1867) 19 described a case of gangrene in an eight-year-old boy who lost both legs. Hattute (1867 ) 2 0 reported that gangrene occurred in six individuals which he ascribed to malnutrition and to L. cicera. He believed that lathyrus, ergot, and spur of rye act upon the sympathetic nervous system producing irritation of the vasomotor nerves which results in a severe contraction and toxic paralysis of arteries with stasis of the circulation. Verrier (1867) 21 reported that because of the high price of oats, a large omnibus company replaced it by L. cicera. Fifty-five horses were fed on L. cicera for two months. Each horse received three kilograms of Lathyrus cicera for each thirteen kilograms of oats. Twentynine horses became paralyzed in the waist or in the throat muscles. Nine
Dufour, Recueil de Memoires de Medicine Militaire. Vol. 3, 1860. Sue, Quoted by Semidalov (see 45), p. 736. -19 Ibid. 20 Ibid. 21 Ibid.
18 17
168
Gardner/Sakiewicz
169
horses died; twenty others were saved by tracheotomy. One hundred and fifty horses which ate the same amount of feed without the L. cicera were free from symptoms. The main credit for clinical analysis of the symptoms of this disease belongs to Cantani. He1 called this disease "lathyrism" in 1873. He observed three ill brothers8, 10 and 20 years of agewho ate a diet containing flour made from L. clymenwm. All three developed paralysis of the lower extremities and would fall down when attempting to walk. All of the muscles of the body were weak. The muscles of the lower extremities, particularly those of the calves, became some\vhat smaller in size. In the prostrated position the legs would stretch and would bend with difficulty. When walking the individual's chest was deformed anteriorly and the pelvis posteriorly. Two of the brothers had their legs in close approximation while walking, and on occasion one leg would cross the other. The1 third brother walked with widely spread legs. All three brothers leaned on their metatarsal phalanges, while slightly raising their heels. It was especially difficult for them to move backward due to the weakness of the knee and ankle joints, which functioned better when walking forward. In the standing position they would rock forward and to the side, and were obliged to support their arms by leaning on their pelvis. Contraction of the muscles of the body, face, neck and upper extremities appeared normal. Closing the' eyes did not increase the difficulty in walking. Sensation and skin reflexes were normal. Electrically induced contractions were decreased, Wid this decrease affected, particularly, the psoas, iliacus, leg flexors, {ibialis anterior, extensor pollicis longus, and extensor pollicis brevis. The younger brother recovered; the eldest improved; but the middle brother showed no change 22 . Brunelli reported his findings about lathyrism in London in 1880. The first symptoms of his 11 patients were a weakness and tremor of the legs. Some became intoxicated, particularly after eating only bread containing 50 per cent L. cicera flour. The disease did not progress further when the bread was discontinued in/the diet. In other cases the disease progressed and finally after two or three months individuals developed characteristics of spastic paralysis: With severe rigidity of the legs, walking became difficult, steps became smaller, the legs dragged on the ground as a result of the contraction of the adductors of the hips, the large toes were flexed, and the heel was raised. One of the patients walked on tip toes. All were unsteady on their fefet and required the aid of crutches.
A. Cantani, "Latirismo (Lathyrismus) Ulustrata de tre Gasi Clinici." II Morgagni XV, 1875, p. 745.
22
The knee reflex was intensly increased. There were tremors and a clonus of the soles23. Bourlier (1880) 24 conducted several experiments with ether and alcohol extracts of L. cicera. Frogs and small birds perished in a few days with symptoms of paralysis. Turtles given injections for three to four days became paralyzed in the hind legs. Brunelli (1880) fed L. cicera flour to small rabbits; however, as they died shortly, it was impossible to observe chronic lathyrus poisoning. Marie and Londe (1880) 25 injected alkaloids from L. cicera into guinea pigs, without any result. In 1882 Giorgieri reported a sharp increase in the tendon reflex26. Finally, the last epidemic of lathyrism in Kabilia (1883) was observed by Proust, Prengrueber, Bourlier and Grandjean. In Algiers during the years of the' failing harvests, the seeds of L. cicera replaced the rare barley, and bread contained two thirds wheat or barley and one third lathyrus. Lathyrism increases almost every 1520 years corresponding to the period of poor harvest. Astier (1883) 27 observed this endemic, in which 1200 people were ill or 1 out of every 20. There was one sick female to every five or six males. Proust (1883) 28 and Bourlier (1883) 29 described the beginning of the disease as sudden. The ill individuals could not lift their feet upon awakening. During the first 5 days there was a general tremor and the movements of arms were erratic. There were sporadic pains in the abdominal spine, hyperesthesia, then anesthesia. The skin reflexes decreased, and the tendon reflexes increased. When walking there was severe forward deflection to the body. I t appeared that the hips, which tremble and shake, are supporting considerable weight. The leg remained extended; the knee was slightly bent or completely straight: the soles were turned inward. There were a hesitation in walking and difficulty in standing, and the patient readily fell. Patients with lathyrism, therefore, must be carried. Early in the disease there was retention of urine.
B. Brunelli, "Due Casi di Paraplegia Spastica." 7th Internat. Med. Congr. II, 1880, p. 45. 24 A. Bourlier, "Le Lathyrisme." Gaz. Med. d'Algerie (Alger) XVII, 1882, p. 139. 25 Marie and Londe, Quoted by Semidalov (see 45), p. 739. 28 Ibid. 27 L. Astier, "Contribution a. l'etude du Lathyrisme; Intoxication Chronique par les Gesses." These Lyon, 1883. 28 A. Proust, "Du Lathyrisme Medullaire Spasmodique." Bull. Acad. de Med. XII, 1883, p. 829. 29 A. Bourlier, Quoted by Semidalov (see 45), p. 735.
23
170
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The reaction to the faradic current, according to Proust (1883), was' less noticeable in the lower extremities than in the upper. Grandjean (1883) 30 studied 14 new patients who had consumed bread containing L. clymenum. Pain occurred in 6 to 8 weeks in the waist, and heaviness developed in their legs. The patients had poor control of their leg movements. They felt numbness in their legs and experienced needlelike pains. However, sensation was normal. There was a shakiness during walking; some individuals had bodies inclined forward, while others had to take long steps in walking. Sensitivity to stimulation by electricity was present. Sometimes there was a paralysis of the pelvic organs. There were no instances of gangrene or headaches. Proust reports that some patients recovered completely. The above described disease was studied by Bouchard in 1883, several months before Proust31. Not one of the patients was paralyzed; all walked with the aid of a stick or were supported by another person. It was said that some were so afflicted that they could not walk or stand at all. All individuals walked with a slightly forward bend to the body; their movements were slow and rigid. Every step was accompanied by shaking consisting of two or three movements. They could keep their balance if they leaned with both arms upon a long cane; without this support they would have fallen. They walked with extended legs, without bending their knees, and dragged their feet. The insteps were directed downward, the feet turned slightly inword, and the large toes gripped the uneven surface of the ground. \ Because of the latter almost all patients had excoriations, or wounds 6n the dorsal side of their toes. At first the foot gripped the ground with the toes; then the heel was raised by two or three convulsive motions. If the patient stopped, the convulsive tremors of the muscles continued, the1 whole body began to rock, and he had to lean on the cane to maintain his equilibrium. But soon these uncontrollable movements became uncomfortable and the patient sat down with extended legs, and one could notice that the leg tremors continued for several minutes. There was an absence of muscular atrophy and no damage to sensation. The tendon/reflexes were increased. The lower extremities were constantly extended; however, it was possible to bend the knees and the soles. There was a great resistance, and a clonus of the sole resulted. Ascribing the reasons for the disease to various circumstances, the patients all agreed on the fact that the disease appeared
30 Grandjean, "Paralysie Ataxique Observee Chez des Kabyles a la Suite de l'ingestion d'une Variete de Gesse." Arch, de Med. ct Pharm. / , 1895, p. 95. 31 Bouchard, Quoted by Semidalov (sec 45), p. 738.
suddenly at night without any warning. Some told about a cold and rainy night. When they awoke they could not move their le'gs. They also felt pains in the waist and lower extremities. It seemed that the initial symptom was always paralysis and that contractions developed later. A common initial phenomenon was a lack of bladder control. Another consistent early symptom was impotency, which disappeared later. The general appearance of the patients was not cachectic; there were no disturbances in the internal organs. Kir res (1883) 32 observed similar attacks of lathyrism in horses and oxen. Tenore (1883) observed animals which became sick after eating the ripe pods. The unripe parts of the plants did not provoke the disease. F err are si (1883) 33 observed 18 pigs with paralyzed hind limbs which developed after they had grazed in a field growing L. cicera. Proust (1883) also mentioned that horses which were fed on L. cicera had developed a paralysis of muscles innervated by the inferior laryngeal nerve. The action of lathyrus was localized in the region of the vagus nerve. Gabory (1883) 34 reported that 18 ducks perished from paralysis. Three peacocks out of five perished after eating lathyrus seed and two recovered. Astier (1883) injected dogs with an alcohol extract of lathyrus. In ten minutes it brought on a general excitement and tremors in the hind limbs, which disappeared in half an hour. The next day another injection 0.6 gm.) brought on tremors in the hind limbs, paraplegia, and refusal to eat. The third-day 0.8 gm. injection resulted in tremors in one quarter of an hour; in half an hour full paraplegia developed, which partially disappeared the next day. However, walking remained jumpy, the hips were drawn it, the' knee was pulled out. In a few days the paralysis disappeared. The experiments terminated. Schuchardt (18861887)35 reported that when lathyrus was added to the bread which was used by the poor population, lathyrism spread endemically. The views of various scientists concerning the role and effects of the lathyrus seeds, as a cause of lathyrism may be divided into three basic categories:
32
33
34
Ibid., p. 739.
Ibid.
R. Gabory, "Discussion sur le Lathyrisme Medullaire Spasmodique." Bull. Acad. de Med. XII, 1883, p. 871. 35 R. Schuchardt, "Zur Geschichte und Casuistik des Lathyrismus." Deutsches Arch. f. klin. Med.
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1. the disease develops because of a special effect of lathyfus seeds, or at least because of certain varieties; 2. the origin of the disease is necessarily due to the addition of other seeds to lathyrus, such as "gioglio ne'ro" (agrostemma githago) from the family "Caryophill," or "gioglio bianco" and "zizania" (lotium temulentum) from the family. "Gramineae," which the Roman academician Lanzi believed to be more toxic than lathyrus; and 3. the disease is due to the spoilage of lathyrus, similar to ergot or spur of rye, especially because of soil or meteorological influences (humidity, moisture, marshy ground). Against the third point of view are certain observations of Cantani (1873) who examined the seeds of lathyrus in the regions where endemic lathyrism broke out, and he found these seeds to be normal. Mingazzini and Buglioni (1896) 36 conducted experiments with rabbits. They fed rabbits the vetch of lathyrus, and after one month of such treatment spastic paraplegia appeared in the animals. However, gross examination of the nervous system revealed negative results. Mirto (1897) 37 fed vetch to rabbits and guinea pigs and was successful in producing symptoms of severe poisoning. Histopathologically he found severe changes in the cells of gray matter of the brain, particularly in the cells of the anterior horns of the spinal cord. The changes noted were extranuclear chromatolysis and atrophy of dendrites. He also reported changes in the white matter of the spinal cord, namely in the lateral pyramidal system and in the funiculi of Goll. Spirtoff (1903) 38 experimented dp. dogs feeding them with different types of vetch and discovered that all1 species of lathyrus are capable of producing paralysis; however, L. syltiestris produces it more rapidly. L. sylvestris affects the cells of the brain r whereas L. sativus affects the gray matter of the spinal cord. Lathyrism was described by Oppenheim (1913) and Kursman (1913) in connection with their discussion of lateral sclerosis. But the histopathologic investigations did not. document any relationship between these two diseases39. Buzzard and Greenfield (1913)'* indicated that there is degeneration of the pyramidal system, mainly the lateral tracts, with smaller changes in the funiculi of Goll that are similar to the' changes seen in pellagra and
36 G. Mingazzini and G. B. Buglioni, "Studio Clinico col Anatomico sul Lathyrisms." Rev. Sperim. Freniat. Med. Leg. XL, 1896, p. 79. 37 Mirto, "Lathyrism." II Pisani XVIII, 1897, p . 109. 38 Spirtoff, "Lathyrism in Russia." Obozr. Psych. V, 1903, p . 675. 39 Oppenheim and Kursman, Quoted by Kozniewska (see 5 1 ) , p . 242. 40 Ibid.
are not due to severe degeneration of the spinal cord. The changes seen in neurolathyrism do not have the character of a systemic disease, although they are concerned mainly with the ascending and descending tracts of the spinal cord. It was not known what damaging agents caused the degenerative phenomenon in the spinal cord because the results of experimental investigations performed on animals were contradictory. Furanda and Zonelli (1914) 41 were unable to produce poisonous symptoms in animals fed with L. sativus species. Anderson (1924) 42 attributed the damaging effects in lathyrism to Vicia sativa and not to the variety of L. sativus. Seeds of this type of vetch contain the glycoside vicin which on hydrolysis yields divicin which is harmful to experimental animals. Nevertheless, from the seeds of L. sativus an extract of alkaloid can be obtained which is similar to divicin and has a poisonous effect on animals. Therefore, Filimonoff (1926) 43 examined a case of lathyrus poisoning that presented a typical clinical picture. The ill man spent about 30 years in Filimonoff''s clinic, and for more than 10 years was under personal observation. The patient died at age 53, from an intercurrent ailment. This case stems from the only Russian lathyrism endemic (18911892). This endemic of lathyrism was described by three' Russian scientists: Schabalin (1893) 44 , Semidalov (1893) 45 and Kojewnikoff (1894) 46 . A brief account of their reports is of interest. In Russia endemic lathyrism was non-existent until 1892. This is explained by the fact that lathyrus cultivation began in 1891 in Russia, and that it was cultivated principally for feeding cattle. The lathyrus cultivated in Russia is of the genus L. sativus. On the government estate of Sara toff 134 to 140 workers received a great deal of so-called "Tschina" (Lathyrus sativus). Their bre'ad consisted of V3 L. sativus and 2/a corn, or V3 corn and 2/3 L. sativus. Furthermore, the Russians used "Tschina" as a kind of flour mush.
Ibid., p. 243. Ibid. 43 / . N. Filimonoff, " Z u r pathologisch-anatomischen Charakteristik d e s Lathyrismus." Ztschr. f. d. ges. Neurol. u. Psychiatr. DV, 1926, p . 76. 44 V. IA. Shabalin, "Epidemiia Spasticheskogo Paralicha, Vyzvannogo Otravleniem T c h i n o i . " ( A n Epidemic of Spastic Paralysis: Caused by Lathyrus Poisoning). Meditsinskoe Obozrenie (Medical Review) XXXIX, April, 1893, p. 365. 45 V. Semidalov, " O L a t h y r i z m e " ( O n L a t h y r i s m ) . Meditsinskoe Obozrenie XXXIX, August, 1893, p. 733. 46 Kojewnikoff, "Lathyrism in Russia." Vestnik Psychiatr. X, 1894, p. 2.
42 41
12 Exp. Med. Surg. Vol. 21, Fasc. 2/3 (1963).
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By the end of December 1891 there were two cases of lathyrism. In the following months there were more, until in April 1892 the endemic suddenly stopped. A total of 34 persons became ill, among them only one female. The first 11 cases were observed by Schabalin, who diagnosed and described them. Two additional cases were described by Semidalov, and five cases were sent to the Moscow Nerveclinic, where Kojewnikoff examined them in detail and published his results. Adrianowski, a botanist in Moscow, determined that the "Tschina" fed in Saratoff had been L. sativus. However, Buliginski attempted to produce a toxic substance from Tschina flour. He was unsuccessful. The crystallized substance he obtained after a complicated procedure had no toxic effect on rabbits, frogs or dogs, who were injected with the crystalline substance. Kojewnikoff could obtain no damaging results on a piglet which he nourished for two months exclusively on L. sativus. He fed the animal about 50 kg. of L. sativus. The clinical picture presented by patients studied by Kojewnikoff were stereotyped, as was the development of lathyrism. The outstanding and most prevalent symptom was lower spastic paraplegia. In the early stages Schabalin observed manifestations of palsy, lameness in the musculature of the upper extremities, and at times even in the cervical muscle's. When the patients were examined about a year after the initiation of lathyrism, the manifestations of palsy were intense and had markedly disseminated; however, Kojewnikoff found no alteration in the throat muscles and in the upper extremities and in the rump there was only a slight paresis. In the lower extremities the appearance of paresis was less pronounced than in the case described by Schabalin; however, recovery only reached a certain stage and then ceased. Furthermore, Kojewnikoff indicated a peculiar disturbance in urination, which he noticed in all his patients during the early stages of lathyrism. Symptoms consisted of pain and frequent urination. All patients suffered from impotency; in fact, erections completely disappeared. Disturbances of the functions of the pelvic organs were of a temporary nature. They showed an advanced alteration in a short period of time which disappeared within the course of a few months. The symptoms characteristic of the instances of lathyrism reported by Kojewnikoff consisted of strong circulatory disturbances in the lower extremities, and sometimes, though to a weaker degree in the upper extremities. The patients constantly suffered from coldness and at times from heat. Objective symptoms included cyanosis, reduction of skin temperature and edema.
Painful cramps in the lower extremities, especially in the calf muscle are additional typical symptoms. Lathyrism presents a rather rapid progression of symptoms until they attain their maximum, and then a gradual improvement occurs when the' L. sativus is removed from the diet. If L. sativus is continued in the diet, certain residual features occur, namely, a more or less pronounced lower spastic paraplegia. In analyzing these cases, Kojewnikoff concluded that he was dealing with a disease of the spinal cord, especially of the thoracic and lumbar sections. He further deduced that the upper part of the spinal cord was pathologically altered, but to a lesser degree, while the cerebrum remained completely intact. The past history, as well as the status of the patients examined, there was not a single bulbar or cerebrum symptom to be found. The most difficult to ascertain would be changes in the pyramidal tracts, but the gray matter was partially damaged. This latter assumption was based on circulatory disturbances and on the functional disorders of the pelvic organs, which, although temporary and transient, were noted in all patients. On the basis of the latter symptom, Kojewnikoff was forced to discard any identification of his cases with spasmodic tabes, although he surmised a kind of similar process. The disease produced pathological changes in some tissues, while leaving others unalterated; some tissues were injured at distant sites and the symptoms were not localized but spread to other tissues. The above mentioned case was observed clinically and later examined pathologically. The following is a description of this case of Kojewnikoff; the findings include autopsy and histological examination. The patient, Markul Gal, wasadmitted to the clinic on January 11, 1893. He had lower spastic paraplegia and slight disturbances during urination. The patient had always been perfectly healthy. He came from a peasant family, whose members were all strong and healthy individuals. In September 1891 he was employed on an estate and commenced receiving L. sativus as food October 14, 1891. At the beginning of February 1892 he started to suffer from painful cramps in the calf muscles during the night. He noticed weakness and spasticity of the lower extremities, and tremors in the upper extremities. By the end of February he could move only with great effort. At the' very beginning of his illness he had painful disturbances of bladder function, and often had loss of bladder control. At the same time erections and ejaculations disappeared. By April the disturbed bladder function began to improve. By the end of June there was also slight improvement in the condition
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of his lower extremities; the patient could walk with some assistance.The tremors of the1 upper extremities disappeared. But there were no other noticeable improvements when he was admitted to the clinic. The patient said that after his legs became weak he noticed a cyanotic condition when his legs were hanging down. In the beginning of April 1892 L. sativus was completely removed from his diet. Examination on January 11, 1893 revealed the following: The patient was medium sized with a powerful build. He walked with great effort. He dragged his feet with effort, heels upwards, knee joints unbent; with each step his legs crossed. Atrophy was absent in the muscles of the lower extremities, with only a slight quantitative absorption of electric excitability. Muscle tone was highly increased, especially in the ankle1 joint where there was no dorsal flexion of the foot, due to stability of pes equinovarus. Muscle tone of extensors was increased in knee joints; the flexors were less hypertonic. Spasticity was weak in the hip joint. Active motion in the ankle joints was impossible. In the knee and hip joints the power of the flexors was greatly diminished. While lying quietly in bed, there was often an involuntary flexion or extension of the lower extremities. Under voluntary motion, the lower extremities had clonic twitches of such intensity that to suppress them the patient had to immediately change his position. Manifestations of lameness (palsy) and spasticity were about equal in severity. Nutrition and electric excitability of the muscles of the upper extremities we're normal. Power was weakened; manual pressure was 30, against a 5060 normal. Muscle tone heightened, but was far less that in the lower extremities. Noticeable weakness occurred in body muscles. The patient was bent forward when sitting and claimed that his back was weak and convulsively pulled together. In bending and straightening he was unable to withstand the slightest pressure; and without the help of his hands could not sit upright in bed. The cervical muscles and motor nerves were normal. At times he had painful cramps in the legs. Muscles and nerve trunks were insensitive to pressure. All sensory organs were normal. The tendon reflexes in the .upper extremities were increased. The patella and Achilles tendon reflexes were greatly increased. Abdominal reflexes and cremaster reflexes were maintained. Sphincter, sexual, and inner organs were normal. When standing or sitting with legs hanging down for a long time, the feet and lower parts of the leg showed a slight but decided edema and a cyanotic color; the skin temperature fell to 2523 C. At night
was sometimes a rise in foot temperature; skin temperature rose to 3233 C. even when his feet remained uncovered. On March 1893, muscle tone in the upper extremities had disappeared. Bodily motions improved since his admission to the clinic. Voluntary motions of lower extremities we're somewhat freer, but hypertension remained very noticeable. Tendon changes in the lower extremities were unchanged; in the upper extremities they were normal. Cramps in the legs lessened compared to those observed when he was first admitted to the' clinic. On May 20, 1893, spasticity and tremors of upper extremities were lessened; tendon reflexes (biceps and triceps) were not increased. Body muscles had become considerably stronger. The patient now walked with the aid of only one cane. He was able to move faster and walk longer distances; but his gait had not changed. On May 23, 1893, the patient went home'. According to his report there was decided initial improvement, so that he could walk short distances (up to 100 meters) without a cane, and with a cane he could walk up to 7 kilometers. However, his condition soon became worsened and the lower extremities became much weaker. On December 3, 1899, he returned to the clinic. On April 17, 1900, examination revealed that brain nerve's and cervical muscles were normal. Active motions of the upper extremities were normal; the tone was not increased. Straightening and especially bending movements of his body had weakened. In the lower extremities the flexion and abduction of hip joints were considerably, weakened. The power of extensors diminished. The voluntary motions of ankle joints were limited, almost unnoticeable in the toe joints. The tone of his hip joint greatly increased. His walking gait appeared unchanged since 1893. Sensitivity and sensory organs were normal. Greatly increased tendon reflexes were present in the lower extremities. The sphincter, sexual, and internal organs were normal. On March 10, 1909, the only changes present were in the lower extremities. The lower portion of the legs were diffusely atrophied. Muscle tone was greatly increased, particularly in the ankle joint. On July 18, 1921, changes were present only in the lower extremities. Voluntary motions were as follows: bending on both sides of hip joints 30, minimal power abduction almost entirely lacking, sufficient power in extensors and adductors, extension of corresponding motion was normal. Bending of knees was almost absent; extension was almost normal. Dorsal flexion of ankle joints was absent. Motion in the toe
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joints was barely noticeable. Spasticity was present in adductors and extensors of hip joints, in extensors of lower leg and in the plantar reflexes of ankle joints. There was a lessened sensitivity to pain, heat and cold in the extremities. Formication occurred on front planes of upper and lower leg, sometimes with dull pains. Joint and peristaltic reflexes increased on lower extremities. Stomach and cremaster reflexes were normal. Strongly noticeable were Babinski, Oppenheim, Mendel-BechtereW and Rossolimo signs. Manifestation of defense reflexes depended on temperature and deep (Marie-Foix) stimulus accompanied by tonic and extensio hallucis. He reacted to the pricking irritant only in the front part of the sole and the outer border of foot. On September 24, 1923, the patient complained of itching on hands and in throat, with a feeling of contraction in the neck and also in the throat. Symptoms also included reddening of face, swelling in the glands of throat, submandibular and axillary lymph nodes were palpable. The patient was transferred to the clinic because of internal ailments. The diagnosis of acute lymphatic leukemia was made. Blood picture showed hemoglobin 73%, erythrocytes 3,200,000, leukocytes 37,000, neutrophiles 10.7%, and lymphocytes 74%. During his hospitalization he became worse. Temperatures were remittent, with elevation to 39 and 40 C. in the evening. On November 2, 1923, death resulted from cardiac insufficiency. Autopsy: Acute lymphatic leukemia: hype'rplasia of lymph glands in cervical region, inguinal, mediastinal and respiratory; hyperplasia of spleen and thymus, lymphadenomas of the skin in the upper regions of the body; atherosclerosis; and pulmonary emphysema. Central nervous system: Cerebrum and coverings were microscopically examined. The spinal cord was considerably thinned in the thoracic, lumbar and sacral regions. Histologic examinations of all sections of the central nervous system were conducted using Weigert-PalS, Snessareff's (Glia) and von Gieson's methods as well as thionin stain'after alcohol fixation. The spinal cord and brain trunk were dissected and stained according to Weigert-Pal and Nissl methods. The following changes in the spinal cord were found. The- white substance of the spinal cord showed slight sclerotic changes in the Goll column and in the lateral columns. Degeneration of the Goll column was absent.
Von Giesen's stain of tissues from the cervical and upper thoracic segments showed a thickening of the pia mater. Vessels were sclerotic and occasionally obliterated. In the region of the lateral columns the septa was thickened and at the same time decreased in cells. In the region of the commissura grisea, the vessels were sclerotic and sometimes obliterated, with a great increase in the number of sclerotic vessels. They occupied the main part of the commissure, and were closely approximated. In connection with changes in the vessels there were numerous but minute fields of rarefaction in the gray matter, especially in the commissure, and also partially in the medial section of the anterior horns. The're was disappearance of nerve fibers in the white matter of the posterior columns, in the rear part of the lateral columns and in the region of the marginal sclerosis. Using the Nissl stain, the number of motor cells was practically normal. Only occasionally was there shrinking or contraction of cells. Pigmentation accumulated throughout the entire length of the spinal cord. Compared to those in the spinal cord the changes in the brain trunk were unimportant. There was a slight diffuse rarefaction in the base of the medulla oblongata. Very significant changes were found in the Nissl preparation of the cerebral cortex, namely, in the lobulus paracentralis and in the upper part of the anterior central convolution. Betzschen cells were present but rarely appeared normal, since only 1 or 2 were present in the entire histologic section. As a rule they occurred as isolated cells and seldom were 2 cells found lying adjacent to one another. Large groups of cells, characteristically seen in normal tissue were completely missing. The cells present were often deformed, sometimes shrunken with widened pericellular spaces. An increase of pigment was present. Lamina magnopyramidalis changes were present. Although these cells were not numerous, their quantity was reduced as well as their size. Morphologically they were far better preserved than the Betzschen cells, and any intracellular pigmentation was insignificant. There were changes in the middle and lower parts of the anterior central cerebrum; whereas changes in the lobulus paracentralis were quite obvious. There were no apparent cellular changes in the striatum, thalamus, hypothalamus, in the nuclei of the brain nerves, in the cortex, in the nuclear dentatus of the cerebellum and in the olivary bodies. In the tissue sections there were numerous small lymphoid nodules seen in the cerebrum, the' cortex, the basal ganglia, as well as in the cerebellum
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and the medulla oblongata. The lymphoid nodules did not exist in. the spinal cord. A review of the results of the histological examination of the central nervous system of this specific case in no way agreed with the previously cited pathologic findings in the literature. Only Barron's autopsy on horses agreed with Filimonoff's results of sclerosis of the pyramidal column threads, and an intensive cellular atrophy of the anterior horns, which Althaus (1884) attempted to explain as amyotropic lateral sclerosis. On the other hand, Mirto and Spirtoff found far greater changes in the nerve cells they examined. Mingazzini found no changes in the nerve tract of the spinal column, although he reported a definite paraplegia. In Kojewnikoff's case the cellular changes in the spinal cord were insignificant, and cellular changes in the cerebral cortex were in no way comparable with the severe alterations reported by Mirto and Spirtoff using poisoning with L. sylvestris. Mirto and Spirtoff found diffuse changes, while Filimonoff reported advanced focal changes, namely, in the cells that functionally combine with the degenerated pyramidal strands of the spinal cord. Judging from the different results, Filimonoff concluded that lathyrus poisoning in animals may not be similar to human lathyrus poisoning. In his case, there were the residual effects of the poisoning, while in the other reported cases there were only acute changes. It is quite possible that at one time in Kojewnikoff's patient the cells of the spinal cord were acutely affected, and thaUby the time Filimonoff found the unimportant cellular changes repair had taken place. However, Kojewnikoff's pathologic changes agreed to a great extent with the known clinical symptoms observed in individuals treated for lathyrus poisoning. Mirto and Spirtoff agreed with the postulate of Kojewnikoff, who surmised that lathyrism was a pathological process involving the spinal column; and concluded that the unimportant changes observed in medullar sections oftih^ebrain trunk as well as focal atrophy of the Betzschen cells in lobulus paracentralis can be completely based on retrograde changes. In the spirial cord the greatest changes were in the pyramidal columns, which were especially intensive in the pectoral segments and toward the caudals. In this re'spect, the clinicians were correct when they placed' lathyrism in a category similar to lateral sclerosis. The finding in pure lateral sclerosis was not similar to the slight sclerosis present in the Goll column in the upper cervical cord and the marginal sclerosis. Therefore, based on the findings of the autopsy Filimonoff agreed with the views held by Brunelli, Marie, Trachtenberg,
Tuczek, and Kojewnikoff but disagreed with the conclusions of Cowerd, Mingazzini and Buglioni. Filimonoff only partially answered the pathological changes because his case dealt with the residual effects of a process that had ended long ago. However, Filimonoff was certain that there was no systemic disease, as in the case of StrumpeWs lateral sclerosis. Only suspicion of a systemic disease would be negated by the course of the disease, with its acute1 and subacu'te course and with improvement up to a specific point. The pathologic examination completely excluded lateral sclerosis; Filimonoff observed a decided pyramidal degeneration only from the lower cervical segments caudelwise. In the cerebral trunk the change's in the pyramidal area were only slight. The degeneration of the lateral columns did not include the entire pyramidal tracts region. Finally the pathologic process spread until reaching the periphery of the lateral column. For this reason Filimonoff considered a residual disease or a myelitis process, and suspected a myelitis funicularis, i. e., a myelosis according to Henneberg's definition. A small primary acute degeneration of myelin fibers started from the white substance of the spinal cord with dissemination to certain areas of predilection. This assumption presented the possibility of explaining the incomplete degeneration of the pyramidal column and the absence of changes in the pyramidal ventricle. The typical pathologic findings were: Glial thickenings in the re'gion of specific alterations, while in all other parts of the cerebral cortex there was a picture of a lacunae, i. e., wide meshed tissue in the spinal cord as a result of disappearance of nerve fibers. The minimal participation of the gray substance was typical, for according to Henneberg it was "astonishingly" immune to the pathologic effects of lathyrus toxin. Slight changes were not unusual. They we're partly the result of hemorrhages and partly due to degeneration of threads. In Filimonoff's case changes were apparent and seemed of vascular origin. Filimonoff believed that pellagra closely approaches the etiology of lathyrism, for one observes the restiform degenerations in the spinal cordof course, in a different location (not simply in the lateral columns but also in the posterior columns). Henneberg believed the changes in pellagra indicated a kind of funicular myelitis. Filimonoff assumed that myelitis funicularis had occurred, but he emphasized the peculiar characteristics of his case. As a rule there was a combined degeneration of the lateral and posterior columns in funicular myelitis. Cases in which only the posterior column was affected were rare, and those with lateral column degeneration were
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unknown (Henneberg). Filimonoff found that the Goll columns' were slightly involved, therefore, he was justified in speaking solely of a degeneration of the lateral columns. Such a peculiarity is undoubtedly due to the peculiar characteristic of the etiology of lathyrism. It was difficult to report with certainty about the vascular changes in the region of the commissura grisea. It is possible that Filimonoff might have been dealing with a proliferation of vessels, which had undergone repair after the lathyrus poisoning of the gray matter. It is also possible that residual manifestations of a proliferative leptomeningitis had occurred at one time which caused an invagination of the pia-mater in the commissure region and partly in the medial region of the anterior horns, therefore producing an increased number of vessels. The findings were very unusual and were difficult to explain, as Filimonoff was dealing with residual effects of disease and was not familiar with the incipient pathologic features of lathyrism. Filimonoff raised one important question in respect to the diagnosis of lathyrism in his case. If the disease presents the finding of funicular myelitis in a patient with symptoms of leukemia, one must ask if he is justified in considering the participation of the' leukemic disease in the development of the pathologic changes. However, in Filimonoff'?, case the leukemia was so acute that it appeared impossible to attribute the changes discovered in the spinal cord to leukemic processes. The changes found were in accord with the clinical findings that Filimonoff had already observed on patients for many years. Filimonoff observed almost complete' paralysis o the lower extremities which was. associated with increased tone of ankle reflexes; with patellar and foot clonus. Accordingly the autopsy revealed a decided degeneration of the pyramidal columns in the lower part of the spinal column. Minimal degeneration of the pyramidal columns in the cervical segments was caused at the beginning of lathyrism by an existing paresis in the upper extremities. The changes and disorders Filimonoff observed at the beginning of lathyrism in the sphincter vasomotors rapidly disappeared. They probably were caused by changes in the cells of the lumbar and sacral spinal cord, which were more or less analogous to the changes that Mirto and Spirt-off found in their experiments with lathyrus poisoning. In the course of lathyrism no traces of these changes remained, nor were their symptoms observed clinically. An interesting question concerns the pathologic reflexes and sensitivity. I n 1893 pathologic reflexes were not observed and clear Babinski phenomena was not obtained. In following years all pathologic
as well as defense reflexes were very pronounced. Also, the sensitivity that was always carefully and repeatedly tested, remained unchanged. In 1921 we observe slight sensitized disturbances in the sense of a lessened sensibility to pain and heat. The anatomic basis for these disturbances could be in the marginal sclerosis of Gower's column. The marginal sclerosis may be an early manifestation of senile changes that occurred in the patient's spinal cord weakened by the pathologic changes from the lathyrus poisoning. Filimonoff concluded that in examining the motor cells he found severe changes in the pyramidal column's Betzschen cells, while there were only slight changes in the large pyramidal cells. Filimonoff's findings led him to the conclusion that the pyramidal tracts originate in the first line with the Betzschen giant cells, and that in this respect the large pyramidal cells are only of secondary importance. Gilde's (1930) 47 investigations showed that deficiency in B complex vitamins resulted in spastic paraplegia of the lower extremities of dogs. Histopathologic examination of these cases revealed irregular atrophy of myelin in the nerve fibers of the spinal cord and in the peripheral nerves. Vitamin deficiency caused degenerative changes in the spinal cord which were similar to the alterations seen in lathyrism. Indeed, the experimental investigations of Mellanby (1934) 48 indicated that this unknown factor was a vitamin deficiency. Mellanby withdrew vitamin A from the diet and produced degenerative changes in the spinal cord of dogs similar to those which have been described in humans with neurolathyrism. In Mellanby's opinion Vicia sativa and, to a le'sser degree, L. sativus caused degenerative changes if the animal also suffered from vitamin A deficiency. Investigations of Stockman (1943) 49 produced the following results: From an aqueous extract of many leguminous seeds such as green pea, lentil, and soybean, Stockman derived phytic acid which causes severe damage to the brain and spinal cord when administered to experimental animals. Small doses of phytic acid caused a state of inhibition and depression, but larger doses caused spasms of the muscles. Histopathologic examinations of the nervous system of the animals receiving phytic acid showed degeneration of the cells and nerve fibers in the central nervous system and in the sympathetic nervous system.
47 48 49
Gilde, Q u o t e d b y Kozniewska Ibid. Ibid., p. 243.
(see 5 1 ) , p . 2 4 4 .
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The contradictory results of the experimental investigations dealing with the' poisonous characteristics of L. sativus and Vicia sativa suggested that perhaps other unknown factors play an important role in neurolathyrism of humans and animals. Spillane (1947) 50 observed in the prison camps in Singapore and in Siam symptoms of spastic paraplegia of the lower extremities resembling symptoms of neurolathyrism which occurred in 63 individuals. Death did not result from the advanced disease. The findings closely resembled the clinical picture of lathyrism; however, the history obtained from these people did not reveal the slightest indication that they had been fed the seeds of vetch or peas. Kozniewska (1952) 51 observed a rare case of lathyrism in the Neurosurgery Clinic in Warsaw, Poland. The patient underwent Forster's operation (posterior rhizotomy) which considerably improved his ability to walk due to the' complete disappearance of muscular tension in the lower extremities. Prior to Kozriiewska study there was no positive cure for lathyrism, but the postoperative improvements of this patient encouraged further investigation. Neurolathyrism usually occurs in individuals between the ages of 15 and 30, or during their most active periods of life. Men were affected twelve' times as often as woman. Symptoms differ, depending on the amount of daily consumption of the vetch and duration of its consumption. The disease appears insidiously but only after two to three months of consumption of the lathyrus. Prodromal symptoms consisted of fever, chills, backache, and pain in the legs. Lathyrism generally occurs suddenly in the lower extremities. Weakening of the legs increases slowly in intensity accompanied by pain, formication and stiffness or spasms of muscles, after which the disease reaches its full development. Deep reflexes are intensified and Babinski symptoms appear. A pathognomonic feature is the suffering experienced by the patient while walking. Any movement by the patient required the use of a cane. Crawling depends on the involvement of the' spinal centers. Sphincters of the bladder and the rectum are rarely affected. I n the majority of instances there is no atrophy of muscles. The spasmodic paresis of the upper extremities was very rare and was present only during the height of the disease.
Ibid., p. 244. H. Kozniewska, "Porazenie Kurczowe Konczyn Dolnych w Nastepstwie Zatrucia Ustroju Wyke z Gatunku Lathyrus Sativus" (Spastic Paraplegia Following Ingestion of the Seeds of Lathyrus Sativus). Neurologia, Neurochirurgia i Psychiatria Polska. Warsaw: / / (March and April, 1952, pp. 239-246.
51 50
There is an increase in the protein content of the spinal fluid. Lathyrism is chronic in character; however, the' disease has a good prognosis. The development of the spinal degeneration can be stopped; however, the previously lost functions never return to normal. Therefore, the degree of paralysis which occurred during initial stages of the disease remained for life. Recognition of lathyrism is accomplished by noting that the patient used lathyrus seeds as nourishment, by the symptoms of paralysis of lower extremities, and by finding other cases of this disease in the same locality. The treatment for lathyrism is effective only when large amounts of proteins and vitamins are administered. Case Report A 23-year-old male was admitted to the Neurosurgery clinic in Warsaw because' of paralysis of the lower extremities accompanied by very strong muscular contractions causing difficulty in walking. His symptoms had begun 8 years ago following an exclusive diet of lathyrus seeds during the famine of 19421943. The lathyrus seeds constituted the entire diet of two thousand people in a village situated in the Tian Shian mountains. This patient, together with his brother and father was among 200 people who became ill at the same time' and under the same circumstances. Only a few women became ill, and the disease was much less severe than among men. The disease began with a stiffening of the lower extremities and a gradual weakening of the muscles of the feet. In a period of two months the symptoms were fully developed. During the first two years of the disease the 23-year-old male was treated in the Clinic of Neurological Diseases in Tashkent, and the diagnosis of lathyrism was made. Upon admission to the Clinic the gait of the patient attracted the attention of the doctors. He walked with difficulty on his toes; however, his lower extremities were straight. The torso of the' patient moved upwards when walking, and that was followed by the rise and fall of the shoulders. The difficulty in walking was caused by the continuous contraction of the muscles of the toes and legs. The general examination was uneventful. There were no abnormalities in the cranial nerves, and nerves of the upper extremities and the abdominal reflexes were normal. While examining the patient in the recumbent position the following observations were made on the lower extremities: straight positioning of all joints, very noticeable tension, pyramidal type of all muscular groups, particularly in the region of
186
Gardner/Sakiewicz
187
extensor muscles of the leg and foot, and loss of strength of the sole flexors. Bilateral shaking of the knee cap, and Babinski and Rossolimo symptoms were noticed. Simple laboratory tests and radiographs of the spinal column did not show any deviation from the normal. Before the operation the patient was given vitamins and D-tubocurarine in such small doses that it was not possible to achieve any results. In September 1951 the patient underwent laminectomy. Dilatation occurred in the arteries with a turous course bifurcating into numerous branches. The appearance of the arteries was similar to the findings in the' blood vessels seen in cases of the mid-spinal tumors. Postoperative recovery was uneventful. On the third day following surgery, it was affirmed that the muscular tonus in the region of knee joints was normal; flexors of the foot were functioning freely; and the dorsal flexors were limited in function. Achille's reflexes were weaker than before surgery; however, the knee reflexes were strong but limited in their normal functional range. Eighteen days following surgery the patient was out of bed, and in six weeks the patient left the clinic in a greatly improved state. He walked sufficiently well using the entire foot. The bending and straightening of the knee joints were profuse'. It also was noticeable that the patient's strength was not sufficient to elevate the foot from the floor, particularly the right foot. When the patient was in a horizontal position there was limited upward movement of the extremities. The muscular tonus was flaccid in the region of the knee joints; however, in the re'gion of ankle joints, muscle tonus was considerably increased. There was an absence of the left knee reflex, and the Babinski symptoms were not present. At the time1 of discharge the patient was instructed1 to continue rehabilitation. The question why neurolathyrism spares the fetnale even during epidemics is certainly not clear. It should be accepted that this difference in distribution is related to the difference in the metabolism, of the female. The female is more resistant to nutritional deficiencies because of her ability during pregnancy to, store in the placenta and in vital organs various vitamins and nutritional elements. Further investigations have established that lathyrism is due to the group of chemical compounds related to the nitriles. Lee (1950) 52 isolated a chemical substance from L. pusillus, and Lalich (1956) 53 isolated a substance from L. odoratus termed "glutaminaminopropionitrile." This chemical substance produces characteristic
52 53
changes of neurolathyrism in experimental animals. Furthermore, it has been proven that neurolathyrogenic properties are conne'cted with the aminopropionitrile. A similar compound, i. e., aminoacetonitrile which is not present in the sweet pea seeds, also has strong lathyrogenic properties. Clinical observations indicate that lathyrism occurs more often when the seeds of L. sativus and L. odoratus are included in the diet. During neurolathyrism there are structural changes in the nervous system: atrophy of pyramidal systems, degeneration of Nissl's bodies. There occurred marginal sclerosis of the spinal cord, also necrosis of anterior horn cells of the spinal cord, and of the Purkinje's cells in the cerebellum. Experiments were conducted by Banuzov on two groups of albino rats of different ages. The first group consisted of adult rats 120130 gm. in weight. This group received daily subcutanious injections of iminodipropionitrile' for 14 days. The dosage used was 100 mg. of IDPN per kilogram of body weight. A second group of 15 rats received 200 mg. per kilogram of body weight. The control group consisted of 20 rats, which received the same dosage of saline solution. A third experimental group of 15 young rats, 5062 gm. in weight, received iminodipropionitrile at the dosage of 100 mg. per kilogram of body weight, and 15 additional rats received 200 mg. per kilogram of body weight. All animals were kept under observation for 150 days. Rats of all groups were kept on a consistent diet. The rats receiving iminodipropionitrile failed to gain weight as rapidly as the control group, and this phenomenon was consistent during the entire 150 days of observation. The initial symptoms of poisoning by iminodipropionitrile in the rats receiving a dosage of 200 mg. per kilogram of body weight occurred on the third or fourth day and appeared as drowsiness and limited movements. On the fifth or sixth day excitement, choreiform, and backward movements of the head occurred. These movements increased until the rats were falling on their backs with the nose pointing upward. On the ninth or tenth day the rats developed advanced neurolathyrism. The rats were quiet and usually were close together. Their behavior and appearance seemed quite normal when undisturbed. However, if disturbed, they suddenly began to jump up. During the jumps the animals fell out of their cages causing injury to themselves. Healthy
54 55
/ . C. Lee, Quoted by Banuzov (see 56), p. 35. Ibid.
Ibid. Ibid.
188
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rats are able to jump from the height of the cage and land without injury. The characteristic siens of poisoning by iminodipropionitrile were the symptoms of incorrect landing and swimming of the animals. If a healthy rat is held by the tail and gradually lowered to a horizontal surf ace, the head is bent toward the back and front legs are stretched forward to touch the surface. Rats poisoned with iminodipropionitrile under similar circumstance's sharply bend their heads toward the chest and do not reach out with stretched front limbs toward the' surface where they are placed, but instead touch the surface with the frontal or occipital portion of the head. If an animal poisoned with iminodipropionitrile is dropped into water, it moves in a circle gradually sinking deeper and eventually drowns. Healthy rats can swim for a long time and tend to climb out of the water. In the initial days of IDPN experiments, the fur of the animals became dirty and disorderly. However, after three to three and a half weeks the fur was smooth and shiny. In two adult rats all of the symptoms of iminodipropionitrile poisoning were sharply manifested. The animals showed signs of being paralyzed for long periods of time. When they were layed on their side with legs stretched upward, they were able to remain in this same position for a long period of time. The heads of the animals, which were give'n IDPN, were sharply bent toward the hind limbs on which they were sitting. The treated animals showed loss of weight and they died on the 15th experimental day. The rats who received 100 mg. iminodipropionitrile per kilogram of body weight had all the symptoms of neurolathyrism; however, they were of-a milder form. No differences existed in the clinical findings between old and young rats poisoned.with iminodipropionitrile. Nevertheless, the symptoms of poisoning were more advanced in young rats receiving 100 mg. per kilogram of body weight than in old rats. In three young rats receiving 200 mg. per kilogram of body weight and in two young rats receiving 100 mg. per kilogram of body weight a catatonic behavior and characteristic sitting position developed. These animals showed a rapid loss of weight and then all died on the 15th or 20th day 56 . Summary Lathyrism is a disease caused by the poisonous effects of certain types of vetch called lathyrus. In Russia it is called "Tschina." The harmful effects of lathyrus were known to Hippocrates, who reported
56 JB. /. Banuzov, "Lathyrism." Adravookhranenie Belorussii (Public Health in Belorussia) VII, September, 1961, pp. 34-37.
weakness in the lower extremities among the population of Ainos who were consuming peas in their diet. In the 17th century in Wiirtemberg there were so many instances of poisoning by vetch of the lathyrus type that a spe'cial law was passed forbidding the usage of this vetch in the diet. During the 18th and 19th centuries there were many reports of this disease appearing as epidemics and endemics. In India in 1856 there were thousands of people affected by the disease. In Russia there was reported only one mass poisoning involving 140 individuals in the Sara toff region during the famine of 1891. The bread which was consumed during the famine1 containing x/s vetch flour and 2/s rye flour. In addition the population was using vetch cereal in their diet. The spastic paraplegia of the lower extremities occurring as a result of poisoning with vetch is a characteristic phenomenon occurring in an epidemic after an exclusive diet of L. sativus. The disease has a diffuse character and shows irreversible degenerative changes in the spinal cord. The1 main histopathological changes in man were seen in the spinal cord. The lateral pyramidal systems underwent degeneration. Marginal sclerosis of the spinal cord and funiculi of Goll appeared to a lesser degree. Considerable changes were found in the cells of the gray matter of the brain, occurring mainly in the Betz's cells. These changes included a reduction in the number of Betz's cells, shrinkage and dilatation of the extracellular spaces. The etiology of the disease is the poisonous element which is part of the composition of the vetch or lathyrus type seeds whose injurious effect is potentiated by vitamin deficiency. The epidemic occurrences of lathyrism during famines and the existence of a clinically similar disease among prisoners of war who were exposed to dietary, deficiencies, and very rare instances of this disease among women shows the role of body metabolism in the production of neurolathyrism. Aminonitriles such as IDPN cause nervous disturbances in experimental animals. The clinical findings are similar to those observed in animals receiving a diet consisting of vetch seeds (L. sativus) or of the extracts prepared from the vetch. The clinical picture of the disease is rather stereotyped. Hippocrates observed that in the first stage of the disease a spastic paraplegia of the lower extremities developed. During this early stage paresis of body musculature became evident in the upper extremities and in the neck. There we're also noticeable disturbances in the urination habits of the
13 Exp. Med. Surg, Vol. 21, Fasc. 2/3 (1963).
190
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affected patients. There were irregularities in bowel movements. Finally, the later symptom was a disturbance in the circulation of blood in the lower extremities, with a constant feeling of cold, cyanosis, and a decrease in the skin temperature. After a few months the disease reached its peak and subsequently subsided when the vetch was excluded from the diet. The disturbances which occurred in several parts of the body, caused by the lathyrus poisoning, were as a rule of a temporary character. However, the spastic paraplegia of the lower extremities remained after withdrawal of the lathyrus diet. The latter symptom was a paralysis with increased muscular tonus, muscular reflexes, and pathologic reflexes. No noticeable atrophy was present; however, regeneration was absent. The diagnosis of lathyrism is not difficult if the signs, symptoms, and histopathology are known. But it is extremely difficult to arrive at a definitive diagnosis when only the clinical findings are available or when the disease shows a picture similar to that of ordinary lateral sclerosis. The prognosis was good in instances when the severity of the neurolathyric phenomenon had passed although the symptoms may have not disappeared. If the treatment used is similar to the therapeutic methods utilized for spastic paraplegia, no results occur. Prophylaxis or prevention of the disease is achieved only with a total exclusion of lathyrus from the diet. Bibliography Althaus, ].: t)ber Sklerose des Riickenmarkes etc. Leipzig 1884, 46-47. Al'tschuller, E. A.: Toksicheskie Miolozy Alimentarnogo Proizkhozhdenija (Latirizm) [Toxic Myelitis of Alimentary prigin (Lathyrism)]. Sbornik Trudov Kliniki Nervnykh Boleznei Kazanskogd Meditsinskogo Instituta (Collection of Works of the Nervous Disease Clinic of the Kazan Medical Institute), 104, 1948. Astier, L.: Contribution a l'etude du Lathyrisme par les Gesses. These, Lyon 1883. Banuzov, B. I.: Lathyrism. Zdravookhranenie Belorussii (Public Health in Belorussia) VII, 34-37, September 1961. Belmondo, E.: Le Alterazioni Anatomiche del Midollo Spinale Nella Pellagra. Reggio-Emilia, 110, 1890. Bol'shaia Meditsinskaja Entsiklopediia (Soviet Medical Encyclopedia). 2nd ed. XV, 273-274. Moscow 1960. Brunelli, B.: Due Casidi Paraplegia Spastica. Trans. 7th Internat. Med. Congr. II, 45, London 1880. ' Cantani, A.: Latirismo (Lathyrismus )/Mustrata de tre Casi Clinici. II Morgagni XV, 745, 1873. Desparanches: Le Lathyrisme. Bull. Scient. Med. XVIII, 433, 1829. Duvernoy, G. D.: Dissertazione de Lathyri Quadan Venenata Specie in Comitatu Montbelgardensi Cults. Basilliae 1770. Filimonoff, I. N.: Zur pathologisch-anatomischen Charakteristik des Lathyrismus. Ztschr. f. d. ges. Neurol. u. Psychiatr. DV, 76, 1926. Gabory, R.: Discussion sur le Lathyrisme Medullaire Spasmodique. Bull. Acad. de Med. XII, 871, Paris 1883.-
Grandjean, M.: Paralysie Ataxique Observee Chez des Kabyles a la Suite de l'ingestion d'une Variete de Gesse. Arch, de Med. et Pharm. I, 95, 1895. Hippocrates: On Epidemics, Book II, Sec. IV, 3. Hirzel, F. von: Uber das Getreide und Bred. Zurich: Linguet und Tissot, VII, 1780. Irving, ].: Notice of a Form of Paralysis of the Lower Extremities, Extensively Prevailing in Part of the District of Alia Habod, Produced by Use of Lathyrus Sativus as an Article of Food. Indian Ann. M. Sc, VI, 424, 1859. Kojewnikoff: Lathyrism in Russia. Vestnik Psychiatr. X, 2, 1894. Korsakofj, S. S.: Ob Alkogolnom Paraliche (About Alcoholic Paralysis). Zemlyelcheskaya Gazeta. Kozniewska, H.: Porazenie Kurczowe Konczyn Lolnych w Nastepstwie Zatrucia Ustroju Wyka z Gatunku Lathyrus Sativus (Spastic Paraplegia Following Ingestion of the Seeds of Lathyrus Sativus). Neurologia, Neurochirurgia i Psychiatria Polska. Warsaw, II (March and April) 192, 239-246. Marie, P.: Des Manifestations Medullaires de l'Ergotisme et du Lathyrisme. Progress Medic. XI, 842, 1883. Mirto, Lathyrism. II Pisani XVII, 109, 1897. Proust, A.: Du Lathyrisme Medullaire Spasmodique. Bull. Acad. Med. XII, 829, Paris 1883. Ramarzini: Lathyrism in Italy. Constituto Epidem. Anni. Modena 1691. Schuchardt, R.: Zur Geschichte und Casuistik des Lathyrismus. Deutsch. Archiv. f. Klinische Medizin XL, 312, 1886-87. Semidalov, V.: O. Lathyrizme (On Lathyrism). Meditsinskoe Obozrenie (Medical Review) XXXIX, 733, August 1893. Shabalin, V. IA.: Epidemiia Spasticheskogo Paralicha, Vyzvannego Otravleniem Tchinoi (An Epidemic of Spastic Paralysis, Caused by Lathyrus Poisoning). Meditsinskoe Obozrenie (Medical Review) XXXIX, 315, April 1893. Spirtoff: Lathyrism in Russia. Obozr. Psych. V, 675, 1903.
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A Review of Neurolathyrism Including the Russian and Polish Literature

A Review of Neurolathyrism Including the Russian and Polish Literature*

Ramarzini, "Lathyrism in Italy." Constituto Epidem. Anni., Modena,

A Review of Neurolathyrism Including the Russian and Polish Literature

A Review of Neurolathyrism Including the Russian and Polish Literature

A Review of Neurolathyrism Including the Russian and Polish Literature*

Ramarzini, "Lathyrism in Italy." Constituto Epidem. Anni., Modena,

A Review of Neurolathyrism Including the Russian and Polish Literature

A Review of Neurolathyrism Including the Russian and Polish Literature

A Review of Neurolathyrism Including the Russian and Polish Literature

A Review of Neurolathyrism Including the Russian and Polish Literature

12 Exp. Med. Surg. Vol. 21, Fasc. 2/3 (1963).

A Review of Neurolathyrism Including the Russian and Polish Literature

A Review of Neurolathyrism Including the Russian and Polish Literature

A Review of Neurolathyrism Including the Russian and Polish Literature

A Review of Neurolathyrism Including the Russian and Polish Literature

A Review of Neurolathyrism Including the Russian and Polish Literature

Gilde, Q u o t e d b y Kozniewska Ibid. Ibid., p. 243.

A Review of Neurolathyrism Including the Russian and Polish Literature

A Review of Neurolathyrism Including the Russian and Polish Literature

/ . C. Lee, Quoted by Banuzov (see 56), p. 35. Ibid.

A Review of Neurolathyrism Including the Russian and Polish Literature

A Review of Neurolathyrism Including the Russian and Polish Literature

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