NUCLEIC ACID ANTIMETABOLITES AND CNS 111 



J^loo// V I— I = 25 m^ed. 



Fig. 2. Fasciculations recorded electromyographically in the hamstrings 3 days 

 after FO. 



hypertonia of flexor muscles in the hindlimbs. In some animals this may not 

 progress beyond a hyperreflexic paraparesis. In more severely affected 

 animals, the signs of neuronal irritation diminish and paraplegia with loss 

 ot muscle tone and stretch reflexes ensues. Sensation becomes obtunded, and 

 the sphincters are paralyzed. These signs indicate a loss of neuronal function. 

 Denerxation atrophy with fibrillary potentials may appear in the 2nd week, 

 presumablv because some motoneurons are destroyed. Animals with a mild 

 myelopathy, i.e.. a hyperreflexic paraparesis, after a period of stability or 

 improvement enter a second stage of illness during the 3rd to 4th week. 

 Their condition worsens, and within a day or two they exhibit an extensor 

 paraplegia with dulling of sensibility in the hindquarters and acute urinary 

 retention. Spastic weakness of the forelimbs sometimes occurs later. In 

 most severely afflicted animals, flaccid paraplegia appears in 4 to 5 days. The 

 forelimbs are affected early, and death occurs from respiratory failure by 5 

 to 7 days. In general, the larger the dose of the analog, the more severe is the 

 myelopathy. 



The histopathology of the myelopathy produced by FO has been carefully 

 in\estigated ( Koenig, 1960). The changes initially are confined to neurons. 

 Inflammatory or vascular lesions do not occur. The nucleoli of nerve cells 

 become small and less basophilic. Within 3 or 4 days a fragmentation and 

 loss of peripherally situated Nissl substance is seen in spinal motoneurons 

 and interneinons i Fig. 3 ) . Depletion of Nissl substance progresses to involve 

 much of the perikaryon by 7 to 10 days i Fig. 4). Signs of recovery then ap- 

 pear in \iable neurons. These consist of a striking hypertrophy and an in- 

 crease in basophilia of nucleoli i Fig. 5 ) followed by increasing amounts of 

 Nissl substance. Regeneration is well ad\anced by 35 to 50 days, and some 

 neurons are even chromophilic. White matter is structurally intact for 2 to 3 

 weeks, but thereafter it almost always exhibits some spongy or mycrocystic 

 degeneration with \arying Cjuantities of neural fat, either free or in macro- 

 phages I Fig. 6 j . A thinning of oligodendroglia is seen in white matter at this 



