We performed a neuropathological study on 13 patients with amyotrophic lateral sclerosis (ALS) who had been on respirator support. Twelve patients had developed upper and lower motor neuron signs, exclusively, before being placed on respirators. One patient was diagnosed as having the pseudoneuritic type of ALS. The main pathological findings in the 13 cases were the simultaneous involvement of both motor neurons and the presence of Bunina bodies and ubiquitinated filaments in the anterior horn cells. While on the respirator, two rapidly progressing patients developed supranuclear ophthalmoplegia and ended in totally locked‐in state. These two cases showed widespread systemic degenerative changes in the central nervous system (CNS) that involved the frontoparietal cortices adjacent to the precentral gryrus, the pallido‐luysio‐nigral system, thalamus, hypothalamus, amygdala, brain stem tegmentum, dentate‐rubral system, Clarke's spinocerebellar‐middle root zone and Onuf's nucleus. Eight normally or rapidly progressing patients developed supranuclear ophthalmoplegia, with or without emotional disinhibition and blood pressure lability. Some of the CNS structures affected in the two patients described above, were also altered in these eight cases. We attribute the ophthalmoplegia to the involvement of the brain stem tegmentum and frontal cortices, which are concerned with eye movement. In addition, the emotional and autonomic labilities of some of the patients may be related to alterations of the limbic system. By contrast, the clinicopathological features of the remaining three, slowly progressing patients were confined to both motor neurons. On the basis of these findings we address the intrinsic uniformity of ALS and some of its diversities