Shuichi Kato

Total manifestations of amyotrophic lateral sclerosis: ALS in the totally locked-in state

We report 4 cases of amyotrophic lateral sclerosis (ALS) in the totally locked-in state (TLS); 2 of the cases were autopsied. The clinical and pathological findings of ALS reported previously were essentially included in those studied here. In all cases reported in this paper, the voluntary muscles, including the oculomotor muscles, deteriorated rapidly, resulting in respiratory failure within 1.5 years. Successive observation of the 4 cases confirmed that ontogenetically old motor functions, including oculomotor functions, were preserved in the advanced stage, and that the main lesions in the oculomotor system were supranuclear. The 2 autopsied cases showed widespread pathological lesions other than those of the pyramidal tract and motoneurons commonly seen in ALS. We review these findings, and discuss them from an ontogenetical aspect in terms of the development of motor functions and anatomical myelination, and compare them with clinico-pathological findings of progressive supranuclear palsy (PSP) and anatomical structures of the supranuclear oculomotor system in monkeys.

Participation of the limbic system and its associated areas in the dementia of amyotrophic lateral sclerosis

The topographic distribution of degenerative changes in large brain sections from five sporadic amyotrophic lateral sclerosis (ALS) patients with dementia and three without dementia was examined. The dementia characteristics were impaired shifting from one line of thinking to another, perseveration, and emotional disinhibition as well as impairment of cognition, and judgment. Neuropathological examinations showed definite ALS changes in all the patients studied. In addition, the five patients with dementia showed neuronal loss, gliosis, and sponginess of the superficial layers throughout the cerebral cortices, predominantly in the dorsomedial cortex of the temporal tip and the parahippocampal, ambiens, anterior cingulate, rectal, orbital, and insular gyri as well as neuronal loss in the basolateral nucleus of the amygdala, nucleus accumbens, and subiculum of the hippocampus. Ubiquitin-immunoreactive inclusions were present in some neurons in the granular cell layers of the hippocampus. Fibrous gliosis was extensive in the subcortical and deep white matter of the frontotemporal lobes. The affected regions take in the limbic system and its associated areas which are the sources of the psychological problems, including emotional disturbance, experienced by these ALS patients. The psychological problems of ALS need to be investigated in relation to the involvement of the limbic system.

Loss of cholinergic synapses on the spinal motor neurons of amyotrophic lateral sclerosis

The expression of vesicular acetylcholine transporter (VAChT) was examined immunohistochemically in the cholinergic synapses on the spinal motor neuron of the patient with sporadic amyotrophic lateral sclerosis (SALS). VAChT immunoreactive synapses were deplected on surviving motor neurons in SALS, while synaptophysin immunoreactivity was undiminished on the same neurons. This discrepancy suggests that in SALS, loss of cholindergic input on lower motor neurons is an early event, and may be part of the cause of death of those motor neurons.

Prominent sensory and autonomic disturbances in familial amyotrophic lateral sclerosis with a Gly93Ser mutation in the SOD1 gene

A missense mutation (Gly93-->Ser) was identified in exon 4 of the Cu/Zn superoxide dismutase (SOD1) gene of a 48-year-old Japanese man with familial amyotrophic lateral sclerosis (FALS). The SOD1 activities in the fibroblasts and in a lysate of erythrocytes of the patient did not differ from those of healthy controls. The clinical characteristics of the patient were fairly slow progression of the illness, prominent sensory impairment, urinary disturbance and blood pressure fluctuation due to sympathetic hyperactivity. The severe sensory and autonomic disturbances, association of which with FALS has not been previously reported, may represent specific clinical features associated with the Gly93Ser mutation or may indicate the variability of clinical findings even in patients with the same mutation.

Decrease of medullary catecholaminergic neurons in multiple system atrophy and Parkinson's disease and their preservation in amyotrophic lateral sclerosis

We investigated the number of tyrosine hydroxylase (TH)-immunoreactive neurons in the C1 and A2 regions of the medulla, the sites of the baroreflex arc, in 7 patients with multiple system atrophy (MSA), 8 with Parkinsons disease (PD), 9 with amyotrophic lateral sclerosis (ALS), and 12 age-matched normal subjects to analyze the relationship between cardiovascular dysfunction and medullary catecholaminergic neurons. Orthostatic hypotension (OH) was marked in all the MSA patients and moderate in three PD patients. Three of the five ALS patients who had been on respirators showed lability of blood pressure; paroxysmal hypertension and nocturnal hypotension without compensatory tachycardia. All the MSA patients showed extremely marked decrease of TH-immunoreactive neurons in both the C1 and A2 regions. In the patients with Parkinsons disease, numerous TH-immunoreactive neurons contained Lewy bodies that were immunostained by antibody to TH. TH-immunoreactive neurons were decreased very markedly in the A2 regions of two patients with OH, and three patients without OH showed fairly marked decreases in the C1 or A2 region. In contrast, the number of TH-immunoreactive neurons in ALS was the same as in normal subjects. In MSA and some PD patients, orthostatic hypotension may partly be due to the involvement of the medullary catecholaminergic neurons. The lability of blood pressure in ALS probably is not related to the medullary catecholaminergic neurons.

Neuropathology in Amyotrophic Lateral Sclerosis Patients on Respirators: Uniformity and Diversity in 13 Cases

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, Clarkes spinocerebellar‐middle root zone and Onufs 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

Sporadic amyotrophic lateral sclerosis of long duration mimicking spinal progressive muscular atrophy : a clinicopathological study

We report an autopsy case of amyotrophic lateral sclerosis (ALS) clinically diagnosed as spinal progressive muscular atrophy (SPMA). The patient was a Japanese woman without hereditary burden. She developed muscle weakness of the distal part of the left lower extremity at age 42, followed by muscle weakness and atrophy of the right lower extremity and upper extremities. At age 57, she needed transient ventilatory support. Slight weakness in the facial muscles and fasciculation of the tongue appeared at age 60. At age 61, she died of sudden respiratory arrest. During the clinical course, neurological examination revealed neither Babinski signs nor hyperreflexia. The neuropathological examination revealed not only neuronal loss with gliosis in the facial nucleus, hypoglossal nucleus, and anterior horns of the spinal cord, but also loss of Betz cells and degeneration of the pyramidal tracts. Based on these clinicopathological findings and review of literature, we conclude that sporadic ALS mimicking SPMA is present.

Effect of tamsulosin hydrochloride on sympathetic hyperactivity in amyotrophic lateral sclerosis

We assessed subclinical sympathetic hyperactivity in amyotrophic lateral sclerosis (ALS) patients, which might be followed by an autonomic spell leading to circulatory collapse, or sudden death as the disease progresses, and investigated the effect of tamsulosin hydrochloride (TSHC) on sympathetic hyperactivity. We measured the plasma norepinephrine (NE) concentrations of 41 ALS patients and 10 normal controls. TSHC, a selective alpha 1 blocker. was then administered to 10 ALS patients who had high plasma NE and to the 10 normal controls. Subsequent plasma NE change was evaluated for the possible alleviating effect of TSHC on subclinical sympathetic hyperactivity in ALS. Plasma NE was high in 20 of the ALS patients (48.8%), but had no relation to respiratory problems, which supports the previous speculation that plasma NE increases in ALS are not secondary to respiratory deficit, but reflect the primary pathomechanism of the disease. ALS patients showed a marked decrease in the NE concentration after TSHC administration, whereas there was no change in the controls. In conclusion, TSHC may be useful for suppressing central sympathetic hyperactivity, presumably the primary pathomechanism in ALS, and for preventing autonomic spells during the advanced stage of the disease.

Neuronal inclusions in the dentate fascia in patients with multiple system atrophy.

Ubiquitin-immunoreactive neuronal inclusions in the granular cells in the dentate fascia (UNIDs) of patients with multiple system atrophy (MSA) were examined for immunohistochemical and ultrastructural characterization especially in comparison with those which were recently reported for amyotrophic lateral sclerosis with dementia (ALS-D). Eight of 23 MSA patients had UNIDs which were also identified by Gallyas-Braak impregnation but immunonegative for other antibodies including against tau, neurofilaments, and alphaB crystallin. Ultrastructurally, loosely aggregated fibrils without limiting membrane located around the nucleus, which was confirmed by the results of ubiquitin-immunoelectron microscopy. The formation of UNIDs in MSA and ALS-D was suggested to be caused by different types of degeneration because UNIDs in MSA differ from these in ALS-D in terms of their stainability by Gallyas-Braak impregnation and ultrastructurally. In this study hippocampal involvement in MSA differing from ALS-D was clarified.

Aberrant splicing of human Cu/Zn superoxide dismutase (SOD1) RNA transcripts

Two abnormal SOD1mRNAs, exon 2-skipping and exon 2 and 3-skipping species, were identified from occipital brain tissue of sporadic amyotrophic lateral sclerosis (ALS) patients carrying no mutations in the SOD1 gene. Both transcripts were ubiquitously expressed in non-neuronal as well as neuronal tissues from a subject without neurological diseases. The expression pattern did not show disease specificity or lesional selectivity associated with ALS. Transient expression studies revealed weak expression of the proteins derived from the exon 2-skipping SOD1 cDNA in a cell-free translation system but not in cells. The putative abnormal SOD1 protein may accumulate and exert toxic effects on motor neurons in ALS when the proteolytic system is disturbed by aging or some causal factors.