Gradient subthalamic neurodegeneration and tau pathology in the hypoglossal nucleus as essential pathological markers of progressive supranuclear palsy - Richardson syndrome.

Progressive supranuclear palsy - Richardson syndrome (PSP-RS) was first described in 1964 by Steele et al. Tau pathology has not been reported in the hypoglossal nuclei of PSP-RS patients, whereas Steele et al. described gliosis with no remarkable neuronal losses in the hypoglossal nucleus. This study aimed to investigate the distribution and degree of tau pathology-associated neurodegeneration, with an emphasis on the hypoglossal nucleus, in patients with PSP-RS. Six clinicopathologically proven PSP-RS cases were included in this study. All patients were clinicopathologically and immunohistochemically re-evaluated. This study confirmed the following neuropathological characteristics of PSP-RS: (1) neurodegeneration usually affects the striatonigral system and cerebellar dentate nucleus; (2) the cerebellar afferent system in PSP-RS is affected by absent-to-mild neurodegeneration; and (3) the extent of tau distribution throughout the central nervous system is greater than the extent of neurodegeneration. Furthermore, we found that subthalamic neurodegeneration was more prominent in the ventromedial region than in the dorsolateral region. Nevertheless, the tau pathology showed no remarkable differences between these two sites. Interestingly, the tau pathology was frequently observed in the hypoglossal nuclei of PSP-RS patients. Gradient neurodegeneration of the subthalamus and tau pathology in the hypoglossal nucleus could be regarded as essential pathological features of PSP-RS.

Molecular cloning, heterologous expression, and characterization of a novel member of CYP2A in the Syrian hamster.

The cDNA clone coding for a novel cytochrome P-450 2A subfamily member (CYP2A16) was isolated from a Syrian hamster liver cDNA library. The deduced amino acid sequence of CYP2A16 showed more than 90% identity with those of rat CYP2A3 and mouse CYP2A4/5. The catalytic activity of CYP2A16 was determined by transient expression of its cDNA in transfected COS7 cells and CYP2A16 was found to have the testosterone 2 beta-, 15 alpha-, and 15 beta-hydroxylases, coumarin 7-hydroxylase, and ethoxycoumarin O-deethylase activities. These enzymatic characteristics of CYP2A16 are different from those of other Syrian hamster CYP2A subfamily members, CYP2A8 and CYP2A9. Northern blot analysis showed that CYP2A16 was expressed in kidney and lung while most of the other CYP2A subfamily members have been reported to be expressed in liver and olfactory. These observations indicated that the Syrian hamster CYP2A16 had unique properties compared with those of other CYP2A subfamily members.

Fukuyama-type congenital muscular dystrophy: close relation between changes in the muscle basal lamina and plasma membrane.

Despite the recent advance in genetic study of Fukuyama-type congenital muscular dystrophy (FCMD), the mechanism of muscle degeneration in the disease remains unclear. To clarify it, muscle biopsies from six cases of FCMD were subjected to immunohistochemical and ultrastructural studies. On the muscle cell surface, decreased expression of laminin alpha2 subunit was seen along with aberrant expression of laminin alpha5 and neural cell adhesion molecule. Electron microscopy revealed breach of muscle basal lamina. The electron density of plasma membrane was significantly lower at the places without identifiable basal lamina. Thus in FCMD changes of laminin and other proteins on the cell surface involve a process common to developing muscles, and loss of normal structure of the basal lamina is closely associated with changes of the plasma membrane. This suggests that the primary cause of FCMD is related to formation and maintenance of the basal lamina.

Laryngeal electromyography with separated surface electrodes in patients with multiple system atrophy presenting with vocal cord paralysis.

When recording the activity of the posterior cricoarytenoid muscle (PCA) with surface electrodes, there is contamination from the surrounding muscles such as the cricopharyngeal muscle. We therefore devised a new oesophageal catheter electrode of the separate type, having three individual surface electrodes for the PCA, cricopharyngeal muscle and diaphragm. The records obtained with this catheter demonstrated satisfactory separation between PCA and cricopharyngeal muscle activities. We used this catheter in patients with multiple system atrophy presenting with vocal cord paralysis, who were awake or asleep. There were two interesting electromyographical findings, which were inspiratory activity of the adductor muscle (the thyroarytenoid muscle) and fade-out of the abductor muscle, that is, PCA activity during sleep. Although vocal cord paralysis is one of the most serious life-threatening complications, the precise mechanism has not been clarified. We believe that our catheter may be useful in investigating the mechanism of vocal cord paralysis which could cause sudden death in neurodegenerative disorders, including multiple system atrophy.

Vocal cord abductor paralysis (VCAP) in Parkinson's disease: difference from VCAP in multiple system atrophy.

Vocal cord abductor paralysis (VCAP) is rare in Parkinson's disease (PD), while it is frequent in multiple system atrophy (MSA). Although VCAP is a life-threatening complication it has not yet been clarified whether there is any difference in the mechanism of VCAP between PD and MSA. Examining 3 autopsy-proven PD patients who developed severe VCAP requiring tracheostomy, we found the following differences in the mechanism of VCAP between MSA and PD: (1) clinical and laryngofiberscopic examination showed that VCAP in PD was not exacerbated during sleep, unlike in MSA; (2) On histological examination of the intrinsic laryngeal muscles, the posterior cricoarytenoid muscle demonstrated no abnormalities in PD, while the muscle showed characteristic neurogenic atrophy in MSA. There seemed to be two types of VCAP, namely the nonparalytic type observed in PD, and the paralytic type observed in MSA. Severe dysphagia requiring tube-feeding was common among PD patients who presented with VCAP. Although the relationship between VCAP and dysphagia is unknown, one should be aware of the possibility of fatal VCAP in PD patients with severe dysphagia.

Type III Machado-Joseph disease in a Japanese family: a clinicopathological study with special reference to the peripheral nervous system.

The clinical and pathological findings in a 58-year-old Japanese man suffering from type III Machado-Joseph disease are reported. The patient became affected at the age of 50 years and presented cerebellar ataxia, progressive external ophthalmoplegia and muscular atrophy, although extrapyramidal signs were never detected throughout the whole course of his disease. His mother, sister and son presented progressive ataxia in the third or fourth decade. The mode of inheritance is considered to be autosomal dominant. Pathological examination revealed severe involvement of the dentato-rubral, ponto-cerebellar and subthalamopallidal systems, spinocerebellar tracts and Clarke's column, cranial motor nuclei including the oculomotor systems and anterior horn cells. The involvement of the substantia nigra was relatively mild, and the nerve cells in the inferior olivary nucleus were well preserved. The distal portion of peripheral nerves was severely damaged. Although the striking feature of Machado-Joseph disease is a considerable variability in the individual clinical expression, there have not been many autopsied cases of this disease and efforts to clarify the clinico-pathological correlation in each phenotype have scarcely been made. Relatively mild changes in the substantia nigra and severe involvement of the peripheral nervous system, as in our case, may be the pathological hallmarks of the type III disorder.

Morphometric study of nucleus ambiguus in multiple system atrophy presenting with vocal cord abductor paralysis.

AIM: To identify lesions responsible for vocal cord abductor paralysis (VCAP) in multiple system atrophy (MSA), we performed a morphometric study of the nucleus ambiguus which innervates the intrinsic laryngeal muscles. METHODS: Two autopsied cases of MSA presenting with VCAP and one control were examined. Both cases of MSA showed selective neurogenic atrophy of the posterior cricoarytenoid muscles among the intrinsic laryngeal muscles, while no abnormalities were seen in the control. From a block of the medulla oblongata, sections 10 microm thickness were cut serially without spacing and stained with cresyl violet. The ambiguus neurons were counted in all the sections to make a histogram. RESULTS: In the control case, ambiguus neurons showed densely populated areas and sparsely populated areas alternately with significant difference in the mean neuronal density between two areas. In MSA, ambiguus neurons were significantly decreased in number at all levels. It indicates that the neurogenic atrophy of the posterior cricoarytenoid muscle is derived from the neuronal loss of the nucleus ambiguus. CONCLUSION: Though it has still been controversial whether or not the ambiguus neurons are decreased in number in MSA with VCAP, we speculated possible reasons for the disagreement on the involvement of the nucleus ambiguus as follows: different mechanism of VCAP are playing role, and histometric data have been disturbed by factors such as split-cell counting error and marked variation in the distribution of the ambiguus neurons.

Expression of HLA-DR in peripheral nerve of amyotrophic lateral sclerosis.

To investigate the possibility of local antigen presentation within the peripheral nerve in amyotrophic lateral sclerosis (ALS), cryostat sections of 83 peripheral nerve biopsies were stained for the demonstration of HLA-DR using a monoclonal antibody. Forty samples showed increased expression of HLA-DR in endoneurium. The phenotypic characteristics of the HLA-DR positive cells are chiefly Schwann cells, using S-100 protein as a marker. We did not detect any co-expression between HLA-DR and NF (axons) and HLA-DR and myelin marker. We also detected co-expression between HLA-DR and NGFr in a majority of HLA-DR positive cells. Inflammatory cells were infrequent, being detected only in 11 cases, predominantly around epineurial blood vessels. Motor and sensory nerve biopsies performed simultaneously showed higher expression of HLA-DR in motor nerves in 2 out of 4 patients. The significance of these findings is not clear. The presence of endoneurial cells expressing HLA-DR suggests that an autoimmune mechanism may be involved in ALS having Schwann as the main target.

[Morphological changes in human diaphragm--ragged red fiber, core/targetoid fiber, cytoplasmic body, and ring fiber].

We have already described that ragged red fiber (RRF), core/targetoid fiber and type 1 fiber predominance were found at autopsy in the diaphragm taken from patients with chronic obstructive pulmonary diseases. The purpose of the present study is to investigate morphological and histochemical changes in the diaphragm in denervating neurologic disorders. The diaphragm in the costal portion was taken from 22 autopsy cases including 4 with amyotrophic lateral sclerosis (ALS), 4 cerebrovascular diseases, 3 Parkinson disease, 2 olivopontocerebellar atrophy. In addition, 4 diaphragm muscles were biopsied at the time of surgery for lung cancer. In the diaphragm we observed not only RRF and core/targetoid fiber but also cytoplasmic body and ring fiber in many cases. These findings were, however, not specific for neurologic disorders. Focal cytochrome c oxidase deficiency was found in muscles with RRF. It should be emphasized that RRF was absent in 3 of 4 cases with ALS and in a case with elevated hemidiaphragm from phrenic nerve paralysis. In the previous report, we suggested that RRF was formed under the relative ischemic state in overworking diaphragm. The relative ischemia means a condition that oxygen (energy) demand for respiratory work exceeds over oxygen supply from the blood in the overworking diaphragm. The reason why no RRF was found in the denervated muscle is that the ischemic state in the denervated muscles is relieved by immobilization after denervation. Karpati et al conformed that denervation prevented ischemic state in the muscle. Other histochemical features in the diaphragm included cytoplasmic body and ring fiber.(ABSTRACT TRUNCATED AT 250 WORDS)

[Clinical studies of 23 patients with multiple system atrophy presenting with vocal cord paralysis].

In order to elucidate the clinical features and the prognosis for life in the patients with multiple system atrophy (MSA) presenting with vocal cord paralysis (VCP), we studied the correlation between VCP and other neurological findings including cerebellar, pyramidal, extrapyramidal and autonomic nervous signs. Subjects were 48 MSA patients: 23 with VCP and age- and illness duration-matched 25 without VCP. MSA in this paper comprised clinically Shy-Drager syndrome, olivopontocerebellar atrophy, and striatonigral degeneration. MSA patients with VCP had in general more severe neurological findings, compared with those without VCP. Urinary incontinence developed in the relatively early stage of illness and preceded VCP in all patients. VCP developed not only in far-advanced stage but at any time in the course of illness. As to swallowing function when a diagnosis of VCP was established, about half of the patients with VCP needed nasogastric tube feeding and the remaining half tolerated oral feeding. VCP correlated strongly with urinary incontinence but not always with the severity of orthostatic hypotension or extrapyramidal tract sign such as parkinsonism. Five of the eight patients without tracheostomy came to sudden death. The mean duration from making a diagnosis of VCP to death was 1.1 years. In contrast, nine of the 11 patients with tracheostomy were alive and the survival periods after tracheostomy reached a maximum, five years. These facts suggest that the prognosis for life in the patients with VCP depends in part upon whether tracheostomy was carried out or not.(ABSTRACT TRUNCATED AT 250 WORDS)

[A case of progressive supranuclear palsy presenting mouth opening difficulty with tonic contraction of the orbicularis oris muscle].

A 72-year-old man developed supranuclear ophthalmoplegia, bradykinesia, rigidity, unsteady gait, dementia, dysphagia, retrocollis, grasp reflex and apraxia of eyelid opening. These findings were compatible with progressive supranuclear palsy (PSP). At the age of 66, he presented a peculiar phenomenon characterized by simultaneous tonic contraction of the orbicularis oris muscle (OOM) and the palatal muscles elicited by pronouncing "pa", which resulted in difficulty of voluntary opening of the mouth and the rhinopharynx. Therefore, the respiration air reciprocated between the lung and the closed mouth. The expiratory pressure puffed out the cheeks, while the lips remained tightly closed. While the respiratory movements and the pressure increased by degree, the OOM contracted more strongly in proportion to the pressure. Sixty to ninety seconds after the elicitation, the pressure overcame the contraction of the OOM and the course of the phenomenon was completed. The electromyograms showed that the OOM activity was prolonged after initial voluntary contraction, remaining thus after a tracheostomy for pneumonia at the age of 72, and that it increased in response to the pressure. Apraxia of eyelid opening, one of the other symptoms, resembled this phenomenon in terms of the aspect of difficulty of voluntary mouth opening. The "holding" phase of grasp reflex, yet another symptom, resembled it in the recruitment of the OOM activity. The phenomenon is not common in patients with PSP. However, we concluded that it may be included among the symptoms of PSP because it has similar characteristics to apraxia of eyelid opening and grasp reflex, which are not uncommon in patients with PSP.

[Sibling cases of opsoclonus-polymyoclonus syndrome].

We described a 34-year-old man who developed opsoclonus-polymyoclonus syndrome (OPS) associated with benign encephalitis. His older sister also suffered from the same syndrome 12 years ago. We examined HLA types in 6 patients with OPS who were admitted to our hospital, including these sibling cases. All 6 patients have type A2 antigen and statistical analysis suggested that there is a positive relationship between OPS and HLA A2 antigen. Considering the two facts that the existence of the sibling cases in this relatively rare disorder and sharing of HLA A2 antigen in our 6 cases, some genetic factors might be involved in the development of OPS.

[Myopathology of the intrinsic laryngeal muscles in neurodegenerative diseases, with reference to the mechanism of vocal cord paralysis].

To investigate the mechanism of the vocal cord abductor paralysis (VCAP) in the neurodegenerative diseases, the intrinsic laryngeal muscles (the crycothyroid, the interarytenoid, and the posterior crycoarytenoid muscles) from 41 autopsied cases were histologically examined: 10 cases of amyotrophic lateral sclerosis (ALS), 10 of Parkinson's disease (PD), 9 of multiple system atrophy (MSA), 4 of Machado-Joseph disease (MJD), 4 of progressive supranuclear palsy (PSP), 1 of familial amyloidotic polyneuropathy (FAP), and 3 of cerebrovascular diseases as a control. According to the distribution of the neurogenic changes among above-described three intrinsic laryngeal muscles, three forms were raised: 1. The totally paralytic form showing that all the three muscles developed neurogenic atrophy. This form includes ALS, MJD, and FAP. 2. The posterior muscle-paralytic form showing that only the posterior crycoarytenoid muscle was selectively involved. This form includes MSA. 3. The nonparalytic form showing no morphological abnormalities in any of the intrinsic laryngeal muscles. This type includes PD and PSP. In this nonparalytic form, supranuclear mechanism such as pyramidal or extrapyramidal tract involvement may cause VCAP through the increased laryngeal muscles tone. Considering that VCAP can be seen in any of the above-described forms, our results indicate that the mechanism of VCAP is different among the neurological disorders.

[Vocal cord abductor paralysis in multiple system atrophy--paradoxical movement of vocal cords during sleep].

Bilateral vocal cord abductor paralysis (VCAP) is frequently associated with multiple system atrophy (MSA) and the early clinical manifestation of VCAP is nocturnal inspiratory stridor simulating heavy snoring observed in patients with obstructive sleep apnea syndrome. We examined six MSA patients with nocturnal stridor and four disease controls including sleep apnea syndrome. Vocal cord movements were analyzed by laryngofiberscopy during both wakefulness and sleep induced by intravenous administration of diazepam. The results were as follows: First, the stenotic portion in the upper airway tract was the larynx (the vocal cords) in MSA patients with stridor, while the soft palate or the pharynx in the disease controls. Second, in the MSA patients, while awake-laryngofiberscopy showed abduction restriction suggestive of VCAP in only one of the six patients, sleep-laryngofiberscopy showed obvious paradoxical movement of the vocal cord in all the rests, where the vocal cords abducted in expiration and adducted in inspiration. In addition, there were two patterns in the inspiratory vocal cord position during sleep: one pattern where vocal glottis was still opening at the posterior one-third area and the other pattern where vocal glottis was almost completely closed through total length of the cords. Tracheostomy should be considered in the latter stage of VCAP.

[Hallucination in opsoclonus-polymyoclonus syndrome].

Here we report 2 cases of opsoclonus-polymyoclonus syndrome (OPS) associated with viral encephalitis. They had sleep disturbance, and visual hallucination. Case 1 had auditory hallucination in addition, and case 2 had dreamlike behavior. Those hallucination, which were colorful and vivid, usually appeared at the bed time. Their hallucinations were similar to peduncular hallucinations and you may also call hypnagogic hallucinations, which are often seen in patients with narcolepsy. Dreamlike behavior is observed during REM sleep in patients with brainstem damage or sometimes in the healthy elderly people. The presence of sleep disturbance, hypnagogic hallucination, and dreamlike behavior suggests that there may be some relationship between OPS and REM sleep. Considering that REM sleep is suppressed by serotonergic projection of the dorsal raphe nucleus in addition to several reports about brainstem lesion with serotonergic abnormalities in this disorder, we considered that dysfunction of serotonergic neurons of the dorsal raphe nucleus might be related in the development of OPS.

[Clinical and myopathological studies on rigid spine syndrome].

Rigid spine syndrome (RSS) is thought to be a group of heterogeneous muscle disorders. We reviewed the clinical and myopathologic findings of 55 patients with RSS including 49 previously reported and our own 6 patients. The results were as follows: the first, 80% showed restrictive ventilatory failure and 40% atrophy of the sternocleidomastoid muscle (SCM), which became manifest in the early stage of the illness, namely in less than 5 years from the onset. The second, paraspinal muscles usually began to be involved from the cervical semispinal muscle extending to other paraspinal muscles such as the more laterally located splenium muscle. The third, muscle biopsy demonstrated rimmed vacuoles (RV) in 41% of the 55 patients. RV were more frequently seen in the paraspinal muscles than the limb muscles, where marked myopathic changes of endomysial fibrosis and increased variation of the muscle fiber size were recognized. Based on the anatomical analysis of the paraspinal muscles, alligator sign, a radiological finding of the posterior opening between the cervical spine C1 and C2, seemed to result from the shortening of the cervical semispinal muscle due to its degeneration. This sign may, however, disappear as the whole paraspinal muscles including the semispinal muscles are affected. The RV seen in RSS seems to be a secondary, nonspecific structure related to the muscle degeneration. On the other hand, the above findings, namely the atrophy of SCM, restrictive ventilatory failure, and RV, have not been reported in Emery-Dreifuss muscular dystrophy (EDMD) so far. Accordingly, those findings and the absence of cardiac conduction abnormality are valuable for differential diagnosis of RSS from EDMD.

[HTLV-I associated myelopathy with bilateral abductor vocal cord paralysis--case report].

We have reported a 50-year-old woman with HTLV-I associated myelopathy (HAM) who had bilateral abductor vocal cord paralysis. The symptoms and signs were slowly progressive spastic paraplegia, dysuria, inspiratory stridor, and snoring during sleep. She had no hoarseness. Titers of anti-HTLV-I antibody were elevated in both the serum and cerebrospinal fluid. FEV1.0% on the spirogram was reduced to 66%. The fiberscopic examination demonstrated the abductor limitation of the vocal cords during the inspiratory phase. During induced sleep after the intravenous administration of thiopental sodium, this abductor paralysis was worsened, producing a high pitched inspiratory stridor. The adduction was not disturbed at all. Needle electromyogram of the posterior crico-arytenoid muscle which is a sole abductor muscle revealed the high amplitude up to approximately 1.0 mV (normal less than 0.8 mV) with poor interference pattern, indicating neurogenic changes. After 2 months course of prednisolone (60 mg/alternative day), FEV1.0% was recovered to be 92% with the improvement of the gait disturbance, which suggests the abductor vocal cord paralysis is related to HAM. The abductor vocal cord paralysis in HAM would require a careful follow-up observation to protect the respiratory failure in the advanced stage.

[Rhythmical involuntary movement at rest associated with olivo-ponto-cerebellar atrophy (OPCA)].

The authors analyzed rhythmical involuntary movements at rest, which appeared as complications in 12 (sporadic 11, hereditary 1) out of a total of 139 cases (sporadic 99, hereditary 40) of olivo-ponto-cerebellar atrophy. These movements tended to be seen in patients with sporadic OPCA of longer illness duration and at more advanced stages. They were distributed over the face, neck and extremities. Palatal myoclonus was observed in only one case. The movements were exacerbated by maintenance of a fixed posture, motion and mental stress, and stopped during sleep. In some cases, clonazepam, trihexyphenidyl or 1-Dopa was effective. In the surface electromyogram, rhythmical grouped discharges of 2-4 Hz were recorded only on agonist muscles or on both agonist and antagonist muscles synchronously, which is characteristic of skeletal myoclonus. However, pathological study of 3 cases with involuntary movements revealed marked putaminal degenerations as compared with 3 uncomplicated cases. This suggests that these rhythmical movements might be related to parkinsonian tremor.

[A case of chorea-acanthocytosis successfully treated with posteroventral pallidotomy].

We described a 41-year-old man with chorea-acanthocytosis, who presented severe choreoathetosis in all the limbs, neck, face and tongue. Especially, the oral area was affected most strikingly. He had difficulty in eating, because he pushed foods out of the mouth with the tongue. He received left posteroventral pallidotomy (PVP). His involuntary movements became much less enough for the patient to eat with a spoon in a sitting position by himself. Six months after the first operation, although involuntary movement on the right hand remained reduced, choreoballistic movement appeared on the left side. He received PVP on the right side. The choreoballistic movement was remarkably improved after the right PVP. No neurological aggravation has been found for 7 months after the second PVP. Bilateral PVP was fully effective as for the improvement of the activity of daily life. The output from the internal globus pallidus (GPi) is well-known to be inhibitory. Therefore, it is understandable that the coagulation of GPi results in improvement of hypokinesia and rigidity in patients with Parkinson's disease. However, some clinical reports, including ours, have described the significant reduction of hyperkinetic choreoballistic movement after PVP. The exact mechanism of these surgical effects has not been elucidated yet, and further clinical and basic studies are needed to answer this question.

[A case of Guillain-Barré syndrome (GBS) following human parvovirus B19 infection].

Human parvovirus B19 (HPV-B19) infection is recently known to produce variable clinical manifestations, but neurological disorder associated with this infection is uncommon. We reported a case of GBS associated with transient lupus-like status following HPV-B19 infection. This is the first report describing an adult case of GBS following HPV-B19 infection. A healthy female, aged 33, developed erythema infectiosum simultaneously with her 5-year-old daughter. On the same day, she noticed leg fatigue, which worsened in the following days. On the day 11th, she became unable to walk. Mild pancytopenia, liver injury, proteinuria, hypocomplementemia, and increased anti-nuclear antibody (ANA) were revealed at a hospital. Polymerase chain reaction detected HPV-B19 DNA in the serum. On the day 17th, she was admitted to our hospital because of moderate generalized weakness and mild sensory disturbance, which were symmetrical and distal-dominant. The deep tendon reflexes were absent. Analysis of cerebrospinal fluid showed albuminocytologic dissociation. Other laboratory data were normal except positive ANA. Enzyme-linked immunosorbent assay (ELISA) showed high titer of the serum IgM antibody to GM1 and GD1b. Serum anti HPV-B19 IgM and IgG tested by ELISA were also positive. She improved gradually after 2 courses of double filtrated plasma pheresis.