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.

Clinical and neuroradiological improvement in chronic acquired hepatocerebral degeneration after branched-chain amino acid therapy.

We report two patients with chronic acquired hepatocerebral degeneration (CAHD) who showed neurological and radiological improvement after the administration of branched-chain amino acids (BAA). The first patient with chronic hepatitis C presented with progressive parkinsonism for 7 months, whereas the second patient with liver cirrhosis presented with progressive ataxia for 15 months. T1-weighted magnetic resonance imaging (MRI) showed symmetric high intensity signals in the lenticular nuclei in both patients. In the first patient, single photon emission computed tomography (SPECT) disclosed a marked decrease in cerebral blood flow in the parieto-occipital regions. In the second patient, T2-weighted MRI demonstrated symmetric high intensity signals in the deep cerebral and cerebellar white matter. After the administration of BAA, their neurological signs and radiological abnormalities markedly improved in both patients. CAHD might be a reversible and treatable disorder where aromatic amino acids are deeply involved in its pathogenesis.

[A case of visual agnosia for picture with right occipital lobe infarction].

We report a 74-year-old right-handed man with visual agnosia for picture due to right occipital lobe infarction. The patient had a remarkable impairment in visual recognition for standardized pictures made by Snodgrass and Vanderwart, in addition to left hemianopsia, left visuospatial neglect, and mild prosopagnosia. The visual agnosia for picture was generally recognized as a mild-type of the visual object agnosia, which was extremely rare in the patients with right occipital lesion. We discussed the mechanism of the visual agnosia in the right occipital lesion. Therefore, it raises the possibility that the broad impairment of the right occipital artery territory including parahippocampal gyrus as well as corpus callosum can cause the visual agnosia for picture.

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.

[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.

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.

Cloning and expression analysis of a new member of the cytochrome P450, CYP2A15 from the Chinese hamster, encoding testosterone 7alpha-hydroxylase.

We cloned a new cytochrome P450 cDNA encoding testosterone 7alpha-hydroxylase in the Chinese hamster, designated CYP2A15 which shares significant amino acid sequence homology with members of the CYP2A subfamily. The CYP2A15 cDNA was isolated by screening a liver cDNA library and the sequence contains an open reading frame of 1482 nucleotides encoding a polypeptide of 493 amino acids with a calculated molecular mass of 56,295 Da. This is flanked by a 5'-untranslated region of 2 bp and a 3' untranslated region of 191 bp including the poly(A) tail. We determined the catalytic activity of CYP2A15 using microsomes obtained by transient expression of its cDNA in transfected COS-7 cells. The heterologously expressed CYP2A15 was found to hydroxylate testosterone at position 7alpha in a reconstituted system. RT-PCR experiments revealed that the mRNA of CYP2A15 was expressed in liver, but not detected in kidney, lung, or small intestine. The expression of CYP2A15 mRNA was slightly induced by treatment with either rifampicin or 3-methylcholanthrene.

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.

Apraxia of speech associated with an infarct in the precentral gyrus of the insula.

It has been postulated that the precentral gyrus in the left insula is responsible for co-ordination of speech. We report a patient with this disturbance who showed an acute infarct limited to this region.

Changes in the cytoskeletal proteins, sarcoplasmic reticulum, and capillaries in acute relaxant-steroid myopathy (ARSM) in contrast to the corticosteroid myopathy.

Since we reported a case of acute relaxant-steroid myopathy (ARSM) in 1994, we continued histological studies and compared the findings with those in a case of corticosteroid myopathy (CM). It was revealed that (1) dystrophin, spectrin, beta dystroglycan, and sarcoglycans on the cell surface were decreased, (2) regular arrangement of the sarcoplasmic reticulum was lost, and (3) some capillaries were degenerated. Since none of these changes were seen in CM, it became clear that ARSM is different from CM. It was estimated that continuous administration of non-depolarizing muscle relaxant produces a state akin to denervation. Combination of denervation, immobilization and circulatory disturbance in ARSM not only augments the effects of corticosteroids, but they produce changes different from CM, namely impairment of the cell membrane system (both internal and external) and capillary degeneration.

[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.

[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.

Loss of large myelinated nerve fibres of the recurrent laryngeal nerve in patients with multiple system atrophy and vocal cord palsy.

OBJECTIVES: Vocal cord palsy seen in some patients with multiple system atrophy may result from neuronopathy of the recurrent laryngeal nerve. METHODS: Six controls and six patients with multiple system atrophy, four with and two without vocal cord palsy were studied. The number of myelinated nerve fibres were counted and fibre diameter histograms were established for the motor and sensory divisions of the laryngeal branch of the recurrent laryngeal nerve. RESULTS: Although both groups of patients with multiple system atrophy showed selective loss of the myelinated fibres in the motor branch, the change was greater in those with vocal cord palsy than in those without. The small myelinated nerve fibres (diameter < 7 microm) were decreased in number in both multiple system atrophy groups, whereas the large myelinated nerve fibres (diameter < 8 microm) were decreased only in those with vocal cord palsy, and preserved in those without the symptom. CONCLUSION: In multiple system atrophy, the small myelinated fibres innervating the vocal cord are affected first, without obvious clinical signs. The patient develops vocal cord palsy only after the loss of the large myelinated fibres, which mostly comprise the alpha motor axons that innervate the intrinsic laryngeal muscles.

[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.

[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.

[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.

Early diagnosis and stage classification of vocal cord abductor paralysis in patients with multiple system atrophy.

OBJECTIVES: Vocal cord abductor paralysis (VCAP) is a life threatening complication which may cause nocturnal sudden death in patients with multiple system atrophy. However, the early diagnosis of VCAP is often difficult to make on routine laryngoscopy performed during wakefulness, as stridor, which is the sole symptom of VCAP in the early stage, develops only during sleep. The aim was to investigate laryngeal dysfunction in patients with multiple system atrophy while awake and asleep. METHODS: Seven patients with multiple system atrophy with nocturnal stridor and five control patients were studied. Vocal cord movement was analysed by laryngoscopy while the patients were awake and also during sleep induced by intravenous diazepam. RESULTS: When awake, for the seven patients with multiple system atrophy normal movement of the vocal cords occurred in three, mild abduction restriction in three, and paradoxical movement in one. When asleep, however, all showed obvious paradoxical movement with high pitched inspiratory stridor. In controls, there were no differences in the vocal cord movement between wakefulness and sleep. From these findings, VCAP could be divided into four stages: stage 0 (normal) with normal vocal cord movement during both wakefulness and sleep, stage 1 (mild VCAP) with normal movement during wakefulness and paradoxical movement during sleep, stage 2 (moderately severe VCAP) with abduction restriction during wakefulness and paradoxical movement during sleep, and stage 3 (severe VCAP) with an almost midline position for the vocal cords during both wakefulness and sleep. CONCLUSIONS: Laryngoscopy during sleep can disclose subclinical VCAP, making an early diagnosis of VCAP in patients with multiple system atrophy. Stage 2 of VCAP seems to be a suitable stage for tracheostomy in patients with 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.