[Study of functional rating scale for amyotrophic lateral sclerosis: revised ALSFRS(ALSFRS-R) Japanese version].

Amyotrophic lateral sclerosis(ALS) is progressive, degenerative, fatal disease of the motor neuron. No efficacious therapy is available to slow the progressive loss of function, but several new approaches including neurotrophic factors, antioxidants and glutamate antagonists, are currently being evaluated as potential therapies. Mortality, and/or time to tracheostomy, muscle strength and pulmonary function are used as primary endpoints in clinical trials for treatment of ALS. The effect of new therapies on the quality of patients' lives are also important, so we sought to develop a rating scale to measure it. The revised ALS Functional Rating Scale(ALSFRS-R), which has addition of items to ALSFRS to enhance the ability to assess respiratory symptoms, is an assessment determining the degree of impairment in ALS patients' abilities to function independently in activities of daily living. It consists of 12 items to evaluate bulbar function, motor function and respiratory function and each item is scored from 0(unable) to 4(normal). We translated the English score into Japanese one with minor modification considering the inter cultural difference. And we examined reliability of the translated scale. As a measure of reliability, the intraclass correlation coefficient(ICC) was evaluated for total score and the Kappa coefficient proposed by Cohen and Kraemer was calculated for each item. Moreover, we examined sensitivity to clinical change over time and carried out the factor analysis to analyze the factorial structure. The subjects were 27 ALS patients and each was scored twice for reliability or three times for sensitivity by 2 to 5 neurologists and if possible, nurses. The ICC for total score was 0.97(95% C. I.; 0.94-0.98). Extension of the Kappa coefficients were 0.48 to 1.00 for inter-rater reliability and the averaged Kappa coefficients were 0.63 to 1.00 for intra rater reliability, respectively. Concerning the factorial structure, the contribution of the first factor(the first principal component) were 53.5% principal factor solution. The factor loadings of items were 0.52-0.91 except "salivation" and this factor almost equal to the simple sum of all items was interpreted as the general degree of deterioration. The promax votation revealed the riginally supposed factor structure with 3 factors(groups of items): neuromuscuclar function, respiratory function and bulbar function. The rating scale correlated with Global clinical impression of change(GCIC) scored by neurologists and declined with time, indicating its sensitivity to change. On the bases of these results, ALSFRS-R(Japanese version) is considered to be highly reliable enough for clinical use.

[A 77-year-old man with gait and gaze disturbance].

We report a 77-year-old Japanese man with progressive gait disturbance. He was well until his 71 years of the age (1992), when he noted an onset of disturbance in his speech, which was followed by difficulty in using his left hand. He did not attempt to use his left hand afterwards. He started to fall down in the spring of 1994. He was admitted to our service on October 6, 1994. Neurologic examination revealed an alert and oriented man. He showed limb-kinetic apraxia in his left hand with anosognosia for his apraxia. Vertical gaze was impaired. He walked in small steps. He had moderate axial and limb rigidity. He had no weakness, ataxia, or tremor. Deep tendon reflexes were normal. Plantar response was flexor. Sensation was intact. His gait had progressively become worse and he was admitted to another hospital in April of 1996. At that time he was disoriented to time. He was only able to walk a few steps with support. He continued to show limb-kinetic apraxia in his left hand. He developed dementia and dysphagia and he expired on October 27, 1998. He was discussed in a neurological CPC, and the chief discussant arrived at the conclusion that the patient had corticobasal degeneration. Most of the participants agreed with this diagnosis, but a few of them thought that progressive supranuclear palsy would be more likely. Post-mortem examination revealed no gross cortical atrophy. The right hemisphere was kept frozen for future biochemical analysis. The left precentral gyrus showed spongy changes, neuronal loss and gliosis. The pallidum, putamen, and the subthalamic nucleus were unremarkable, however, neurofibrillary tangles were seen in the subthalamic nucleus. The substantia nigra showed only slight neuronal loss; neuronal pigments were well retained. A few neurofibrillary tangles were seen in the remaining neurons. The cerebellar dentate nucleus showed grumose degeneration. Gallyas-Braak staining revealed many tuft-shaped astrocytes in the precentral gyrus. Pathologic diagnosis was progressive supranuclear palsy. Some participants thought that this diagnosis was unacceptable, because the pathologic changes in the substantia nigra, globus pallidus, and the subthalamic nucleus, which were usually severely involved in PSP, did not show typical changes of PSP. In addition, the predominant clinical feature was limb-kinetic apraxia, although he showed vertical gaze paresis and parkinsonian gait, which could also be seen in corticobasal degeneration. There was a big discussion among participants with regard to the diagnosis.

[An 80-year-old woman with parkinsonism and progressive dementia].

We report an 80-year-old Japanese woman who presented levodopa-responsible parkinsonism followed by progressive dementia. She was well until her 61 years of age (in 1978) when she noted onset of resting tremor in her right hand followed by tremor in her right leg. She was treated with levodopa and trihexyphenidyl with good response, however, later on, she suffered from gait disturbance. In 1985, she had an episode of cardio-pulmonary arrest from which she was resuscitated, however, she started to show hypermetamorphosis, memory defect, and aggressive behaviors. She also developed motor fluctuations and dyskinesias from levodopa. She was admitted to our service in 1986; she showed rather typical parkinsonism and mild dementia. She received left Vim thalamotomy in the same year. Her dyskinesias improved, however, her gait disturbance became progressively worse. In 1995, she was admitted to our service again; she showed marked dementia and advanced parkinsonism; she was unable to walk unsupported. She became bedridden in 1996 and gastrostomy was placed. She was transferred to Zushi Aoki Hospital. Her dementia became progressively worse, and she was in the akinetic and mute state. She expired on April 22, 1998. She was discussed in a neurological CPC. The chief discussant arrived at a conclusion that the patient had Parkinson's disease with complication by Alzheimer's disease in her later clinical course. The diagnoses of participants were divided among Parkinson's disease with dementia, Parkinson's disease and Alzheimer's disease, and diffuse Lewy body disease. Postmortem examination revealed marked neuronal loss in the substantia nigra and the locus coeruleus. Lewy bodies were found in the substantia nigra. In addition, rather many Lewy bodies of cortical type were seen in the cingulate gylus, inferior temporal gylus, and in the amygdaloid nucleus. These Lewy bodies were positive for alpha-synuclein. Also, tau-positive intra-neuronal tangles were seen in the hippocampus and in the substantia nigra. The Meynert nucleus showed marked neuronal loss. Pathologic findings were consistent with the diagnosis of diffuse Lewy body disease.

[An 81-year-old woman with progressive motor disturbance, extrapyramidal features, dementia, and oculomotor palsy].

We report an 81-year-old woman who presented with motor disturbance in her right hand which was followed by parkinsonism, dementia, and supranuclear gaze palsy. She was well until her age of 73 (1989) when she had an onset of difficulty in using her right hand; she did not have weakness. She also developed small step gait. These symptoms had progressively become worse. She was admitted to our hospital in July of 1992 when she was 75 years old. On admission, she was alert and oriented, but she showed some difficulty in recent memory. She did not have aphasia or ideomotor apraxia, but she showed limb-kinetic apraxia in her right hand, ideational apraxia, dressing apraxia, constructional apraxia, tactile agnosia, and left-right disorientation. Alien-hand syndrome was observed in her right hand. Ocular movement was within normal limit for her age. She had oro-lingual dyskinesia. Otherwise, cranial nerves were intact. She walked in small-steps. She had rigidity and fine myoclonic movements in her right upper extremity. Deep reflexes were within normal limits and symmetric. Superficial and deep sensations were intact. Laboratory findings were unremarkable. She was discharged on August 15, 1992 for outpatient follow-up. Her motor and mental symptoms were progressive. By October of 1992, she developed supranuclear vertical gaze palsy, marked rigidity in the neck, and astereognosis. By June 1993, she became unable to walk without support. MRI taken in May of 1994 revealed atrophy of insular cortices, temporal lobe tips and parietal lobes more on the left side; the third ventricle was slightly dilated. She was admitted to another hospital on June 30, 1994. She had become a bed-ridden state with marked dementia and dysphagia. She developed fever on November 5, 1996 and expired on December 16 of the same year. She was discussed in a neurological CPC and the chief discussant arrived at the conclusion that the patient had corticobasal degeneration. Other diagnoses entertained included progressive supranuclear palsy, pallidonigroluysian atrophy, diffuse Lewy body disease, and Pick's disease. But the most of the participants agreed with the chief discussant's diagnosis. Post-mortem examination revealed aspiration pneumonia in the lungs and liver fibrosis apparently due to viral hepatitis. In the central nervous system, frontal and parietal lobes were atrophic more on the left side. Atrophy was accentuated in the superior frontal gyri, precentral and postcentral gyri, and superior and inferior parietal lobuli. Neuronal loss and astrocytosis were seen in these regions with scattered ballooned neurons. The substantia nigra showed marked neuronal loss and gliosis; neuronal loss was also seen in the pars reticulata. The outer and inner segments of globus pallidus and the periacqueductal gray matter showed gliosis, however, no apparent neuronal loss was seen. Putamen, subthalamic nucleus, and the dentate nucleus were preserved. Pathologic changes were consistent with the diagnosis of corticobasal degeneration. It was interesting to note that anti-tau immunostaining and Gallyas staining revealed neuropil threads and astrocytic plaques in the cortical areas, and intracytoplasmic inclusion bodies in the cortical neurons; these inclusions were not stained by Bodian stain. Tuft-shaped astrocytes which may be seen in progressive supranuclear palsy were not observed in this patient. Although corticobasal degeneration and progressive supranuclear palsy share some neurological features in common, this patient showed typical pathologic changes of corticobasal degeneration.

[Neurological CPC.57. An 80-year-old woman with four years history of muscle atrophy involving lower extremities predominantly on the right side].

We report an 80-year-old woman with progressive muscular atrophy predominantly involving her right lower extremity. She was well until 1992 (75 years of age) when she noted an onset of weakness in her right leg which had got progressively worse. She was admitted to our service in July 1994. On admission, general physical examination was unremarkable. She was alert and well oriented without dementia. Higher cerebral functions were normal. Cranial nerves also appeared intact. She dragged her right leg in walking. Mild to moderate weakness (2/5 to 4/5) was noted in muscles in her right lower extremity more in the distal part. Deep tendon reflexes were within normal limits, and the plantar response was flexor bilaterally. Sensation was intact. Laboratory examinations were also unremarkable except for slight increase in CK which was 470 IU/l. CSF was also normal. EMG revealed neurogenic changes in the lower extremities. She was admitted to Aoki Hospital on October 21, 1994, by that time, her weakness in the right lower extremity had gotten worse in that the muscle strength of the right extensor hallucis longus was 0 and tibialis anterior 2; muscle atrophy was also prominent in her right leg; the right ankle jerk could not be elicited. In the subsequent course, weakness and atrophy appeared in her left lower extremity, however, upper extremities and cranial nerves had never been affected. Babinski sign was always negative. In February 1996, she developed delusional ideation of self persecution, and showed difficulty in communication with medical staffs. She developed fever of 38.7 degrees C on June 13, 1996 expired on the next day. The patient was discussed in a neurological CPC, and the chief discussant arrived at the conclusion that the patient had a form of spinal muscular atrophy. Opinions were divided between ALS and spinal muscular atrophy. Post-mortem examination revealed marked loss of anterior horn neurons in the lumbar area with astrogliosis. Bunina bodies were seen in some of the remaining neurons. No myelin pallor was noted in the pyramidal tracts, however, atrophy and loss of Betz cells were noted in the motor cortex. Other cortical areas were unremarkable. The neuropathologist arrived at the conclusion that the patient had ALS. This patient was unique in that she had asymmetric atrophy and weakness limited to the lower extremities. This is quite unusual as ALS of four years duration. In addition, the patient developed some mental change which was thought to represent dementia by some participants. But no clear morphologic changes were seen to account for her mental change.

[(Neurological CPC.55). A 60-year-old woman with progressive cerebellar ataxia, myoclonus, and dementia].

We report a 60-year-old woman with progressive ataxia, myoclonus, choreoathetosis, and dementia. She was well until 27 years of the age when she noted an onset of gait disturbance and speech disturbance. She noted abnormal involuntary movements in her four limbs at 42 years of the age. Her symptoms had progressively become worse and she fell down frequently by her 52 years of the age. In addition, her family members noted gradual decline in her intelligence. She was admitted to our hospital in February of 1993 when she was 57-year-old. On admission, she showed dementia, scanning speech, ataxic gait, limb ataxia, action myoclonus, and choreic movements which involved her four limbs. Deep tendon reflexes were slightly exaggerated in the lower limbs; no Babinski sign was noted. Sensation was intact. Laboratory findings were unremarkable. Cerebral MRI revealed atrophy of the cerebellar cortex, superior cerebellar peduncle, brain stem, and the cerebral cortex; the third ventricle and the lateral ventricles were dilated; furthermore, T2-high signal lesions were seen in the cerebral white matter and in the pontine base. Her clinical course was one of the progressive deterioration of her ataxia, involuntary movements, and dementia. She expired on April 24, 1996 when she was 60-year-old. She was discussed in a neurologic CPC and the chief discussant arrived at the conclusion that the patient had dentatorubral-pallidoluysian atrophy. A minor opinion was that she might have had myoclonus epilepsy with ragged-red fibers. Postmortem examination revealed atrophy, gliosis, and neuronal loss in the external segment of the globus pallidus, subthalamic nucleus, red nucleus, and in the dentate nucleus. In addition, the gracil and cuneiform nuclei showed neuronal loss and spheroid formation; the spinocerebellar tracts were retained. The substantia nigra and the locus coeruleus were intact. No ragged-red fibers were seen in the muscle biopsy specimen taken in February, 1993. The neuropathologic findings were consistent with the diagnosis of dentatorubral-pallidoluysian atrophy.

[A 70-year-old man with a progressive gait disturbance and gaze palsy].

We report a 70-year-old man with progressive gait disturbance and gaze palsy. The patient was well until summer of 1991 when he was 66-year-old, when he noted a gradual onset of difficulty in gait and looking downward. He was evaluated in our hospital in May, 1994 when he was 69-year-old. On admission, he was alert but markedly demented with disorientation and memory loss. Constructional apraxia and dressing apraxia were noted. He had difficulty in gaze to all directions; he could move his eyes only 20% of the normal range. Oculocephalic response was retained. He had small voice and some dysphagia. Other cranial nerves were unremarkable. He could not walk unsupported. Marked retropulsion was noted in which he would fell down spontaneously upon standing unless supported. Moderate to marked rigidity was noted in the neck, trunk, and in the legs, however, in the upper extremities, rigidity was only mild. No tremor was noted. Deep reflexes were symmetrically exaggerated with ankle clonus bilaterally. Plantar response was flexor. Sensation was intact. Routine laboratory tests were unremarkable, however, his cranial MRI showed moderate to marked fronto-temporal atrophy and moderate midbrain and pontine tegmental atrophy. The third ventricle was markedly dilated. He was discharged for out patient care, however, his dysphagia had become progressively worse, and he suffered from frequent bouts of pneumonia. He was admitted to our service on October 17, 1994. His neurologic examination was essentially similar except that he showed more advanced dementia. He was still able to stand with support. Gastrostomy was placed on October 25. Post-operative course was unremarkable. He was discharged on November 1. His motor disturbance showed gradual deterioration, and by the May of 1995, he became bed-ridden, and was admitted to another hospital on May 30, 1995. He was almost totally unable to move his eyes, but oculocephalic response was still elicited. Marked truncal and limb rigidity were noted. He vomited coffee-ground substance on October 31, 1995, and developed hypotension. The subsequent course was complicated by pneumonia and he expired on November 24. The patient was discussed in a neurological CPC. Majority of the participants thought that the patient had progressive supranuclear palsy, but some participants thought that the patient had corticobasal degeneration because cortical atrophy was so marked. Post mortem examination revealed atrophy of the frontal and parietal lobe. The brain stem was atrophic particularly in the tegmental area including the midbrain. The substantia nigra showed marked neuronal loss and globose type neurofibrillary tangles in the remaining neurons. The neurons in the locus coeruleus was well retained, however neurofibrillary tangles were seen. In addition, the cerebellar dentate nucleus, the inferior olivary nucleus, and the internal globus pallidus showed marked neuronal loss and neurofibrillary degeneration. In the frontal cortex, although macroscopic examination showed some atrophy, microscopic examination failed to show neuronal loss or gliosis. The pathologic findings were consistent with the diagnosis of progressive supranuclear palsy.

[A 65-year-old woman with dysarthria, dysphagia, weakness, and gait disturbance].

We report a 65-year-old woman with progressive dysarthria, dysphagia, weakness, and gait disturbance. The patient was well until 59 years of age (January of 1986) when she noted bilateral ptosis. One year later, she noted a gradual onset of difficulty in speech (articulation). Her speech slowly deteriorated and she noted weakness in chewing power and difficulty in swallowing in addition. In October 1987, she developed emotional incontinence. In January of 1988, she started to drag her left foot. She was admitted to our hospital on June 13 of 1988. On admission, she was alert and general physical examination was unremarkable. Neurologic examination revealed no dementia; her higher cerebral functions appeared intact. Ptosis was present bilaterally more on the right. She showed difficulty in opening her eyes on command; no contraction of the frontal muscles was seen upon attempted eye opening. There was a moderate limitation in the vertical gaze. Forced laughing and crying were seen. Facial muscles were moderately weak without apparent atrophy. The movement of the soft palate was very weak, and swallowing disturbance was more prominent for liquid staff. The tongue appeared somewhat small, however, no fasciculation was noted. Her step was small and the posture was stooped. Retropulsion was present, however, Romberg's sign was absent. No muscle atrophy was apparent, however, diffuse mile to moderate muscle weakness was noted in all four limbs. Cerebellar sign was absent. Deep tendon reflexes were exaggerated bilaterally, and Babinski sign was present on the left side. Sensation was intact. Routine blood tests were unremarkable as was a cranial CT scan. Her ptosis did not improve after 10 mg of edrophonium injection. CSF was also normal. She was transferred to another hospital but her neurological disabilities further progressed. In 1989, she was totally unable to move her limbs; she could only move her eyes; still consciousness was clear without dementia. She developed respiratory difficulty and expired on July 25, 1992. She was discussed in a neurological CPC, and the opinions were divided into ALS and primary lateral sclerosis (PLS). The chief discussant arrived at the conclusion that the patient might have had the pyramidal form of ALS. Postmorten examination revealed marked myelin pallor in the anterior as well as lateral corticospinal tracts. Pyramidal tract degeneration was prominent starting at the level of the cerebral peduncle and was continued to be seen until the level of lumbar cord. The number of anterior horn cells showed only slight decrease in the cervical level, however, it was normal in the lumbar cord.(ABSTRACT TRUNCATED AT 400 WORDS)

Angiographic and angioscopic observations of the arterial luminal changes induced by vasospasm.

Angiography and angioscopy were used to examine arterial luminal changes induced by experimental vasospasm. The right common carotid artery of the dog was perfused with Krebs-Henseleit solution at a constant pressure, 3,4-diaminopyridine (DAP), a selective potassium channel blocker was applied on the adventitia, and the luminal changes were observed with angiography and angioscopy. Angiographically vasospasm (defined as a reduction in the internal diameter to less than 50% of the control value) was always induced by the topical application of 5 X 10(-1) mol/L DAP. The internal diameter decreased to 25% +/- 7% (mean +/- standard error, n = 6) 15 minutes after the application. The vasospasms propagated 2.7 +/- 0.6 and 1.1 +/- 0.3 cm downstream and upstream, respectively. Angioscopy showed that the lumen narrowed gradually and concentrically. Perfusion of the artery during vasospasm for 15 minutes with a backflow of blood from the contralateral artery resulted in thrombosis at the spastic segment. The results indicate that carotid vasospasm can be constantly induced by DAP, thrombosis occurs in the spastic artery, and angioscopy is useful for serial observation of the luminal changes induced by vasospasm.

Phasic contractions of canine and human coronary arteries induced by potassium channel blockers.

To gain insight into mechanisms underlying phasic coronary vasospasm in patients with variant angina pectoris, we studied whether phasic contractions could be induced in isolated canine and human coronary arteries by agents which block potassium channels. Phasic contractions of canine coronary arteries were always induced by 3,4-diaminopyridine (10(-2) M) and less frequently by 4-aminopyridine (10(-2) M). These agents also caused phasic contractions in human, swine and monkey coronary arteries and in canine basilar, carotid, renal and femoral arteries. The cycle length of phasic coronary contractions ranged from 30 sec to 1 hour, and the developed tension was 2.5 times greater than for potassium contractions. The contractions continued for more than 11 hours. Morphologically, perinuclear vacuolization, a characteristic change of vasospasm, appeared in the coronary smooth muscles. The phasic contractions were not eliminated by tetrodotoxin, atropine, phentolamine or yohimbine, but they were eliminated by nicorandil which activates potassium channels and nifedipine which blocks slow calcium channels. The results indicate that potassium channel blockers can induce phasic arterial contractions.

Necropsy finding in a patient with apical hypertrophic cardiomyopathy.

Whether apical hypertrophic cardiomyopathy is a variant of classic hypertrophic cardiomyopathy or a separate entity is controversial. This is a case report of an apical hypertrophic cardiomyopathy. The patient was a 67-year-old man associated with giant negative T waves in electrocardiogram and asymmetric apical hypertrophy on echocardiogram. He died of liver cirrhosis and liver cell carcinoma. At necropsy the heart showed apical hypertrophy grossly and extensive disarray of myocardial fibers near the apex of the left ventricle histologically. The necropsy findings were indistinguishable from those of classic hypertrophic cardiomyopathy. This suggests that apical hypertrophic cardiomyopathy is a variant of hypertrophic cardiomyopathy.

The size of kidney with renovascular hypertension in patients with aortitis syndrome.

Renal atrophy due to the renal artery stenosis associated with aortitis syndrome was studied in seven patients. Severe hypertension, high plasma renin activity and normal overall renal functions were present in all. The luminal diameter of the stenosed renal artery seen on the angiogram was less than 1.5 mm at the maximum area of stenosis in all patients. The size of the kidney with renal artery stenosis was diminished, ranging from 8.0 to 14.0 cm in longitudinal diameter on the nephrogram. Histological findings of the small kidney revealed ischemic atrophy. Although the rate of progression of the arterial stenosis was uncertain, the collateral circulation was found to be rich. Renal atrophy was not frequent and not marked even in the presence of high grade renal stenosis or obstruction in case of renovascular hypertension secondary to the arteritis.

Familial amyloid polyneuropathy with marked hypertrophy of the peripheral nerves.

Autopsy findings in a 40-year-old male with heredofamilial amyloidosis and polyneuropathy are reported. He had been suffering from progressive autonomic as well as sensorimotor dysfunctions. Prominent amyloid deposit was found in the kidney, heart, thyroid, and testis, and less in the interstitium and small vessels of almost all organs. The peripheral nerves, some showing prominent hypertrophy, were most severely involved by amyloid deposit in a form of stellate mass, which ultrastructurally consisted of radially arranged amyloid filaments. In the hypertrophied nerves and ganglia, in addition to amyloid, massive accumulation of acid mucopolysaccharide (AMPS) was seen filling up the interstitial space, which was the cause of hypertrophy. Ultrastructurally, AMPS was seen as finely granular substance. An extracted amyloid from the kidney showed 8 nm filament on negative staining and was estimated of having a molecular weight of 14,000.

Hypertrophic cardiomyopathy without asymmetric hypertrophy.

A 49-year-old women with congestive heart failure and heart block died of cerebral embolism. Clinical and echocardiographic findings suggested a diagnosis of atypical dilated cardiomyopathy with predominantly right ventricular involvement. At necropsy, all the cardiac chambers were slightly dilated and the interventricular septum and the left ventricular wall were of normal thickness and symmetry. Histological examination, however, disclosed extensive disarray of abnormal myocardial tissue, especially in the interventricular septum. Her father had similar clinical and echocardiographic findings, while one of her brothers had typical hypertrophic cardiomyopathy at necropsy. It is likely that the patient actually had inherited hypertrophic cardiomyopathy. The case illustrates the difficulty in diagnosing hypertrophic cardiomyopathy when based solely on the left ventricular gross anatomy.