Cervical myelopathy due to ossification of the posterior longitudinal ligament: a clinicopathologic study.

A clinicopathologic study was done of a Japanese patient with symptomatic ossification of the posterior longitudinal ligament in the cervical spine. Post-mortem specimen showed characteristic distribution of degenerations at C5-6 segments similar to chronic cervical spondylosis or disk protrusion. The degenerative changes were confined to the ventral two thirds of the posterior and lateral columns. In addition to demyelination, loss of axons, and neuronal cell death, thickening of venular wall and fine capillary neovascularization strongly suggested chronic circulatory insufficiency. Spinal immobilization produced by the ossified ligament may have contributed to the long clinical course, lasting for 30 years. Review of literature showed that the myelopathy can be distinguished clinically and radiographically from that produced by cervical spondylosis.

Sensory ataxia. A residual disability of Guillain-Barré syndrome.

Four patients had idiopathic acute polyradiculoneuritis (Guillain-Barré syndrome) with sensory ataxia as the most prominent symptom. Sensory ataxia remained as a residue even three to five years after onset, despite good recovery of muscle weakness in five to 14 months. Sural nerve biopsy specimens disclosed a severe loss of large myelinated fibers and a high incidence of active axonal degeneration.

Ophthalmoplegia-plus. Its occurrence with periventricular diffuse low density on computed tomography scan.

Familial cases of progressive external ophthalmoplegia, deafness, generalized weakness, and hypogonadism were studied. A muscle biopsy specimen showed increased amounts of glycogen particles, lipid droplets, and mitochondria that frequently contained paracrystalline inclusion bodies between intramitochondrial and extramitochondrial membranes. Involvement of the CNS was suspected from a computed tomography scan that revealed diffuse, low-density deep cerebral white matter. Therapy with corticosteroids (prednisolone) was effective for recovery of muscular strength in the extremities. Possible involvement of the CNS in ophthalmoplegia-plus might be related to an abnormal metabolism of mitochondria.

Severe orthostatic hypotension in a female carrier of Fabry's disease.

A 21-year-old woman in a family with a history of Fabry's disease showed orthostatic hypotension and whorl-like corneal opacity typical for Fabry's disease. Biochemical studies revealed that she was a heterozygote of the Fabry gene. A variety of autonomic function tests demonstrated both sympathetic and parasympathetic dysfunction. To our knowledge, the present case is the first report of a heterozygous female carrier of Fabry's disease presenting dysfunction of the autonomic nervous system.

Bedside and electro-oculographic analysis of abnormal ocular movements in spinocerebellar degenerations: effects of thyrotropin-releasing hormone.

We studied ocular movements in 130 patients with spinocerebellar degenerations. Patients had blurred vision (33.3%), diplopia (40.2%), oscillopsia (18.6%), ocular flutter (22.3%), rebound nystagmus (25.4%), square-wave jerks, (29.2%), macro square-wave jerks (6.2%), and macro saccadic oscillations (10.8%). Electro-oculographic abnormalities included reduction of saccadic velocity, dysmetria, and saccadic smooth pursuit. All the abnormal movements were improved by the injection of thyrotropin-releasing hormone.

A family with beta-galactosidase deficiency: three adults with atypical clinical patterns.

Three adult patients in a single family showed severe myoclonus, ataxia, and pyramidal signs. Enzymatic analysis of lymphocytes, plasma, and cultured skin fibroblasts showed marked deficiency of beta-galactosidase activity, more profound with GM1 ganglioside than with another natural substrate, asialofetuin. Other lysosomal hydrolases were normal. Although the physical signs were similar to those of types 1 and 2 GM1 gangliosidosis, none had bony abnormalities.

Degenerating compartment and functioning compartment of motor neurons in ALS: possible process of motor neuron loss.

Using a morphometric method, we studied ventral spinal roots and anterior horn neurons of the fourth lumbar segment in 17 patients with ALS. Both populations of large myelinated fibers and anterior horn cells had significantly high correlations to muscle strength in the legs and duration of symptoms. However, active axonal degeneration was consistently present in terms of either large myelinated fibers or anterior horn cells.

Effect of L-threo-3,4-dihydroxyphenylserine on muscle sympathetic nerve activities in Shy-Drager syndrome.

We observed changes in postganglionic efferent discharges of muscle sympathetic nerve (muscle sympathetic activity, MSA) microneurographically before and after the oral administration of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS), a precursor of norepinephrine, in a patient with Shy-Drager syndrome and irregular fluctuations of blood pressure. Before drug administration, MSA was only rarely observed with the patient in the supine position. There was a slight increase in MSA during head-up tilting to 40 degrees, and orthostatic hypotension (OH) occurred just after the body was tilted head upward to 40 degrees. MSA became prominent 30 minutes after the oral administration of 200 mg of L-threo-DOPS while the patient was in a 40 degree head-up position, and the OH was improved. The MSA discharge rate decreased and OH reappeared 3 hours after oral administration, when the plasma concentration of norepinephrine was at its highest level. We suggest that the OH improved mainly because of the increase in MSA due to L-threo-DOPS, and that the drug may activate sympathetic outflow at a site proximal to the sympathetic ganglion.

The Crow-Fukase syndrome: a study of 102 cases in Japan.

Clinical manifestations of 102 cases with the Crow- Fukase syndrome (the syndrome of polyneuropathy, anasarca, skin changes, endocrinopathy, dysglobulinemia, and organomegaly), with or without myeloma, were reviewed. Fifty-six cases with myeloma consisted of 31 with osteosclerotic, 17 with mixed osteosclerotic and osteolytic, and 8 with osteolytic. Forty-six cases without myeloma consisted of 2 with extramedullary plasmacytoma, 33 with M protein alone, and 11 with polyclonal protein alone. There was no significant difference in incidence of the major clinical manifestations between the two groups with and without myeloma. They had a common characteristic histologic finding of the lymph node resembling that of Castleman's disease.

Tyrosine hydroxylase and tryptophan hydroxylase activities and its cofactor biopterin level in brain regions of the rolling mouse: The influence of thyrotropin releasing hormone.

Biopterin, the cofactor for tyrosine hydroxylase and tryptophan hydroxylase, was decreased in caudate nucleus, hypothalamus and cerebellum of the rolling mouse. Though there were not significant differences of tyrosine hydroxylase and tryptophan hydroxylase activities between the rolling and normal control mouse in the hypothalamus, the rolling showed significant increase of biopterin concentration and tyrosine hydroxylase activity after administration of thyrotropin releasing hormone (TRH). These results suggest that ataxic gait of the rolling mouse may be partly due to some abnormalities of catecholaminergic neurons, especially noradrenergic neurons, and that TRH may improve the abnormalities of catecholaminergic neurons. The changes of biopterin concentration by TRH administration indicate that biopterin may be a regulatory factor in catecholamine biosynthesis.

Neurotransmitter receptors of the rolling mouse Nagoya: a quantitative autoradiographic study.

The distribution of neurotransmitter and neuromodulator receptors was studied in the brain of the rolling mouse Nagoya (RMN) and in controls, using in vitro receptor autoradiography. Quantitative autoradiography was used to map adenosine A1 (labeled with [3H]cyclohexyladenosine), GABAA [( 3H]muscimol), opiate [( 3H]naloxone), L-glutamate [( 3H]L-glutamate), benzodiazepine [( 3H]flunitrazepam), and muscarinic cholinergic [( 3H]quinuclidinyl benzilate) receptors. In the cerebellar cortex, GABAA and adenosine A1 binding sites were significantly reduced in the RMN, whereas other transmitter binding sites were not significantly altered. Adenosine A1 binding sites were also reduced in the cerebral cortex and caudate-putamen. Benzodiazepine binding was significantly decreased in the cerebral cortex and increased in the CA1 subfield of the hippocampus. These results suggest that neurochemical alterations in the caudate-putamen as well as in the cerebellar cortex play important roles in the ataxia and motor dysfunction of the RMN.

Experimental ethambutol neuropathy in rats. Morphometric and teased-fiber studies.

Eight rats were given 500 mg/kg body weight of the antituberculous drug ethambutol orally every day for 3 months (group A), and 7 took 150 mg/kg of the drug for 9 months (group B). The sciatic nerves at midthigh level and the posterior tibial nerves at ankle level were studied with morphometric examination and teased-fiber method. The number of myelinated fiber/mm(2) of fascicular area was significantly reduced in both sciatic and posterior tibial nerves of group B. The pattern of frequency distribution of myelinated nerve fiber diameters of both groups was not different from that of the controls. Teased-fiber study revealed that many fibers were undergoing axonal degeneration in both groups A and B. In addition, regenerating fibers after axonal degeneration were observed in group B. These results showed that the predominant pathologic change in ethambutol neuropathy was axonal degeneration and that regeneration was already occurring in the animals taking a small dose of the drug for a long period. The fact that the degree of pathologic change was rather more severe in the sciatic nerve than in the posterior tibial nerve indicated that this was not a "dying-back" neuropathy.

The fluctuation of serum myoglobin levels in Duchenne muscular dystrophy and the carrier.

The diurnal changes of serum myoglobin level and CK activity were investigated in 20 cases of Duchenne dystrophy and 6 normal males under ordinary circumstances in their daily lives. Changes of myoglobin levels were also checked in 25 cases of Duchenne carrier and 11 control females with muscular exercise by ergometer of 70 W for 3 min. In Duchenne dystrophy, the myoglobin level was rather low before waking up, then it abruptly increased thereafter and remained high until retiring. The fluctuation range of myoglobin was greater than that of CK. The myoglobin level of control males was extremely low compared with that in Duchenne dystrophy. In Duchenne carriers, although CK activity did not significantly change after the exercise, 5 of 11 known carriers showed an increased myoglobin level.

Serum muscle-specific enolase in progressive muscular dystrophy and other neuromuscular diseases.

Serum muscle-specific enolase ( MSE , beta beta and alpha beta enolases) levels were determined in 162 patients with progressive muscular dystrophy (PMD) and other neuromuscular diseases by means of an enzyme immunoassay method. The relationships were examined between serum MSE , creatine kinase (CK) and other markers of muscle disease. Serum MSE was strikingly increased in Duchenne muscular dystrophy, and this elevation was more prominent in younger patients. Serum MSE was also increased in other types of PMD and certain other diseases. Serum MSE showed the highest correlation with CK. In the PMD group, the frequency of cases with elevated MSE was the same as in CK. These results indicated that serum MSE may well be a specific marker of muscle disease on a par with CK.

Serum carbonic anhydrase III in progressive muscular dystrophy.

Serum carbonic anhydrase III (CA-III) levels were determined by means of an enzyme immunoassay method and compared with serum creatine kinase (CK) and muscle-specific enolase (MSE) levels in 143 patients with four types of progressive muscular dystrophy (PMD), namely, Duchenne muscular dystrophy (DMD), limb-girdle dystrophy, facioscapulohumeral dystrophy and congenital dystrophy. Serum CA-III levels were raised in the majority of patients, especially in those with DMD. In DMD patients, the gradual decline in the CA-III level was observed with age. High correlations were found between CA-III, CK and MSE levels. The frequency of cases with elevated CA-III levels was the same as or greater than that of elevated CK or MSE levels in four types of PMD. These results suggest that serum CA-III may be a useful marker of muscle disease.

Pathology of myelinated fibers in cervical and lumbar ventral spinal roots in amyotrophic lateral sclerosis.

Pathological alterations were evaluated by morphometry and by a teased-fiber study on the 6th cervical (C6) and the 4th lumbar (L4) ventral spinal roots of cases of amyotrophic lateral sclerosis (ALS). The large-diameter fibers were severely affected in both spinal segments. However, small-diameter myelinated fibers were numerically well preserved. The number of large fibers in C6 and L4 ventral roots was strongly correlated to the strength of muscles innervated by C6 or L4 segments. There was no correlation of the number of small fibers with muscle strength. Teased fiber studies revealed a marked increase in the incidence of fibers showing axonal degeneration. Fibers considered to be regenerative were rarely observed. These observations suggest that large myelinated fibers, which correspond to alpha-motoneuron fibers, are selectively affected, and that small myelinated fibers, which are considered to correspond to gamma-motoneuron fibers, are preserved to some extent in the C6 and L4 ventral spinal roots in ALS.

Neuron-specific enolase and S-100 protein levels in cerebrospinal fluid of patients with various neurological diseases.

Neuron-specific enolase (NSE) and S-100 protein (S-100) levels in cerebrospinal fluid (CSF) were determined in 129 patients with various neurological diseases. The chronological changes of these nervous system-specific proteins in CSF were also examined in 3 patients with acute disorders. NSE and S-100 levels were elevated in many cases with acute conditions. These specific proteins did not increase simultaneously but independently. These results suggested that NSE and S-100 in CSF would be useful markers for damage of the nervous system and that measurement of both NSE and S-100 might positively indicate whether the damage was neuronal, glial or mixed in origin. Moreover, from the serial determination of these substances, they would be better markers than cell counts and total protein in CSF for the active injury for the nervous tissues.

Concentrations of immunoreactive thyrotropin-releasing hormone in the brain of patients with olivoponto-cerebellar atrophy.

The concentrations of immunoreactive thyrotropin-releasing hormone (ir-TRH) in the brain of patients with olivoponto-cerebellar atrophy (OPCA) were studied. Three patients with OPCA and 8 non-central nervous system degenerative diseases were subjects in this study. Ir-TRH concentration in the brain was measured by radioimmunoassay. Ir-TRH was present in all parts of the dissected brain tissues (hypothalamus, frontal lobe, cerebellar cortex, olivary n., dentate n. and caudate n.) of patients with OPCA and non-central nervous system degenerative diseases. Ir-TRH concentration in the brain of case 1 and 2 was lower in the cerebellar cortex and olivary n., in contrast, ir-TRH concentration in case 3 was higher in the dentate n. The regions and the severity of pathological changes were different in each case of OPCA and changes in ir-TRH concentration in the brain did not always correlate with the severity of pathological changes. These findings suggest that changes in ir-TRH concentration in the brain of patients with OPCA may differ in each case, and may play some pathophysiological role in OPCA.

The role of macrophages in demyelination in experimental allergic neuritis.

The role of macrophages and serum factors in demyelination in experimental allergic neuritis (EAN) was examined by a simple in vitro method. Cultivated rabbit peritoneal macrophages, preincubated with serum obtained from rabbit EAN produced by sensitization with bovine spinal nerve roots, could agglutinate and phagocytize purified bovine or rabbit peripheral nerve myelin. Sera from normal animals or from controls given adjuvant alone could not. Adhesion and phagocytosis were inhibited if EAN sera were absorbed with peripheral nerve myelin. Rabbit red blood cells were not phagocytized by macrophages exposed to EAN serum. Concomitant to these observations, three lysosomal acid hydrolases: acid proteinase, acid phosphatase and beta-glucuronidase, were assayed with respect to their topographical and chronological distribution. In the group examined at clinical onset, increases in the specific activities were 1.5-3.0-fold in the spinal roots and 1.0-1.5-fold in the sciatic nerves compared with control. The degree of increase in total activities per whole root or sciatic nerve was much higher for specific activities. The topographical distribution of the increase closely corresponded to the histological distribution of EAN lesions. These observations suggested that the increased lysosomal activity originated from lysosomal-rich infiltrating cells. These observations strongly indicated the significant role of macrophages activated by EAN serum in the demyelination of EAN.

Controlled trial of thyrotropin releasing hormone tartrate in ataxia of spinocerebellar degenerations.

The clinical efficacy, dose-response relationship, and safety of TRH-T (thyrotropin releasing hormone tartrate) were assessed in 290 patients with spinocerebellar degeneration (SCD) in a 2-week, double-blind study using placebo as control. 254 patients satisfied the criteria for inclusion in evaluation of the drug efficacy. The patients were treated with TRH-T in an intramuscular dose of 2 mg, 0.5 mg or 0 mg (placebo) as TRH once a day for 2 weeks. Clinical responses to these treatments were evaluated 3 times: at the end of weeks 1 and 2 of treatment and a week after the end of treatment. The results of "global improvement rating" as well as those of "ataxia improvement rating" showed that both 2 mg and 0.5 mg TRH-T treatments were significantly superior to placebo treatment in patients with predominantly cerebellar form of SCD. The effect was well maintained a week after the end of the 2-week treatment in the patients who were given TRH-T in daily dose of 2 mg and showed improvement at the end of treatment. The results of "improvement rating of each symptom" revealed that 2 mg treatment was significantly more effective than placebo for disorders of standing, gait, speech and writing. In the patients who had no pyramidal involvement or disorder of deep sensation, the drug efficacy and dose-response relationship were evident. Adverse reactions to the drug such as headache, feeling febrile and nausea were observed in 50% of the patients on 2 mg treatment, in 38% of those on 0.5 mg treatment and in 21% of those on placebo patient, however, discontinued treatment because of adverse reactions.