Kazuyo Ikeda

Regional- and temporal-dependent changes in the differentiation of Olig2 progenitors in the forebrain, and the impact on astrocyte development in the dorsal pallium.

Olig2 is a basic helix-loop-helix transcription factor essential for oligodendrocyte and motoneuron development in the spinal cord. Olig2-positive (Olig2+) cells in the ventricular zone of the ventral telencephalon have been shown to differentiate into GABAergic and cholinergic neurons. However, the fate of Olig2 lineage cells in the postnatal forebrain has not been fully described and Olig2 may regulate the development of both astrocytes and oligodendrocytes. Here, we examined the fate of embryonic Olig2+ progenitors using a tamoxifen-inducible Cre/loxP system. Using long-term lineage tracing, Olig2+ cells in the early fetal stage primarily differentiated into GABAergic neurons in the adult telencephalon, while those in later stages gave rise to macroglial cells, both astrocytes and oligodendrocytes. Olig2+ progenitors in the diencephalon developed into oligodendrocytes, as observed in the spinal cord, and a fraction developed into glutamatergic neurons. Olig2 lineage oligodendrocytes tended to form clusters, probably due to local proliferation at the site of terminal differentiation. In spite of the abundance of Olig2 lineage GABAergic neurons in the normal neocortex, GABAergic neurons seemed to develop at normal density in the Olig2 deficient mouse. Thus, Olig2 is dispensable for GABAergic neuron specification. In contrast, at the late fetal stage in the Olig2 deficient mouse, astrocyte development was retarded in the dorsal neocortex, but not in the basal forebrain. Olig2 functions, therefore, in gliogenesis in the dorsal pallium. Short-term lineage tracing experiments revealed that the majority of late Olig2+ cells were not direct descendants of early Olig2+ progenitors in the fetal forebrain. These observations indicate that embryonic Olig2+ progenitor cells change their differentiative properties during development, and also that Olig2 plays a role in astrocyte development in a region-specific manner.

Effects of daily water drinking on orthostatic and postprandial hypotension in patients with multiple system atrophy.

ObjectiveIt has been demonstrated that the increased blood pressure (BP) caused by a single dose of water alleviates orthostatic hypotension (OH) and postprandial hypotension (PPH) in patients with autonomic failure (AF). The aim of this study was to evaluate the practical effect of daily water drinking on OH and PPH in the morning when patients with AF are usually most affected.MethodsIn five patients with multiple system atrophy (MSA) characterized by intractable OH and PPH, we measured seated, standing and postprandial BP in the morning without and with ingestion of 350 ml tap water at 07.30 hours for seven successive days. The changes from the basal BP level at 07.30 hours (ΔBP) were assessed as an index of the effect of water drinking.ResultsWater drinking elicited a rapid pressor response in all patients. The ΔBP during sitting, standing and after a meal following water drinking (day 1 and day 7) was significantly higher than without water drinking (day 0). The effects of reducing OH and PPH on day 7 were equivalent to those on day 1. No adverse effects associated with daily water drinking were observed, except later diuresis, which occurred in one patient.ConclusionsDaily water drinking demonstrated constant pressor effects in the morning with no severe adverse effects in MSA patients. This finding suggests that water drinking should be tried as a practical measure to prevent or reduce OH and PPH.

An autopsy case of Creutzfeldt‐Jakob disease with a V180I mutation of the PrP gene and Alzheimer‐type pathology

We report an autopsy case of Creutzfeldt‐Jakob disease with a codon 180 point mutation of the prion protein gene (PRNP). A 77‐year‐old woman developed gait instability, followed by dementia and limb/truncal ataxia. She became akinetic and mute 18 months and died of pneumonia 26 months after the disease onset. Analysis of the PRNP gene revealed a codon 180 point mutation. Post‐mortem examination revealed marked spongiosis, neuronal loss, and astrocytic gliosis in the cerebral cortex. Mild to moderate spongiosis and neuronal loss were observed in the limbic cortex and basal ganglia. There was no spongiform change in the hippocampus, brain stem or cerebellum. Many senile plaques and neurofibrillary tangles were found, and the Braak stages were stage C and stage IV, respectively. Immunostaining for prion protein (PrP) revealed granular (synaptic‐type) and patchy PrP deposition in the cerebral cortex and especially in the hippocampus. Most patchy PrP deposits were colocalized with amyloid β plaques, but some of them were isolated. The relatively strong PrP deposition and coexistence of Alzheimer‐type pathology of this case are remarkable. We suppose that amyloid β plaques might act as a facilitating factor for PrP deposition.

Painful legs and moving toes syndrome associated with herpes zoster myelitis

A 75-year-old woman developed painful legs and moving toes syndrome (PLMT) 16 months after the onset of herpes zoster (HZ) myelitis. Although the scattered extensive lesions due to HZ myelitis were observed to be eccentric near the posterior horn on MRI, these changes had disappeared upon the development of PLMT. Combined median and tibial nerve somatosensory evoked potentials demonstrated abnormal findings only in the tibial nerve stimuli, suggesting that a severe alteration occurred in the somatosensory fibers coming selectively from the lower legs. These findings suggest plasticity in the ascending somatosensory pathway including the posterior horn cells, probably involving the interneuron networks, for the lower legs may underlie the development of PLMT associated with HZ myelitis.

Absence of orbito-ocular signs in dural carotid–cavernous sinus fistula with a prominent anterior venous drainage

A 55-year-old woman developed an intractable right orbitofrontal headache. The symptoms subsided spontaneously 2 months after onset, but diplopia due to right abducens nerve palsy had occurred, and gradually worsened. Orbito-ocular signs were never observed throughout the clinical course. Brain MRI and MR angiography demonstrated abnormal signal changes corresponding to the right cavernous sinus. Angiography confirmed a dural carotid-cavernous sinus fistula (CCF) with three directional drainage routes in the arterial phase. Although the most prominent draining vein was the superior ophthalmic vein (SOV), an outflow with a high flow rate into the angular facial vein prevented prolonged enhancement of the SOV in the venous phase. These findings suggest that the absence of orbito-ocular signs in dural CCF with an anterior venous drainage could be attributed to the relief of venous hypertension of the SOV.

Paraneoplastic necrotizing myelopathy in a patient with advanced esophageal cancer : An autopsied case report

We report the first autopsied case of paraneoplastic necrotizing myelopathy associated with esophageal cancer in the literature. The patient had acute flaccid paraplegia and urinary retention, and had a good recovery of strength of both legs in response to corticosteroids. MRI showed a characteristic lesion with post-gadolinium enhancement of the cervical to mid-thoracic spinal cord at the onset, which has never been reported. Taken together, these results suggest that there is an underlying autoimmune mechanism in paraneoplastic necrotizing myelopathy.

Improvement of cardiovascular autonomic dysfunction following anti–copper therapy in Wilson’s disease

Sirs: Detailed autonomic function tests (AFTs) have recently revealed significant abnormalities in almost one-third of patients with Wilson’s disease (WD) [1–4]. However, the time course and reversibility of the autonomic dysfunction in WD are unknown [5]. In addition, it remains unclear whether or not the autonomic dysfunction results from central nervous system lesions. We report a patient with WD who underwent AFTs before and after anti-copper therapy. A 47-year-old woman was referred to our outpatient clinic because of tremors in her right arm and leg, which developed at 43 years of age. She had had a history of transient liver damage of unknown origin at 27 years of age. She had no family members with neurological and/or hepatic problems. She was alert, oriented and cooperative. The neurological examination revealed slight dysarthria and resting, postural and intention tremor involving the head and upper and lower extremities. A full-scale IQ on the Wechsler Adult Intelligence Scale-Revised Version (WAIS-R) was 78 (verbal, 89; performance, 68). A KayserFleischer (K-F) ring was found by slit lamp examination. Laboratory investigations showed decreased serum copper (20 μg/dl) and ceruloplasmin (3.0 mg/dl), and elevated urinary copper excretion (868 μg/day). The liver enzymes were normal. A liver biopsy confirmed the diagnosis of WD. T2-weighted magnetic resonance imaging (MRI) showed an increased signal in the thalamus, hypothalamus, midbrain and pons, and a decreased signal intensity in the putamen and globus pallidum (Fig. 1). Apart from lightheadedness upon standing, no clinical features of autonomic dysfunction were observed. AFTs revealed orthostatic hypotension upon a 60° head-up tilt, decreased pressor responses to isometric exercise and mental arithmetic and decreased heart rate responses to deep breathing and the Valsalva maneuver. A pressure “overshoot” during phase IV of the Valsalva maneuver was absent (Table 1). She had no other causes of autonomic dysfunction. Since she found treatment with penicillamine was intolerable, triethylene tetramine dihydrochloride (trientine) was administered alternatively at 2000 mg/day as a maintenance dose. Consequently, her tremor nearly disappeared within 24 months. A follow-up MRI made 36 months later revealed that the increased signal intensity lesions had disappeared (Fig. 1). The WAIS-R showed marked improvement (full-scale, 100; verbal, 99; performance, 101). Reassessment of AFTs no longer revealed orthostatic hypotension, and cardiovascular responses to pressor and respiratory stimuli were normal or increased toward the normal levels. The phase IV of the Valsalva maneuver showed a slight pressure “overshoot” (Table 1). In this case, AFTs before the anti-copper therapy revealed the latent sympathetic and parasympathetic dysautonomia, similar to previous reports [1–4]. In addition, this case showed for the first time LETTER TO THE EDITORS

Low-dose tacrolimus for two cases of myasthenia gravis with invasive thymoma that relapsed shortly after thymectomy.

Two patients with myasthenia gravis (Ossermann IIb) involving invasive thymoma who underwent extensive thymectomy manifested myasthenic crisis shortly after the procedure; however, both patients were treated with intravenous immunoglobulin and recovered from myasthenic crisis that had been deteriorating for about 1 week. Subsequently, the patients were administered a low-dose of tacrolimus (3 mg/day) in addition to prednisolone. Several months later, tacrolimus continued to control fluctuations of myasthenic symptoms and maintained remission in these patients. The serum titer of anti-Ach-receptor antibodies decreased in parallel with clinical improvement due to tacrolimus, and we accordingly reduced the dosage of prednisolone. Tacrolimus is a new immunosuppressive agent acting through the selective inhibition of helper-T-cell activation that can be reduced dosage of steroids and can maintain remission of myasthenia gravis with invasive thymoma.

Neuromyelitis optica spectrum disorder presenting with repeated hypersomnia due to involvement of the hypothalamus and hypothalamus-amygdala linkage.

We report the case of a 46-year-old Japanese woman with neuromyelitis optica spectrum disorder presenting with repeated hypersomnia accompanied by decreased CSF orexin level. First episode associated with hypothalamic-pituitary dysfunction showed bilateral hypothalamic lesions that can cause secondary damage to the orexin neurons. The second episode associated with impaired memory showed a left temporal lesion involving the amygdala. The mechanism remains unknown, but the reduced blood flow in the hypothalamus ipsilateral to the amygdala lesion suggested trans-synaptic hypothalamic dysfunction secondary to the impaired amygdala. A temporal lesion involving the amygdala and hypothalamus could be responsible for hypersomnia due to neuromyelitis optica spectrum disorder.

The close relationship between life-threatening breathing disorders and urine storage dysfunction in multiple system atrophy

Survival of multiple system atrophy (MSA) depends on whether a variety of sleep-related breathing problems as well as autonomic failure (AF) occur. Since the brainstem lesions that cause respiratory and autonomic dysfunction overlap with each other, these critical manifestations might get worse in parallel. If so, the detection of AF, which is comparatively easy, might be predictive of a latent life-threatening breathing disorder. In 15 patients with MSA, we performed autonomic function tests composed of postural challenges and administered a questionnaire on bladder condition, as well as polysomnography and laryngoscopy during wakefulness and under anesthesia. Polysomnographic variables such as the apnea-hypopnea index (AHI) and oxygen saturation (SpO2) and the findings of laryngoscopy were compared with the degree of cardiac and urinary autonomic dysfunction. AHI, mean SpO2 and the lowest SpO2 showed significant correlations with urine storage dysfunction. In addition, patients with vocal cord abductor paralysis (VCAP) or central sleep apnea (CSA) contributing to nocturnal sudden death had more severe storage disorders than those without. On the other hand, no significant relationship between polysomnographic variables and orthostatic hypotension was observed except in the case of mean SpO2. These results indicate that life-threatening breathing disorders have a close relationship with AF, and especially urine storage dysfunction. Therefore, longitudinal assessment of deterioration of the storage function might be useful for predicting the latent progress of VCAP and CSA.