Takemori Yamawaki

Experimental Model of Small Deep Infarcts Involving the Hypothalamus in Rats Changes in Body Temperature and Postural Reflex

BACKGROUND AND PURPOSE Intraluminal middle cerebral artery (MCA) occlusion in rats has been reported to cause hyperthermia assumed to be caused by hypothalamic damage. To clarify the effects of hypothalamic ischemia on body temperature and to obtain a model simulating lacunar infarction, we attempted to produce small infarcts in deep structures (including the hypothalamus). METHODS A surgical suture was advanced to occlude the origin of the hypothalamic (HTA) and/or anterior choroidal arteries (AChA) without compromise of the anterior or middle cerebral artery origins. After treatment, rectal temperature and postural reflex were examined repeatedly for 3 days under nonanesthetic conditions. The AChA and HTA and their link with small deep infarction were then confirmed by TTC, hematoxylin and eosin, and TUNEL stains and by microsurgical dissection after colored silicone perfusion into the cerebral arteries. RESULTS Advancement of the suture near to but not occluding the MCA origin (0.5 to 1.9 mm proximal) produced small, deep, nonneocortical strokes in 25 of 36 animals without producing MCA ischemic changes. These infarctions mainly affected the hypothalamus in 13 animals (HTA area: infarct volume 6+/-1 mm(3)) and involved both the internal capsule and hypothalamus in 12 animals (HTA+AChA area infarct volume 48+/-10 mm(3)). Rats with HTA infarction alone exhibited persistent hyperthermia for 72 hours; some also had transient mild postural abnormality. The AChA+HTA infarct group showed a transient elevation of body temperature for 24 hours and definitive postural abnormality. In the remaining 11 animals, the suture was inadvertently advanced across the MCA origin, producing a large infarct that affected both the neocortex (MCA territory) and nonneocortical structures (volume 381+/-30 mm(3), n=11). The MCA infarct group displayed a transient hyperthermia and severe postural abnormality. CONCLUSIONS When properly positioned, the intraluminal suture method permits selective AChA and/or HTA obstruction without inducing MCA territory ischemia. This model confirms that selective hypothalamic infarction produces significant and sustained temperature regulation abnormalities. The model also may be useful in investigating the pathophysiology of small, deep, end-vessel infarction.

Definition of the anterior choroidal artery territory in rats using intraluminal occluding technique

This manuscript delineates the territory of the anterior choroidal artery (AChA) in rats, as defined by the induction of an AChA infarction. By advancing a 0.24-mm surgical suture up the internal carotid artery (ICA) to a point 0.5-2 mm proximal to the middle cerebral artery (MCA) origin, the AChA could be occluded and a reliable AChA distribution infarction was produced in 62% (23/37) of animals. The infarct volume, as defined by TTC staining, was 55+/-7 mm(3). Maps of the infarction, generated by measuring the entire area of overlapping coronal slices, demonstrated that the internal capsule was always damaged. Other areas that might be affected included the hippocampus, thalamus, amygdaloid complex, piriform cortex, dorsal caudatoputamen, and lateral ventricular wall. Positioning the coated suture proximal to the AChA produced a much smaller infarct involving the medial and lateral hypothalamus, preoptic region, optic chiasm, and marginal region of the internal capsule near to the lateral hypothalamus exempt from AChA territory damage. A causative relationship between AChA occlusion and a deep cerebral infarct centered on the internal capsule was further established by: (1) identifying the AChA on the non-ischemic side with colored silicone perfusion, and subsequent similar delineation on the ischemic side, and (2) delineating infarction in the silicone perfused AChA region using hematoxylin and eosin staining and the TUNEL method. The AChA usually originated from the ICA (91% of cases), 1.75+/-0.12 mm proximal to the MCA bifurcation. Approximately 27% of the AChAs had periamygdaloid branch(es) on its initial segment.

Neurological and MRI Findings as Predictors of Progressive-Type Lacunar Infarction

Aims: To find neurological or neuroimaging signs to predict neurological deterioration in acute lacunar infarctions. Methods: Sixty-one consecutive patients with a supratentorial lacunar infarct, who were admitted within 48 h, were studied retrospectively. Progressive-type stroke (PS) was defined as progressive motor deficits that arose within 7 days after onset, by using the motor ratings of the National Institutes of Health Stroke Scale. Results: Sixteen patients (26%) were classified into the PS group. In the PS group, fluctuating or progressing onset (81 vs. 42%, p = 0.009), leg-predominant motor deficits on admission (63 vs. 16%, p = 0.001) and corona radiata lesion on diffusion-weighted MRI (100 vs. 69%, p = 0.013) were all more frequent than in the non-PS group. Conclusion: Bedside neurological assessment and MRI findings may allow us to predict PS and start early intensive treatment for preventing further neurological deterioration.

Reversible stenosis of major cerebral arteries demonstrated by MRA in thrombotic thrombocytopenic purpura.

Sirs: Thrombotic thrombocytopenic purpura (TTP) is a rare disease characterized by central nervous system abnormalities, microangiopathic hemolytic anemia, thrombocytopenia, renal insufficiency, and fever [6, 8]. Several workers have reported the manifestation of multiple small cerebral lesions on MRI in the acute phase of TTP which disappeared afterwards [1, 3]. Vascular changes, however, have rarely been evaluated in TTP patients. We report a patient with TTP whose major cerebral arteries were narrowed in the acute phase and later normalized as demonstrated by serial MR angiography (MRA). A 36-year-old Japanese woman with a history of systemic sclerosis was administered prednisolone and D-penicillamine for 3 weeks prior to admission. On the night before admission, she had headache, nausea and vomiting. In the next morning, she was admitted to our hospital because of disturbance of consciousness and mild fever. On admission, she was somnolent with eyes closed. The blood pressure was 90/50 mmHg. The skin was thickened, sclerotic and reddish. The palpebral conjunctiva showed jaundice, and both eyelids were markedly edematous. She was barely able to move her limbs towards the horizontal direction because of severe flaccid weakness of four extremities. The diagnosis of TTP was established on the basis of following laboratory findings: LDH 805 U/L, indirect bilirubin 4.5 mg/100 mL, schistocytic anemia with Hb 8.4 g/100 mL, haptoglobin 2.4 mg/100 mL, platelet count 71x103/mm3, creatinine 3.5 mg/100 mL, BUN 60 mg/100 mL. Von Willebrand factor and its analysis were normal. Perinuclearanti-neutrophil cytoplasmic antibody was negative. She was treated with osmotic diuretic agents, methylprednisolone, dipirydamole and two weeks course of daily plasma exchange. Two weeks later, her neurological symptoms had disappeared almost completely. CT on admission demonstrated faint hypodensity areas in the brain stem and basal ganglia bilaterally. The first noncontrast MRI on day 2 revealed multiple hypointense areas on T1-weighted images and hyperintense areas on T2-weighted and FLAIR images in the brain stem, basal ganglia including internal and external capsules, frontal and occipital cortices and cerebellar hemispheres bilaterally (Fig. 1A). Diffusion-weighted images (DWI) showed somewhat high intensity areas in the basal ganglia areas bilaterally. The first time-offlight MRA at the same time disclosed multiple stenotic changes mainly in the right internal carotid artery, the distal portion of left middle cerebral artery trunk, left anterior cerebral artery (A1), and left vertebral artery (Fig. 1B). The second MRI on day 15 demonstrated moderately decreased intensity of all the lesions on T2weighted and FLAIR images, and the second MRA showed a slight improvement of stenotic changes. The third MRI and MRA on day 50 displayed nearly complete resolution of all the lesions (Fig. 1C, D). Both the second and third DWI showed no abnormal intensity areas. Neuroradiological features in TTP are characterized by a variety of brain lesions such as reversible small lesions [1, 3], lacunar or small cortical infarctions [1, 4, 7, 10, 11] or large infarctions [1, 6, 7]. The reversible lesions were considered to represent multifocal cerebral edema caused by occlusive changes of microvessels rather than ischemic changes [1, 3]. Occlusive microangiopathy is a unique pathogenesis underlying clinical manifestation of TTP, where arteriolar and/or capillary endothelium may be damaged by multifactorial mechanisms resulting in the development of microthrombi. Bakshi et al. documented that the reversible cerebral lesions are probably attributable to edematous changes [1]. Several MRI features of our case suggest that the lesions are based on edematous changes. The lesions were symmetrical in distribution, depicted only as unremarkable changes on DWI, and resolved following the treatment with osmotic diuretic agents. Mechanisms for the development of small or large infarction are not yet fully understood. It is considered likely that stenotic changes are first developed in small or large arteries due to endothelial damages. Stenotic lesions may be accompanied by thrombus formation, which can lead to artery-to-artery embolism or complete vascular obstruction, thereby producing cerebral infarction. Vascular changes have rarely been evaluated in TTP except in autopsy cases [6], probably because conventional angiography may accelerate renal dysfunction. To our knowledge, only two publications LETTER TO THE EDITORS

Recurrent limbic and extralimbic encephalitis associated with thymoma

A 33-year-old woman, with a 7-year clinical history of invasive thymoma treated at ages 26 and 30 years by thymectomy and radiation, presented with a generalized convulsion and loss of consciousness. Following the seizure there was no neurological deficit and normal tendon reflexes. Magnetic resonance imaging (MRI) of the brain without gadolinium enhancement revealed multiple small lesions of high signal intensity on T2 and diffusion weighted images located in the cortical area beyond the temporal lobes. Brain biopsy demonstrated encephalitis with activated microglias and activated T-cell infiltration. Within 4 months of treatment with nothing other than anticonvulsant therapy, the lesions visible on the original MRI had completely disappeared and the patient was discharged with no neurological symptoms. The patient subsequently had two more episodes with a variety of symptoms such as incontinence, confusion, aphasia, apallial syndrome, and motor paresis. MRI following these episodes again revealed multiple lesions of similar appearance to those of the first episode, although in different locations, and much larger and more numerous. The patient had steroid pulse therapy after both episodes and the lesions noted on brain MRI disappeared within a few months with minimal neurological complications.

Neurological deficits in a patient with selenium deficiency due to long-term total parenteral nutrition.

The neurological symptoms of selenium deficiency are unclear. We report a patient with neurological deficits associated with selenium deficiency following long-term total parenteral nutrition (TPN). A 40-year-old man was referred complaining of visual loss followed by slurred speech and staggering gait that had developed over the preceding 2 months. He had suffered from Crohn’s disease for 22 years and had received home TPN management for 3 years following extensive surgical resection of the gastrointestinal tract. As a result of shortbowel syndrome, he received only a little water and gastric coating agents. Neurological examination showed visual loss, bradyarthria, truncal and limb ataxia, and loss of limb proprioception. Physical examination showed curly hair and whitened nail beds on the fingers and toes, which had developed 3 months before the neurological manifestations (Fig. 1a, b). Brain magnetic resonance (MR) imaging and MR spectroscopy appeared normal. Ophthalmological examination showed large optic disc cupping, concentric visual field constriction and diminished flicker sensitivity without elevation of intraocular pressure, suggesting optic nerve disorder. Blood examination revealed an elevated mean corpuscular volume (MCV) of 109.1 fl. Blood concentrations of vitamins A, B1, B2, B6, B12, C and E, folic acid and trace metals (Fe, Cu, Zn, Pb and Al) were all normal. Serum inflammatory and autoimmunological markers, including antineuronal antibodies, and cerebrospinal fluid findings showed no abnormalities. Clinical history, nail and hair abnormalities, and macrocytosis were suspicious for selenium deficiency. The serum selenium level was below the detection limit of 2.0 lg/dl. He was diagnosed with systemic dysfunctions caused by selenium deficiency, and 100 mg/day sodium selenite was administered intravenously. By continuous administration, his curly hair and whitened nail beds gradually disappeared (Fig. 1c, d), and the MCV returned to normal over several months. Although deterioration of his neurological symptoms stopped shortly after initiation of replacement, improvements were insufficient to allow resumption of daily activities. Visual, speech and gait disturbances were unchanged by 3 years of selenium replacement. Selenium is an essential trace element that acts as an antioxidant in tissues [1, 2]. Selenium deficiency may occur as a result of long-term unphysiological nutrition, and is known to present macrocytosis [3], nail bed or hair abnormalities [3–5], skeletal muscle disorders [6, 7] and cardiomyopathy [8], between 1 month and 6 years [6, 8, 9]. The scarcity of cases, however, means that the neural symptoms of selenium deficiency remain unknown. To the best of our knowledge, only seven cases with neurological symptoms have been reported, including the present and three in Japanese abstracts (not available via MEDLINE) [10, 11]. Visual disturbance was the major symptom in six of these, and other neurological symptoms included consciousness disturbance, dysarthria, spasticity of the extremities, ataxia and sensory disturbances. These were manifested over 1–12 years after initiating TPN or T. Oguri M. Hattori T. Yamawaki N. Matsukawa (&) K. Ojika Department of Neurology and Neuroscience, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-ku, Nagoya 467-8601, Japan e-mail: norim@med.nagoya-cu.ac.jp

Predicting the motor outcome of acute disseminated encephalomyelitis by apparent diffusion coefficient imaging: Two case reports.

We present two cases of young adults with acute disseminated encephalomyelitis (ADEM) who developed severe conscious and motor disturbances. Despite their similar initial clinical course and MRI findings, their motor function outcomes were quite different. In both cases, fluid attenuated inversion recovery (FLAIR) sequenced MRI showed multiple symmetric hyperintense lesions in the internal capsule and the brainstem at the subacute stage. However, in case 1 the apparent diffusion coefficient (ADC) was pathologically decreased in the internal capsule, whereas the ADC for case 2 was normal. At the end of the examination period, severe motor disability (bedridden state) with brain atrophy apparent on MRI remained in case 1, whereas case 2 made an almost full recovery without brain atrophy. These two cases suggest that altered ADC in the internal capsules at the subacute stage may reflect a different pathogenesis between cytotoxic and vasogenic edema, and may be a valuable indicator for the prognosis of motor disturbance.

Experimental Model of Small Deep Infarcts Involving the Hypothalamus in Rats

BACKGROUND AND PURPOSE Intraluminal middle cerebral artery (MCA) occlusion in rats has been reported to cause hyperthermia assumed to be caused by hypothalamic damage. To clarify the effects of hypothalamic ischemia on body temperature and to obtain a model simulating lacunar infarction, we attempted to produce small infarcts in deep structures (including the hypothalamus). METHODS A surgical suture was advanced to occlude the origin of the hypothalamic (HTA) and/or anterior choroidal arteries (AChA) without compromise of the anterior or middle cerebral artery origins. After treatment, rectal temperature and postural reflex were examined repeatedly for 3 days under nonanesthetic conditions. The AChA and HTA and their link with small deep infarction were then confirmed by TTC, hematoxylin and eosin, and TUNEL stains and by microsurgical dissection after colored silicone perfusion into the cerebral arteries. RESULTS Advancement of the suture near to but not occluding the MCA origin (0.5 to 1.9 mm proximal) produced small, deep, nonneocortical strokes in 25 of 36 animals without producing MCA ischemic changes. These infarctions mainly affected the hypothalamus in 13 animals (HTA area: infarct volume 6+/-1 mm(3)) and involved both the internal capsule and hypothalamus in 12 animals (HTA+AChA area infarct volume 48+/-10 mm(3)). Rats with HTA infarction alone exhibited persistent hyperthermia for 72 hours; some also had transient mild postural abnormality. The AChA+HTA infarct group showed a transient elevation of body temperature for 24 hours and definitive postural abnormality. In the remaining 11 animals, the suture was inadvertently advanced across the MCA origin, producing a large infarct that affected both the neocortex (MCA territory) and nonneocortical structures (volume 381+/-30 mm(3), n=11). The MCA infarct group displayed a transient hyperthermia and severe postural abnormality. CONCLUSIONS When properly positioned, the intraluminal suture method permits selective AChA and/or HTA obstruction without inducing MCA territory ischemia. This model confirms that selective hypothalamic infarction produces significant and sustained temperature regulation abnormalities. The model also may be useful in investigating the pathophysiology of small, deep, end-vessel infarction.

Therapeutic effects of intensive inpatient rehabilitation in advanced Parkinson's disease

The importance of rehabilitation therapy in Parkinsons disease is well recognized. However, the effects of an inpatient rehabilitation program for advanced Parkinsons disease have not been fully investigated.

Familial amyloid polyneuropathy involving a homozygous Val30Met mutation in the amyloidogenic transthyretin gene presenting with superficial siderosis: a case report.

A 76-year-old woman was admitted to our hospital because of transthyretin-related familial amyloid polyneuropathy (TTR-FAP). She had developed bilateral vitreous opacity at the age of 58 and paroxysmal atrial fibrillation at the age of 62. She suffered gait disturbance and dysesthesia of the limbs at the age of 68 and was diagnosed with FAP involving a homozygous Val30Met mutation in the amyloidogenic transthyretin (ATTR) gene after a genetic test. Her parents were cousins, and her aunts medical history included pacemaker implantation and polyneuropathy. At the age of 74, the patient developed gait disturbance and dysesthesia of her extremities. A neurological examination revealed visual loss, hearing impairment, distal muscle weakness, dysesthesia, and decreased sensation in all modalities in her extremities. She could neither walk nor remain standing without support. Brain magnetic resonance imaging (MRI) revealed a low intensity lesion on the surface of the cerebellum on T2*-weighted images and susceptibility-weighted images. A low intensity pattern that was indicative of the classical type of superficial siderosis was detected. At the age of 76, when she was admitted to our hospital because of the deterioration of her gait disturbance and dysesthesia, brain MRI showed that the patients cerebellar atrophy and hemosiderin deposition had worsened. Some reports suggest that FAP patients that are homozygous for the ATTR Val30Met mutation are more likely to develop central nervous involvement than those that are heterozygous for the mutation. Superficial siderosis may be responsible for the central nervous involvement.