Hiroyuki Yahikozawa

Hemiballism with striatal hyperintensity on T1-weighted MRI in diabetic patients: A unique syndrome

We report 3 diabetic patients who developed hemiballism without involvement of the subthalamic nucleus. Each patient exhibited vigorous, flinging, ballistic involuntary movements in the extremities and slight facial grimacing involving one side of the body. Although diabetes was poorly controlled in all 3, each patient was nonketotic at the onset of hemiballism. Magnetic resonance imaging (MRI), in these patients showed abnormalities in the striatum contralateral to the hemiballism that were characterized by an increase in intensity on T1-weighted images and a slight decrease in intensity on T2-weighted images, and these changes persisted for more than 2 months. The striatal lesions are presumed to have developed following mild ischemia in the territory of the lateral striate branches of the middle cerebral artery. This combination of hemiballism and striatal lesions in diabetic patients may constitute a unique syndrome.

Cerebral amyloid angiopathy in posttransplant patients with hereditary ATTR amyloidosis

Objective: To investigate the prevalence and clinical features of posttransplant CNS symptoms in patients with hereditary ATTR amyloidosis and their Pittsburgh compound B (PiB)–PET imaging correlates. Methods: We monitored prevalence and type of CNS symptoms in 53 consecutive posttransplant patients with hereditary ATTR amyloidosis. 11C-PiB-PET was performed in 15 patients with various disease durations. We also analyzed pathologic and biochemical characteristics of ATTR amyloid deposition in the brain of a posttransplant patient. Results: Transient focal neurologic episodes (TFNEs) attributed to ATTR-type cerebral amyloid angiopathy (CAA) were found in 11.3% of posttransplant hereditary ATTR amyloidosis patients. TFNE occurred on average 16.8 years after onset of the disease. Patients with longer duration of illness (≥10 years) showed increased 11C-PiB retention in the brain. The 11C-PiB accumulation pattern in hereditary ATTR amyloidosis was unique and different from those in Alzheimer disease or Aβ-type CAA. In the autopsy case, ATTR amyloid deposition was mainly localized to leptomeningeal vessels and leptomeninges of the brain. Amyloid fibrils in the brain were almost completely composed of variant transthyretin (TTR). Conclusions: TFNE due to ATTR-type CAA occurred frequently in posttransplant patients with long disease durations. 11C-PiB-PET is a useful diagnostic tool for ATTR-type CAA. ATTR amyloid deposition in the CNS, as measured by PiB-PET, was detected approximately 10 years before onset of TFNE.

Persistent hemiballism with striatal hyperintensity on T1-weighted MRI in a diabetic patient: a 6-year follow-up study.

The combination of hemiballism, hyperglycemia and hyperintensity of the striatum on T1-weighted MRI constitutes a unique syndrome. We report the follow-up of a patient with this disorder whose hemiballism was sustained for over 5 years. High density on CT of the right striatum turned into normodensity in 4 months, and hyperintensity on T1-weighted MRI and hypointensity on T2-weighted MRI of the lesion were resolved in 18 months. A decreased perfusion of the lesion by SPECT remained 37 months after onset. There was no volume change of the lesion during the course of the illness. The radiological features support the possible pathology of either or both petechial hemorrhage and astrocytosis with high protein concentration after ischemic insult. The hemiballism may result from selective damage of GABA/enkephalin-containing neurons in the striatum and can persist without the primary histological changes causing the striatal T1-hyperintensity in this disorder.

MTCL1 plays an essential role in maintaining Purkinje neuron axon initial segment

The axon initial segment (AIS) is a specialized domain essential for neuronal function, the formation of which begins with localization of an ankyrin‐G (AnkG) scaffold. However, the mechanism directing and maintaining AnkG localization is largely unknown. In this study, we demonstrate that in vivo knockdown of microtubule cross‐linking factor 1 (MTCL1) in cerebellar Purkinje cells causes loss of axonal polarity coupled with AnkG mislocalization. MTCL1 lacking MT‐stabilizing activity failed to restore these defects, and stable MT bundles spanning the AIS were disorganized in knockdown cells. Interestingly, during early postnatal development, colocalization of MTCL1 with these stable MT bundles was observed prominently in the axon hillock and proximal axon. These results indicate that MTCL1‐mediated formation of stable MT bundles is crucial for maintenance of AnkG localization. We also demonstrate that Mtcl1 gene disruption results in abnormal motor coordination with Purkinje cell degeneration, and provide evidence suggesting possible involvement of MTCL1 dysfunction in the pathogenesis of spinocerebellar ataxia.

Congenital fibrosis of the extraocular muscles (CFEOM) syndrome associated with progressive cerebellar ataxia

We here report on a Japanese family with congenital fibrosis of the extraocular muscles (CFEOM) syndrome associated with slowly progressive cerebellar ataxia. The pedigree indicated autosomal dominant inheritance. All affected individuals showed a complete loss of upgaze function with ptosis, and severe or moderate restriction of downgaze function probably from the birth. Horizontal gaze function was well preserved, except for the eldest patient, who showed both eyes almost totally fixed in exotrophic position. The primary vertical and horizontal position of each eye varied from patient to patient. Aberrant eye movements were observed on attempted upgaze. They showed amblyopia and/or astigmatism, but none of them complained of diplopia. Pupillary reactions were normal, and retinal pigmentary degeneration or optic atrophy was not observed. These ophthalmological findings were consistent with the CFEOM phenotype. The two middle‐aged patients, but not the two younger patients, showed slowly progressive gait ataxia with juvenile onset. Magnetic resonance images of the brain indicated cerebellar atrophy in addition to congenital hypoplasia in the cerebellar vermis. Molecular genetic analysis provided a negative linkage to the FEOM3 locus. Linkage to the FEOM1 locus could not be excluded in our family, but mutation in KIF21A, a major cause of the CFEOM1 phenotype, was not detected. We consider that this family may broaden the spectrum of the clinical features of CFEOM or the related disorders presenting with the CFEOM phenotype.

Clinical Phenotype and Segregation of Mitochondrial 3243A>G Mutation in 2 Pairs of Monozygotic Twins.

IMPORTANCE The regulatory factors explaining the wide spectrum of clinical phenotypes for mitochondrial 3243A>G mutation are not known. Crosstalk between nuclear genes and mitochondrial DNA might be one factor. OBSERVATIONS In this case series, we compared 2 pairs of male twins with the mitochondrial 3243 A>G mutation and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome with a female control patient. One pair of monozygotic twins presented with diabetes and deafness in their 30s, stroke-like episodes in their 40s, and cardiac events and death in their 50s. Another pair of twins presented with deafness and stroke-like episodes in their 20s. The degree of heteroplasmy of 3243A>G mutation in the various tissues and organs was similar in the first pair of twins compared with the control patient. CONCLUSIONS AND RELEVANCE The clinical phenotype and segregation of mitochondrial 3243A>G mutation was similar in monozygotic twins. The onset age and distribution of the symptoms might be regulated by nuclear genes. Our findings might help to predict the clinical course of the surviving twins and afford an opportunity for therapy before the onset of mitochondrial disease, especially for monozygotic twins caused by nuclear transfer with a small amount of nuclear-donor mitochondrial DNA.

Recurrent steroid-responsive trismus and painful ophthalmoplegia

A 63-year-old woman experienced two episodes of trismus and painful ophthalmoplegia at an interval of six years. She suffered left visual loss, and enhanced CT scan and MR imaging revealed heterogeneous enlargement of the left extraocular muscles extending to the orbital apex. In addition, the left pterygopalatine fossa was filled with a mass isointense with muscle without evidence of surrounding tissue invasion; 67Ga scintigraphy showed high uptake in this lesion. Steroid administration dramatically resolved the trismus, and the mass in the orbit and extraorbit vanished completely. Orbital pseudotumor is characterized by self-limited, relapsing, steroid-responsive painful ophthalmoplegia, and this case could be a variant of this entity with inflammation extending into the extraorbital area.

Axonal TDP-43 aggregates in sporadic amyotrophic lateral sclerosis.

Axonal aggregates of phosphorylated (p‐) transactive response DNA‐binding protein 43 kDa (TDP‐43) in sporadic amyotrophic lateral sclerosis (sALS) were examined in relation to propagation of the protein in the nervous system.

Left Upper Lung Lobectomy Is an Embolic Risk Factor for Cerebral Infarction

Cerebral embolism is typically caused by a cardiogenic thrombus. The patent foramen ovale is a well-known cause of paradoxical embolism. However, some idiopathic cases of stroke have been reported. Such strokes are designated as embolic stroke of undetermined sources. Among them, lung lobectomy may be a new embolic risk factor for cerebral embolism. The risk of thrombus formation is high at the pulmonary vein stump after lung lobectomy, especially in the left upper lobe. Interestingly, the risk remains several years after surgery. This condition is mostly overlooked, and reported cases of this condition are rare. Methods of early detection, prevention, and treatment have not been established. Here we report the case of a 66-year-old man who suffered a cerebral infarction 2 days after left upper lobectomy. Three-dimensional computed tomography scan clearly revealed the structural feature of the pulmonary vein stump. The stump of patients with cerebral infarction after lung lobectomy should be checked.

Shinshu Brain Resource Net

“Shinshu Brain Resource Net” is a database of pathological reports, stained sections and paraffin blocks of brains, clinical information and images of nervous systems of patients with neurological diseases autopsied in core hospitals in Nagano prefecture, Japan (Fig. 1). The Net was established in August 2010 and is now managed by 17 Board Members. The total number of patients registered was 841 in February 2016. The materials of the registered patients autopsied have been used for various collaborative researches, and for education and enlightenment of medical students and doctors at lectures and clinical and pathological conferences (Shinshu NeuroCPC) which were held featuring particular neurological themes. Papers reported using the autopsy cases of the Net, ongoing researches and themes of the Shinshu NeuroCPC are noted below. All of the materials are kept in each hospital where the autopsies were done, and the principle data of each patient are gathered in the Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, Nagano, Japan. The “Shinshu Brain Resource Net” contains 63 sporadic amyotrophic lateral sclerosis (ALS), eight familial ALS containing L106 V and C111Y mutations of SOD1, 18 spinocerebellar ataxia containing SCA31, 21 familial amyloid polyneuropathy, four transthyretin amyloid angiopathy, three citrullinemia and two aceruloplasminemia. The “Shinshu Brain Resource Net” is open for collaborative studies by researchers as well as the members of the Board.