Takashi Konishi

Two different clinical phenotypes of Creutzfeldt-Jakob disease with a M232R substitution.

ObjectiveTo describe the clinical features of Creutzfeldt-Jakob disease with a substitution of arginine for methionine (M232R substitution) at codon 232 (CJD232) of the prion protein gene (PRNP).Patients and methodsWe evaluated the clinical and laboratory features of 20 CJD232 patients: age of onset, initial symptoms, duration until becoming akinetic and mute, duration until occurrence of periodic sharp and wave complexes on EEG (PSWC), MRI findings, and the presence of CSF 14-3-3 protein. Immunohistochemically, prion protein (PrP) deposition was studied.ResultsNone of the patients had a family history of CJD. We recognized two clinical phenotypes: a rapidly progressive type (rapidtype) and a slowly progressive type (slow-type). Out of 20 patients, 15 became akinetic and mute, demonstrated myoclonus, and showed PSWC within a mean duration of 3.1, 2.4, and 2.8 months, respectively (rapid-type). Five showed slowly progressive clinical courses (slow-type). Five became akinetic and mute and four demonstrated myoclonus within a mean duration of 20.6 and 15.3 months, respectively, which were significantly longer than those in the rapid-type. Only one demonstrated PSWC 13 months after the onset. Diffuse synaptic-type deposition was demonstrated in four rapidtype patients, and perivacuolar and diffuse synaptic-type deposition in two, and diffuse synaptic-type deposition in one slow-type patient. Three of 50 suspected but non-CJD patients had the M232R substitution.ConclusionsPatients with CJD232 had no family history like patients with sCJD, and showed two different clinical phenotypes in spite of having the same PRNP genotype. More studies are needed to determine whether M232R substitution causes the disease and influences the disease progression.

Extrastriatal spreading of microglial activation in Parkinson’s disease: a positron emission tomography study

BackgroundThe neuroinflammatory glial response contributes to the degenerative process in Parkinson’s disease (PD). However, the pattern of microglial progression remains unclear.MethodsWe evaluated microglial activation in early stage PD patients by quantifying changes in neuroinflammation using PET with [11C]DPA713, a selective PET tracer for microglial activation. Eleven PD patients (Hoehn and Yahr stages 1–2) without dementia underwent the [11C]DPA713 PET scan two times with 1xa0year apart. The binding potential (BPND) was estimated with the simplified reference tissue model. Voxelwise and regions of interest analyses were used to compare the regional BPND among groups.ResultsSignificant increase in [11C]DPA713 BPND was found extrastriatally in the occipital, temporal and parietal cortex in PD patients, and the degree of BPND became much higher over the brain regions predominantly in the temporal and occipital cortex 1xa0year later.ConclusionThe current results indicated that an extrastriatal spreading of microglial activation reflects one of PD pathophysiology occurring at an early stage.

Benign hereditary chorea: dopaminergic brain imaging in patients with a novel intronic NKX2.1 gene mutation

Mutations in the NKX2.1 gene, which is essential for the development, differentiation and organization of the basal ganglia, cause benign hereditary chorea (BHC) characterized by childhood-onset non-progressive chorea. We herein report the clinical features of six patients from a single family with a novel intronic mutation and present the dopaminergic neuronal imaging by using positron emission tomography (PET) imaging to assess the integrity of the striatal dopaminergic system using [11C]-CFT for the presynaptic dopamine transporter function and [11C]-raclopride for the postsynaptic D2 receptor function. The patients showed mild generalized chorea without either congenital hypothyroidism or a history of pulmonary infection and some of the patients had goiter. Genetic analyses of NKX2.1 gene showed a novel heterozygous c.464-9C>A mutation that created a new acceptor splice site resulting in the production of an aberrant transcript with a 7-bp insertion identical to a intronic sequence of genomic DNA. Oral levodopa failed to improve the involuntary movement, while haloperidol, a dopamine D2 receptor blocking agent, exacerbated the choric movement in a single patient. The dopaminergic PET studies in the two patients revealed decreased raclopride binding in the striatum, while the CFT binding was not altered. The impairment of D2 receptor function in the basal ganglia may result in exacerbation of the chorea induced by haloperidol. The molecular brain imaging and therapeutic response may help elucidate the pathophysiological mechanism of the motor control in the BHC-associated NKX2.1 mutation.

Orbital myositis associated with discoid lupus erythematosus

Sir, Discoid lupus erythematosus is a chronic autoimmune connective tissue disorder characterized by specific skin manifestations of lupus erythematosus, which is a part of the spectrum of systemic lupus erythematosus. The cutaneous lesions observed in the patients are typically circumscribed, raised, erythematous and scaly and found on the face, scalp and ears in 70% of patients. Orbital myositis is a rare inflammatory disorder of the extraocular muscles, resulting in painful diplopia exacerbated by eye movement. Some case reports have shown that orbital myositis is often associated with widespread systemic immunological inflammatory diseases. Systemic lupus erythematosus complicated with the orbital myositis is very rare, and there have been no reports of orbital myositis associated with discoid lupus erythematosus. We herein report the case of a discoid lupus erythematosus patient who manifested orbital myositis with subacute progressive ophthalmoplegia and pain with ocular movement. A 42-year-old Japanese female complained of progressive diplopia in all directions with eyelid edema and ocular pain lasting for two weeks. She had a 10-year history of discoid lupus erythematosus treated with 50mg/day of mizoribine. Discoid lupus erythematosus was diagnosed based on a facial discoid rash and a skin biopsy exhibiting lymphocytic infiltration throughout the dermis and epidermal layers. Although the patient also had arthralgia, she had experienced no active discoid lupus erythematosus episodes for five years. A physical examination revealed hyperpigmentation on her face, and a neurological examination showed bilateral ophthalmoplegia with a total limitation of eye movements, particularly vertical movement of the left eye (Figure 1(a)) and bilateral ocular pain in all directions. The laboratory evaluation revealed no leukopenia, thrombocytopenia or hemolytic anemia. The values of creatine phosphokinase, C3, C4, CH50 and thyroid function were normal. An immunological test revealed an increased antinuclear antibody titer of 1:40 (normal <40) with a speckled pattern while there were no serum autoantibodies, including anti-acetylcholine receptor, antithyroid and antidsDNA antibodies. No myositis-associated autoantibodies, including anti Jo-1, PM-Scl-100, PL-7, PL-12, M2, Ku (p70/80), SRP and Rib-P antibodies, or antimitochondrial antibodies of the M2 subtype were detectable in the serum. No malignant tumors were observed on whole-body computed tomography (CT). Orbital magnetic resonance imaging (MRI) scans revealed high-intensity signals of the extraocular muscles on fat-suppression T2-weighted images (Figure 1(b)) and an increased thickness of the extraocular muscles (Figure 1(c)). A diagnosis of orbital myositis was made based on the patient’s clinical features and abnormal MRI findings. Treatment was initiated with three courses of intravenous methyl prednisolone (1 g/day) for three days followed by oral prednisolone (20mg/day). The patient’s ocular pain rapidly improved within several days, and the diplopia and abnormal MRI findings markedly improved two months after the steroid therapy. Orbital myositis is characterized by the onset of painful and limited extraocular movements, diplopia, ptosis and swelling of the eyelids. Imaging of orbital myositis on MRI shows enlargement and high-intensity signals on T2-weighted images of the extraocular muscles, suggesting an inflammatory process in the orbital muscles. Orbital myositis may be a component of more widespread autoimmune-mediated inflammatory processes, such as systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, Crohn’s disease and the more recently described IgG4-related disease. These reports indicate that an immune-mediated mechanism may underlie the pathology of orbital myositis. The pathological analysis showed a nonspecific inflammatory process with the infiltration of neutrophils, lymphocytes, macrophages and fibroblasts. An immunohistochemical study showed infiltration with mast cells that was associated with the pathological condition. However, it is not known why the extraocular muscles are specifically targeted. There has been no report of any specific autoantibody found in orbital myositis. A previous clinical case report demonstrated presymptomatic enlargement of the extraocular muscles on CT imaging in a patient with discoid lupus Correspondence to: Satoshi Kono, First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1, Handayama, Hamamatsu 431-3192, Japan. Email: satokono@hama-med.ac.jp Received 10 September 2013; accepted 18 November 2013

GABA-A receptor impairment in cerebellar ataxia with anti-glutamic acid decarboxylase antibodies

Antibodies against glutamic acid decarboxylase (GAD-Abs) are associated with cerebellar ataxia, which is refractory to treatment with GABAergic drugs. To investigate the GABAergic neuronal system in vivo, we performed a combined positron emission tomography (PET) study with [11C]-flumazenil and [18F]-fluorodeoxyglucose (FDG) in three patients with cerebellar ataxia with GAD-Abs. The GABA-A receptor function was investigated using flumazenil, which is a selective GABA-A receptor ligand, while FDG-PET using a three-dimensional stereotactic surface projection analysis was performed to estimate the metabolic rates of glucose (MRGlc) in the patients. GABAergic drugs showed no efficacy for the cerebellar ataxia in all three patients, and all three displayed a significant decrease in flumazenil binding in the cerebellum. No MRGlc decrease in the cerebellum was found in the two patients who presented with amelioration of cerebellar ataxia following intravenous immunoglobulin (IVIG) therapy, whereas a significant MRGlc decrease in the cerebellar hemisphere was observed in another patient who showed severe cerebellar atrophy on magnetic resonance images and no response to the IVIG therapy. The decreased flumazenil binding in the present patients indicated cerebellar GABA-A receptor impairment, which may be due to either neuronal cell loss, as demonstrated by the decreased MRGlc, or a dysfunction in GABAergic neuronal inhibition. Although GAD-Abs have been postulated to prevent the synthesis of GABA, resulting in decreased GABAergic transmission, the GABA-A receptor impairment may play another pathogenic role in cerebellar ataxia associated with GAD-Abs resulting in a condition refractory to GABAergic drug therapy.

Hashimoto’s encephalopathy associated with an elevated intrathecal IgG4 level

Hashimoto’s encephalopathy is a steroid-responsive encephalopathy associated with the existence of anti-thyroid antibodies, which is characterized by various neuropsychiatric symptoms [2, 4, 6]. Autoimmune mechanisms are thought to play a pathogenic role in the disorder due to its association with other autoimmune disorders and response to steroid therapy; however the pathological mechanism underlying the disease has not been completely elucidated. We herein report a patient who manifested with steroid-responsive progressive memory disturbance, cerebellar ataxia and dystonia associated with an elevated immunoglobulin G4 (IgG4) level in both the serum and cerebrospinal fluid (CSF). The patient was a 60-year-old Japanese male who presented with a 6-month history of progressive gait disturbance. He developed memory disturbance and involuntary movements of his face and neck 2 months after presentation. There were no vascular risk factors, such as hypertension, diabetes mellitus or dyslipidemia. A neurological examination revealed cerebellar ataxia and grimacing face with cervical dystonia. Neuropsychological assessments revealed that the Mini-Mental State Examination score was 26 and the Frontal Assessment Battery score was 14, which was normal compared to age-matched normal subjects. Laboratory tests showed a high titer of anti-thyroglobulin antibodies (213 IU/ml; normal, 100) while the titer of anti-thyroid peroxidase antibodies in the serum was negative. The results of routine blood tests, the levels of antinuclear and anti-DNA antibodies, anti-SS-A/Ro, antiSS-B/La antibodies, anti-gliadin antibodies, anti-glutamic acid decarboxylase antibodies, myeloperoxidase-antineutrophil cytoplasmic antibodies (ANCA), proteinase-3ANCA, anti-voltage-gated potassium channel antibodies, angiotensin-converting enzyme, T3, T4, TSH and serum

Subacute progressive ophthalmoplegia associated with dermatomyositis

Dermatomyositis is a systemic autoimmune disorder that primarily affects the skin and skeletal muscle in the extremities, and is characterized by weakness of the proximal groups of limb muscles. Extraocular muscle involvement is a very rare manifestation of dermatomyositis [5, 8]. We herein report a patient who manifested dermatomyositis with subacute progressive ophthalmoplegia. The patient was a 53-year-old Japanese male who presented with myalgia and difficulty in climbing stairs. He developed progressive diplopia with eyelid edema and ocular pain 2 weeks after presentation, followed by difficulties in raising his arms. No autoimmune, endocrinopathy, or malignant diseases were observed. The physical examination revealed the presence of Gottron’s papules on the dorsal surface of the hands, and a neurological examination showed symmetrical weakness of the proximal muscles, including the upper limbs muscles, and bilateral ophthalmoplegia with total limitations of eye movements (Fig. 1). There was no weakness of the facial muscles or bulbar palsy. Laboratory tests revealed an increased creatine kinase (CK) level (10,808 U/l; normal range, 25–190). There was no abnormal thyroid function or serum autoantibody, including antinuclear antibody, anti-acetylcholine receptor antibody, and anti-thyroid antibodies. No malignant tumors, including thymoma or thymic hyperplasia, were observed using whole-body CT and PET imaging. Intravenous edrophonium had no effect on the ophthalmoplegia. The repetitive nerve stimulation test was normal. The muscle biopsy at the left vastus medialis muscle revealed inflammatory myopathic changes, which showed the invasion of mononuclear cells into the interfascicular septae and within the fascicles, perifascicular atrophy, and variations in the muscle fiber size. An immunohistochemical analysis showed the mononuclear cells to be CD4and CD8-positive lymphocytes. Ragged red fiber or cytochrome c oxidase-negative fibers were absent. The patient was treated with 60 mg/day oral prednisolone. His ocular impairment, weakness of the proximal muscles, and elevated CK values became markedly improved 1 month after the steroid therapy. Orbital magnetic resonance imaging (MRI) scans revealed an increased thickness of the extraocular muscles on T1-weighted images (Fig. 2a) and high-intensity signals of the extraocular muscles on fat-suppressed T2-weighted images (Fig. 2c), which were both improved after the steroid therapy (Fig. 2b, d). No myositis-associated autoantibodies, including anti Jo-1, PM-Scl-100, PL-7, PL-12, EJ, OJ, KS, M2, Ku (p70/80), SRP, Rib-P antibodies and the antimitochondrial antibody of M2 subtype, were detectable in the serum. Previous reports have suggested that the ophthalmoplegia observed in inflammatory myopathies is caused by the S. Kono (&) T. Bunai T. Konishi K. Shirakawa H. Miyajima First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1, Handayama, Hamamatsu 431-3192, Japan e-mail: satokono@hama-med.ac.jp

A Video Report of Brain–Lung–Thyroid Syndrome in a Japanese Female With a Novel Frameshift Mutation of the NKX2-1 Gene

Benign hereditary chorea is a rare autosomal-dominant disorder that is characterized by childhood-onset nonprogressive chorea and normal cognitive function. Defects in NKX2-1 on chromosome 14q13, which encodes thyroid transcription factor 1, produce a concurrent clinical manifestation of chorea, respiratory distress, and hypothyroidism known as “brain–lung–thyroid syndrome.” Here, the authors describe a video report of benign hereditary chorea in a Japanese female with a novel frameshift mutation of NKX2-1 (c.915_916insC) (p.Ala303ArgfsX132) that was initially misdiagnosed as ataxic cerebral palsy. In early infancy, especially before the appearance of chorea, benign hereditary chorea can be misdiagnosed as ataxic and dyskinetic cerebral palsy due to shared clinical features including motor delay, hypotonia, ataxic gait, and dystonia.

The Possible Link between GABAergic Dysfunction and Cognitive Decline in a Patient with Idiopathic Hypoparathyroidism.

Idiopathic hypoparathyroidism (IHP) is accompanied by cognitive impairment. We report the case of a 70-year-old IHP patient with cognitive disturbance. Brain computed tomography showed bilateral calcification in basal ganglia, thalamus, and cerebellum. Neuropsychological assessment revealed low scores for intelligence, memory, and perseverative errors. Brain positron emission tomography showed a significant reduction in [(18)F]-Fludeoxyglucose (FDG) uptake in bilateral frontal, left temporal and parietal cortices, along with a marked reduction in [(11)C]-flumazenil binding in left frontal, temporal, parietal, and bilateral cerebellum. These findings suggest cognitive impairment in IHP may be ascribed to GABAergic dysfunction, thus leading to, or coexisting with, cerebral hypometabolism.

Altered GABAergic system in the living brain of a patient with spinocerebellar ataxia type 8

Spinocerebellar ataxia type 8 (SCA8) is a dominantly inherited neurodegenerative disorder caused by the expression of a CTA/CTG repeat expansion in the SCA8 gene on chromosome 13q21 [6, 9]. Here we report in vivo alterations in the GABAergic system and glucose metabolism in the brain of a patient with SCA8 using positron emission tomography (PET). The patient, a 45-year-old Japanese female non-drinker, has suffered from myoclonus in all her limbs since 18. The involuntary movement responsive to clonazepam at an early stage became resistant at diagnosis for SCA8. Gait disturbance with dysarthria developed at around 28, followed by writing difficulty and frequent fall within 10 years. Her father also having progressive gait disturbance became bed-bound at 78. Her neurological examinations at 45 revealed abnormal motor functions (saccadic eye movement, scanning speech, limb and truncal ataxia, posture-induced myoclonus in her limbs and trunk) without abnormality in limb reflexes, sensory and autonomic systems. Cognitive tests showed low scores in intelligence (Total IQ 76, verbal 85, and performance 70 on WAIS III), memory (verbal 86, visual 81, general 83, attention/concentration 99, and delayed recall 81 on WMS-R), and executive function (two points on the Wisconsin Card Sorting Test in which four or more is considered normal) [15]. MRI showed marked cerebellar atrophy without abnormality in the brainstem or frontal lobes. Genetically, the number of SCA8 CTA/CTG repeats in genomic DNA was 9/131 (8/18 for a normal allele). The PET measurement showed reduced brain glucose metabolism in the cerebellum and frontal cortex (Fig. 1a) and a marked reduction in [C]-flumazenil binding in the whole brain particularly in the cerebellum (Fig. 1b; Table 1). As shown in the cognitive assessments, remarkable executive dysfunction was manifest, whereas intellectual and memory functions were mildly affected. Although SCA8 has been considered as a pure cerebellar ataxia [6], some evidence shows that executive dysfunction is one of its clinical features [7, 14]. The reduction of frontal glucose metabolism in the present study supports this finding [5, 7, 10, 14]. Although cerebellar injury itself would secondarily affect frontal lobe functions (reverse crossed cerebellar diaschisis) [3, 13, 14], a global reduction in brain GABA receptors with the frontal hypometabolism provides molecular evidence that frontal dysfunction is an important clinical feature of SCA8. Since a previous report on SCA8 showed the degeneration of Purkinje cells [5], the neuronal loss may by the main cause of reduction in both [F]FDG and [C]flumazenil uptake in the cerebellum. Global reduction in [C]flumazenil binding might reflect extensive functional impairment of cerebral cortical neurons because interneurons have GABAergic property and because SCA8 reportedly seems a kind of channelopathy [4] that would alter GABAergenic neurotransmission globally. Recent biochemical evidence that the SCA8 mutation is bidirectionally expressed and produces both CUG and CAG-expansion transcripts [1, 8] suggest that SCA8 CUGexpansion transcripts could enhance expression of the T. Terada (&) Y. Ouchi Department of Biofunctional Imaging, Medical Photonics Research Centre, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan e-mail: tatuhiro@hama-med.ac.jp