Sporadic Myotonic Dystrophy Type 2 in a Japanese Patient.

We herein report a Japanese patient with myotonic dystrophy type 2 (DM2), which is rare in Japan. A 64-year-oldman had proximal muscle weakness and grip myotonia. Electromyography showed myotonic discharges, but dystrophia-myotonica protein kinase (DMPK) was negative for CTG repeats. A muscle biopsy revealed increased central nuclei, pyknotic nuclear clumps and muscle fiber atrophy, mainly in type 2 fibers, raising the possibility of DM2. The diagnosis was genetically confirmed by the abnormal CCTG repeat size in cellular nucleic acid-binding protein (CNBP) on repeat-primed polymerase chain reaction, which was estimated to be around 4,500 repeats by Southern blotting.

Correlation between Serum Zinc Levels and Levodopa in Parkinson's Disease.

Long-term intake of potential zinc-chelating drugs may cause zinc deficiency. We postulated that zinc deficiency in Parkinson's disease (PD) patients was related to the intake of drugs such as levodopa. We investigated the relationship between zinc levels and levodopa administration period, dosage, and symptoms of zinc deficiency in PD patients. We measured serum zinc levels and analyzed correlations between serum zinc levels, the levodopa oral administration period, dosage, dosing frequency, and zinc deficiency symptoms including taste disorders. Data analyses were performed using Spearman's rank correlation coefficient. The mean serum zinc level was 60.5 ± 11.6 µg/dL. The mean administration period for levodopa was 8.0 ± 5.5 years, mean administration frequency 3.4 ± 0.9 times/d, and mean administration dose 420.6 ± 237.1 mg/d. Negative correlations between zinc levels and levodopa dosage and dosing frequency were found. Multiple regression analysis showed a significant correlation with the frequency of levodopa (ß = -0.360, p = 0.007). No significant change in clinical symptoms was observed after zinc administration, but anxiety tended to improve. Our results indicated that frequent levodopa administration strongly influenced serum zinc levels which may have alleviating effects on psychiatric symptoms; therefore, preventing zinc deficiency can be important during PD treatment.

Long-term MRI changes in a patient with Kelch-like protein 11-associated paraneoplastic neurological syndrome.

BACKGROUND AND PURPOSE: The aim of this study was to identify the long-term radiological changes, autoantibody specificities, and clinical course in a patient with kelch-like protein 11 (KLHL11)-associated paraneoplastic neurological syndrome (PNS). METHODS: Serial brain magnetic resonance images were retrospectively assessed. To test for KLHL11 autoantibodies, longitudinal cerebrospinal fluid (CSF) and serum samples were screened by Phage-display ImmunoPrecipitation and Sequencing (PhIP-Seq). Immunohistochemistry was also performed to assess for the presence of KLHL11 in the patient's seminoma tissue. RESULTS: A 42-year-old man presented with progressive ataxia and sensorineural hearing loss. Metastatic seminoma was detected 11 months after the onset of the neurological symptoms. Although immunotherapy was partially effective, his cerebellar ataxia gradually worsened over the next 8 years. Brain magnetic resonance imaging revealed progressive brainstem and cerebellar atrophy with a "hot-cross-bun sign", and low-signal intensity on susceptibility-weighted imaging (SWI) in the substantia nigra, red nucleus and dentate nuclei. PhIP-Seq enriched for KLHL11-derived peptides in all samples. Immunohistochemical staining of mouse brain with the patient CSF showed co-localization with a KLHL11 commercial antibody in the medulla and dentate nucleus. Immunohistochemical analysis of seminoma tissue showed anti-KLHL11 antibody-positive particles in cytoplasm. CONCLUSIONS: This study suggests that KLHL11-PNS should be included in the differential diagnosis for patients with brainstem and cerebellar atrophy and signal changes not only on T2-FLAIR but also on SWI, which might otherwise be interpreted as secondary to a neurodegenerative disease such as multiple system atrophy.

Micro-MRI improves the accuracy of clinical diagnosis in cerebral small vessel disease.

Even with postmortem pathological examination, only limited information is provided of the foci of in vivo clinical information. Cerebral small vessel disease, which is associated with ageing, dementia and stroke, highlights the difficulty in arriving at a definitive diagnosis of the lesions detected on in vivo radiological examination. We performed a radiological-pathological comparative study using ex vivo MRI to examine small cerebral lesions. Four patients with small vessel disease lesions detected on in vivo MRI were studied. Exact pathological findings of in vivo MRI-detected lesions were revealed. The ischaemic lesion after 17 days from onset showed positivity for peroxiredoxin, cluster of differentiation 204 and glial fibrillary acidic protein, indicating sterile inflammation and neuroprotective reaction. Cortical microinfarcts beneath the cortical superficial siderosis were associated with inflammation from the superficial layer in a patient with cerebral amyloid angiopathy; in this patient, a bilinear track-like appearance of the cortical superficial siderosis on the ex vivo MRI was compatible with iron deposition on the pia matter and within cortical layers II-III. An in vivo MRI-detected cerebral microbleed was revealed to be heterogeneous. An in vivo MRI-detected cerebral microbleed was revealed to be a venous angioma. Furthermore, a neuropathologically confirmed embolic cerebral microbleed was firstly detected using this method. Our results suggest that in vivo MRI-detected lobar cerebral microbleeds can be caused by non-cerebral amyloid angiopathy aetiologies, such as microembolism and venous angioma. Venous angioma and embolic microbleeds may mimic cerebral amyloid angiopathy markers on in vivo MRI. To clarify the clinical importance of these lesions, we should investigate their rate and frequency in a large cohort of healthy individuals and patients with cardiac risk factors. Thus, we provide evidence that ex vivo micro-MRI improves the clinical diagnosis of small vessel diseases.

Cerebral Embolism Associated with Calcified Amorphous Tumor: A Review of Cerebral Infarction Cases.

Calcified amorphous tumor (CAT) is a non-neoplastic tumor composed of calcified nodules consisting of amorphous fibrous material, and it may eventually cause cerebral infarction (CI). We experienced a 67-year-old woman with CAT who had recurrent CI. After excision of the CAT, the CI did not show recurrence. A review of previous papers on CI due to CAT in Pubmed revealed that 7 of 13 studies originated in Japan and that CI can occur even with small CAT. Surgical treatment is recommended to prevent CI recurrence, especially when CAT is accompanied by mitral annular calcification or has marked mobility.

Impairment of intermediate somatosensory function in corticobasal syndrome.

Corticobasal syndrome (CBS) is characterized by unilateral atrophy of the brain. New diagnostic criteria for CBS include intermediate somatosensory dysfunction. Here, we aimed to carefully examine intermediate somatosensory function to identify tests which can assess impairment in CBS patients. Using voxel-based morphometry (VBM), we also aimed to show the anatomical bases of these impairments. Subjects included 14 patients diagnosed with CBS and 14 patients with Parkinson's disease (PD). Patients were evaluated using intermediate somatosensory tests and neuropsychological assessments. VBM was used to analyze differences in gray matter volumes between CBS and PD patients. In the PD group, no tests showed a significant difference between the dominant-side onset and the non-dominant-side onset. In the CBS group, all tests showed worse scores on the affected side. For detecting intermediate somatosensory dysfunction in CBS, two tests are recommended: tactile object naming and 2-point discrimination. VBM analysis showed that the volume of the left post- and pre-central gyrus, and both sides of the supplementary motor area were significantly decreased in the CBS group compared to the PD group. Although CBS remains untreatable, early and correct diagnosis is possible by performing close examination of intermediate somatosensory function.

Clinical Features and Experimental Models of Cerebral Small Vessel Disease.

Cerebral small vessel disease (SVD) refers to a group of disease conditions affecting the cerebral small vessels, which include the small arteries, arterioles, capillaries, and postcapillary venules in the brain. SVD is the primary cause of vascular cognitive impairment and gait disturbances in aged people. There are several types of SVD, though arteriolosclerosis, which is mainly associated with hypertension, aging, and diabetes mellitus, and cerebral amyloid angiopathy (CAA) comprise most SVD cases. The pathology of arteriolosclerosis-induced SVD is characterized by fibrinoid necrosis and lipohyalinosis, while CAA-associated SVD is characterized by progressive deposition of amyloid beta (Aß) protein in the cerebral vessels. Brain magnetic resonance imaging (MRI) has been used for examination of SVD lesions; typical lesions are characterized by white matter hyperintensity, lacunar infarcts, enlargement of perivascular spaces (EPVS), microbleeds, cortical superficial siderosis (cSS), and cortical microinfarcts. The microvascular changes that occur in the small vessels are difficult to identify clearly; however, these consequent image findings can represent the SVD. There are two main strategies for prevention and treatment of SVD, i.e., pharmacotherapy and lifestyle modification. In this review, we discuss clinical features of SVD, experimental models replicating SVD, and treatments to further understand the pathological and clinical features of SVD.

Hopelessness is associated with repeated suicidal behaviors after discharge in patients admitted to emergency departments for attempted suicide.

BACKGROUND: Hopelessness may be associated with an increased risk of suicide. However, findings regarding the long-term predictive ability of the Beck Hopelessness Scale (BHS) for suicide are inconsistent. This study investigated the long-term predictive ability of BHS scores for subsequent self-harm episodes in individuals admitted to an emergency department after attempting suicide. METHODS: The BHS was administered to 805 adult patients with a DSM-IV-TR axis I disorder admitted to an emergency department following a suicide attempt. The patients were followed for at least 18 months and up to 5 years. The incidence of the first subsequent suicidal behavior (attempt or dying by suicide) was examined and the numbers per person-year of overall repeat self-harm episodes, suicide attempt episodes, and non-suicidal self-harm episodes were evaluated. RESULTS: The total BHS scores showed significant associations with the overall number of self-harm episodes per person-year (incidence rate ratio [IRR], 1.05; 95% confidence interval [CI], 1.03-1.07; p < 0.0001), the number of suicide attempt episodes per person-year (IRR, 1.05; 95%CI, 1.03-1.08; p < 0.0001), and the number of non-suicidal self-harm episodes per person-year (IRR, 1.05; 95%CI, 1.03-1.07; p < 0.0001). LIMITATIONS: The study excluded children and adolescents. The sample size, while large, was insufficient to ensure generalizability, or to allow subanalyses based on specific disorders. CONCLUSIONS: Hopelessness scores assessed in the emergency department after a self-harming episode were associated with a rate of repetition of suicidal behaviors after discharge. Additional strategies to address hopelessness of these patients are warranted.

Cortical Microinfarcts Detected by 3-Tesla Magnetic Resonance Imaging: Differentiation Between Cerebral Amyloid Angiopathy and Embolism.

Background and Purpose- Cortical microinfarcts (CMIs) are small ischemic lesions found in cerebral amyloid angiopathy (CAA) and embolic stroke. This study aimed to differentiate CMIs caused by CAA from those caused by microembolisms, using 3-Tesla magnetic resonance imaging. Methods- We retrospectively investigated 70 patients with at least 1 cortical infarct <10 mm on 3-dimensional double inversion recovery imaging. Of the 70 patients, 43 had an embolic stroke history (Emboli-G) while 27 had CAA-group. We compared the size, number, location, and distribution of CMIs between groups and designed a radiological score for differentiation based on the comparisons. Results- CAA-group showed significantly more lesions <5 mm, which were restricted to the cortex (P<0.01). Cortical lesion number was significantly higher in Emboli-G than in CAA-group (4 versus 2; P<0.01). Lesions in CAA-group and Emboli-G were disproportionately located in the occipital lobe (P<0.01) and frontal or parietal lobe (P=0.04), respectively. In radiological scoring, ≥3 points strongly predicted microembolism (sensitivity, 63%; specificity, 92%) or CAA (sensitivity, 63%; specificity, 91%). The areas under the receiver operating characteristic curve were 0.85 and 0.87 for microembolism and CAA, respectively. Conclusions- Characteristics of CMIs on 3T-magnetic resonance imaging may differentiate CMIs due to CAA from those due to microembolisms.

MEFV gene mutations in neuro-Behçet's disease and neuro-Sweet disease.

Mediterranean fever (MEFV) gene mutations are associated with familial Mediterranean fever (FMF). Recent studies have suggested that MEFV gene mutations may act as disease modifiers in neuro-Behçet's (NBD) disease and neuro-Sweet disease (NSD). We investigated MEFV genes and clinical features in 17 patients with NBD or NSD. MEFV gene mutations were frequently observed (70.6%). Headaches and exertional leg pain were associated with MEFV gene mutations (P < 0.05). Moreover, higher frequency of white matter lesions without sites predilection (P < 0.05) and non-parenchymal lesions (P < 0.05) were also observed. MEFV gene mutations may be associated with particular findings and lesion sites.

Cortical microinfarcts in patients with multiple lobar microbleeds on 3 T MRI.

The pathogenesis of cortical microinfarcts (CMIs) is considered to be heterogeneous including cerebral small vessel disease (SVD) such as hypertensive vasculopathy (HV) and cerebral amyloid angiopathy (CAA). Recent advances in MRI have enabled the detection of CMIs in vivo. To investigate the characteristics of CMIs in advanced cerebral SVD, we performed a retrospective analysis of 85 patients with cognitive impairment who had multiple lobar cerebral microbleeds (CMBs) on 3 T MRI. Among them, 41 (48.2%) patients were classified into the strictly lobar CMB group (i.e. probable-CAA group), and 44 (51.8%) patients were classified into the non-lobar with lobar CMBs group (i.e. mix-CMBs group). The relationship between CMIs and CMBs, cortical superficial siderosis (cSS) and white matter hyperintensity was evaluated. Nine of the 41 (22.0%) patients with probable-CAA had a total of 19 CMIs, while 12 of the 44 (27.3%) patients with mix-CMBs had a total of 38 CMIs. In the probable-CAA group, the presence of CMIs was significantly associated with the presence of cSS (p < 0.001). In addition, a close spatial association between CMIs and cSS was observed. On the contrary, in the mix-CMB group, the presence of CMIs was significantly associated with the number of lobar CMBs in the frontal lobe (p = 0.034). Our results suggest that CMIs in the probable-CAA may be attributable to more severe CAA, while CMIs in the mix-CMBs indicate an advanced HV, especially when observed with more numerous lobar CMBs.

Chronic cerebral hypoperfusion upregulates leptin receptor expression in astrocytes and tau phosphorylation in tau transgenic mice.

Alzheimer's disease (AD) is the most common type of dementia in aging adults. Increasing evidence has revealed that vascular risk factors influence the midlife development of AD and that diet-induced obesity accelerates tau phosphorylation in tau transgenic mice and increases the level of serum leptin receptor (leptin-R). Leptin-R is upregulated in the peri-infarct cortices after acute cerebral ischemia. Leptin may be protective against the development of AD as it can inactivate GSK-3ß through the phosphorylation of Ser-9, leading to the reduction of tau phosphorylation. Using tau transgenic mice, the present study examined whether chronic cerebral hypoperfusion affects leptin-R signaling and tau phosphorylation. Eight-month-old tau transgenic mice (T44) overexpressing the shortest human tau isoform were subjected to chronic cerebral hypoperfusion with bilateral common carotid artery stenosis (BCAS) using microcoils or sham surgery. Their brains were analyzed four weeks later to evaluate the expression of phosphorylated tau and leptin-R via immunohistochemistry and Western blot analysis. In addition, expression of leptin-R was examined in the rat primary astrocyte cultures subjected to prolonged chemical hypoxic stress, as well as in autopsied brains. BCAS upregulated leptin-R expression and promoted the expression of phosphorylated tau in T44 Tg mice. In primary astrocyte cultures, leptin-R was upregulated under hypoxic conditions via the phosphorylated AKT/pAKT pathway, possibly suppressing the expression of caspase 3. Leptin-R was also strongly expressed in autopsied brains with AD and cerebrovascular diseases. These results collectively indicate that chronic cerebral hypoperfusion promotes leptin-R signaling and tau phosphorylation.

Proposition of zinc supplementation during levodopa-carbidopa intestinal gel treatment.

OBJECTIVES: Levodopa-carbidopa intestinal gel (LCIG) infusion is a useful therapy for the wearing-off phenomenon of advanced Parkinson's disease (PD) patients. Recently, we found three PD patients that may have had a zinc deficiency after the LCIG infusion, possibly due to the zinc-chelating action of levodopa. This study aims to evaluate changes in serum zinc levels in three patients that received LCIG treatment and to determine possible remedies for zinc deficiency during treatment. MATERIALS AND METHODS: We performed a prospective blood analysis of serum zinc levels before, when possible, and after LCIG treatment in our three PD patients. RESULTS: The serum zinc levels of the first patient before treatment and 4 months after beginning LCIG treatment were 69 and 58 µg/dl, respectively. For the second patient, serum zinc levels before treatment and two months after starting LCIG treatment were 87 and 46 µg/dl, respectively. The baseline serum zinc level for the third patient was not examined, but was 48 µg/dl 5 months after starting the LCIG infusion. CONCLUSIONS: Levodopa-carbidopa intestinal gel infusion might have caused a zinc deficiency through levodopa zinc chelation. Zinc deficiency with LCIG infusion has not yet been reported, though preventing zinc deficiency may be an important factor in future LCIG treatment strategies.

Comparison of Premortem Magnetic Resonance Imaging and Postmortem Autopsy Findings of a Cortical Microinfarct.

An 85-year-old woman diagnosed with amyotrophic lateral sclerosis died of pneumonia and was autopsied. Magnetic resonance imaging (MRI) performed 16 days before death revealed an intracortical high-intensity lesion in her right temporal cortex on three-dimensional (3D)-double inversion recovery (DIR) and 3D-fluid-attenuated inversion recovery (FLAIR) images. Histopathological examination indicated a cortical microinfarct (CMI) juxtaposed to cerebral amyloid angiopathy. Recently, in vivo detection of CMIs using 3D-DIR and 3D-FLAIR on 3-tesla MRI has been reported, and postmortem MRI study confirmed the presence of CMIs. This is the first case study to compare CMI findings detected upon premortem MRI to the CMI itself discovered upon postmortem neuropathological examination.

Diffusion tensor imaging and magnetic resonance spectroscopy in a patient with adult onset tuberous sclerosis complex.

Tuberous sclerosis complex (TSC) 1 or TSC2 is mutated in most TSC patients. TSC2 mutations are more frequently associated with worse outcomes, earlier age at seizure onset, more severe intellectual disability, and higher tuber load than TSC1. The degree of white matter involvement is thought to be associated with the severity of neurological impairment. At present, genotype-phenotype correlations and relationship between tuber burden and neurological disability in TSC are debatable. We presented a 43-year-old patient with TSC2 mutation, whose symptom was only incomplete quadrantic visual field deficit in spite of multiple brain tubers. The visual field deficit was thought to be due to a small lesion in the upper medial part of the optic radiation revealed by diffusion tensor imaging. Her brain tubers showed normal findings in magnetic resonance spectroscopy. Our case suggested that neurological and neuropsychiatric manifestations of TSC are affected by the quality rather than number of the lesions. In addition, MRS may be useful to identify the correlation between brain tubers and neurological disability in TSC patients.

Comparative Analysis of Cortical Microinfarcts and Microbleeds using 3.0-Tesla Postmortem Magnetic Resonance Images and Histopathology.

Microvascular lesions including cortical microinfarctions (CMIs) and cerebral lobar microbleeds (CMBs) are usually caused by cerebral amyloid angiopathy (CAA) in the elderly and are correlated with cognitive decline. However, their radiological-histopathological coincidence has not been revealed systematically with widely used 3-Tesla (3T) magnetic resonance imaging (MRI). The purpose of the present study is to delineate the histopathological background corresponding to MR images of these lesions. We examined formalin-fixed 10-mm thick coronal brain blocks from 10 CAA patients (five were also diagnosed with Alzheimer's disease, three with dementia with Lewy bodies, and two with CAA only) with dementia and six non CAA patients with neurodegenerative disease. Using 3T MRI, both 3D-fluid attenuated inversion recovery (FLAIR) and 3D-double inversion recovery (DIR) were examined to identify CMIs, and T2* and susceptibility-weighted images (SWI) were examined to identify CMBs. These blocks were subsequently examined histologically and immunohistochemically. In CAA patients, 48 CMIs and 6 lobar CMBs were invariably observed in close proximity to degenerated Aß-positive blood vessels. Moreover, 16 CMIs (33%) of 48 were detected with postmortem MRI, but none were seen when the lesion size was smaller than 1 mm. In contrast, only 1 undeniable CMI was founded with MRI and histopathology in 6 non CAA patients. Small, cortical high-intensity lesions seen on 3D-FLAIR and 3D-DIR images likely represent CMIs, and low-intensity lesions in T2* and SWI correspond to CMBs with in vivo MRI. Furthermore, a close association between amyloid-laden vessels and these microvascular lesions indicated the contribution of CAA to their pathogenesis.

Double-seropositive myasthenia gravis with acetylcholine receptor and low-density lipoprotein receptor-related protein 4 antibodies associated with invasive thymoma.

We describe two cases of myasthenia gravis (MG) with double seropositivity for acetylcholine receptor (AChR) and low-density lipoprotein receptor-related protein 4 (LRP4) antibodies (AChR/LRP4-MG) with invasive thymoma. Both cases showed myasthenic weakness, which was restricted to the ocular muscles for >5 months from onset, and then unprovoked severe clinical deterioration supervened with predominant bulbar symptoms. The patients responded adequately to therapeutic intervention. Serum AChR antibody levels at post-intervention were markedly decreased, whereas LRP4 antibodies were almost unchanged in case 1 and slightly decreased in case 2. Although our results suggest that patients with AChR/LRP4-MG are likely to present with more severe symptoms than those with LRP4-MG, none of the previously reported cases had thymomas. Coexistence of autoantibodies may reflect breakdown of self-tolerance caused by invasive thymomas. The main cause affecting symptoms of MG in our cases was probably AChR antibodies, and anti-LRP4 antibodies might have been an exacerbating factor.