Kazuo Mano

CSF1R mutations identified in three families with autosomal dominantly inherited leukoencephalopathy

Genetic and phenotypic heterogeneities are considerably high in adult‐onset leukoencephalopathy, in which comprehensive mutational analyses of the candidate genes by conventional methods are too laborious. We applied exome sequencing to conduct a comprehensive mutational analysis of genes for autosomal dominant leukoencephalopathies. Genomic DNA samples from four patients of three families with autosomal dominantly inherited adult‐onset leukodystrophy were subjected to exome sequencing. On the basis of the results, 21 patients with adult‐onset sporadic leukodystrophy and one patient with pathologically proven HDLS were additionally screened for CSF1R mutations. Exome sequencing identified heterozygous CSF1R mutations (p.I794T and p.R777W) in two families. I794T has recently been reported as a causative mutation for hereditary diffuse leukoencephalopathy with spheroids (HDLS), and R777W is a novel mutation. Although mutational analysis of CSF1R in 21 sporadic cases revealed no mutations, another novel CSF1R mutation, p.C653Y, was identified in one patient with autopsy‐proven HDSL. These variants were located in the PTK domain where the causative mutations cluster. Functional prediction of the mutant CSF1R as well as cross‐species conservation of the affected amino acids supports the notion that these variants are pathogenic for HDLS. Exome sequencing is useful for a comprehensive mutational analysis of causative genes for hereditary leukoencephalopathies, and CSF1R should be considered a candidate gene for patients with autosomal dominant leukoencephalopathies.

VZV vasculopathy associated with myelo-radiculoganglio-meningo-encephalitis: An autopsy case of an immunocompetent 66-year-old male

Encephalitis is the most severe manifestation of central nervous system (CNS) infection by Varicella-Zoster-Virus (VZV). VZV associated encephalitis is now recognized to be a vasculopathy that affects large or small cerebral arteries. This report describes an autopsy case of an immunocompetent 66-year-old male who developed a progressive small vessel vasculopathy and clinically presented with a zosteriform rash and myelo-radiculoganglio-meningo-encephalitis followed by subarachnoid bleeding. This is an extremely rare manifestation of VZV vasculopathy associated with widespread CNS damage, and what is more, the spinal lesions were different from those of the cerebrum, brainstem and cerebellum, where the former were predominantly demyelinative changes and the latter were ischemic. To the best of our knowledge, few cases have been described pathologically in an immunocompetent individual. Further studies are needed to investigate the pathogenesis and treatment of VZV vasculopathy.

Early Pathologic Changes in Hereditary Diffuse Leukoencephalopathy With Spheroids

Abstract Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a familial neurodegenerative disease clinically characterized by progressive cognitive and motor dysfunction. Mutations in the colony-stimulating factor 1 receptor (CSF1R) gene have recently been identified in HDLS patients. The presence of diffuse axonal spheroids, myelin loss, and pigmented microglia in the white matter are pathologic hallmarks of HDLS; however, early pathologic findings have not been described in HDLS patients. We report a Japanese family with HDLS. A novel heterozygous c.653 C>Y mutation in the CSF1R gene was identified in the female proband who died at the age of 63 years; postmortem findings were compatible with HDLS. We also autopsied her sister who was considered to be neurologically asymptomatic and died of tuberculosis at the age of 44 years. Postmortem studies revealed patchy axonal degeneration and myelin loss, predominantly in the subcortical white matter. Pigmented microglia were distributed diffusely throughout the cerebral white matter and expressed CSF1R poorly. In conclusion, our observations suggest that the pathology of HDLS may initially be characterized by multifocal lesions in subcortical white matter regions. Moreover, pigmented microglia poorly express CSF1R and are distributed diffusely throughout the white matter at the early disease stage, preceding axonal damage and myelin loss.

Hypophosphataemic neuropathy during total parenteral nutrition

Intravenous glucose administration is the most common cause of hypophosphataemia in hospitalised patients. While most of these cases are asymptomatic, severe hypophosphataemia, when combined with phosphorus depletion, can cause acute neuropathy that mimics Guillain–Barré syndrome. A malnourished patient who received intravenous hyperalimentation (IVH) without intravenous phosphate (IP) developed hypophosphataemia and acute sensorimotor neuropathy. F waves in the peripheral nerve trunk were absent or diminished, while nerve conduction velocities were nearly normal. The sural nerve biopsy revealed the presence of some subperineurial oedema and mild axonal atrophy. Prompt IP administration reversed the patients’ neurological symptoms and normalised F waves. Our data suggest that hypophosphataemia plays a role in the pathogenesis of neuropathy that develops in patients following IVH without IP.

Abnormal MRI and EEG findings in thyroid storm resulting from Graves' disease.

A 44-year-old woman was brought to the hospital because of severe cardiopulmonary symptoms including tachycardia, respiratory distress, and pulmonary edema. The electrocardiogram revealed atrial fibrillation. Body temperature was 38.18C. There was proptosis, eyelid swelling, diffuse enlargement of the thyroid gland, and pitting edema of lower limbs. On neurological examination, she was drowsy but could follow simple commands. There was no apparent paresis, abnormal sensations, or ataxia. Thyroid function tests were indicative of thyrotoxicosis (serum thyrotropin [TSH]1⁄4 0.009 mU=L; free thyroxine1⁄4 4.13 ng=dL; free triiodothyronine1⁄4 2.11 ng=dL). The serum anti–thyroid peroxidase (TPO) antibody level was 36.9 U=mL (normal < 0.3 U=mL), the anti-thyroglobulin antibody level was 0.4 U=mL (normal < 0.3 U=mL), and the antiTSH binding inhibitory immunoglobulin level was 78.9%. Studies were therefore consistent with Graves’ disease. Tests for serum markers of cancer were negative. These were squamous cell carcinoma antigen (SCC), carcinoembryonic antigen, neuron-specific enolase, monoclonal antibody cytokeratin, pro gastrin releasing peptide, cancer antigen (CA) 19-9, and CA 125. Similarly serum markers for collagen diseases were negative. These included rheumatoid factor, antinuclear antibody, and seven tests for antibodies against various forms of DNA and related substances. Although the cerebrospinal fluid (CSF) protein concentration and cell count was normal, the ratio of serum to CSF albumin was less than 130, indicating disruption of the blood– brain barrier. Herpes simplex virus (HSV)-1, HSV-2, varicella zoster virus, cytomegalovirus, Epstein-Barr virus, and human herpes virus 6, were not detected by polymerase chain reaction–amplified DNA analysis of the patient’s serum and CSF. Tests in blood and CSF for anti-neuronal antibodies against the voltage-gated potassium channel (VGKC), the ionotropic glutamate receptor epsilon 2 (GluR epsilon 2), and the amino terminal of alpha-enolase (NAE) were negative. Magnetic resonance imaging (MRI) of the head showed a hyperintense signal in the left mesial temporal lobe. This was present on fluid-attenuated inversion recovery and a diffusion-weighted image (Fig. 1). The electroencephalogram (EEG) revealed diffuse slow waves dominant in left temporal lobe. She was initially treated with methimazole, stable iodine, beta-adrenergic receptor antagonists, and intravenous methylprednisolone. On the second day of hospitalization, she developed shock and generalized seizures with delirium. The seizures were both complex partial and generalized tonic clonic. She was intubated and sedated and gradually recovered. By the 10th hospitalization day she was free of neuropsychiatric symptoms and could be weaned from the ventilator. The head MRI and EEG had normalized. In summary, this was a 44-year-old woman with thyroid storm due to Graves’ disease, multiple neurological complications, and head MRI and EEG findings typical of limbic encephalitis. Limbic encephalitis was first described in the 1960s in adults (1). Its defining characteristics are acute encephalitis, MRI abnormalities in the limbic system, mild elevation of CSF protein concentration and cell count, negative tests for HSV in the CSF, no co-existing cancer, and a favorable long-term course. The diagnosis in our patient was supported by lack of evidence for HSV, and negative blood and imaging studies for cancer. Encephalopathy has been reported in association with Hashimoto’s thyroiditis and other autoimmune diseases. Castillo et al. (2) suggested that it would be preferable to refer to this as steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT) rather than Hashimoto’s encephalopathy and indicated that anti-TPO antibodies were not likely to be involved in it. Yoneda et al. (3) have proposed that anti-neuronal antibody against NAE is probably a diagnostic marker for SREAT. We did not find anti-NAE antibody in our patient’s blood or CSF and therefore do not think that our patient’s disorder belongs in the category of SREAT. Nor do we think that our patient belongs in the categories described by Thieben et al. (4) or Mochizuki et al. (5) because tests for anti-VGKC and anti-GluR epsilon 2 antibodies were negative. Rather we think this patient’s encephalopathy might be considered a new entity specific to thyroid storm. We suspect that disruption of blood–brain barrier due to the hyperdynamic state in thyroid storm might lead to reversible focal brain edema in the limbic system with multiple neurologic complications. To the best of our knowledge, there are few reports of brain images in thyroid storm due to Graves’ disease. Further studies are needed to document the frequency of abnormal neurological images in thyroid storm.

Hypophosphataemic neuropathy in a patient who received intravenous hyperalimentation

A malnourished patient that received intravenous hyperalimentation (IVH) without inorganic phosphate (IP) developed hypophosphataemia and acute sensorimotor neuropathy. F waves in the peripheral nerve trunk were absent or diminished, while nerve conduction velocities were nearly normal. The sural nerve biopsy revealed the presence of some subperineurial oedema and mild axonal atrophy. Prompt IP administration reversed the patients’ neurological symptoms and normalised F waves. Our data suggest that hypophosphataemia plays a role in the pathogenesis of neuropathy that develops in patients following IVH without IP. Figure 1 Sural nerve pathology. Transverse section of the right sural nerve of the patient (toluidine blue stain). (A) Oedematous tissue is shown in the subperineural space (arrowheads). (B) Myelinated fibre densities were well preserved but there were signs of mild axonal atrophy. Intravenous glucose administration is the most common cause of hypophosphataemia in hospitalised patients.1 While most of these cases are asymptomatic, severe hypophosphataemia, when combined with phosphorus depletion, can cause acute neuropathy that mimics Guillain–Barre syndrome. However, prompt IP administration can reverse this clinical condition. While there have been several reports of acute neuropathies caused by hypophosphataemia, most are anecdotal and no report has described an associated peripheral nerve pathology. Thus the clinical and pathological features of acute neuropathy that develops as a result of hypophosphataemia have not been well characterised. A 60-year-old Japanese man who had suffered from diabetes for 5 years and a prior myocardial infarction was admitted to our hospital with melaena and diarrhoea. Colonoscopy confirmed a diagnosis of ulcerative colitis. Despite treatment with mesalamine and low dose prednisolone, the diarrhoea did …

Elderly-onset familial myasthenia gravis in two siblings

Myasthenia gravis (MG) occasionally occurs in a family, but elderly-onset (≥65 years) familial MG has been rarely reported. We here report the case of two siblings with elderly-onset MG (mean onset age: 72.5 years) and present the human leukocyte antigen (HLA) profiles (HLA-A, -B, -DR) of their family. Both patients developed generalized MG with elevated serum acetylcholine receptor antibody titers at their seventies. Of six siblings, the two patients and one unaffected sibling shared the same HLA haplotypes. Our study indicates that elderly-onset MG can occur in a family and that familial occurrence of MG may be related to certain HLA alleles.

[Aggregatibacter segnis endocarditis mimicking antineutrophil cytoplasmic antibody-associated vasculitis presenting with cerebral hemorrhage: a case report].

A 56-year-old man who underwent a tooth extraction in the previous year presented with weakness of the right upper extremity. Brain CT and MRI scans showed subcortical hemorrhage in the left frontal lobe. His body temperature was 37.5°C. Blood examination revealed anemia, elevated levels of C-reactive protein, and a positive result for PR3-ANCA. Aggregatibacter segnis was identified in the incubated blood cultures, and transesophageal echocardiograms showed infectious growth in the anterior mitral leaflet. He was diagnosed with infectious endocarditis. After treatment with ceftriaxione, the clinical symptoms were improved. We concluded that infectious endocarditis caused cerebral hemorrhage and that the positive result for PR3-ANCA was a false positive. Infectious endocarditis can mimic ANCA-associated vasculitis. When ANCA-associated vasculitis is suspected, infectious endocarditis must be ruled out.

Examination of factors associated with aspiration pneumonia following stroke

Abstract Background Studies have investigated factors related to aspiration pneumonia (AP) onset in stroke patients. However, no study has examined the influence of swallowing function assessment-based strategies. Purpose The purpose of this study is to investigate factors related to the onset of AP that differ before and after swallowing function assessment. Methods and subjects Subjects consisted of 143 patients admitted to acute-stage hospitals within 7 days of stroke onset. We examined the association between AP onset within 1 year after stroke and several parameters. Results AP incidence was 24.5% overall, 20.3% before swallowing function assessment, and 7.7% after assessment. In patients who developed AP prior to swallowing function assessment, the onset was associated with male gender [odds ratio (OR): 6.206, 95% confidence interval (CI): 1.871–28.937], dysarthria (OR: 5.683, CI: 1.432–38.713), and denture usage (OR: 2.843, CI: 1.011–8.048). In those who developed AP after swallowing function assessment, AP was associated with cerebral atrophy (OR: 4.225, CI: 1.071–16.705), infracted foci in the basal ganglia (OR: 8.914, CI: 1.489–77.776), and Barthel Index (BI) Conclusions Onset of AP after stroke was associated with gender, dysarthria, denture usage at before swallowing function assessment and cerebral atrophy, infarcted foci in the basal ganglia, and BI before admission at after swallowing function assessment. It is necessary to pay attention to the fact that factors related to AP differ before and after swallowing function assessment to identify patients at high risk of developing AP after stroke.

Paraneoplastic autoimmune encephalitis associated with pleomorphic lung carcinoma: An autopsy case report: Report of paraneoplastic encephalitis

A 64‐year‐old man was admitted with acute onset disturbed consciousness. Cerebrospinal fluid analysis revealed pleocytosis and elevated protein, with negative cultures and PCR. Serum antibodies for autoimmune encephalitis were also negative. Brain magnetic resonance imaging (MRI) was unremarkable, but whole‐body CT scan showed a tumor in the left lower lung lobe. Bronchial brush cytology demonstrated clusters of malignant cells, and 18F‐fluorodeoxyglucose positron emission tomography showed multiple lesions and increased uptake in the lung tumor. Clinically the patient had a stage IV lung carcinoma, graded as T3N3M1b (OSS). Steroid therapy had limited efficacy, but chemotherapy dramatically improved his neurological symptoms. Therefore, he was diagnosed with paraneoplastic autoimmune encephalitis based on the diagnostic criteria for paraneoplastic neurological syndromes. He died due to disease progression 14 months later. Subsequent postmortem examination revealed white ill‐defined nodules in the left lung, with similar nodules in other organs. The brain weighed 1500 g before fixation, and a nodule was observed in the right precentral gyrus. Microscopically, the lung tumor was a pleomorphic carcinoma with an adenocarcinoma component. Multiple areas of micro‐softening (≤500 μm) were identified in the cerebral cortex, gray–white matter junction and basal ganglia, and were distributed diffusely in both the limbic and non‐limbic systems. Mild lymphocytic infiltrates were observed involving few intraparenchymal vessels. Few tumor metastases were observed in the right precentral gyrus. The multiple micro‐softenings may reflect a chronic neuropathologic change of paraneoplastic autoimmune encephalitis. They were too small to be detected by brain MRI. However, these lesions may have the potential to cause the neurological symptoms in the acute phase because they were observed in many anatomical regions. We should pay attention to subtle findings such as micro‐softenings when estimating the neuropathology of autoimmune encephalitis. Further investigations are needed to understand the characteristic neuropathology of this condition.