Frontotemporal lobar degeneration (FTLD) encompasses frontotemporal dementia and related neurological disorders including motor neuron disease and movement disorders. During the 21th century, analyses of aggregative proteins suggested powerful hypotheses of gain-of-neurotoxicity or loss-of-function for aggregation-related proteins. However, recent translational researches in collaboration of basic studies and human pathology indicate that FTLD arises from more complex molecular mechanisms than dyshomeostasis of single molecules. Additionally, accumulation of clinicopathological evidences from various countries, genetic backgrounds or clinical specialties (e.g. neurology and psychiatry), suggests diverse phenotypes of FTLD, which are indicative of future paradigm-shift in the concept of FTLD. In this paper, we discuss FTLD pathomechanism on the basis of human pathology.

Induced pluripotent stem cells (iPSCs) have been used in research for the development of treatments for various intractable diseases due to their unlimited proliferative and multipotent potential. We are aiming to develop novel therapies for intractable muscular diseases using iPS cells by two approaches i.e. cell therapy and drug screening. In this presentation, I focus on the cell therapy research. We have developed a differentiation induction method that mimics the developmental stages and have succeeded in inducing skeletal muscle stem cells that are applicable to cell transplantation therapy. We have found that cell transplantation into Duchenne muscular dystrophy (DMD) model mice is effective in regenerating more than 10% of dystrophin-positive fibers. In addition, some of the cells have been engrafted as satellite cells in vivo, and it is expected that the therapeutic effect will continue for a long period of time. As for the efficacy to the motor function, we have recently revealed that the regeneration of dystrophin positive myofibers in DMD model mice mainly ameliorates muscle fatigue tolerance rather than maximal contraction force in vivo. We have also developed a differentiation method to induce mesenchymal stromal cells (MSCs) from iPSCs. Transplantation of iPSC-derived MSCs (iMSCs) into Ullrich congenital muscular dystrophy (UCMD) model mice enabled the restoration of collagen type VI which resulted in enhancement of muscle regeneration. Interestingly, somatic MSCs such as bone marrow-derived MSC or adipose-derived MSC do not have therapeutic effect even they can also restore collagen type VI by the transplantation. We have recently found one of the candidates which is responsible for the muscle regeneration and is specifically expressed in the iMSCs.

There are very few organ transplants from brain-dead donors (BD transplants) in Japan compared with other countries. The neuroemergency section of the Japanese Society of Neurology (JSN) conducted a survey on the participation of neurologists in BD determination. The target of the survey was educational and quasi-educational institutions of the JSN. It was found that neurologists served as doctors to legally declare BD in 38% of institutions. Many institutions had neurological staffs with the skills required for BD determination, such as EEG reading (97%), neurological evaluations of BD (93%), judgment of the apnea test (75%), or interpretation of auditory brainstem responses (67%). As many as 96% of the responders considered that neurologists should participate in legal BD determination, although 20% felt that the lack of human resources prevented them from active participation. An inquiry to the Japan Organ Transplant Network revealed that neurologists served as a doctor to legally declare BD in around 80% of legal BD determination cases so far. The neuroemergency section conducted another survey regarding the duration of high-sensitivity and bipolar recording in EEG for BD determination. This was because simplification of EEG recording was planned for the revision of the official manual for legal BD determination. It was found that high-sensitivity and bipolar recording was conducted for 15 minutes or shorter in 52% of institutions. Many existing overseas as well as Japanese guidelines require 30-minute EEG recording for BD determination. However, the only basis was the reports of two cases with drug intoxication in whom EEG reappeared after 20 minutes’ electrocerebral inactivity: such patients would not be candidates for donors according to the Japanese guideline. Based on the present results, the minimal required duration of (high-sensitivity and bipolar) EEG recording for legal BD determination was shortened to 15 minutes in the revised manual.

A 50-year-old Japanese man, who experienced cold symptoms for 11 days, presented to our hospital complaining of hoarseness and dyspnea from the morning of the day of the visit. Laryngoscopy revealed bilateral vocal cord paralysis, and tracheotomy was performed. Specific post-admission interviews revealed that he had suffered from postural finger tremor from 30 years of age, fasciculations of his facial muscle from 47 years of age, and mild dysphagia from 49 years of age. Blood tests showed high serum CK levels, chest computed tomography (CT) revealed gynecomastia, and needle electromyography showed neurogenic changes. An abnormal expansion of the CAG repeat in the androgen receptor gene (47) was found, and spinal and bulbar muscular atrophy (SBMA) was diagnosed. Although SBMA is a rare cause of vocal cord paralysis, this disease should be considered as a differential diagnosis in patients with history or physical findings that are characteristic of SBMA.

The patient is a 17-year-old male. He had a history of hospitalization for influenza at the age of 11, and Brain MRI at that time showed reversible brain lesions in the splenium of the corpus callosum and cerebral white matter. Fifteen months ago, he visited the pediatrics department due to dysphagia, dysarthria, facial paralysis, and muscle weakness. Brain MRI revealed lesions similar to those observed here, and nerve conduction study revealed demyelinating neuropathy. He was treated with intravenous immunoglobulin (IVIg) and intravenous methylprednisolone, and his symptoms disappeared within a few days and Brain MRI 5 weeks after treatment revealed that the lesions had disappeared. Three months ago, while walking, the patient developed a knee strain, which was thought to be a recurrence of the immune-mediated neuropathy. His subjective symptom disappeared after administration of IVIg. The patient was diagnosed with X-linked Charcot–Marie–Tooth disease (CMTX1) based on genetic testing, which revealed a pathological variant of GJB1, c.124A>T (p.Ser42Cys). Peripheral neuropathy in CMTX1 may present with fluctuating symptoms and can be responsive to IVIg treatment. Recurrent brain lesions should also be considered in the diagnosis of CMTX1.

Case: A woman in her 70s. In May, a pancreatic tumor was detected during a medical checkup, and she visited the Department of Gastroenterology of our hospital. She had no subjective symptoms, but she was diagnosed with primary pancreatic cancer and multiple bone metastases. She was undergoing outpatient chemotherapy. In November of the same year, she became aware of numbness in the right cheek area and was referred to our department. Neurologically, abnormal sensation in the area of the second branch of the right trigeminal nerve was observed. Head computed tomography (CT)/MRI showed a mass lesion in the right Meckel’s cave, and FDG-PET showed multiple bone lesions as well as abnormal accumulation in the right Meckel’s cave. Based on the above, we diagnosed the patient with numb cheek syndrome due to metastasis of pancreatic cancer to Meckel’s cave. Neurologists should be aware that numb cheek syndrome can occur in association with an underlying malignancy.

Anti-NF155 antibody positive autoimmune nodopathy typically presents with symmetric deep sensory disturbance, muscle weakness and tremor. Here, we report a unique case of anti-NF155 antibody positive autoimmune nodopathy presenting as multiple mononeuropathy with predominantly superficial sensory disturbances. A 35-year-old woman presented with progressive superficial sensory disturbances on the right side of her tongue and lip, the left lower limb, the right toes, and the right forehead over a period of 4 years. There was no deep sensory disturbance, muscle weakness, or tremor. Cerebrospinal fluid protein levels were markedly elevated (423 ‍mg/dl), and nerve conduction studies indicated demyelinating neuropathy. MRI revealed swelling and high signal intensity of both the lumbosacral plexuses and the right lingual nerve on short T₁ inversion recovery images. Later, serum anti-NF155 antibody was found out to be positive. Even when the neurological symptoms are not typical as nodopathy, we should explore the possibility of nodopathy in the cases in which cerebrospinal fluid protein levels are markedly high.