Sporadic amyotrophic lateral sclerosis (SALS) and many cases of familial ALS (FALS) demonstrate cytoplasmic transactive response DNA-binding protein 43 kDa (TDP-43)-positive inclusion bodies. Thus, TDP-43 plays a vital role in ALS pathogenesis. Functional analysis of the ALS causative genes advanced the elucidation of the mechanism associated with the formation and degradation of TDP-43 aggregates. Stress granules, which are non-membranous organelles, are attracting attention as sites of aggregate formation, with involvement of FUS and C9orf72. Concurrently, ALS causative genes related to the ubiquitin-proteasome and autophagy systems, which are aggregate degradation mechanisms, have also been reported. Therefore, therapeutic research based on the molecular pathology common to SALS and FALS has been advanced.
The recent development of a cell-based assay that can detect specific autoantibodies revealed the clinical features of diseases associated with the anti-myelin oligodendrocyte glycoprotein (MOG) antibody. The anti-MOG antibody associated diseases may include inflammatory demyelinating central nervous system diseases such as neuromyelitis optica spectrum disorders, optic neuritis, myelitis, atypical multiple sclerosis, and encephalitis. Among them, anti-MOG antibody associated cortical encephalitis may develop seizure as one of the primary symptoms, present unique lateral or bilateral medial frontal cortical lesions on brain MRI FLAIR images. In acute phase, steroid pulse therapy and anti-epileptic drugs are required. In chronic phase, immunosuppressive drugs are often required to prevent relapses.
To reveal current status of medical practice, we made a nationwide self-questionnaire survey to Japanese certified Neurologists and Child Neurologists. Most specialists seeing patients with myotonic dystrophy (DM) were aware that genetic analysis is approved in health insurance. The ratio of pre-explanation about genetic analysis was also high however written informed consent was not always obtained. Over 60% of specialists regarded motor dysfunction, conduction block/arrhythmia, heart failure, dysphagia, hypoventilation as important complications, while no more than 35% of specialists regarded hypoxia/apnea, multi-organ complications, which are feature of myotonic dystrophy, as important. Over half specialists did not check Holter electrocardiogram, sleep respiratory examination, or swallowing function regularly. This fact implied that cumbersome examinations tended to be refrained from regular assessment. Child neurologists were more aggressive in respiratory care and consultation of cardiovascular specialists. A few neurologists hesitated to introduce mechanical ventilation and tube feeding.
We conducted a comprehensive anonymous questionnaire survey on medical care and treatment for patients with myotonic dystrophy, who registered in the Japanese national registry (Remudy) or were undergoing care in seven hospitals specializing neuromuscular diseases. The questionnaire consisted of 49 questions were distributed to 813 patients, and 342 valid responses were collected. Most prevalent symptoms or complaints were dysfunction of fingers and fatigue. One-third of the adult patients left the job, half of which was due to the disease. Twelve percent of the patients did not visit the specialist regularly, the main reason being distance. The most common reason that the patients did not follow the advice of using a ventilator by medical professionals was lack of feeling the need. One-fourth of the adult female patients had infertility treatment, 80% of which was before a diagnosis of this disorder. This first-time nationwide survey revealed the actual condition of Japanese patients with myotonic dystrophy and raised various care-related issues.
A 41-year-old woman presented with short-stepped gait from 20 years old and with repeated loss of consciousness from 21 years old. She had a deep cerebral white matter lesion on brain MRI at 34 years of age, but she did not reach a definitive diagnosis. At the age of 41, the gait disorder rapidly worsened after fall and fall-related head trauma. She had fixation nystagmus, dysphonia, speech disorder and exaggerated tendon reflexes. Her bilateral plantar reflex was positive, and she was not able to walk by herself. The brain and cervical MRI showed atrophy of the medulla and upper spinal cord and a deep cerebral white matter lesion. As these imaging features were suggestive of Alexander disease (AxD), we sequenced the GFAP gene. As a result, we identified a heterozygous p.R79H (c.250 G>A) missense mutation of the GFAP gene in the patient. This case suggests that loss of consciousness may be caused by autonomic disorder due to orthostatic hypotension and reflex syncope (vasovagal syncope), psychogenic non-epileptic seizures (PNES) by mental and physical stress. It is important to consider the pathophysiology and management of Alexander disease, in which the progression of gait disorder caused by pyramidal tract disorder is rapidly exacerbated by fall and head injury.
A 22-year-old woman was admitted to our hospital with persistent nausea and no apparent cause. There was no preceding infection. The patient lost consciousness for several seconds. Based on an electrocardiographic diagnosis of paroxysmal sinus arrest (PSA), a temporary pacemaker was implanted. She did not develop syncope, but vertigo, nystagmus, diplopia, and limb paresthesia were observed. Brain MRI revealed a high-intensity lesion in the dorsal medulla on FLAIR images. As the serum anti-aquaporin 4 (AQP4) antibody was positive, the patient was diagnosed with neuromyelitis optica spectrum disorder (NMOSD). After she received steroid pulse therapy (methylprednisolone at 1,000 mg/day for three days) twice, her symptoms markedly improved. In this patient, PSA was considered to be a symptom of area postrema syndrome of NMOSD. Therefore, NMOSD should be considered as a possible cause of PSA.
An 87-year-old blind man was admitted due to repeatedly disturbed consciousness and fever. Brain CT showed a pituitary tumor with a hematoma and an occlusive lesion of the right internal carotid artery. He experienced consciousness disturbance and left limb weakness with hypotension for a few minutes on the day of admission. We considered pituitary apoplexy caused adrenal failure with hypotension and transient ischemic attack (TIA) induced by a hemodynamic mechanism. An increased dose of hydrocortisone improved the fever and hypotension, and resolved consciousness disturbance. This is a unique example of TIA caused by the occlusive lesion of the internal carotid artery compressed as a result of pituitary apoplexy and a hemodynamic mechanism.
A 27 year-old Canadian man suffered from fluctuating muscle weakness in the past several years. The patient had a past history of intestinal bleeding, bifid uvula and hypothyroidism in his childhood. Repetitive nerve stimulation tests showed a decrement pattern in the left deltoid muscle. The single fiber electromyography of the left extensor digitorum muscle showed an increment of jitter. Both findings were improved by the edrophonium test. He was diagnosed as having phosphoglucomutase 1 (PGM1) deficiency, as the compound heterozygote mutation of the PGM1 gene was recognized in the whole-exome sequencing and the enzyme activity of PGM1 was defective in the biopsied muscle. Treatment with the galactose lead to improvement of the fluctuating muscle weakness and decremental pattern in the repetitive stimulation test. PGM1 deficiency should be listed in the differential diagnosis of the neuromuscular junction disorder, when the patient is seronegative for antibodies related with myasthenia gravis and shows symptoms or signs consistent with PGM1 deficiency.
Influenza encephalopathy is characterized by high fever, disturbance of consciousness following influenza virus infection. We encountered 2 adult patients with influenza-associated acute necrotizing encephalopathy (Case 1, a 70-year-old woman with diabetes; Case 2, a 49-year-old woman with multiple myeloma), showing hemorrhagic lesions in the bilateral thalamus. Case 1 presented with fever and disturbance of consciousness followed by status epilepticus, and Case 2 developed fever and drowsiness as initial manifestation. Influenza type A was positive in Case 1 and influenza type B was positive in Case 2. In the acute phase, 2 patients required respiratory ventilation and were treated with anti-influenza drug, steroid and immunoglobulin. Cognitive impairment remained in the both patients in the chronic phase. When acute necrotizing encephalopathy is suspected, intensive treatment should be started as early as possible to improve clinical outcome of patients.