The association of acute pan- with recovery and chronic renal failure was reported. A 22 year-old uremic patient under treatment with intermittent hemodialysis presented with internal ophthalmoplegia, orthostatic hypotension, anhidrosis, miction syncope, loss of penile erectile function, abdominal pain, constipation and diarrhea. Investigation established the impairment of both peripheral sympathetic and parasympathetic fibers. A subclincal somatic neuropathy was evident from a depressed motor nerve conduction velocity. It appeared that recovery from autonomic dysfunction was concurrent with intermittent hemodialysis. Therefore, we discussed the possibility that the uremic neuropathy relates to an acute pan-.

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The sympathetic skin response (SSR) is considered as one of the indexes of autonomic nervous system functions, especially related with the sudomotor function of unmyelinated sympathetic fibers. SSRs are recorded as the potentials with biphasic or multiphasic waveforms by conventional electromyography. SSRs are evaluated by measuring latency (time from the stimulus to the onset), amplitude, and area (the space under the curve of the waveform). Although is a feature of chronic obstructive pulmonary disease (COPD), as demonstrated by acetylcholine sweat-spot test, there are no data concerning SSR in COPD patients. In this study, we electrophysiologically investigated the sudomotor function of the sympathetic nervous system in patients with COPD. SSRs were recorded in 30 patients with COPD and 21 healthy volunteers. Normal responses were obtained from all subjects in the control group. No response was observed in three patients with COPD. The mean latency, amplitude and area values of the potentials recorded of the remaining 27 patients were compared to the control. The mean latency was longer (p < 0.01) and the mean amplitude and area values were lower (p = 0.012, p = 0.021, respectively) in the patients compared to the control. We also demonstrated significant correlations between the latency, amplitude, or area values of the SSR and two parameters of pulmonary function tests forced expiratory volume one second/forced vital capacity (FEV1/FVC) and FEV1/FVC %. In conclusion, SSR is impaired in patients with COPD, which indicates the dysfunction of the sympathetic nervous system. Furthermore, the degree of impairment in SSR may reflect the severity of airway obstruction in patients with COPD.

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In clinical practice, photophobia resulting from persistent mydriasis may be associated with dysfunction of ocular parasympathetic nerves or primary iris lesions. We encountered a 5-year-old Miniature Dachshund and a 7-year-old Shih Tzu with mydriasis, abnormal pupillary light reflexes, and photophobia. Except for sustained mydriasis and photophobia, no abnormalities were detected on general physical examination or ocular examination of either dog. We performed pharmacological examinations using 0.1% and 2% pilocarpine to evaluate and diagnose parasympathetic denervation of the affected pupillary sphincter muscles. On the basis of the results, we diagnosed a pupillary abnormality due to parasympathetic dysfunction and not to overt primary iris lesions. The test revealed that neuroanatomic localization of the lesion was postciliary ganglionic in the first dog.

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Paroxysmal sympathetic hyperactivity (PSH) is a form of autonomic instability, following acute neurological insults, such as severe traumatic brain injury. PSH is characterized by intermittent agitation, diaphoresis, hyper­thermia, hyper­tension, tachycardia, or tachypnea, accompanied by hypertonic movement. We treated a 13-year-old girl who suffered from autonomic instability, associated with elbow flexion of both arms, two months after a traffic accident. Her conscious was disturbed and she did not respond to verbal commands. Magnetic resonance imaging showed diffuse axonal injury signs in the basal ganglia. Ictal body temperature was >39ﾟC, with prominent sweating on the forehead. Physical and laboratory examination revealed no abnormalities besides elevated creatine kinase levels. These episodes lasted approximately a few minutes twice a day. Given the extreme episodes and background, PSH was suspected. However, conventional therapy with antipyretic, anti-convulsants, and sedatives was ineffective. Oral baclofen was not effective. The severe spasticity in both arms prevented full rehabilitation, and she was transferred to our hospital. Following lumbar intrathecal baclofen therapy (ITB), autonomic instability resolved, and she appeared to be more comfortable. A pump was implanted for continuous ITB, and good recov­ery was seen after the procedure. The patient was transferred to a rehabilitation hospital. Comatose status was gradually relieved. ITB appears to offer a useful therapeutic option for intractable PSH with severe spasticity.

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重症頭部外傷にひき続いて生じたparoxysmal sympathetic hyperactivity（PSH）の2症例を経験した。2症例はいずれもGlasgow come scale（GCS）4で来院した交通事故の患者であり，頭蓋内圧管理を含む神経集中治療を行った。1例は第7病日から，もう1例は第1病日からPSHが生じた。頭蓋内環境を改善させ全身状態を良好に維持するために，異常高血圧や高体温をコントロールすることが必要となり，ICU管理が長期化したが，ガバペンチンの投与によってPSHを抑えることに成功した。本邦におけるPSHの報告例は多くないが，認識不足が背景にある可能性がある。集中治療医はPSHの病態を十分に認識する必要がある。

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Acute autonomic, sensory and motor neuropathy (AASMN) is a rare peripheral nerve disorder characterized by prominent with somatic sensory and motor impairment. in AASMN is intractable even with corticosteroid therapy or plasmapheresis. Here we report a case of AASMN with severe orthostatic hypotension. Although the effectiveness of corticosteroid was insufficient, high dose intravenous immunoglobulin therapy (IVIg) was effective for not only sensorimotor symptoms but also autonomic symptoms. This is the first case of AASMN showing favorable responses to IVIg treatment, suggesting that IVIg should be considered when corticosteroid therapy or plasmapheresis is ineffective or insufficient.

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【目的】Paroxysmal sympathetic hyperactivity

（以下PSH）は，重症脳損傷後に発作性に生じる頻脈・高血圧・過呼吸・高体温・発汗などの交感神経亢進症状と，過度の筋緊張亢進を特徴とする症候群である．しかし，頭部外傷に続発するPSHの本邦での報告は少ないので，当科におけるPSH症例の実態を検討した．

【対象・方法】2013年1月から2018年5月までに，当科へ入院した頭部外傷例を対象とした．PSHはBaguley IJらの基準に準じて診断し，十分な鎮痛・鎮静と全身管理，及びbromocriptineあるいはbaclofenの投与が行われた．PSH発症に関わる因子及び受傷3ヵ月後の予後に関連する因子については，疫学，生理・生化学，画像のパラメーターに基づき検討した．

【結果】対象患者97名中，PSH群は11人で，発症率は11.3%であった．受傷後5.6±4.0日目で診断されていた．Traumatic Coma Data Bank（TCDB）分類では，focal injury 7名，diffuse injury 4例で，MRで診断された間脳/脳幹病変は2例だった．手術は8例に施行された．PSH未発症群に比べ，PSH発症群の年齢，来院時のGlasgow coma scale（GCS）は有意に低く，頭蓋内圧は高値であり，またD-dimer高値，fibrinogen低値を認めた．PSH発症群ではfocal injuryが有意に多く，間脳/脳幹病変はPSH発症群と未発症群では差がなかった．受傷3ヵ月後の予後に関連した因子の検討では，GCS低値，PSH発症群，diffuse injuryが独立した予後因子であった．

【結語】当科におけるPSH発症例は，これまでの報告と異なり間脳/脳幹病変が少なく，focal injuryに多く発症していた．頭部外傷の予後に関しては，PSHの発症が来院時GCS低値と独立して予後不良に関連していた．すなわち，来院時GCSが低い重症例であっても，PSHを早期に発見して治療することにより，予後改善を図れる可能性がある．

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Anti-IgLON5 disease shows various neurological manifestations, of which

is one of the major symptoms and is rarely improved by immunotherapy. We herein report a patient with anti-IgLON5 disease who showed several autonomic failures, including vocal cord palsy for four months. The patient presented with cognitive impairments, bulbar symptoms accompanied by myorhythmia in the pharynx and tongue, cerebellar ataxia with tremor, motor neuron symptoms in the limbs, gastrointestinal dysfunction, orthostatic hypotension, non-rapid eye movement sleep disorder on polysomnography, and severe vocal cord palsy. Combined immunotherapy improved his symptoms, including vocal cord palsy, suggesting that combined immunotherapy might improve in anti-IgLON5 disease.

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Patients of congenital diseases have abnormalities in their chromosomes and/or genes. Therefore, it has been considered that drug treatments can serve to do little for these patients more than to patch over each symptom temporarily when it arises. Although we cannot normalize their chromosomes and genes with chemical drugs, we may be able to manipulate the amounts and patterns of mRNAs transcribed from patients DNAs with small chemicals. Based on this simple idea, we have looked for chemical compounds which can be applicable for congenital diseases and found INDY, TG003, and SRPIN340 are promising as clinical drugs for Down syndrome (ref 1) and Duchenne muscular dystrophy (ref 2), respectively.

Familial

(FD), a hereditary sensory and autonomic neuropathy, is caused by mis-splicing resulting from an intronic mutation in IKBKAP gene. FD would be treatable if we can develop &quot;a splicing modulator&quot; which promotes exon20 inclusion of IKBKAP and increases the expression of IKAP protein in FD patient cells. In order to find the modulator, we established splicing reporter assay with dual color (SPREAD) using a segment of human IKBKAP spanning from exon19 to exon21. SPREAD allows us to visualize the splicing in cells, and to identify RBM24 and RBM38 as the tissue-specific modulators for exon20 inclusion of IKBKAP. This also enabled us to find a chemical compound RECTAS, which can rectify the aberrant IKBKAP splicing in FD patient fibroblasts. Our data implicate the mis-splicing of IKBKAP in the reduced tRNA modification in FD patient and demonstrated that RECTAS could be the therapeutic drug (ref 3). Recently, we found small molecules which can normalize aberrant splicing and are potentially applicable for cardiac Fabry disease and Cystic fibrosis (unpublished).

Reference

1. Nakano-Kobayashi A et al. (2017) Prenatal neurogenesis induction therapy normalizes brain structure and function in Down syndrome mice. Proc Natl Acad Sci USA.114(38):10268-10273.

2. Nishida A et al. (2011) Chemical treatment enhances skipping of a mutated exon in the dystrophin gene. Nature Communications 2, 308. doi: 10.1038/ncomms1306.

3. Yoshida M et al. (2015) Rectifier of aberrant mRNA splicing recovers tRNA modification in familial

. Proc Natl Acad Sci USA. 112(9):2764-2769.

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Global warming is a major threat affecting “increasing heat stroke” and “chronic inactivity related to summer heat (Natsubate (summer fatigue))”. Numerous review articles have described heat stroke in detail, however to our knowledge, there is no review article on the prevention of both heat stroke and Natsubate. In this paper, we speculated on the pathophysiology of Natsubate with reference to findings of heat stress, exercise, and water regulation. Subsequently, a balanced heat stroke and Natsubate prevention methods is discussed based on the pathophysiology of heat stroke and the inferred pathophysiology of Natsubate. Heat stress due to summer heat can lead to leaky gut and also via the brain-gut axis. On the other hand, intensified drinking behavior to reduce heat stress (overhydration, rapid rehydration, and extreme internal cooling) also leads to water intoxication and . Water intoxication and due to these factors are assumed to be the pathophysiology of Natsubate. If too much focus is placed on heat stroke prevention, healthy lifestyle and heat acclimatization may be impaired, and the body and mind may become more susceptible to heat stroke and Natsubate. In order to prevent both of heat stroke and Natsubate, it is thought that by daring to improve maximal oxygen intake and heat acclimatization even under summer heat, we can create a body and mind that prevents heat stroke and Natsubate. On the other hand, these efforts under summer heat may lead to heat stroke and Natsubate, making it difficult to strike a balance. The key to this balance is to refrain from raising the body core temperature too high and engaging in too strenuous activities, and to practice proper hydration.

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A 19-year-old man with Philadelphia chromosome-positive acute lymphoblastic leukemia received an allogeneic hematopoietic cell transplant with unrelated bone marrow. On day 20, the patient developed impaired consciousness and disorientation. Examination of the cerebrospinal fluid showed 2×10⁴ copies/mL of HHV6B. HHV6 encephalitis was diagnosed, as had HHV6 myelitis based on symptoms that included lancinating pain/pruritus in the lower limbs and dysuria/dyschezia. Concurrently, he showed sinus tachycardia. Even after clearance of the HHV6 genome from the plasma and CSF was achieved by treatment with foscarnet, sinus tachycardia persisted for another 100 days. We suspected prolonged sinus tachycardia due to caused by HHV6 encephalomyelitis.

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This report describes a 59-year-old woman who presented with progressive encephalomyelitis with rigidity and myoclonus (PERM)-like symptoms and severe

, including orthostatic hypotension, sinus bradycardia, dysuria, and prolonged constipation. Her neurological symptoms improved after immunotherapy, but the persisted. Anti-ganglionic acetylcholine receptor (gAChR) α3 subunit antibodies, which are frequently identified in patients with autoimmune autonomic ganglionopathy, were detected in the pre-treatment serum. The central distribution of the nicotinic acetylcholine receptors, a target of anti-gAChR antibodies, and immunotherapeutic efficacy observed in this case indicate that anti-gAChR α3 subunit antibodies are associated with the PERM-like features accompanied by autonomic manifestations.

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Patients of congenital diseases have abnormalities in their chromosomes and/or genes. Therefore, it has been considered that drug treatments can serve to do little for these patients more than to patch over each symptom temporarily when it arises. Although we cannot normalize their chromosomes and genes with chemical drugs, we may be able to manipulate the amounts and patterns of mRNAs transcribed from patients DNAs with small chemicals. Based on this simple idea, we have looked for chemical compounds which can be applicable for human diseases targeting kinase families of CDKs, CLKs and DYRKs which are involved in the regulation of gene expression, and eventually succeeded to find FIT039 (1), TG003 (2), and ALGERNON (3) as potential therapeutic drugs to cure diseases such as viral infections, Duchenne muscular dystrophy, and Down syndrome, respectively. In addition, we established splicing reporter assay with dual color (SPREADD) using a segment of pathogenic genes, and found a splicing modulator, RECTAS (4), which can rectify the aberrant IKBKAP splicing in patient iPS cells of Familial

. EDA-ID (anhidrotic ectodermal dysplasia with immunodeficiency), cardiac Fabry diseas, and type V cystic fibrosis are often induced by pseudo-exon recognition, and our chemical therapeutics can normalize the splicing patterns (5).

(1) Yamamoto et al. (2014) J Clin Invest. 124(8):3479–3488.

(2) Nishida A et al. (2011) Nature Communications 2, 308.

(3) Nakano-Kobayashi A et al. (2017) Proc Natl Acad Sci USA. 114(38):10268-10273.

(4) Yoshida M et al. (2015) Proc Natl Acad Sci USA. 112(9):2764-2769.

(5) Boisson B et al. (2019) J Clin Invest. 129(2):583-597.

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