Ataxic Dysarthria Research Articles

Protein molecular modeling shows residue T599 is critical to wild-type function of POLG and description of a novel variant associated with the SANDO phenotype

Sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO) is a rare phenotype resulting from pathogenic variants of mitochondrial DNA polymerase gamma (POLG). We modeled a novel POLG variant, T599P, that causes the SANDO phenotype and another variant at the same residue, p.T599E, to observe their effect on protein function and confirm the pathogenicity of T599P. Through neoteric molecular modeling techniques, we show that changes at the T599 residue position introduce extra rigidity into the surrounding helix–loop–helix, which places steric pressure on nearby nucleotides. We also provide a clinical description of the T599P variant, which was found in a 42-year-old female proband. The proband presented a 1-year history of progressive gait instability, dysarthria and foot numbness. Her neurologic examination revealed ataxic dysarthria, restricted eye movements, head and palatal tremors, reduced lower limb reflexes, distal multimodal sensory loss and a wide, unsteady ataxic gait. Electromyography studies indicated a sensory neuropathy. Whole-exome sequencing was pursued after tests for infectious, inflammatory and paraneoplastic causes were negative.

The role of rhythm in adaptation to dysrhythmic speech, continued

Rhythm cues have been shown to be important for deciphering speech in adverse listening conditions, even when the rhythm cues are corrupted. In an initial attempt to document the relationship between rhythm perception and processing of a naturally dysrhythmic speech signal, we found that listeners with expertise in rhythm perception were not advantaged with initial intelligibility of ataxic dysarthria but were significantly advantaged with adaptation to the degraded speech signal [Borrie, Lansford, and Barrett, Journal of Speech, Language, and Hearing Research, 60, 561–570 (2017)]. We speculated that listeners with skills in rhythm perception are better able to exploit experience (familiarization) with the degraded speech, learning something useful about corrupted rhythm cues for subsequent processing. This current study investigated whether the relationship between rhythm perception and perceptual adaptation of dysrhythmic speech, observed in our previous study with ataxic dysarthria, holds for other forms of dysrhythmic speech. Here, we replicate our original study with two different forms of dysarthria: the largely irregular and unpredictable speech of hyperkinetic dysarthria secondary to Huntington’s disease, and the relatively regular and predictable speech of hypokinetic dysarthric speech secondary to Parkinson’s disease. Results will bear on models of dysrhythmic speech perception as well as clinical practice.

He Struggled With Walking and Talking … But Why?

He Struggled With Walking and Talking … But Why?

Generalized Adaptation to Dysarthric Speech.

Generalization of perceptual learning has received limited attention in listener adaptation studies with dysarthric speech. This study investigated whether adaptation to a talker with dysarthria could be predicted by the nature of the listener's prior familiarization experience, specifically similarity of perceptual features, and level of intelligibility. Following an intelligibility pretest involving a talker with ataxic dysarthria, 160 listeners were familiarized with 1 of 7 talkers with dysarthria-who differed from the test talker in terms of perceptual similarity (same, similar, dissimilar) and level of intelligibility (low, mid, high)-or a talker with no neurological impairment (control). Listeners then completed an intelligibility posttest on the test talker. All listeners benefited from familiarization with a talker with dysarthria; however, adaptation to the test talker was superior when the familiarization talker had similar perceptual features and reduced when the familiarization talker had low intelligibility. Evidence for both generalization and specificity of learning highlights the differential value of listeners' prior experiences for adaptation to, and improved understanding of, a talker with dysarthria. These findings broaden our theoretical knowledge of adaptation to degraded speech, as well as the clinical application of training paradigms that exploit perceptual processes for therapeutic gain.

Cerebellar induced differential polyglot aphasia: A neurolinguistic and fMRI study

Research has shown that linguistic functions in the bilingual brain are subserved by similar neural circuits as in monolinguals, but with extra-activity associated with cognitive and attentional control. Although a role for the right cerebellum in multilingual language processing has recently been acknowledged, a potential role of the left cerebellum remains largely unexplored.This paper reports the clinical and fMRI findings in a strongly right-handed (late) multilingual patient who developed differential polyglot aphasia, ataxic dysarthria and a selective decrease in executive function due to an ischemic stroke in the left cerebellum. fMRI revealed that lexical-semantic retrieval in the unaffected L1 was predominantly associated with activations in the left cortical areas (left prefrontal area and left postcentral gyrus), while naming in two affected non-native languages recruited a significantly larger bilateral functional network, including the cerebellum. It is hypothesized that the left cerebellar insult resulted in decreased right prefrontal hemisphere functioning due to a loss of cerebellar impulses through the cerebello-cerebral pathways.

P.70 - Mitochondrial disorders in adults: clinical and genetic correlations in ten patients with nuclear DNA mutations

Mitochondrial diseases are multisystem heterogeneous disorders caused by dysfunction of the mitochondrial respiratory chain. They can be related to mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). The diagnosis is essential for both genetic counseling as well as further treatment. Among 30 patients with multiple mtDNA deletions, nDNA mutations were confirmed in 8 patients. Additionally, 2 relatives of the already diagnosed patients were included in the study. Patients were assessed clinically, electrophysiologically and morphologically. The POLG and C10orf2 genes coding sequences analyses were performed. Different clinical syndromes were identified in examined patients: progressive external ophthalmoplegia (PEO) in 5, progressive external ophthalmoplegia plus proximal myopathy (PEO+) in 2, sensory ataxic neuropathy, dysarthria and ophthalmoparesis syndrome (SANDO) in 2 and myoclonic epilepsy in one. Electromyography studies presented myopathic pattern in 2 patients (with PEO and PEO+), in other it was normal. Ragged-red fibers were detected in 6 biopsies. Fibers devoid of cytochrome c oxidase activity were present in 3 of 6 investigated cases. Genetic analysis of POLG gene revealed following mutations in PEO: p.[Arg309Leu];[Gln968Glu], p.[Ala518Thr];[=] and p.[Trp748Ser];[Ser998Pro]. In PEO+ mutations: p.[Thr251Ile; Pro587Leu];[Thr251Ile;Pro587Leu] and p.[Thr251Ile;Pro587Leu];[Lys1191Asn] were present. In patients with SANDO syndrome the mutation p.[Arg290Cys];[Arg309Cys] was confirmed. And in patient with myoclonic epilepsy the mutation p.[Trp748Ser];[Trp748Ser] was detected. Additionally the analysis of the C10orf2 gene proved the mutation p.[Arg374Gln];[=] in two patients with PEO. Identification of nuclear genes mutations in adults is important for the evaluation of clinical spectrum and natural history of mitochondrial disorders.

Apraxia of speech and cerebellar mutism syndrome: a case report

BackgroundCerebellar mutism syndrome (CMS) or posterior fossa syndrome (PFS) consists of a constellation of neuropsychiatric, neuropsychological and neurogenic speech and language deficits. It is most commonly observed in children after posterior fossa tumor surgery. The most prominent feature of CMS is mutism, which generally starts after a few days after the operation, has a limited duration and is typically followed by motor speech deficits. However, the core speech disorder subserving CMS is still unclear.Case presentationThis study investigates the speech and language symptoms following posterior fossa medulloblastoma surgery in a 12-year-old right-handed boy. An extensive battery of formal speech (DIAS = Diagnostic Instrument Apraxia of Speech) and language tests were administered during a follow-up of 6 weeks after surgery. Although the neurological and neuropsychological (affective, cognitive) symptoms of this patient are consistent with Schmahmann’s syndrome, the speech and language symptoms were markedly different from what is typically described in the literature. In-depth analyses of speech production revealed features consistent with a diagnosis of apraxia of speech (AoS) while ataxic dysarthria was completely absent. In addition, language assessments showed genuine aphasic deficits as reflected by distorted language production and perception, wordfinding difficulties, grammatical disturbances and verbal fluency deficits.ConclusionTo the best of our knowledge this case might be the first example that clearly demonstrates that a higher level motor planning disorder (apraxia) may be the origin of disrupted speech in CMS. In addition, identification of non-motor linguistic disturbances during follow-up add to the view that the cerebellum not only plays a crucial role in the planning and execution of speech but also in linguistic processing. Whether the cerebellum has a direct or indirect role in motor speech planning needs to be further investigated.

Speech Signal Analysis and Pattern Recognition in Diagnosis of Dysarthria.

Background:Dysarthria refers to a group of disorders resulting from disturbances in muscular control over the speech mechanism due to damage of central or peripheral nervous system. There is wide subjective variability in assessment of dysarthria between different clinicians. In our study, we tried to identify a pattern among types of dysarthria by acoustic analysis and to prevent intersubject variability.Objectives:(1) Pattern recognition among types of dysarthria with software tool and to compare with normal subjects. (2) To assess the severity of dysarthria with software tool.Materials and Methods:Speech of seventy subjects were recorded, both normal subjects and the dysarthric patients who attended the outpatient department/admitted in AIMS. Speech waveforms were analyzed using Praat and MATHLAB toolkit. The pitch contour, formant variation, and speech duration of the extracted graphs were analyzed.Results:Study population included 25 normal subjects and 45 dysarthric patients. Dysarthric subjects included 24 patients with extrapyramidal dysarthria, 14 cases of spastic dysarthria, and 7 cases of ataxic dysarthria. Analysis of pitch of the study population showed a specific pattern in each type. F0 jitter was found in spastic dysarthria, pitch break with ataxic dysarthria, and pitch monotonicity with extrapyramidal dysarthria. By pattern recognition, we identified 19 cases in which one or more recognized patterns coexisted. There was a significant correlation between the severity of dysarthria and formant range.Conclusions:Specific patterns were identified for types of dysarthria so that this software tool will help clinicians to identify the types of dysarthria in a better way and could prevent intersubject variability. We also assessed the severity of dysarthria by formant range. Mixed dysarthria can be more common than clinically expected.

Individual differences in the perception of regional, nonnative, and disordered speech varieties.

Speech perception abilities vary substantially across listeners, particularly in adverse conditions including those stemming from environmental degradation (e.g., noise) or from talker-related challenges (e.g., nonnative or disordered speech). This study examined adult listeners' recognition of words in phrases produced by six talkers representing three speech varieties: a nonnative accent (Spanish-accented English), a regional dialect (Irish English), and a disordered variety (ataxic dysarthria). Semantically anomalous phrases from these talkers were presented in a transcription task and intelligibility scores, percent words correct, were compared across the three speech varieties. Three cognitive-linguistic areas-receptive vocabulary, cognitive flexibility, and inhibitory control of attention-were assessed as possible predictors of individual word recognition performance. Intelligibility scores for the Spanish accent were significantly correlated with scores for the Irish English and ataxic dysarthria. Scores for the Irish English and dysarthric speech, in contrast, were not correlated. Furthermore, receptive vocabulary was the only cognitive-linguistic assessment that significantly predicted intelligibility scores. These results suggest that, rather than a global skill of perceiving speech that deviates from native dialect norms, listeners may possess specific abilities to overcome particular types of acoustic-phonetic deviation. Furthermore, vocabulary size offers performance benefits for intelligibility of speech that deviates from one's typical dialect norms.

初期投与量のLamotrigineでStevens–Johnson症候群を発症し，リチウム中毒によると思われる失調性構音障害を呈した双極性障害の1例(A case of woman with bipolar disorder presented with Stevens–Johnson syndrome induced by an initial dosage of Lamotrigine and ataxic dysarthria possible to be caused by lithium toxicity)

Lamotrigine（LTG）は，てんかんや双極性障害に対し小児から成人まで幅広く投与されている薬剤である。今回我々は，初期投与量のLTG 25mg/dayで皮膚粘膜眼症候群（Stevens–Johnson症候群：SJS）を発症し集中治療の末救命しえたが，リチウム中毒によると思われる失調性構音障害を残した症例を経験した。本例の初期症状は急性咽頭炎様の所見を呈し，口腔粘膜症状や皮疹に乏しく感染症との鑑別を要し，SJSの診断に難渋した。症例報告をするとともに文献的考察を行い，近年報告されているLTGによる重症薬疹の注意喚起をし，リチウム服用者の留意点についてリチウム中毒による神経学的後遺症の観点から述べる。 Recently, patients with epilepsy or bipolar disorder increasingly are prescribed lamotrigine (LTG). A 31–year–old woman presented with Stevens–Johnson syndrome (SJS) because of an initial dosage of LTG 25mg/day and was treated by intensive care. Furthermore, she also suffered from ataxic dysarthria possible to be caused by lithium toxicity. She initially presented with only fever and throat pain, and so it was difficult to differentiate SJS from other infectious diseases. We report and describe this case using a literature study. We call attention to serious adverse drug eruption induced by Lamotrigine and to neurological sequelae due to lithium toxicity. 患 者：31歳女性 主 訴：発熱，咽頭痛 現病歴：双極性障害の既往があり，当院の精神神経科に通院中であった。入院10日前（投薬0日目）に当院の精神神経科にて服用中の炭酸リチウム800mg/day（血中濃度0.93mEq/L）に加えてLamotrigine（LTG）25mg/dayが開始された。入院2日前から38°Cの発熱と頭痛が出現し，入院日（第1病日，投薬10日目）に40°Cの発熱と悪寒があり当院に救急受診され，同日緊急入院となった。 内服薬：炭酸リチウム（200mg）4錠 分2夕後眠前，ラモトリギン（25mg）1錠 分1朝後，酸化マグネシウム（330mg）6錠 分3後，ビフィズス菌製剤 3錠 分3後，エスゾピクロン（2mg）1錠 分1眠前，フルニトラゼパム（1mg）1錠 眠前 アレルギー：和そば，パイナップルで皮疹の出現あり 既往歴：双極性障害 家族歴：特記事項なし 宗教歴：本人・母親がエホバの証人，＊父親・同胞2人（兄，弟）は無宗教 来院時身体所見：意識清明，体温40.0°C，脈拍97/min，血圧155/84mmHg，SpO2 97%（room air），呼吸数24/min，両側の眼球結膜は充血し，顔面は紅潮し両眼瞼浮腫を認めた。咽頭は発赤し，右頸部に圧痛を認めたが，リンパ節は触知できなかった。項部硬直はなく，呼吸音は清，腹部は特記すべき所見なく，発疹は顔面の紅潮以外は認めなかった。神経学的な異常所見も認めなかった。 細菌培養（咽頭，尿，血液2セット）：すべて細菌陰性 胸部X–ray：特記すべき所見なし 血算・生化学分析結果（第1病日）：WBC 6,000/mm3（Neut 90.6%），Hb 12.8g/dL，Ht 38.8%，Plt 8.5万/mm3，T–Bil 0.4mg/dL，AST 71IU/L，ALT 29IU/L，LDH 489IU/L，ALP 185IU/L，γ–GTP 28IU/L，Alb 3.2g/dL，BS 107mg/dL，Amy 124IU/L，BUN 14.6mg/dL，Crea 0.7mg/dL，CK 129IU/L，Na 133mEq/L，K 4.1mEq/L，Cl 104mEq/L，CRP 5.2mg/dL，PT 13.3sec，APTT 35.6sec，Fib 297mg/dL，FDP 72.0µg/mL その他の検査結果： ・薬物血中濃度（第3病日）炭酸リチウム1.43mmol/L（0.6–1.2），ラモトリギン0.91µg/mL ・プロカルシトニン（第4病日）2.05（0.00–0.05ng/mL） ・ウイルス検査 アデノウイルス迅速検査陰性，CMV–IgM（EIA）陰性，CMV–IgG（EIA）陽性，EB VCA–IgM（FA）<10倍，EB VCA–IgG（FA）320倍，EB EBNA 320倍，ムンプスIgM（EIA）陰性，ムンプスIgG（EIA）陽性 ・HHV–6検査 1回目（第8病日）HHV–6 IgM 10倍未満，HHV–6 IgG 40倍，HHV–6 PCR 陰性 2回目（第22病日）HHV–6 IgM 10倍未満，HHV–6 IgG 80倍 ・DLST（ラミクタール）：薬剤誘発性リンパ球刺激試験（drug–induced lymphocyte stimulation test） 1回目（第8病日）陰性（最大SI 1.5<1.8） 2回目（第22病日）陽性（最大SI 10.5≧1.8） 入院後経過（Fig. 1）：急性咽頭炎を考え入院時から抗生剤（CTRX 2g/day）を点滴投与し，内服薬は続行としていた。しかし発熱の改善はなく顔面の浮腫が増悪（Fig. 2），第3病日に収縮期血圧70mmHgのショック状態となり集中治療室に転棟となった。入院時に採取した細菌培養はすべて陰性であった。LTGを含め内服薬はすべて中止したところ，第4病日には精神状態が不安定（LTG服薬への焦燥感）になり精神科医と相談しLTG（25mg）1錠のみ再開した。これが結果的にチャレンジテストとなり，服用後に播種状紅斑が全身に出現し（Fig. 3），38°Cまで軽快しつつあった発熱も40°Cへ再上昇しLTGによる薬疹と診断した。鑑別疾患としたCMV，EBV，ムンプスウイルスはいずれも既感染パターンであった。第5病日よりprednisolone（PSL）30mg/dayを開始したが，口唇及び口腔内のびらん・出血が出現し始め（Fig. 4），SJSの診断基準 1（Fig. 5）のうち主要所見3項目を満たしSJSと診断し，第6病日よりステロイドパルス（methylprednisolone 1g/day × 3日間）を開始した。しかし同日より意識状態が悪化してJCS III–100まで低下し，第7病日より全身痙攣を来した。頭部CTでは異常はなく，腰椎穿刺はDICのため実施できず原因は特定できなかった。重症薬疹の鑑別疾患である薬剤性過敏症症候群（drug– induced hypersensitivity syndrome: DIHS）はHHV–6の再活性化を認めず否定的であった。PSLは第9病日より60mg/dayから5日ごとに漸減し，徐々に意識状態及び全身状態は改善した。第18病日に一般病棟に転棟となったが，失調性の構音障害を残した。第50病日にPSL 7.5mgで退院となり，第90病日にPSLは中止となった。第26病日及び退院3か月後の頭部MRIでは異常はなく，1年経過した現在も外来通院中であるが，構音障害の改善は認めていない。なお第22病日のLTGのDLSTは陽性であった。 Summary of the clinical course. She presented with throat pain and fever on hospitalization (day1), but gradually she was getting into shock. She was treated in the ICU (intensive care unit) between day3 and day18. On day4 she presented with maculopapular eruption of her trunk and extremities soon after re–exposure to LTG 25mg. On day7 she presented with erosions and bleeding of her lips and oral cavity. So we diagnosed SJS due to LTG and treated by steroid pulse (mPSL 1g/day × 3days). After that we started PSL 60mg/day and gradually decreased every 5days. She suffered from generalized seizure during day7–9 and pleural effusions during day5–16, but she was treated by anticonvulsants and NPPV. Then she was gradually getting better and discharged ICU on day18. Y axis means body temperature (BT). CTRX: ceftriaxone, LTG: lamotrigine, PSL: prednisolone, mPSL: methylprednisolone, NPPV: non–invasive positive pressure ventilation Facial edema (day3). She presented with facial edema, especially bilateral eyelids’ edema on day3. Maculopapular eruption of her knee (day4). She presented with maculopapular eruption of her trunk and extremities after re–exposure to LTG 25mg on day4. Erosions and bleeding of her lips (day7). She presented with general edema. Furthermore we found erosions and bleeding of her lips and oral mucosa. But on this photograph we slightly can see erosions and bleeding of her lips. According to this symptoms, we clinically diagnosed SJS due to LTG on day7. Diagnostic criteria for Stevens–Johnson syndrome. 1 本例では最終的に強い口腔粘膜のびらん・出血を呈し診断基準（Fig. 5）よりSJSと診断したが，皮膚病変は病像の最終段階においても全身性の播種状紅斑が見られたのみで，初期は口腔粘膜症状や皮疹に乏しく，感染症との鑑別を要し診断に難渋した。重症薬疹の死亡例では，皮疹よりも発熱が先行するケースがSJS・TENで各々75%・47%と高く 2，皮疹が出ない場合の重症薬疹の診断の難しさを裏付けている。本例では結果的にチャレンジテストとなり臨床診断したが，重症薬疹の補助診断である皮膚の迅速病理診断は本例のように皮疹に乏しい症例では実施できない。またDLSTもLTGでは福田らの「薬疹情報」によるとSJS 7/8（87.5%），中毒性表皮壊死症（toxic epidermal necrolysis: TEN）6/6（100%），DIHS 15/16（93.8%），その他の薬疹タイプでも19/21（90.5%）と陽性率は高い 3ものの，結果に時間を要することが欠点であり早期の診断は難しく，病歴及び臨床症状が診断に最も重要である。LTGによる重症薬疹については，本例加療中の2015年2月4日に厚生労働省より安全性速報（ブルーレター）が通達され，16名の死亡報告 4がなされた。さらに2016年1月20日に3学会合同ステートメント（日本うつ病学会，日本神経精神薬理学会，日本臨床精神神経薬理学会）が発表され，注意喚起がなされている 5。LTGによる重症薬疹の頻度は小児で0.3～0.8%，成人で0.08～0.3%とされる 6が，LTGは投与方法が少し複雑で，用法用量の非遵守例で死亡に至る重症化が顕著とされる。しかし，重症薬疹発症例のうち57.8%は用法用量が守られており，必ずしも回避できるわけではなく 5，本例でも用法遵守はされていたが初期投与量（25mg/day）の服薬8日目で発症している。一般的にSJS・TENの死亡率は各々3%・19%とされ 2，たとえ救命できても後遺症として失明に至る視力障害，眼瞼癒着，ドライアイなどの眼後遺症を残すことが多く 7，その社会的な問題は大きい。LTGは催奇形性において若年女性に使用しやすい抗てんかん薬であり，双極性障害においても，うつ病エピソードの再発予防に効果のある数少ない薬剤であり，使用頻度は今後も増えることが予想され，LTGによる重症薬疹に遭遇する頻度は稀とはいえ減る可能性は低い。本例のように重症薬疹の発症形態が非典型的な場合，皮膚科または眼科を受診せず，一般当直医が対応するケースがありうる。まずは発熱・口腔咽頭の発赤腫脹が初期症状になる重症薬疹症例があることを銘記し，基本的なことだが，薬剤の服用歴について問診し，早期の診断治療を心がけるべきである。 本例ではステロイドパルスが奏効したが，後遺症として構音障害を残した。以前よりリチウム中毒による遅発性の小脳失調症状は報告 8があり，症状出現後数か月後から1年後に画像上小脳萎縮を呈する報告 9もある。1987年にAdityanjee 10は，「the Syndrome of Irreversible Lithium–Effectuated Neurotoxicity」の頭文字をとってSILENTと提唱しており，神経学的異常所見が以前になくリチウム服薬中止後2か月以上経過をしても改善しない神経学的後遺症を残すものとされている 11, 12。症状は小脳失調症状が最も多く，他にも錐体外路症状，認知機能障害，脳幹機能障害があり，非典型的なものに視神経炎，垂直性眼振，myopathy（ミオパチー）などがある 8, 12。本例でも失調性構音障害の特徴とされる断綴性言語を確認したが，他の神経学的所見は異常なく，画像上も変化を確認できなかった。しかし，他の薬剤等では失調性構音障害の原因は説明できず，リチウム中毒による後遺症を考えた。詳細な病態は分かっていないが，SILENTは病理学的に多発する脱髄所見が見られ，中枢神経を中心に末梢神経でも確認されており，小脳に多く，Purkinje細胞の減少，小脳の萎縮，小脳皮質のgliosis等が見られるとされる 12, 13, 14。このようなリチウム中毒による神経学的後遺症は急性の大量服用だけでなく，長期服用者で血中濃度が正常範囲内でも1.25%で起こるとされ 15，危険因子は肺炎などの感染症の併発，脱水，急性腎不全などのリチウムの血中濃度が上昇する病態，他の薬剤（抗精神病薬，三環系抗うつ薬，抗てんかん薬，一部のNSAIDs，ACE阻害薬など）との併用とされている 16, 17。機序として発熱により血液脳関門（blood–brain barrier）の透過性が亢進し，リチウムの取り込みが増加することが考えられていることに加え 8, 18，急性期の大量服用と異なりリチウムを以前から服用している場合は常用による細胞内への蓄積があり，急性中毒と異なりすでにリチウムに暴露されており，中毒症状として重症になる傾向が報告 19されている。本例では第3病日のリチウム血中濃度は1.43mmol/Lと軽度の上昇であったが，SJS発症に伴い細胞内のリチウム濃度が上昇した可能性がある。リチウム中毒の治療の根幹は既知のごとく血液透析であるが，血中濃度と細胞内のリチウム濃度が必ずしも相関しないことは以前から報告 17, 18があり，透析後リチウム血中濃度の再上昇予防のためCHDF（continuous hemodiafiltration：持続的血液濾過透析）併用もされている。血液透析の適応は，①4mmol/L以上，服薬量として40mg/kg以上の服薬，②2.5mmol/L以上で重篤な症状（痙攣や意識障害など）がある，または腎機能障害や心不全等の合併がある場合，③2.5mmol/L以下でも末期腎不全や入院後にリチウム濃度が上昇する場合，また治療30時間後でも1mmol/L以下にならないときとされる 17。本例の場合は③の適応が考えうるが，本例ではSJSへの対応をしている最中で状態も悪く，リチウム中毒について失念しておりフォローできなかった。本例のようにリチウム服用者が感染症や脱水，急性腎不全など血中濃度が上昇するような病態を併発した際には，原疾患が重篤であればリチウム中毒の対応に注意が向かない可能性がある。また急性中毒だけでなくSILENTも念頭において治療にあたる必要があり，とくに血液透析については従来の急性中毒の適応のみでは不十分であり 20，リチウム長期服用者では閾値を下げて考えたほうがよい。 LTGによるSJSの症例を経験した。重症薬疹であっても，急性上気道炎様の症状で一般医が診療する可能性もあるため注意が必要である。また本例では，リチウム中毒によるであろう失調性構音障害を残した。リチウムの長期服用者では，その血中濃度と中毒症状の発現が相関しないことがある。リチウム長期服用者の中毒に対する血液透析の適応については，十分なコンセンサスが得られていないものの，神経学的な後遺症の観点からは血液透析を考慮する必要がある。 本報告の一部は第43回日本救急医学会総会（2015年10月22日）で発表した。 利益相反はない。

The wide POLG-related spectrum: An integrated view

The aims of this study were to describe the spectrum of recessively inherited POLG-related disorders, to report new POLG mutations and to discuss genotype-phenotype correlations in order to propose a strategy for diagnosis. Twenty eight patients diagnosed with two POLG mutations at 12 tertiary European centers of adult neurology were studied. Exhaustive phenotypic data, brain MRI, muscle analysis, mitochondrial DNA and POLG analysis findings were collected. Five distinct phenotypes were observed: Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoparesis (SANDO), autosomal recessive Progressive External Ophthalmoplegia (arPEO), Spino Cerebellar Ataxia with Epilepsy (SCAE), Mitochondrial Neuro Gastro Intestinal Encephalopathy (MNGIE)-like phenotype and Sensory Ataxic Neuropathy with Ophthalmoparesis but without dysarthria which we propose to name SANO. An increasing gradient of functional severity was appreciated from PEO with the best prognosis, to SANO, SANDO and finally SCAE respectively. Four new missense mutations were found. Regarding genotype/phenotype correlations, P587L mutation was associated with SANO rather than with SANDO (p<0.005) and W748S mutation was associated with SANDO or SCAE (with more severe disease progression), rather than with SANO or PEO (p<0.004). Distinguishing between various phenotypes can have important diagnosis and prognosis implications. POLG mutations should be priority searched for in cases of SANDO or SANO. Mitochondrial respiratory chain and mitochondrial DNA studies should be considered in the case of negative POLG analysis or other phenotypes.

Report of progressive myoclonus ataxia (PMA) in two Chinese pedigrees

Objective: To describe the clinical characteristics of patients diagnosed with progressive myoclonus ataxia (PMA) from two Chinese pedigrees.Methods: An analysis of clinical data is presented and inferences drawn. Results: The propositus from pedigree-I (9-year-old female) could not walk stably and had a history of frequent falls. The symptoms aggravated over time until she lost the ability to take care of herself. Her physical and mental development (including cognitive ability) was normal. She had an ataxic gait, ataxic dysarthria, bilateral horizontal nystagmus and visible limb myoclonus. She failed the bilateral finger-to-nose and heel-knee-tibia tests and could not walk in a straight line. Babinski signs were not observed. EEG tracing during sleep showed low-amplitude spikes and spike-and-slow waves in the bilateral frontal and mid-frontal areas. Her magnetic resonance imaging scan was normal. In pedigree-II, the propositus (a 54-year-old male) could not walk stably and had a history of occasional falls for the past 34 years. The symptoms aggravated gradually until he lost the ability to perform routine daily activities. There was no history of convulsions. His physical and mental faculties, as well as the neurological findings were similar to those of the pedigree-I. Both proposituses did not respond well to symptomatic treatment. A novel mutation has been identified in SGCE gene (NM_003919:exon3:c.360delT:p.A120fs) using exome sequencing.Conclusion: PMA patients from the two pedigrees had autosomal dominant mode of inheritance, with variability in the age of onset and disease severity. The cardinal symptoms were myoclonic seizures and ataxia without mental retardation.

Perceptual ratings of subgroups of ataxic dysarthria.

The speech characteristics of ataxic dysarthria are known to be quite diverse. The varied presentation of this dysarthria challenges researchers and clinicians alike, and brings into question whether it is a single entity. While the possibility of subtypes of ataxic dysarthria has been suggested, the nature of these putative groups remains unclear. The purpose of this pilot study was to determine if perceptual speech characteristics would align with a pattern of unusual variability or unusual consistency across speech subsystems and speaking tasks. A framework of speech characteristics was created from the existing literature that clustered speech attributes according to notions of instability (unusual variability) or inflexibility (unusual consistency). These speech features were used to develop a perceptual rating form. Ten experienced speech-language pathologists listened to pre-recorded, exemplary samples of 10 speakers with ataxic dysarthria and rated the perceptual speech features. Results suggested that five speakers fit the pattern of instability, one speaker aligned with inflexibility and four speakers had a mixed presentation. Intra-rater reliability was satisfactory. This study adds to the sparse, yet growing, literature to support the existence of subgroups in ataxic dysarthria. The more frequent occurrence of the instability profile is consistent with primary disruption to the timing function of the cerebellar circuit. Identification of subgroups has important clinical and research implications and further research is warranted.

A Case of Legionella Pneumonia Causing Neurological Symptoms Related to a Reversible Corpus Callosum Lesion

A 51-year-old man presented at the emergency department with a one-day history of fever, altered mental status, slurred speech, worsening gait instability, nausea, vomiting, and diarrhea. The patient did not have a history of alcoholism or drug abuse. On physical examination, crackles were heard over the right lower lobe. Neurological findings revealed ataxic gait, dysarthria and bilateral dysmetria upon finger-nose testing. The results of laboratory tests revealed leukocytosis, renal failure, and hyponatremia. Chest radiography and lung computed tomography (CT) revealed right lower lobe infiltrates with air bronchograms. The result of a urinary Legionella antigen test was positive. The results of brain CT and cerebrospinal fluid (CSF) analyses did not reveal any signs of infection, but brain magnetic resonance imaging (MRI) revealed a corpus callosum lesion upon admission. The patient's symptoms began to resolve after the administration of intravenous levofloxacin. A subsequent brain MRI examination performed 9 days after admission showed the complete resolution of the lesion. He was discharged 11 days after admission without any neurological sequelae. He was finally diagnosed as having clinically mild encephalitis/ encephalopathy with a reversible splenial lesion (MERS).

Clinical and Neuroradiological Spectrum of Metronidazole Induced Encephalopathy: Our Experience and the Review of Literature.

Metronidazole is an antimicrobial agent mainly used in the treatment of several protozoal and anaerobic infections, additionally, is often used in hepatic encephalopathy and Crohn disease. Apart from peripheral neuropathy, metronidazole can also cause symptoms of central nervous system dysfunction like ataxic gait, dysarthria, seizures, and encephalopathy which may result from both short term and chronic use of this drug and is collectively termed as "metronidazole induced encephalopathy"(MIE). Neuroimaging forms the backbone in clinching the diagnosis of this uncommon entity, especially in cases where there is high index of suspicion of intoxication. Although typical sites of involvement include cerebellum, brain stem and corpus callosum, however, lesions of other sites have also been reported. Once diagnosed, resolution of findings on Magnetic Resonance Imaging (MRI) of the Brain along with clinical improvement remains the mainstay of monitoring. Here we review the key clinical features and MRI findings of MIE as reported in medical literature. We also analyze implication of use of this drug in special situations like hepatic encephalopathy and brain abscess and discuss our experience regarding this entity.

Speech changes after coordinative training in patients with cerebellar ataxia: a pilot study.

Although rehabilitative training is a necessary adjunct in the management of gait ataxia, it remains unknown whether the possible beneficial effect of intensive coordinative training may translate to activities of daily living, which are closely connected with postural alignment. The aim of the present study was to examine the effectiveness of a 2-week intensive coordinative motor training on speech production. Speech and motor performances in a cohort of ten individuals with cerebellar degeneration were examined three times; before the introduction of training, directly and 4 weeks after the last training session. Each patient was instructed to perform a speaking task of fast syllable repetition and monologue. Objective acoustic analyses were used to investigate six key aspects of speech production disturbed in ataxic dysarthria including accuracy of consonant articulation, accuracy of vowel articulation, irregular alternating motion rates, prolonged phonemes, slow alternating motion rates and inappropriate segmentation. We found that coordinative training had a mild beneficial effect on speech in cerebellar patients. Immediately after the last training session, slight speech improvements were evident in all ten patients. Furthermore, follow-up assessment performed 4 weeks later revealed that 90 % of the patients showed better speech performance than before initiation of the therapy. The present study supports evidence that the intensive rehabilitative training may positively affect fine-motor movements such as speech in patients with cerebellar ataxia.

Relación entre las pendientes del segundo formante y las alteraciones motoras del habla en la disartria

Transitions represent the vocal tract movement of the articulatory configuration from the consonant to the vowel. The acoustic analysis of the velocity of these transitions in the second-formant is a procedure used in the evaluation and investigation of dysarthric speech, as it provides information on the movements of the tongue in the joint.The aim of this work is to study the values of the speed of the transitions in diphthongs through the second-formant slopes and establish their relationship with the severity of dysarthria.Twelve subjects with ataxic dysarthria and ten neurologically healthy subjects participated. The characteristics of the second-formant transitions were obtained in the diphthongs of the words causa, piojo and tierra, and a study was made of the relationship of the slopes with the values obtained in the scale of intelligibility for speech motor disorders.The results show slopes significantly lower in the dysarthric group in the transitions of the diphthongs of the three words studied. As regards the severity of dysarthria, high correlations were found with the intelligibility scale used.Acoustic analysis of the speed of the second formant transitions has proved a useful tool in the objective assessment of dysarthria. It provides information about the severity of motor speech disorders and gives objective data on the progression of speech therapy.

Spectral Measures of Loudness in Patients with Ataxic Dysarthriag

Dysarthria refers to a group of speech disorders characterized by neuromuscular involvement. This may affect different subsystems of speech like respiration, phonation, articulation and prosody differentially. Ataxic dysarthria is caused due to damage to the cerebellum. Excessive fluctuation in loudness or monoloudness typically characterizes ataxic dysarthria. These characteristics may be different in ataxic dysarthria due to lesions in different cerebellar loci. There is a need to address the spectral measures related to loudness in patients with lesions in different cerebellar loci.Seventeen subjects with ataxic dysarthria due to lesions in different cerebellar loci and matched controls performed an alternating motion rate (AMR) task. The recorded and digitized speech samples were analysed for spectral measures of maximum and minimum intensity. Intensity range was reduced in subjects with left (left superior paravermal, left anteroinferior), superior vermis, right superior paravermal and right anterosuperior lesions compared to normal controls in AMR task. It was comparable to normal controls in subjects with right posterosuperior lesions. Reduced intensity range seems to be because of increase in energy minima and decrease in energy maxima or due to decrease in energy maxima only.

Steroid-responsive intracranial germinoma presenting as Holmes’ tremor: Importance of a tissue diagnosis

Holmes’ tremor (rubral or midbrain outflow tremor) refers to a hyperkinetic movement disorder characterized by mild resting and more severe postural and action tremor often with associated brainstem symptoms, dystonia and cerebellar deficits. This syndrome should prompt lesional evaluation with neuroimaging focused on the dorsal midbrain, cerebellar outflow tracts, and thalamus. Herein we report a 26-year-old previously healthy male who presented with 4years of progressive horizontal diplopia, right Parinaud syndrome, and appendicular ataxia. Neuroimaging revealed a right dorsal midbrain enhancing lesion which completely resolved with intravenous methylprednisolone prompting a diagnosis of neuroinflammatory syndrome. Subsequent clinical and radiographic evaluations, however, revealed steadily progressive left dorsal midbrain syndrome with an expansile enhancing lesion which culminated 4years from symptom onset with a right upper extremity low-frequency rest, postural and action tremor, ataxic dysarthria, and mild right dystonia with dysdiadochokinesia. Uncomplicated brainstem biopsy confirmed intracranial germinoma and the patient underwent definitive radiation therapy with dramatic radiographic response and partial clinical improvement. This case, which to our knowledge is only the second report of intracranial germinoma presenting as Holmes’ tremor, highlights the critical importance of definitive tissue diagnosis in the evaluation of lesional brainstem pathology presenting as Holmes’ tremor. Steroid responsiveness can be seen in non-inflammatory pathology including intracranial germinoma. Prompt evaluation and appropriate treatment are important as Holmes’ tremor responds poorly to symptomatic therapies and response to radiation therapy is favorable for germinomas.

Metronidazole‐induced encephalopathy and myoclonus: Case report and a review of the literature

AbstractWe describe a 36‐year‐old man with metronidazole‐induced encephalopathy in the course of alcoholic liver cirrhosis who developed periodic myoclonus on the head and fixed eye position with ocular myoclonus in the vertical direction. Involuntary movements are rare in patients with metronidazole‐induced encephalopathy, because neurological manifestations of metronidazole‐induced encephalopathy usually include ataxic gait, dysarthria and confusion. Involuntary movements including myoclonus should be considered as the clinical manifestation of metronidazole‐induced encephalopathy. In addition, we review the literature of metronidazole‐induced encephalopathy patients who developed myoclonus with regard to the clinical characteristics.