出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/04/14 17:11:28」(JST)
| スティッフパーソン症候群 | |
|---|---|
| 分類及び外部参照情報 | |
| ICD-10 | G25.8 |
| ICD-9 | 333.91 |
| OMIM | 184850 |
| DiseasesDB | 12428 |
| eMedicine | neuro/353 |
| MeSH | D016750 |
| プロジェクト:病気／Portal:医学と医療 | |
| テンプレートを表示 | |
スティッフパーソン症候群（ - しょうこうぐん、Stiff person syndrome; SPS）とは、非常に稀な進行性の神経性疾患で、自己免疫疾患の一種。 筋肉を弛緩させるための神経系統がうまく働かず、痛みを伴う体の硬直や筋けいれんを起こし、音や接触などの体感によって症状が誘発、悪化する（別名：スティッフマン症候群（Stiff man syndrome; SMS）、スティフ・マン症候群、全身強直症候群、全身硬直症候群、stiff-person症候群、stiff-man症候群、Moersch-Woltman syndrome）。
体を動かす際に本来は交互に働く主動筋と拮抗筋が、力を緩めることができず同時に収縮したままとなり、筋肉の硬直やけいれん、ミオクローヌスを引き起こす。また、感覚・刺激への反応が敏感になり、大きな音や体の接触、状況の急な変化などによって筋肉の症状が誘発、悪化する。これらの症状は中枢神経における抑制性神経伝達（GABA作動性、グリシン作動性）の低下により生じる。これらの低下は、グルタミン酸デカルボキシラーゼ (GAD) やアンフィフィシン、ゲフィリン、グリシン受容体など、GABAやグリシンに関連する体内物質が自己免疫により失われたために起こると考えられている。
1956年、メイヨークリニックのMoerschとWoltmanによりはじめて報告された[1]。
初期に報告されたSPS（古典的SPS）は体幹の硬直を主症状とする。一方、別の臨床症状を特徴とするSPSの亜型がいくつか報告され、その後、これらをSPSプラス症候群とする考えが提起された[2]。この中には、筋硬直を伴う進行性脳脊髄炎 (PER) 、筋反射性スティッフマン症候群、四肢・脚部を主部位とするSLSの3タイプが上げられている。
数年単位で慢性的に進行する。主に体幹（胸、腹部、腰、背中）を主部位として、筋硬直（強直）やけいれんが発生する。しだいに症状は近位四肢（ふとももや二の腕）にも現れ、さらには全身へと症状が進行する。長期のSPSでは、PERMの症状（突然死、脳幹障害）が現れることもある。
(Progressive encephalomyelitis with rigidity; PER) 全身に症状が現れる。数週間から数か月で急激に悪化し、突然死を起こす場合もある。脳幹障害（眼球運動障害、難聴、構音・嚥下障害など）、長経路徴候が顕著に表れ、典型的なSPSと区別される。しかし、長期のSPSはPERM様の症状が出現することもある。
別名：筋硬直とミオクローヌスを伴う進行性脳脊髄炎 (Progressive encephalomyelitis with rigidity and myoclonus; PERM) 。
(jerking stiff-man syndrome) ミオクローヌス反射 (myoclonic jerks) のあるスティッフパーソン症候群。この反射は脳幹症状と考えられるが、PERと異なり、長経路障害は見られない。この病気については、筋硬直を伴う進行性脳脊髄炎と同じ病気とする文献もある一方[3]、ミオクローヌス反射を古典的SPSの症状の一つとする考え方[4]のように、SPSの亜型として扱わない文献もある。
別名：筋反射性SMS (jerking SMS) 、ミオクローヌス関連SPS (SPS associated with myoclonus) 。
障害の発生部位が、一部の四肢（腕、脚）に限定される（限局性SPS）。全身に進行することは少ないとされたが、現在は、典型的SPSに進行する前段階とも言われている。ミオクローヌス反射は見られない。
別名：stiff-limb症候群 (stiff-limb syndrome; SLS) 、stiff-leg症候群 (stiff-leg syndrome) 。
主な合併症として、自己免疫疾患、傍腫瘍症候群がある（#原因 - #腫瘍随伴性も参照）。
SPSでは、さまざまな自己免疫疾患、自己抗体が現れる。抗GAD抗体陽性のSPSで多いのが1型糖尿病で、最大35%という報告もある[5]。甲状腺疾患（橋本病、バセドウ病）、悪性貧血、白斑の併発例も多いとされる[4]。その他、重症筋無力症[6]、多発性硬化症[7]などの併発例がある。
SPSでは、運動失調（10%）、てんかん（5-10%）、眼球運動障害、単一恐怖・不安症などの神経性症状を併発することが多い[5]。
この病気は自己免疫疾患と考えられており、数種類の自己抗体が原因物質とされている。しかし、抗体が検出されない（陰性の）症例もある。特に重要とされるのはグルタミン酸デカルボキシラーゼに対する自己抗体・抗GAD抗体、抗アンフィフィシン抗体である。
SPSの症状に関連すると考えられる抗体は、抗GAD抗体、抗アンフィフィシン抗体、抗ゲフィリン抗体、抗GABARAP抗体、抗GLRA1抗体がある。抗GAD抗体は患者の60%で見つかるとされるが[8]、85%とする文献もある[5]。抗アンフィフィシン抗体は患者の数%で発見される[9]。抗GABARAP抗体はSPSの新たなマーカーとされ[10]、患者の65%で検出されるとも言われる[5]。抗ゲフィリン抗体は腫瘍随伴性SPSの1例[11]、抗GLRA1抗体はグリシン受容体α1サブユニットに対する抗体で、最初PERMの1例[12]で確認された後、複数のSPS患者からも検出されるようになった[13]。
腫瘍の発生に伴い、SPSを併発することがある（傍腫瘍症候群、腫瘍随伴症候群）。この場合、抗アンフィフィシン抗体が高い割合で検出される。
抗アンフィフィシン抗体陽性の場合、SPSの症状は首や腕回りに強く現れることが多い。主な症例として、乳がん、胸腺腫、ホジキンリンパ腫、肺がんなどがある[3]。
典型的なSPSは、体幹（軸）周囲の筋肉を主部位とするが、そのほか全身性、特定部位に顕著な症状など多岐にわたる。各部位の筋肉では、硬直 (stiffness) 、固縮 (rigidity) 、けいれん (spasm) 、ミオクローヌス (myoclonus) などが発生する。
発作性の自律神経障害として、一時的な異常高熱、発汗、頻呼吸、心搏急速、瞳孔拡大、高血圧がおきる場合がある。
診断基準として、以下の4点が提起された[14]。
その他、抗GAD65抗体・抗アンフィフィシン抗体などの自己抗体の検出が診断の一助となる。以前は、ジアゼパムによる症状の改善が診断基準の一つであった[15]が、陰性率が高いために、現在では診断基準としては推奨されない[3]。
診断を補助する検査として、表面筋電図による測定と、自己抗体検査がある。
根治できる治療はなく、基本的に対症療法となる。日常的な服用の内服治療と、免疫状態を改善する免疫治療がある。また、傍腫瘍症候群の場合は腫瘍の除去が行われる。
一時的に筋肉を弛緩させる薬として、ジアゼパム（セルシン、エリスパン、ジアパックス、セエルカム）、バクロフェン（ギャバロン、リオレサール）などのGABA作動薬を服用する。これらは通常経口で投与される。特別な治療法として、体内のポンプで持続的にバクロフェンを投与するITB療法（バクロフェン髄注療法）も行われた例がある。
主な治療法として、免疫グロブリン大量療法 (IVIg) 、アフェレーシス療法（血漿交換、免疫吸着）、免疫抑制療法（ステロイド、免疫抑制剤の投与）がある。リツキシマブ（リツキサン）を使用し、改善した症例もあるが、NINDS による第2相臨床試験は、明確な効用が認められなかったとの発表[16]があり、その効果については不透明である。
| この項目は、医学に関連した書きかけの項目です。この項目を加筆・訂正などしてくださる協力者を求めています（プロジェクト:医学／Portal:医学と医療）。 |
Stiff person syndrome (SPS) is a rare neurologic disorder of unclear etiology characterized by progressive rigidity and stiffness. The stiffness primarily affects the truncal muscles and is superimposed by spasms, resulting in postural deformities. Chronic pain, impaired mobility, and lumbar hyperlordosis are common symptoms. The exact mechanism of the condition is unclear.
SPS occurs in about one in a million people and is most commonly found in middle-aged people. A small minority of patients have the paraneoplastic variety of the condition. Variants of the condition, such as stiff-limb syndrome which primarily affects a specific limb, are often seen.
SPS was first described in 1956. Diagnostic criteria were proposed in the 1960s and refined two decades later. In the 1990s and 2000s the roles of antibodies in the condition became more clear. SPS patients generally have GAD antibodies, which seldom occur in the general population. In addition to blood to tests for GAD, Electromyography tests can help confirm the condition's presence.
Benzodiazepine-class drugs are the most common treatment; they are used for symptom relief from stiffness. Other common treatments include Baclofen, Intravenous immunoglobin and rituxan. There has been limited but encouraging success with stem-cell treatment.
Patients with stiff person syndrome (SPS) suffer progressive stiffness in their truncal muscles,[1] which become rigid and stiff because the lumbar and abdominal muscles engage in constant contractions.[2][3] Initially, stiffness occurs in the thoracolumbar paraspinal and abdominal muscles.[4] It later affects the proximal leg and abdominal wall muscles.[1] The stiffness leads to a change in posture,[5] and patients develop a rigid gait.[1] Persistent lumbar hyperlordosis often occurs as it progresses.[3] The muscle stiffness initially fluctuates, sometimes for days or weeks, but eventually begins to consistently impair mobility.[1] As the disease progresses, patients sometimes become unable to walk or bend.[4] Chronic pain is common and worsens over time but sometimes acute pain occurs as well.[6] Stress, cold weather, and infections lead to an increase in symptoms, and sleep decreases them.[1]
SPS patients suffer superimposed spasms and extreme sensitivity to touch and sound.[1] These spasms primarily occur in the proximal limb and axial muscles.[7] There are co-contractions of agonist and antagonist muscles. Spasms usually last for minutes and can recur over hours. Attacks of spasms are unpredictable and are often caused by fast movements, emotional distress, or sudden sounds or touches.[4] In rare cases, facial muscles, hands, feet, and the chest can be affected and unusual eye movements and vertigo occur.[8][9] There are brisk stretch reflexes and clonus occurs in patients.[1] Late in the disease's progression, hypnagogic myoclonus can occur.[10] Tachycardia and hypertension are sometimes also present.[11]
Because of the spasms, patients may become increasingly fearful, require assistance, and lose the ability to work, leading to depression, anxiety, and phobias,[1] including agoraphobia.[12] Most patients are psychologically normal and respond reasonably to their situations.[13]
Paraneoplastic SPS tends to affect the neck and arms more than other variations.[14] It progresses very quickly, is more painful, and is more likely to include distal pain than classic SPS.[15] Patients with paraneoplastic SPS generally lack other autoimmune issues[16] but may have other paraneoplastic conditions.[15]
Stiff-limb syndrome is a variant of SPS.[6] This syndrome develops into full SPS about 25 percent of the time. Stiffness and spasms are usually limited to the legs and hyperlordoisis generally does not occur.[17] The stiffness begins in one limb and remains most prominent there. Sphincter and brainstem issues often occur with stiff-limb syndrome.[14] Progressive encephalomyelitis with rigidity, another variant of the condition,[6] includes symptoms of SPS with brainstem issues and autonomic disturbances.[14] It involves polio-encephalomyelitis in the spine and brainstem. There is cereballar and brainstem involvement. In some cases, the limbic system is affected, as well. Most patients have upper motoneuron issues and autonomic disturbances.[18] Jerking man syndrome or jerking SPS is another subtype of the condition.[12][17] It begins like classical SPS[17] and progresses for several years, up to 14 in some cases. It is then distinguished by the development of myoclonus as well as seizures and ataxia in some cases.[18]
Patients with SPS generally have high amounts of high glutamic acid decarboxylase antibody titers.[19] About 80 percent of SPS patients have GAD antibodies, compared with about one percent of the general population.[20] The overwhelming majority of people who have GAD antibodies do not contract SPS, indicating that systematic synthesis of the antibody is not the sole cause of SPS.[21] GAD, a presynaptic autoantigen, is generally thought to play a key role in the condition, but exact details of the way that autoantibodies affect SPS patients are not known.[22] Most SPS patients with high-titer GAD antibodies also have antibodies that inhibit GABA-receptor-associated protein (GABARAP).[1] Amphiphysin and gephyrin are also sometimes found in SPS patients.[22] The antibodies appear to interact with antigens in the brain neurons and the spinal cord synapses, causing a functional blockade with gamma-aminobutyric acid.[1] This leads to GABA impairment, which probably causes the stiffness and spasms that characterizes SPS.[19] There are low GABA levels in the motor cortexes of SPS patients.[1]
It is not known why GAD autoimmunity occurs in SPS patients,[23] and whether SPS qualifies as a neuro-autoimmune disorder has been questioned.[24] It is also unknown whether these antibodies are pathogenic.[23] The amount of GAD antibody titers found in SPS patients does not correlate with disease severity,[19] indicating that titre levels do not need to be monitored.[2] It has not been proven that GAD antibodies are sole cause of SPS, and the possibility exists that they are a marker or an epiphenomenon of the condition's cause.[25]
In SPS patients, motor unit neurons fire involuntarily in a way that resembles a normal contraction. Motor unit potentials fire while the patient is at rest, particularly in the stiff muscles.[1] The excessive firing of motor neurons may be caused by malfunctions in spinal and supra-segmental inhibitory networks that utilize GABA.[1] Involuntary actions show up as voluntary on EMG scans;[10] even when the patient tries to relax, there are agonist and antagonist contractions.[20]
In a minority of patients with SPS, breast, ovarian, or lung cancer manifests paraneoplasticly as proximal muscle stiffness. These cancers are associated with the synaptic proteins amphiphysin and gephyrin. Paraneoplastic SPS with amphiphysin antibodies and breast adenocarcinoma tend to occur together. These patients tend not to have GAD antibodies.[1] Passive transfer of the disease by plasma injection has been shown in paraneoplastic SPS but not classical SPS.[25]
There is evidence of genetic risk of SPS. The HLA class II locus makes patients susceptible to the condition. Most SPS patients have the DQB1* 0201 allele.[1] This allele is also associated with type 1 diabetes.[26]
SPS is diagnosed by evaluating clinical findings and excluding other conditions.[1] There is no specific laboratory test that confirms its presence.[6] Underdiagnosis and misdiagnosis are common.[19]
The presence of antibodies against GAD is the best indication of the condition that can be detected by blood and cerebrospinal fluid (CSF) testing. Anti-GAD65 is found in about 80 percent of SPS patients. Anti-thyroid, anti-intrinsic factor, anti-nuclear, anti-RNP, and anti-gliadin are also often present in blood tests. Electromyography (EMG) demonstrates involuntary motor unit firing in SPS patients.[1] EMG can confirm the diagnosis by noting spasms in distant muscles as a result of subnoxious stimulation of cutaneous or mixed nerves.[10] Responsiveness to diazepam helps confirm that the patient is suffering from SPS, as this decreases stiffness and motor unit potential firing.[1]
The same general criteria are used to diagnose paraneoplastic SPS as the normal form of the condition.[13] Once SPS is diagnosed, poor response to conventional therapies and the presence of cancer indicate that it may be paraneoplastic.[1] CT scans are indicated for SPS patients who respond poorly to therapy to determine if this is the case.[27]
A variety of conditions have similar symptoms to SPS, including myelopathies, dystonias, spinocerebellar degenerations, primary lateral sclerosis, neuromyotonia, and some psychogenic disorders.[1] Tetanus, neuroleptic malignant syndrome, malignant hyperpyrexia, chronic spinal interneuronitis, serotonin syndrome,[28] Multiple sclerosis, Parkinson's disease,[20] and Isaacs syndrome should also be excluded.[28]
Patients' fears and phobias often incorrectly lead doctors to think their symptoms are psychogenic,[5] and they are sometimes suspected of malingering.[9] It takes an average of six years after the onset of symptoms before the disease is diagnosed.[5]
The progression of SPS depends on whether it is a typical or abnormal form of the condition and the presence of comorbidities. Early recognition and neurological treatment can limit its progression. SPS is generally responsive to treatment,[29] but the condition usually progresses and stabilizes periodically.[30] Even with treatment, quality of life generally declines as stiffness precludes many activities.[6] Some patients require mobility aids due to the risk of falls.[9] About 65 percent of SPS patients are unable to function independently.[31] About ten percent of SPS patients require intensive care at some point;[30] sudden death occurs in about the same amount of patients.[29] These deaths are usually caused by metabolic acidosis or an autonomic crisis.[30]
There is no evidence-based criteria for treating SPS, and there have been no large controlled trials of treatments for the condition. The rarity of the disease complicates efforts to establish guidelines.[28]
GABAA agonists,[1] usually diazepam but sometimes other benzodiazepines,[32] are the primary treatment for SPS. Drugs that increase GABA activity alleviate muscle stiffness caused by a lack of GABAergic tone.[1] They increase pathways that are dependent upon GABA and have muscle relaxant and anticonvulsant effects, often providing symptom relief.[32] Because the condition worsens over time, patients generally require increased dosages, leading to more side effects.[1] For this reason, gradual increase in dosage of benzodiazepines is indicated.[32] Baclofen, a GABAB agonist, is generally used when individuals taking high doses of benzodiazepines have high side effects. In some cases it has shown improvements in electrophysiological and muscle stiffness when administered intravenously.[32] Intrathecal baclofen administration may not have long-term benefits though, and there are potential serious side effects.[1]
Treatments that target the autoimmune response are also used.[27] Intravenous immunoglobin is the best second-line treatment for SPS. It often decreases stiffness and improves quality of life and startle reflex. It is generally safe, but there are possible serious side effects and it is expensive. The European Federation of Neurological Sciences suggests it be used when disabled patients do not respond well to diazepam and baclofen.[33] Steroids, rituximab, and plasma exchange have been used to suppress the immune system in SPS patients, but the efficacy of these treatments is unclear.[28] Botulinum toxin has been used to treat SPS, but it does not appear to have long-term benefits and has potential serious side effects.[1] In paraneoplastic cases, tumors must be managed for the condition to be contained.[1] Opiates are sometimes used to treat severe pain, but in some cases they exacerbate symptoms.[33][34]
SPS is estimated to have a prevalence of about one per million. Underdiagnosis and misdiagnosis hinder epidemiological information about the condition[19] and may have led to its prevalence being underestimated.[12] In the United Kingdom, 119 cases were identified between 2000 and 2005.[31] It does not predominantly occur in any racial or ethnic group.[19] The age of onset varies from about 30 to 60,[2] and it most frequently occurs in people in their 40s.[19] Five to ten percent of patients with SPS have the paraneoplastic variant of the condition.[15] In one group of 127 patients, only 11 of them had paraneoplatic symptoms.[35] About 35 percent of SPS patients have type I diabetes.[1]
SPS was first described by Moersch and Woltman in 1956. Their description of the disease was based on 14 cases that they had observed over 32 years. Using electromyography, they noted that motor-unit firing suggested that voluntary muscle contractions were occurring in their patients.[31] Previously, cases of SPS had been dismissed as psychogenic problems.[11] Moersch and Woltman initially called the condition "stiff-man syndrome", but the first female patient was confirmed in 1958[7] and a young boy was confirmed to have it in 1960.[36] Clinical diagnostic criteria were developed by Gordon et al. in 1967. They observed "persistent tonic contraction reflected in constant firing, even at rest" after providing patients with muscle relaxants and examining them with electromyography.[31] In 1989, criteria for an SPS diagnosis were adopted that included episodic axial stiffness, progression of stiffness, lordosis, and triggered spasms.[36] The name of the disease was shifted from "stiff-man syndrome" to the gender-neutral "stiff-person syndrome" in 1991.[36]
In 1988, Solimena et al. discovered that autoantibodies against GAD played a key role in SPS.[31] Two years later, Solimena found the antibodies in 20 out of 33 patients examined.[12] In the late 1980s, it was also demonstrated that the serum of SPS patients would bind to GABAergic neurons.[23] In 2006, the role of GABARAP in SPS was discovered.[22] The first case of paraneoplastic SPS was found in 1975.[35] In 1993, antiamphiphysin was shown to play a role in paraneoplastic SPS,[22] and seven years later antigephyrin was also found to be involved in the condition.[22]
In 1963, it was determined that diazepam helped alleviate symptoms of SPS.[1] Corticosteroids were first used to treat the condition in 1988, and plasma exchange was first applied the following year.[22] The first use of intravenous immunoglobulin to treat the condition came in 1994.[22]
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| リンク元 | 「スティッフパーソン症候群」 |
| 拡張検索 | 「stiff-man syndrome」 |
| 関連記事 | 「man」「Man」「syndrome」 |
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