Multiple sclerosis

Japanese: 多発性硬化症

Concept Multiple sclerosis is the most common demyelinating disease of the central nervous system. It primarily affects young adults, and multifocal demyelinating lesions appear over time in central nervous tissues such as the brain, spinal cord, and optic nerves, causing a variety of neurological symptoms that go through repeated remissions and exacerbations. In other words, it is a disease characterized by multiplicity in time and space.
Diagnosing multiple sclerosis is not easy, as the neurological symptoms and their progression vary from patient to patient. The diagnosis is based on the "temporal and spatial multiplicity of central nervous system symptoms," and currently, brain MRI findings play an important role in the diagnostic criteria. The cause of multiple sclerosis is unknown, but in terms of treatment, immunomodulatory drugs such as interferon-β and fingolimod are being used to improve the condition and suppress recurrences.
Epidemiology Multiple sclerosis is one of the most common neurological disorders affecting young adults in the West, but is relatively rare in Japan and other Asian countries. Its prevalence is high (50-100 cases per 100,000 people) in the northern United States, southern Canada, the Nordic Islands, and southern Australia, but low (5 cases per 100,000 people) in Asia and Africa. The higher the latitude, the higher the incidence of multiple sclerosis. In Japan, according to an epidemiological survey by the Ministry of Health, Labor, and Welfare, the estimated number of multiple sclerosis patients is over 12,000, and the prevalence of multiple sclerosis is thought to be about 5-10 cases per 100,000 people. Multiple sclerosis is most common in young adults, with the peak age of onset being in the late 20s to early 30s, and approximately 80% of all cases occurring between the ages of 15 and 50. The male-to-female ratio is 1:1.3-3.2, with more women than men. There are various reports that the incidence of multiple sclerosis within families varies worldwide, ranging from 0% to 10%, but in Japan it is extremely low at less than 1%.
EtiologyAlthough it has been about 140 years since the disease concept of multiple sclerosis was proposed, its cause remains unknown. Currently, the most likely theories of etiology are the involvement of disease susceptibility genes, immune abnormalities such as autoimmunity, and infectious factors such as viruses. In other words, it is thought that "patients with a certain susceptibility to multiple sclerosis may become infected with a virus or other pathogen, which triggers an abnormal immune response that leads to demyelination."
1) Involvement of disease susceptibility factors:
It is believed that some genetic factors are involved in the onset of multiple sclerosis. In terms of racial differences, the prevalence of multiple sclerosis in Asian people, including the Japanese, is extremely low compared to Caucasians in Europe and the United States. Furthermore, while the prevalence of multiple sclerosis is high in Caucasians, the incidence of multiple sclerosis is not necessarily high in indigenous people living in so-called high-risk areas or in ethnic groups who have migrated to these areas from low-risk areas, indicating the importance of genetic factors over environmental factors. Studies of familial multiple sclerosis suggest that the disease susceptibility gene is not a single gene, but that many genes are involved in the onset of multiple sclerosis.
2) Infectious agent (especially virus) hypothesis:
Based on epidemiological studies and the pathology of relapse and remission, the involvement of infectious factors, particularly viral infections, has been suggested. Searches for viral antibodies in the serum and cerebrospinal fluid of multiple sclerosis patients, and viruses from patient specimens (brain, blood, cerebrospinal fluid) have been reported to be related to the etiology of multiple sclerosis. These include measles, mumps, influenza, parainfluenza, herpes simplex virus, EB virus, rubella, coxsackievirus, coronavirus, HTLV-1, and HHV-6, but none of them have been shown to be specifically related to the etiology of multiple sclerosis.
3) Immune abnormality involvement hypothesis:
The most widely held belief about the etiology of multiple sclerosis is that it is an autoimmune disease. However, there is still insufficient evidence regarding the target antigen and immune pathology to say that it is an autoimmune disease. There are several reasons for the belief that immune abnormalities are involved in the etiology and pathology of the disease, as follows:
1. Pathologically, accumulations of lymphocytes and plasma cells are observed around small veins in multiple sclerosis lesions, and immunoglobulin deposition is also seen. 2. Examination of peripheral blood lymphocytes reveals a decrease in suppressor T cell subsets and a bias in the Th1/Th2 balance in favor of Th1. 3. Increased IgG and oligoclonal IgG bands (OB) are observed in cerebrospinal fluid. 4. Experimental allergic encephalomyelitis (EAE), which is produced by sensitization to myelin antigens, shows central nervous system lesions similar to those of multiple sclerosis. 5. Immunosuppressants and immunomodulators, including interferon beta, are effective in treating multiple sclerosis.
Pathology Multiple sclerosis demyelinating lesions are seen in the central nervous tissue; they are grayish-white and translucent, measuring several millimeters to several centimeters to the naked eye, with a clear border from the surrounding normal tissue, and they come in a variety of shapes and extents. New lesions are reddish and soft, while older lesions are grayish-white and hard due to gliosis, and a variety of new and old lesions are scattered throughout. They are more common in the white matter than in the gray matter of the central nervous system. Lesions most commonly occur around the lateral ventricles of the cerebral hemispheres, particularly the calloso-caudate angle (Wetter Winkel), corpus callosum, third ventricle and periaqueductal area, floor of the fourth ventricle, optic nerve, pons, medulla oblongata, near the dentate nucleus of the cerebellum, and spinal cord.
Demyelinating lesions are clearly observed as areas without staining in myelin staining. The lesions are anatomically distributed non-systematically and irregularly, but periventricular and perivenular distributions are relatively common. Within the lesions, the myelin sheath is significantly destroyed, but axons and nerve cells remain relatively intact. However, in severe cases, axons are also destroyed to a large extent. Infiltration of mononuclear cells, mainly lymphocytes, and macrophages is observed around the venules. As the lesions age, infiltration of inflammatory cells and macrophages is no longer observed, and proliferation of astrocytes and glial fibers occurs (gliosis), resulting in the formation of sclerotic lesions (plaques). Demyelination only affects the myelin sheaths of the central nervous system, not the myelin sheaths of the peripheral nervous system. Therefore, the spread of demyelinating lesions in the spinal cord stops at the spinal roots and does not extend beyond them to the periphery (Figure 15-9-3). Regeneration of myelin by oligodendroglia can sometimes be observed in the peri-lesional areas of demyelinated lesions, but this is generally not very active.
Clinical symptoms and courseThere are no specific triggers for the onset of the disease, although overwork, stress, and infection may be cited as triggers in some cases. In most cases there are no prodromal symptoms, and approximately 10% of patients begin with headache, fever, cold-like symptoms, nausea, and vomiting. The onset of the disease at first onset and recurrence is acute in 1/2 to 2/3 of cases, with symptoms reaching their peak within a week. Occasionally, the disease develops gradually, and this tendency is stronger in multiple sclerosis known as primary progressive.
1) Initial neurological symptoms:
It does not begin with a specific neurological symptom, and visual impairment, numbness, motor paralysis, gait disturbance, diplopia, urinary difficulty, sensory hypotension, and speech disorders are relatively common. As described below, multiple sclerosis cannot be diagnosed according to the diagnostic criteria at the time these initial symptoms appear, but it is clinically extremely important to predict whether or not the disease will progress to multiple sclerosis in the future. In patients with initial symptoms originating from the optic nerve (optic neuritis), brain stem, or spinal cord, if asymptomatic multifocal lesions are found on brain MRI or oligoclonal IgG bands are confirmed in the cerebrospinal fluid, there is a high possibility that the disease will progress to multiple sclerosis in the future, and this is called a clinically isolated syndrome (CIS) suggestive of MS.
2) Neurological symptoms observed during the course of the disease:
Any symptom based on central nervous system damage may appear in multiple sclerosis. Table 15-9-2 shows the types and frequency of neurological symptoms seen over the entire course of the disease in a survey of multiple sclerosis patients in South Glamorgan, UK. The main neurological signs related to these neurological symptoms are frequently decreased vision accompanied by color tone abnormalities, increased muscle tone such as spasticity, sensory disturbances (vibration sense, temperature and pain sense), increased tendon reflexes, loss of abdominal wall reflexes, foot pathological reflexes, impaired coordination of the limbs, and sphincter disorders. Thus, a variety of symptoms based on lesions in the cerebrum, brain stem, cerebellum, optic nerves, and spinal cord relapse and remission repeatedly, resulting in a chronic course. Conversely, rare symptoms of multiple sclerosis include aphasia, apraxia, agnosia, generalized convulsions, and hemianopsia. Extrapyramidal symptoms such as rigidity and dystonia are also rare.
Test results: There are no test abnormalities specific to multiple sclerosis, but MRI is the most important test for diagnosing and understanding the disease state. General blood test results are almost normal. Analysis of peripheral blood lymphocytes using cytokine and chemokine receptors shows that the Th1/Th2 balance is Th1 dominant.
1) Cerebrospinal fluid test:
Cerebrospinal fluid tests show a mild increase in lymphocytes (10-30/μL) during the exacerbation phase, which returns to normal as symptoms resolve. Lymphocytes are the predominant cellular fraction. Elevated total protein (55 mg/dL or higher) is seen in approximately one-third of cases, but in the majority of cases it remains below 100 mg/dL. Increased IgG (45 mg/dL or higher) is seen in approximately half of cases. The IgG index ((IgG CSF/IgG SERUM)/(Alb CSF/Alb SERUM)) is often elevated (0.66 or higher), suggesting a pathological condition in which IgG is abnormally produced in the central nervous system.
In relation to this, electrophoresis of cerebrospinal fluid reveals oligoclonal IgG bands (OB) in the gamma globulin region. OB is an IgG band (Figure 15-9-4), and because no corresponding band is found in serum, it has been suggested that it may be involved in the pathogenesis of multiple sclerosis. OB is said to be detected in 80-95% of multiple sclerosis patients in Europe and the United States, but the detection rate in Japanese patients with multiple sclerosis is relatively low. Additionally, myelin basic protein (MBP) often increases in cerebrospinal fluid during the acute phase, but this is not disease-specific.
2) Brain imaging test:
Brain lesions of multiple sclerosis are seen as low-density areas on CT scans, but spinal cord and optic nerve lesions have low detection sensitivity, so MRI scans are necessary. On MRI, demyelinating lesions are depicted as low signal areas on _T1- weighted images and high signal areas on _T2- weighted images (Figure 15-9-5). MRI abnormalities are detected in 70-95% of multiple sclerosis patients, and head MRI often detects lesions in the cerebral white matter, especially around the ventricles. In acute-stage lesions, the blood-brain barrier is disrupted, so gadolinium DTPA (gadolinium) has an enhancement effect, which lasts for 2-3 months. Thus, MRI scans are important for diagnosing multiple sclerosis because they can show the number of lesions, i.e., multiplicity in space, and the difference between the age of each lesion depending on whether or not gadolinium enhances, i.e., multiplicity in time.
In addition, mild electroencephalographic abnormalities are observed in 1/2 to 2/3 of patients with this disease, but these are not characteristic of multiple sclerosis. Evoked potential tests include visual evoked potentials (VEP), somatosensory potentials (SEP), and brainstem auditory evoked potentials (BAEP), and are performed to confirm the presence of multiple sclerosis lesions, as well as their spread, the degree of damage, and to detect occult lesions.
Diagnosis and Differential DiagnosisThe cause of multiple sclerosis is unknown, and since there are no specific test abnormalities for diagnosis, the diagnosis relies mainly on clinical characteristics. Many diagnostic criteria for multiple sclerosis have been proposed to date, but the basic points are spatial multifocality, which means "the presence of lesions in two or more locations in the central nervous system," and temporal multifocality, which means "symptoms based on central nervous system lesions show relapse and remission."
1) Diagnostic criteria for multiple sclerosis by the Ministry of Health, Labor and Welfare Specific Disease Research Group:
As shown in Table 15-9-3, the main points are the aforementioned spatial and temporal multiplicity, as well as the exclusion of other diseases. Although this is a simple diagnostic criterion, in practice brain MRI findings are often used as a reference.
2) International diagnostic criteria for multiple sclerosis:
The most recent and widely used international diagnostic criteria for multiple sclerosis are those of McDonald et al. Although these criteria are based on the traditional approach of diagnostic criteria centered on clinical symptoms, they place emphasis on MRI findings when determining "spatial and temporal multifocality." The defining feature of these criteria is that they clarify the definition of spatial multifocality of lesions on MRI scans, and clarify the temporal element based on the presence or absence of gadolinium enhancement of the lesions.
3) Differential diagnosis of multiple sclerosis:
To accurately diagnose multiple sclerosis, it is important to thoroughly rule out other diseases. There are a wide variety of diseases that must be differentiated, but in addition to the diseases listed in the diagnostic criteria of the Ministry of Health, Labor and Welfare's Specific Disease Research Group (Table 15-9-3), it is necessary to differentiate neuromyelitis optica, viral encephalitis, Wernicke's encephalopathy, etc. These diseases that must be differentiated and the key points for differentiation are shown in Table 15-9-4.
Course and prognosis: Multiple sclerosis generally shows relapses and remission, but the majority of cases overall show a progressive worsening course. The clinical course of multiple sclerosis is broadly classified into relapsing-remitting, secondary progressive, and primary progressive (Figure 15-9-6). Relapses and remission, which are characteristic of multiple sclerosis, are seen in 65-85% of cases, and more than half of these will progress to secondary progressive type, which worsens chronically, in the future. In contrast, approximately 10-15% of cases will follow a chronic progressive course from the time of onset. The frequency of relapses is generally considered to be about 0.5 to 1 per year for the first 5 years after onset. The number of relapses tends to decrease as the disease progresses.
It is somewhat difficult to uniformly discuss the prognosis of multiple sclerosis, but factors that generally worsen the prognosis include 1) older age at onset, 2) progressive symptoms from onset, and 3) frequent relapses. Regarding life expectancy, it has been reported that patients who are left untreated have a 5 to 10 year shorter prognosis.
Treatment
1) Treatment of relapse and acute exacerbation:
At the time of recurrence or acute exacerbation, corticosteroid pulse therapy (methylprednisolone 500-1000 mg per day administered intravenously for three days) is used as early as possible. Corticosteroids are not said to have any effect in suppressing the recurrence of multiple sclerosis, but they are effective in shortening the period of acute exacerbation and reducing sequelae. If symptoms at the time of recurrence are mild, corticosteroids (30-60 mg per day in the case of prednisolone) are administered orally and the dose is gradually tapered. In addition, patients are advised to rest, and therapy is given for respiratory disorders, bladder and rectal disorders, and spasms that may occur depending on the location of the lesion.
2) Drugs to prevent recurrence:
Progress is being made in the development of drugs that suppress relapses and improve long-term prognosis. Injectable interferon (IFN)-β has been shown to reduce the average annual relapse rate of multiple sclerosis by approximately 30%, and to clearly reduce the lesion area on MRI scans. Recently, the oral drug fingolimod has become available, and it is expected that its effectiveness will reduce the annual relapse rate by approximately 50%. In Europe and the United States, in addition to IFN-β, glatiramer acetate and natalizumab have been shown to suppress the number of multiple sclerosis relapses and significantly improve MRI lesions.
3) Therapy for chronic neurological sequelae:
Even patients with chronic multiple sclerosis, particularly those with spinal cord lesions, often suffer from spastic paralysis of the lower limbs, which makes it difficult to stand or walk, causes urination and defecation problems, and causes painful tonic convulsions, making them major obstacles to daily life. The following treatments are available:
a) For severe paraplegia: It is important to prevent bedsores, maintain benign limb positions and passive movement of joints, take measures to treat urinary disorders, and prevent and treat urinary tract infections. b) For spastic paralysis: Administer various antispasticity drugs. c) For painful tonic convulsions: Carbamazepine (100-400 mg per day), phenytoin (100-300 mg per day), etc. are effective.
In addition, rehabilitation will begin once symptoms have stabilized. Some patients may experience weakness, numbness, and decreased vision (Uhthoff phenomenon) in hot environments such as hot showers, exercise, and fevers, so caution is required. [Itoyama Yasuto]
■ References
Compston A, et al eds: McAlpine's Multiple Sclerosis, 4th ed, Churchill Livingstone Elsevier, Philadelphia, 2006.
Yasuto Itoyama: Changing concepts of disease: Opticospinal multiple sclerosis (OSMS) and optic neuritis (NMO). Annual Review, Nerve, 2008: 238-245, 2008.
Misu T, Fujihara K, et al: Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis. Brain, 130: 1224-1234, 2007.
Vinken PJ, Bruyn GW, et al eds: Handbook of Clinical Neurology: Demyelinating Disease 47, Elsevier Science Publishers, Amsterdam, 1985.

Table 15-9-2
Neurological symptoms over the course of multiple sclerosis (from interviews with 301 multiple sclerosis patients in South Glamorgan, UK)

Table 15-9-2

Table 15-9-3
Diagnostic criteria for multiple sclerosis (revised from the Ministry of Health, Labor and Welfare Specific Diseases Research Group on Immune Neurological Disorders, 2003)

Table 15-9-3

Table 15-9-4
Differential diagnosis and key points for multiple sclerosis ">

Table 15-9-4

Figure 15-9-6
Clinical course of multiple sclerosis ">

Figure 15-9-6

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

概念
　多発性硬化症は中枢神経系脱髄疾患のなかで最も多いものである．主として若年成人を侵し，脳，脊髄，視神経などの中枢神経組織に多巣性（multifocal）に脱髄病変（demyelinating lesions）が時間を変えて生じるため，多彩な神経症状が再発と寛解（remission and exacerbation）を繰り返して起こる．すなわち，時間的・空間的多発性（multiplicity in time and space）を特徴とする疾患である．
　神経症状とその経過が患者ごとに多様であるため，多発性硬化症の診断は容易ではない．「中枢神経症候の時間的空間的多発性」を根拠にして診断がなされるが，現状では脳MRIの所見が診断基準に重要な地位を占めている．多発性硬化症の原因は不明であるが，治療に関してはインターフェロン-βやフィンゴリモドなどの免疫調整薬にて，病態の改善や再発の抑制がはかられるようになった．
疫学
　多発性硬化症は欧米では若年成人に発症する神経疾患のなかで最も多いものの1つであるが，日本をはじめアジア諸国では比較的まれな疾患である．その有病率は米国北部やカナダ南部，北欧諸島，オーストラリア南部では人口10万人あたり50～100と高いが，アジアやアフリカでは人口10万人あたり5以下と低い．緯度が高いほど多発性硬化症が高頻度にみられる傾向がある．　日本では，厚生労働省の疫学調査によると多発性硬化症の患者の推計数は12000人をこえており，多発性硬化症の有病率は人口10万人あたり約5～10と考えられる．　多発性硬化症は若年成人に多く発症し，初発年齢は20歳後半から30歳前半にピークを示し，全症例の約80％が15歳から50歳の間に発症する．男女比は1：1.3～3.2と女性に多い．多発性硬化症の家族内発症は世界的には0～10％とさまざまな報告があるが，日本は1％以下ときわめて低い．
病因
　多発性硬化症の疾患概念が示されてから約140年が過ぎたが，その原因はまだ不明である．現在，最も可能性の高い病因論としては，疾患感受性遺伝子の関与，自己免疫などの免疫異常説およびウイルスなどの感染因子の関与説である．すなわち，「ある種の多発性硬化症感受性をもつ患者が，ウイルスなどの感染をきっかけに異常免疫応答が引き起こされて脱髄を生ずる」のではないかと考えられている．
1）疾患感受性因子の関与：
多発性硬化症の発症には何らかの遺伝的因子の関与が推定されている．人種差としては日本人を含めたアジア系の人種における多発性硬化症の有病率は欧米の白人と比較するときわめて低い．また，白人における多発性硬化症の有病率が高い，いわゆるhigh risk areaに在住する先住民やその地域へlow risk areaから移住した民族では多発性硬化症の発症率が必ずしも高くないことは，環境因子よりも遺伝的因子の重要性を示している．家族性多発性硬化症の検討から，疾患感受性遺伝子は単一の遺伝子ではなく，多くの遺伝子が多発性硬化症の発症に関与していると考えられている．
2）感染因子（特にウイルス）説：
疫学的研究や再発と寛解を示す病態から，感染因子，なかでもウイルス感染の関与が考えられてきた．多発性硬化症患者血清や髄液中のウイルス抗体の検索や，患者材料（脳，血液，髄液）からのウイルスが多発性硬化症の病因に関連すると報告されてきた．それらは麻疹，ムンプス，インフルエンザ，パラインフルエンザ，単純ヘルペスウイルス，EBウイルス，風疹，コクサッキーウイルス，コロナウイルス，HTLV-1，HHV-6などであるが，いずれも多発性硬化症の病因に特異的な関連は示されていない．
3）免疫異常の関与説：
病因論として多発性硬化症が自己免疫疾患であるとの考えは最も強いものである．しかし，標的抗原や免疫病態に関してもまだ自己免疫疾患とするには根拠が不十分である．病因や病態に免疫異常がかかわっている考えには以下のようないくつかの根拠がある．
　①病理学的に多発性硬化症病巣では小静脈周囲性にリンパ球や形質細胞の集簇が観察され，かつ免疫グロブリンの沈着もみられる．②末梢血リンパ球の検索では，サプレッサーT細胞系のサブセットが減少したり，Th1/Th2バランスがTh1優位に偏ったりしている．③脳脊髄液にはIgGの増量やオリゴクローナルIgGバンド（OB）が認められる．④ミエリン抗原を感作して作製する実験的アレルギー性脳脊髄炎（EAE）では多発性硬化症類似の中枢神経病変が認められる．⑤インターフェロンβをはじめ多発性硬化症の治療には免疫抑制薬や免疫調整薬が有効性を示す．
病理
　多発性硬化症の脱髄病巣は中枢神経組織にみられ，肉眼的には数mmから数cmの灰白色半透明の色調で周囲の正常部とは境界は明瞭であり，さまざまな形と広がりを示す．新しい病巣は赤色調でやわらかく，古い病巣はグリオーシスのため灰白色調で硬く，新旧さまざまな病巣が散在する．中枢神経の灰白質に比べ白質に多く認められる．病巣の好発部位としては大脳半球側脳室周囲，なかでも脳梁尾状核角部（calloso-caudate angle，Wetter Winkel），脳梁，第3脳室および中脳水道周囲，第4脳室底，視神経，橋，延髄，小脳歯状核付近，脊髄などである．
　脱髄病巣は髄鞘染色で染色性の抜けた部分として明瞭に観察される．病巣は解剖学的に非系統的かつ不規則に分布するが，脳室周囲性や小静脈周囲性の分布が比較的多く観察される．病巣内では髄鞘は著明に破壊されているが，軸索や神経細胞は比較的残存している．しかし，病変が強い場合には軸索もかなり破壊される．小静脈周囲にはリンパ球を主とした単核細胞やマクロファージの浸潤が認められる．病巣が古くなると炎症細胞やマクロファージの浸潤がみられなくなり，アストロサイトやグリア線維の増殖が起こり（グリオーシス），硬化性病巣（斑）を呈する．脱髄は中枢神経系の髄鞘のみが侵され，末梢神経系の髄鞘は侵されない．したがって，脊髄での脱髄病巣の広がりは脊髄根で止まり，それをこえて末梢部へは広がらない（図15-9-3）．脱髄巣におけるoligodendrogliaによる髄鞘の再生は病巣周囲部で観察されることもあるが，一般にあまり活発ではない．
臨床症状・経過
　発症の誘因として特別なものはないが，なかには過労，ストレス，感染などを誘因としてあげる場合もある．前駆症状のない場合がほとんどで，約10％の患者では頭痛，発熱，感冒様症状，悪心・嘔吐などで発症する．初発時や再発時の発症様式は1/2～2/3の症例において急性であり，症状は1週間以内にピークに達する．ときに徐々に発病してくる症例もあり，一次性進行型といわれる多発性硬化症ではその傾向が強い．
1）初発神経症状：
決まった神経症状から初発することはなく，視力障害，しびれ感，運動麻痺，歩行障害，複視，排尿困難，感覚鈍麻，言語障害などが比較的多い．これらの初発症状が起こった時点では後述するように診断基準上は多発性硬化症と診断はできないが，将来的に多発性硬化症に移行するか否かを予測することは臨床上きわめて重要である．視神経（視神経炎），脳幹あるいは脊髄に由来する初発症状の患者において，脳MRIで無症候性の多巣性病変が認められたり髄液中のオリゴクローナルIgGバンドが確認されれば将来的に多発性硬化症に移行する可能性が高くなるので，clinically isolated syndrome（CIS）suggestive of MSとよばれている．
2）経過中にみられる神経症候：
多発性硬化症では中枢神経障害に基づく症候であればどのようなものでも出現し得る．表15-9-2に英国South Glamorganでの多発性硬化症患者の調査による全経過にみられた神経症状の種類と頻度を示す．これらの神経症状に関係する神経徴候のおもなものは，色調異常を伴う視力低下，痙縮などの筋トーヌス亢進，感覚障害（振動覚，温痛覚），腱反射亢進，腹壁反射の消失，足病的反射，四肢協調運動障害，括約筋障害が高頻度に認められる．このように大脳，脳幹，小脳，視神経それに脊髄などの病変に基づいた多彩な症候が再発と寛解を繰り返し，慢性の経過をとる．逆に，多発性硬化症にまれな症候としては失語，失行，失認，全身痙攣発作，半盲がある．また，固縮やジストニーのような錐体外路症候もまれである．
検査成績
　多発性硬化症に特異的な検査異常はないが，診断や病態を把握するうえでMRIが最も重要である．　一般血液検査は，ほぼ正常である．サイトカインやケモカイン受容体を用いた末梢血リンパ球の解析ではTh1/Th2バランスはTh1優位である．
1）髄液検査：
髄液検査では増悪期に軽度のリンパ球が主体の細胞増加（10～30/μL）がみられ，症状の寛解とともに正常化する．細胞の分画としてはリンパ球が主体である．総蛋白質の上昇（55 mg/dL以上）は約1/3の症例にみられるが，大多数は100 mg/dL以下にとどまる．IgG（45 mg/dL以上）の増加を約半分の症例に認める．IgGインデックス（（IgG CSF/IgG SERUM）/（Alb CSF/Alb SERUM））は上昇（0.66以上）していることが多く，中枢神経系内で異常にIgGが産生されている病態を示唆している．
　それと関連して髄液を電気泳動するとガンマグロブリン領域にオリゴクローナルIgGバンド（OB）が認められる．OBはIgGのバンドであり（図15-9-4），血清にはこれに相当するバンドは認められないため，多発性硬化症の病因にかかわっている可能性が指摘されている．このOBは欧米では多発性硬化症患者の80～95％に検出されるといわれているが，日本人多発性硬化症での検出率は比較的低い．また，急性期の髄液中の髄鞘塩基性蛋白（myelin basic protein：MBP）が増加することが多いが疾患特異性はない．
2）脳画像検査：
多発性硬化症の脳病巣はCT検査では低吸収域として認められるが，脊髄や視神経の病巣はCT検査では検出感度が低いのでMRI検査を行う必要がある．MRIでは脱髄病巣はT₁強調画像では低信号域として，またT₂強調画像では高信号域として描出される（図15-9-5）．多発性硬化症患者の70～95％にMRI異常が検出され，頭部MRIでは大脳白質，なかでも脳室周囲に病変が検出されることが多い．急性期の病巣では血液脳関門が破綻しているためgadolinium DTPA（ガドリニウム）によって増強効果が認められ，この効果は2～3カ月続く．このようにMRI検査は病巣の数，すなわち多巣性（multiplicity in space）とガドリニウム増強の有無による各病巣の新旧の違い，すなわち時間的多発性（multiplicity in time）を示すことができるため多発性硬化症の診断には重要な検査になっている．
　そのほか，本症の1/2～2/3に軽度の脳波異常を認めるが多発性硬化症に特徴的なものではない．誘発電位検査には視覚誘発電位（VEP），体性感覚電位（SEP）および脳幹聴覚誘導電位（BAEP）があり，多発性硬化症病巣の存在の確認，またその広がりや障害の程度，潜在病巣の検出などを目的として施行される．
診断・鑑別診断
　多発性硬化症の病因は不明であり，また診断に特異的な検査異常がないため，その診断はおもに臨床的特徴に頼っている．現在まで多くの多発性硬化症診断基準が提唱されてきたが，その基本事項は，「中枢神経系に2カ所以上の病変が存在する」という空間的多発性と，「中枢神経病変に基づく症候が再発と寛解を示す」という時間的多発性の2点である．
1）厚生労働省特定疾患調査研究班による多発性硬化症診断基準：
表15-9-3に示すが，その骨子は前述した空間的多発性と時間的多発性に加えて，ほかの疾患を除外するという3項目である．簡便な診断基準であるが，実際には脳MRI所見を参考にすることが多い．
2）国際的な多発性硬化症診断基準：
国際的な多発性硬化症の診断基準としてはMcDonaldらの診断基準が最新のもので汎用されている．この基準も従来の臨床症候を中心とした診断基準の考え方には変わりはないが，「空間的および時間的多発性」の判断にMRI検査の所見を重視した基準である．MRI検査上での病巣の空間的な多発性の定義を明らかにし，病変のガドリニウム増強効果の有無にて時間的要素を明確化したことが特徴である．
3）多発性硬化症の鑑別診断：
多発性硬化症の診断を正確にするには他疾患を十分に除外することが重要である．鑑別すべき疾患は多岐にわたるが，厚生労働省特定疾患調査研究班の診断基準（表15-9-3）に示されている疾患以外に視神経脊髄炎，ウイルス性脳炎，Wernicke脳症，などを鑑別する必要がある．これらの鑑別すべき疾患と鑑別の要点を表15-9-4に示す．
経過・予後
　一般に多発性硬化症は再発と寛解を示すというものの全体としては進行性に悪化していく経過をとるものが大多数である．多発性硬化症の臨床経過は再発寛解型，二次性進行型，一次性進行型に大別（図15-9-6）される．多発性硬化症の特徴である再発と寛解を示すものは全体の65～85％にみられ，その半数以上は将来的に慢性的に増悪する二次性進行型に移行する．それに反して約10～15％では初発時より慢性進行性の経過をたどる．再発の頻度としては，一般には発症後5年までは年約0.5～1回とされている．再発回数は病期を経るに従って減少する傾向がある．
　多発性硬化症の予後を一律に論じることは多少の困難はあるが，一般に予後を悪くする因子として，①初発年齢が高い，②初発から症状が進行性である，③再発回数が頻回である，などがあげられている．生命予後に関しては未治療の場合は5〜10年短いとの報告がある．
治療
1）再発時および急性増悪期の治療：
再発時や急性増悪期には，なるべく早期に副腎皮質ステロイドのパルス療法（メチルプレドニゾロン1日量500～1000 mg点滴静注を3日間）を用いる．副腎皮質ステロイドは多発性硬化症の再発を抑制する作用はないとされているが，急性増悪期間を短縮させて後遺症を軽減させる効果がある．再発時の症状が軽度の場合は副腎皮質ステロイド（プレドニゾロンの場合1日30～60 mg）を経口投与し漸次減少していく．その他，安静を守らせ，病変の部位によっては起こり得る呼吸障害，膀胱直腸障害，痙攣に対する療法を行う．
2）再発抑制の治療薬：
再発を抑制し長期予後を改善する薬剤の開発が進んでいる．注射薬インターフェロン（IFN）-βは，多発性硬化症の平均年間再発率を約30％減少させ，またMRI検査にて病巣面積を明らかに減少させる効果が示されている．最近，経口薬のフィンゴリモドが利用可能になり，その有効性は年間再発率を約50％減少させるのではないかと期待されている．欧米においてはIFN-β以外にも，グラチラマー酢酸塩およびナタリツマブなどが多発性硬化症の再発回数を抑制し，MRI病巣を著明に改善させる効果があることが明らかにされてきている．
3）慢性期の神経後遺症に対する療法：
慢性期の多発性硬化症患者でも，特に脊髄に病変をもつ患者では，下肢の痙性麻痺のために起立や歩行障害，排尿便障害，また有痛性強直性痙攣で悩むことが多く，日常生活の大きな障害要素となっている．以下の治療法が行われている．
　a）重篤な対麻痺に対して：褥瘡の予防，良性肢位の保持と関節の他動運動，排尿障害の対策，尿路感染の予防と治療が大事である．　b）痙性麻痺に対して：各種の抗痙縮薬を投与する．　c）有痛性強直性痙攣に対して：カルバマゼピン（1日量100～400 mg），フェニトイン（1日量100～300 mg）などが有効である．
　その他，症候が安定したらリハビリテーションを開始する．患者によっては熱いシャワー，運動および発熱などの温度が高くなる環境下で，脱力，しびれおよび視力低下が起こることがある（Uhthoff現象）ので注意が必要である．［糸山泰人］
■文献
Compston A, et al eds: McAlpine’s Multiple Sclerosis, 4th ed, Churchill Livingstone Elsevier, Philadelphia, 2006.
糸山泰人：変わりつつある疾患の概念－視神経脊髄型多発性硬化症（OSMS）と視神経炎（NMO）－．Annual Review神経，2008: 238-245, 2008．
Misu T, Fujihara K, et al: Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis. Brain, 130: 1224-1234, 2007.
Vinken PJ, Bruyn GW, et al eds: Handbook of Clinical Neurology: Demyelinating Disease 47, Elsevier Science Publishers, Amsterdam, 1985.

表15-9-2
多発性硬化症患者の経過中にみられる神経症状（英国South Glamorgan での301 例の多発性硬化症患者のインタビューから）">

表15-9-2

表15-9-3
多発性硬化症の診断基準（厚労省特定疾患免疫性神経疾患調査研究班，2003 を改変）">

表15-9-3

表15-9-4
多発性硬化症の鑑別診断と鑑別の要点">

表15-9-4

図15-9-6
多発性硬化症の臨床経過">

図15-9-6

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