A patient with anti-aquaporin 4 antibody who presented with recurrent hypersomnia, reduced orexin (hypocretin) level, and symmetrical hypothalamic lesions

Recent studies have demonstrated that hypothalamic lesions associated with brain tumor, head trauma, and encephalopathy can cause symptomatic hypersomnia with a reduced orexin (hypocretin) level in the cerebrospinal fluid (CSF). Aquaporin 4 (AQP4), a member of the AQP superfamily, is strongly expressed in the hypothalamus in which orexin (hypocretin)-containing neurons are primarily concentrated. We report the case of a patient with a serum anti-AQP4 antibody who presented with recurrent hypersomnia, symmetrical hypothalamic lesions with long spinal cord lesions on MRI, and a reduced CSF orexin (hypocretin) level, all of which were improved simultaneously by steroid therapy. Further studies should be performed to determine the roles of anti-AQP4 antibody positivity in patients with hypersomnia associated with orexin (hypocretin) deficiency and hypothalamic lesions.     

Abnormal spinal MRI findings in human T-cell lymphotrophic virus type I-associated myelopathy

We describe three cases of HTLV-I-associated myelopathy (HAM) with abnormal spinal magnetic resonance imaging (MRI) findings. The serum and cerebrospinal fluid (CSF) of all 3 patients tested positive for anti-HTLV-I antibody. Swelling of the spinal cord with high-intensity lesions on T2-weighted images was observed. Corticosteroid treatment in the case of two patients gradually improved the symptoms, decreased the protein and IgG levels as well as the cell count, and reduced the abnormal MRI findings. To confirm the assumption that abnormal spinal MRI findings are reflective of active inflammation, we compared the clinical parameters, namely, the protein content, IgG level, and cell count, in the CSF of patients exhibiting abnormal spinal MRI findings with those in the case of patients without spinal MRI lesions. The protein contents, IgG levels, and number of cells in the CSF of patients with MRI lesions were significantly higher than those in the CSF of patients without lesions. These findings support the fact that abnormal MRI findings in the spinal cord may be reflective of active inflammation in the early stages of rapidly progressive HAM.     

临床孤立综合征转归为视神经脊髓炎的相关因素分析

目的探讨临床孤立综合征(CIS)转归为视神经脊髓炎(NMO)的影响因素。方法收集2004-09-2011-09就诊于作者医院神经内科CIS患者109例。回顾性分析所有患者首次发病时头颅和脊髓MRI特点及临床表现。采用酶联免疫吸附法(ELISA)检测血清水通道蛋白4抗体(AQP4-Ab)水平,另备30份健康者血清作为健康对照组,以高于健康对照组血清AQP4-Ab浓度的均值+3倍标准差者为阳性。结果 (1)随访0.5～7年,中位数为3.0年,四分位数间距为4.6年,转归为NMO 46例,转归为多发性硬化(MS)29例,其余仍是CIS,包括24例脊髓炎,10例视神经炎(ON)。(2)转归为NMO组血清AQP4-Ab水平明显高于MS组、脊髓炎组、ON组和健康对照组(P<0.05)。(3)转归为NMO组AQP4-Ab阳性率为63.03%(29/46),高于转归为MS组的13.79%(4/29)、脊髓炎组的29.17%(7/24)、ON组的20.00%(2/10),差异均有统计学意义(P<0.05)。(4)多因素分析结果提示:AQP4-Ab阳性、NMO颅内典型病灶、脊髓损伤>3个节段、扩展残疾状态量表(EDSS)与CIS转归为NMO有关。结论 AQP4-Ab阳性、NMO颅内典型病灶或者脊髓损伤>3个节段、EDSS评分对预测CIS转归为NMO有临床价值。     

Normal levels of cerebrospinal fluid hypocretin-1 and daytime sleepiness during attacks of relapsing-remitting multiple sclerosis and monosymptomatic optic neuritis

There is emerging evidence that multiple sclerosis (MS), the hypothalamic sleep-wake regulating neuropeptide hypocretin-1 (hcrt-1) and the sleep disorder narcolepsy may be connected. Thus, the major pathophysiological component of narcolepsy is lack of hcrt-1. Dysfunction of the hypocretin system has been reported in MS case reports with attacks of hypothalamic lesions, undetectable cerebrospinal fluid (CSF) hcrt-1 and hypersomnia, but not found during remission in small samples. Finally, daytime sleepiness, the major symptom of narcolepsy, is reported in several MS populations, and there are case reports of co-existent narcolepsy and MS. However, it is unknown whether hcrt-1 and daytime sleepiness generally change during MS attacks. We therefore analyzed whether daytime sleepiness (using the Epworth Sleepiness Scale (ESS)) and CSF hcrt-1 levels differed between MS attack and remission, in 48 consecutively referred patients with relapsing-remitting MS (RRMS) or monosymptomatic optic neuritis (MON). Twenty-seven patients were in attack and 21 in remission. ESS was normal both during attacks (5.4 +/- 3.0) and remission (5.8 +/- 2.6), and mean CSF hcrt-1 was normal (456 +/- 41 pg/ml). No statistically significant differences were found between attack and remission. MRI scans revealed no hypothalamic lesions. The results show that the hypocretin system is intact and sleepiness is not typical in RRMS and MON without hypothalamic lesions on MRI.     

Clinical features of Chinese patients with multiple sclerosis with aquaporin-4 antibodies in cerebrospinal fluid but not serum

The objective of this study was to determine the levels of aquaporin-4 (AQP4) antibodies in the cerebrospinal fluid (CSF) of patients meeting the diagnostic criteria for multiple sclerosis (MS) and to describe some of the clinical features of CSF-positive cases. Thirty-five patients fulfilling the diagnostic criteria for MS but not neuromyelitis optica were included in this study. AQP4 antibodies were detected using a cell-based assay. None of the serum samples were positive for AQP4 antibodies. Five CSF samples (14.3%, 5/35) were positive for AQP4 antibodies. All CSF-positive patients had atypical brain lesions in areas known to have high levels of AQP4 expression. CSF AQP4 antibody testing is an important diagnostic aid in patients meeting MS criteria but with atypical brain or spinal lesions and serum negative for AQP4 antibodies.     

Normal cerebrospinal fluid levels of hypocretin-1 (orexin A) in patients with fibromyalgia syndrome

BACKGROUND: The hypothalamic neuropeptide hypocretin (orexin) modulates sleep-wake, feeding and endocrine functions. Cerebrospinal fluid (CSF) hypocretin-1 (Hcrt-1) concentrations are low in patients with narcolepsy-cataplexy, a sleep disorder characterized by hypersomnolence and rapid eye movement (REM) sleep abnormalities. METHODS: We determined CSF Hcrt-1 concentrations of patients with the fibromyalgia syndrome (FMS), a condition characterized by fatigue, insomnia and in some cases daytime hypersomnolence. RESULTS: Basal CSF levels of Hcrt-1 in FMS did not differ from those in healthy normal controls. CONCLUSIONS: These findings suggest that abnormally low Hcrt-1 is not a likely cause of fatigue in FMS.     

Narcolepsy and low CSF orexin (hypocretin) concentration after a diencephalic stroke.

Idiopathic narcolepsy usually results from a loss of the hypothalamic neuropeptide orexin (hypocretin), but the cause of secondary narcolepsy resulting from focal brain lesions is unknown. The authors describe a young man who developed narcolepsy after a large hypothalamic stroke. His lesion included much of the hypothalamic region in which orexin is produced, and his CSF concentration of orexin was low. The authors hypothesize that a loss of orexin neurons or their relevant targets may be the specific neuropathology causing this and many other cases of secondary narcolepsy.     

Hypothalamic abnormality in patients with inflammatory demyelinating disorders

Background: Hypothalamic lesions in neuromyelitis optica (NMO) patients might be more specific for NMO than multiple sclerosis (MS). However, this is controversial. Objective: To characterize clinical features of patients with inflammatory demyelinating disorders (IDDs) with visible hypothalamic lesions using magnetic resonance imaging (MRI). Methods: Patients with IDDs (n = 429) were recruited retrospectively. Results: Of 52 patients with hypothalamic images enrolled, 42 were positive for aquaporin-4 (AQP4) antibodies, including 28 patients with NMO, 6 with recurrent transverse myelitis, 3 with recurrent optic neuritis, and 5 with brainstem and brain syndrome. The remaining 10 patients were anti-AQP4-negative, including 3 with MS, 3 with acute disseminated encephalomyelitis, and 4 with other disorders. In the AQP4-positive group, manifestations, including ataxia, intractable hiccup and nausea, syndrome of inappropriate antidiuretic hormone secretion and encephalopathy were more frequent in those with hypothalamic lesions than those without. Cell counts of cerebrospinal fluid in patients with hypothalamic lesions differed from patients without lesions. Brain MRI abnormalities were more frequent in brainstem and hemisphere of the hypothalamic lesion group. Conclusions: Hypothalamic lesions were observed frequently in patients with AQP4 antibodies. Clinical manifestations and paraclinical features in AQP4-positive patients with hypothalamic lesions differed from those without lesions.     

Two cases of atypical HTLV-I associated myelopathy (HAM)

We report two cases of HTLV-I associated myelopathy (HAM) who showed high HTLV-I antibody titers with clinically atypical neurological symptoms compared with typical HAM originally reported by Osame et al. Case 1 is a 59 year-old-woman who showed Shy-Drager syndrome-like symptoms such as a slowly progressive gait disturbance, pyramidal and extra-pyramidal symptoms, an orthostatic hypotension and a sweating disturbance. The anti HTLV-I antibody titer was highly positive in both her serum and cerebrospinal fluid (CSF), and there was also a high level of oligoclonal immunoglobulin in her CSF. These symptoms improved slightly with steroid therapy. Therefore, it was suspected that this neurological condition was associated with HTLV-I, which means that HTLV-I can be associated not only with myelopathy but also with various other neurological symptoms. The second case is a 52-year-old woman who had a myelopathy with a slowly progressive course. She had suffered from a transient optic neuritis 5 years before admission that had improved completely with steroid therapy. She had highly positive anti HTLV-I antibody in both her serum and CSF, and also showed a high level of oligoclonal immunoglobulin in her CSF. With administration of steroids, the sensory disturbances and abnormal findings in the CSF improved slightly. Koprowski et al reported that in some MS patients they found positive anti HTLV-I antibody and furthermore proved the presence of CSF cells which hybridized with a HTLV-I probe. They suggested the presence of an unknown HTLV-related agent which may be a pathogenic factor in some subtypes of MS. The transient optic neuritis responding to steroid therapy and the following transverse myelopathy, as seen in case 2, are highly characteristic of MS. Thus, some clinical features of HAM may be very similar to MS.     

脑脊液MOG抗体阳性的视神经脊髓炎谱系疾病患者的临床特征

目的探讨MOG抗体阳性的NMOSD患者的临床特点。方法选择29例NMOSD患者,根据血清AQP-4抗体以及脑脊液MOG抗体检测结果,分为MOG抗体阳性、AQP4抗体阳性的NMOSD(剔除双阳性者),同时选择13例MS患者作为对照。回顾性分析上述三组患者临床信息,统计归纳其临床特点。结果 29例NMOSD患者中血清AQP4抗体阳性者11例,脑脊液MOG抗体阳性者8例。36.4%(4例/11例)AQP4抗体阳性、62.5%(5例/8例)MOG抗体阳性NMOSD患者,以及7.7%(1例/13例)MS患者合并脊髓炎与视神经炎,三组间差异有统计学意义(χ~2=7.128,P=0.028),其中MOG抗体阳性NMOSD患者较MS患者更易合并视神经炎(χ~2=7.289,P=0.014)。MOG抗体阳性NMOSD患者缓解期EDSS分数低于AQP4抗体阳性NMOSD患者[3.50(2.50,4.00),4.00(3.50,6.00),Z=-2.379,P=0.020]。MOG抗体阳性NMOSD脊髓病灶多表现为多发的长节段脊髓病灶,50%(4例/8例)MOG抗体阳性脊髓病灶个数大于1个,与MS组无明显差异,而AQP4抗体阳性组均为单个病灶。MOG抗体阳性NMOSD脊髓病灶长度较AQP4抗体阳性组短[分别(3(2,3)个椎体、4(3,5)个椎体,Z=-2.499,P=0.012],较MS组[(1.25(1,1.5)个椎体]长(Z=-3.447,P0.001)。8例MOG抗体阳性患者中5例存在颅内病灶,3例表现为NMOSD样颅内病灶,余2例表现为MS样颅内病灶,其病灶形态及部位与AQP4抗体阳性组无明显差异,而与MS组存在差异。结论 MOG抗体阳性NMOSD合并视神经炎的患者较多,临床残障程度较轻,预后较好,脊髓病灶为多发的长节段脊髓病灶;颅内病灶的形态及部位与MS无明显差异。     

Neuromyelitis optica with intraspinal expansion of Schwann cell remyelination

We report a case of neuromyelitis optica (NMO) with an unusual pattern of remyelination in the spinal cord. A Japanese woman complained of pain and numbness in the left thumb at the age of 36 years. She mainly presented with optic and spinal symptoms and was initially diagnosed as multiple sclerosis (MS). Her bilateral eyesight decreased, which led to light perception only in the right eye. She became unable to walk without a wheelchair. In spite of steroid pulse therapy, plasma exchange therapy and immunosuppressive therapy, her symptoms gradually worsened. After 33 years of a relapsing–remitting course, she died of septic urinary tract infection at the age of 69 years. Autopsy revealed prominent demyelination in the optic tract and the spinal cord. The optic nerve showed extensive demyelination accompanied by axon depletion. The spinal cord lesions were found in C8 to L2 level (contiguous 15 segments), especially Th5 to Th11 level. The thoracic spinal cord showed extensive remyelination spreading from the entry zone of peripheral nerves to the central portion. Regenerative myelin showed immunopositivity for Schwann/2E, a marker of Schwann cells and myelin of the peripheral nervous system. Expressions of glial fibrillary acidic protein and aquaporin 4 (AQP4) were weakened in the area of Schwann cell remyelination, suggesting that the essential pathogenesis of this case was disturbance of astrocytes. Inhibition of gliosis probably led to cystic cavities, and destruction of basal lamina may have permitted Schwann cells of peripheral nerves to enter the spinal cord and proliferate within empty spaces. Compared with the optic tract and the spinal cord lesions, a large part of the brain plaques was vague and inactive. We pathologically diagnosed this case as NMO for optic neuritis, myelitis, a contiguous spinal cord lesion and loss or decrease of AQP4 expression.     

Neuromyelitis Optica Preceded by Brain Demyelinating Episode

Neuromyelitis optica (NMO) is considered a distinct disease from multiple sclerosis (MS) because of its pathogenesis. It is well accepted that NMO selectively affects the spinal cord and optic nerve and is not associated with brain lesions at the onset of the disease, unlike MS. We present a unique case where the patient's initial lesion was in the brain, and optic neuritis and myelitis were revealed 6 years after the brain lesion. In addition, the patient's serum antiaquaporin 4 (AQP4) antibody was positive. We consider the brain lesion to precede abnormal lesion of NMO, and the AQP4 measurement is important for diagnostics, even if it occurs with brain lesions.     

Temporal dynamics of cerebrospinal fluid anti-aquaporin-4 antibodies in patients with neuromyelitis optica spectrum disorders

Neuromyelitis optica spectrum disorders (NMOSD) are associated with anti-aquaporin-4 autoantibodies (AQP4-IgG). Limited data is available on longitudinal cerebrospinal fluid (CSF) AQP4-IgG and their relation to disease activity and inflammatory parameters. AQP4-IgG titers were measured in matched longitudinal serum and CSF samples of 12 patients with NMOSD by an immunofluorescence assay and correlated with clinical parameters. CSF AQP4-IgG were present in patients with high serum titers and correlated with spinal MRI lesion length and CSF parameters. Clinical improvement was associated with a decrease in CSF, but not serum, AQP4-IgG titers. Thus, CSF AQP4-IgG were associated with clinical activity and neuroinflammation.     

Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression

BACKGROUND: Neuromyelitis optica (NMO)-IgG is a specific autoantibody marker for NMO. It binds selectively to aquaporin 4 (AQP4), which is highly concentrated in astrocytic foot processes at the blood-brain barrier and is not restricted to optic nerve and spinal cord. Although it is conventionally believed that the brain is spared, brain imaging abnormalities are not uncommon in patients with NMO. OBJECTIVE: To investigate the location of brain lesions that are distinctive for NMO with respect to the localization of AQP4 in mammalian brain. DESIGN: Observational, retrospective case series. SETTING: Clinical serologic cohort of patients tested for NMO-IgG for whom brain MRI images were available. PATIENTS: We identified 120 patients seropositive for NMO-IgG for whom brain magnetic resonance images were available. MAIN OUTCOME MEASURE: Magnetic resonance imaging abnormalities. RESULTS: In 8 patients we observed recurring and distinctive magnetic resonance imaging abnormalities in the hypothalamic and periventricular areas that corresponded to brain regions of high AQP4 expression. CONCLUSION: The distribution of NMO-characteristic brain lesions corresponds to sites of high AQP4 expression.     

The Pathophysiologic Basis of Secondary Narcolepsy and Hypersomnia

The symptoms of narcolepsy can occur during the course of other neurologic conditions (ie, symptomatic narcolepsy). Inherited disorders, tumors, and head trauma were the three most frequent causes for symptomatic narcolepsy. Other causes include multiple sclerosis (MS), vascular disorders, and encephalitis. Cerebrospinal fluid hypocretin-1 measures were carried out in some recent cases with symptomatic narcolepsy, and moderate decreases in hypocretin levels were seen in a large majority of these cases. Excessive daytime sleepiness (EDS) in these symptomatic cases was sometimes reversible with an improvement of the causative neurologic disorder and with an improvement of the hypocretin (orexin) status. Recently, we found that several symptomatic narcoleptic cases with MS show unique bilateral symmetric hypothalamic lesions associated with significant hypocretin ligand deficiency. In addition, these patients often share the clinical characteristics of neuromyelitis optica (NMO) and the detection of NMO-IgG (or anti-aquaporin-4 [AQP4] antibodies), suggesting a new clinical entity. Further studies of the involvement of the hypocretin system in symptomatic narcolepsy and EDS are helpful to understand the pathophysiologic mechanisms for occurrence of EDS and cataplexy.     

HIV感染合并视神经脊髓炎谱系疾病一例报道并文献复习

目的总结HIV感染合并视神经脊髓炎谱系疾病(NMOSD)患者的临床特点,以提高临床对其认识。方法报道作者医院收治的1例以视神经脊髓炎症状起病的AIDS患者的临床资料,并结合文献进行复习。结果文献检索HIV感染合并NMOSD患者7例,结合本文报道的1例共8例,年龄8~55岁,平均(39.1±14.4)岁,其中男5例、女3例。8例患者均发生脊髓炎,7例发生视神经炎。血CD4+T细胞降低3例(3/8)。脑脊液(CSF)细胞学检测异常4例(4/8),表现为白细胞轻度升高,以淋巴细胞炎性反应为主,6例蛋白水平升高(6/8)。血清水通道蛋白4抗体阳性3例(3/7)。CSF寡克隆区带阳性3例(3/5)。MRI检查显示颅内多发病灶2例(2/8),颈段或胸段脊髓病灶8例(8/8),其中4例为颈髓至胸髓连续长节段病灶。8例患者接受免疫治疗,其中7例接受糖皮质激素治疗,3例(3/8)肌力完全恢复或能独立行走,1例(1/8)肌力部分恢复,4例(4/8)肌力无明显恢复,3例(3/7)视力恢复至粗测正常,1例(1/7)视力部分恢复,3例(3/7)失明。复发5例,其中4例1年内复发。1例死亡。结论HIV感染合并NMOSD患者致残率高,易复发,部分患者免疫治疗有效。     

Retrobulbar optic neuritis in a two-year-old boy

We report a 2-year-4-month-old boy with retrobulbar optic neuritis. He had a sudden onset of impaired vision, which progressed to total blindness within a day. The visual evoked potential (VEP) showed no activity, but the electroretinogram was normal. Computed tomography (CT) and magnetic resonance imaging (MRI) showed no abnormal findings in the visual tract. The cerebrospinal fluid (CSF) myelin basic protein (MBP) level was elevated and serum anti-myelin antibody was positive. These findings suggested that optic neuritis in our patient was induced by retrobulbar demyelination, perhaps as a result of an autoimmune process. His visual impairment recovered gradually, but not completely, following oral prednisolone therapy. We have followed him for one year since discharge and have found neither recurrence of optic neuritis nor any other neurological disorders. Optic neuritis in children is rare and, to our knowledge, this patient is one of the youngest to be reported. This case suggests that autoimmune mechanisms may induce optic neuritis even in early childhood. In addition to VEP and MRI studies, the CSF MBP and serum anti-myelin antibody can be useful in the diagnosis and follow-up the patients with optic neuritis.     

A case with anti-galactocerebroside antibody-positive Mycoplasma pneumoniae meningoencephalitis presenting secondary hypersomnia

Galactocerebroside (Gal-C) is a major myelin component in the central nervous system. The anti-Gal-C antibody induced by mycoplasma infection may therefore be involved in the pathogenic mechanisms of mycoplasma-associated encephalitis. Here we report an adult case of mycoplasma encephalitis developing excessive daytime sleepiness. Brain MRI suggested that hypothalamic involvement was compatible with hypersomnia. This finding was corroborated by decreased hypocretin-1 in cerebrospinal fluid (CSF) and the manifestation of diabetes insipidus. Screening for anti-glycolipid antibody profiles showed the selective increase of serum anti-Gal-C antibody. After treatment with minocyclin, the patient’s daytime sleepiness was markedly improved and the CSF hypocretin-1 level became almost normal, as well. It is known that CSF hypocretin-1 is decreased in Guillain-Barré syndrome mediated by anti-glycolipid antibody, suggesting a possible mechanistic link between anti-glycolipid antibodies and hypothalamic involvement. The present case further emphasizes the broad spectrum of neurological complications after mycoplasma infection.     

Clinical analysis of neuromyelitis optica presenting as intractable nausea,vomiting and hiccups

Vomiting and hiccups can be the manifestations of numerous systemic and neurological illnesses. Intractable nausea, vomiting and hiccups (INH) are reported as possible initial manifestations of neuromyelitis optica (NMO), but not correctly identified. Awareness of these atypical presentations is conducive to NMO early diagnosis and proper treatment to prevent further disability. In this paper, 12 NMO were reported, whose intractable vomiting and hiccups were the sole manifestations of the first attack and other attacks involving spinal cord and optic nerves developed later. All the patients were women and serum aquaporin 4 antibody (AQP4-Ab) of 83% patients was positive. MRI of 50% patients showed T2-weighted imaging/fluid attenuated inversion recovery hyperintensity which were longitudinally extensive transverse myelitis or linear signal changes. Sixty-seven percent of patients had medulla lesions, in which dorsomedial and area postrema were involved.     

儿童MOG抗体阳性的中枢神经系统脱髓鞘病变12例临床特点分析

目的探讨髓鞘少突胶质细胞糖蛋白(MOG)抗体阳性的儿童中枢神经系统脱髓鞘病变的临床特点。方法回顾性分析2016年1月至2018年12月广东三九脑科医院神经内科收治的12例儿童MOG抗体阳性的中枢神经系统脱髓鞘病患者的临床症状、影像学特点、实验室检查、预后及随诊情况。结果 12例患者中男4例,女8例,起病年龄5~10岁,平均(8.0±3.1)岁。首发症状以意识水平下降、癫痫大发作等急性播散性脑脊髓膜炎(ADEM)样症状最多见(8例,8/12),其次为视力下降(5例,5/12),其中1例以ADEM样症状和视力下降同时起病。另有3例以ADEM样症状首发,起病后1周左右出现视力下降。12例患者行头颅MRI检查,11例(11/12)可见颅内异常病灶,以皮层下白质(10例,10/11)、脑干(7例,7/11)、丘脑(6例,6/11)、视神经(5例,5/11)受累为主,小脑(4例,4/11)、胼胝体(1例,1/11)亦可受累。9例患者行全脊髓MRI检查,5例(5/9)有异常病灶,均累及颈髓(5例,5/5),3例(3/5)累及胸髓,累及胸髓的病灶均为>3个椎体节段的长节段脊髓受累。12例患者行血清MOG抗体检测,11例(11/12)阳性,另1例(1/12)血清抗体阴性而脑脊液抗体阳性;8例患者行脑脊液MOG抗体检测,3例(3/8)阳性。所有患者经糖皮质激素及免疫球蛋白治疗,预后均良好,3例患者出现复发。结论MOG抗体相关的儿童中枢神经系统脱髓鞘病变以ADEM、视神经脊髓炎谱系疾病(NMOSD)最常见,往往以意识水平下降、癫痫大发作或视力下降起病,其预后相对较好,糖皮质激素治疗对缓解临床症状及预防复发有重要作用。