Leukodystrophy 【Overview】 Leukodystrophy (Behcet’s disease, BD) belongs to the systemic, chronic, vascular inflammatory disease, the main clinical manifestations of recurrent oral ulcers, genital ulcers, ophthalmitis, and skin damage, but also can be involved in blood vessels, the nervous system, digestive tract, joints, lungs, kidneys, epididymis and other organs. Most patients have a favorable prognosis, while those with ocular, central nervous and large vessel involvement have a poor prognosis. The disease has a high incidence in East Asia, the Middle East and the Mediterranean region, and is known as the Silk Road disease. There is no precise information about the incidence in China, and the disease can occur at any age, with a prevalence of 16 to 40 years old. China’s female majority, male patients with vascular, neurological and ocular involvement more than women and serious condition. Clinical manifestations: The disease can involve multiple organs and systems, but rarely has multiple clinical manifestations at the same time. Sometimes patients need to go through several years or even longer before various clinical signs and symptoms appear successively. 1, oral ulcers Almost all patients have recurrent, painful oral ulcers (Aphthous ulceration, Aphthous ulceration), and often as the first symptom. Ulcers can occur in any part of the mouth, mostly located in the tongue margin, cheeks, lips, soft palate, pharynx, tonsils and other places. Can be a single, can also appear in batches, isolated scattered distribution, is the size of a grain of rice or soybean, round or oval, the edge is clear, the depth varies, the bottom of the yellow cover, surrounded by a clear edge of the red halo, about 1 ~ 2 weeks after the self-subsorption without scarring, some patients continue to recurring episodes. In severe cases, the ulcers are deep and large, and the healing is slow, occasionally leaving scars. Recurrent oral ulcers are the most basic symptom necessary for the diagnosis of this disease. 2, genital ulcers about 75% of patients with genital ulcers, lesions and oral ulcers are basically similar. However, the number of occurrences is less. The ulcers are deep and large, with severe pain and slow healing. The sites of involvement are the vulva, vagina, perianal area, cervix, scrotum and penis. Vaginal ulcers may be painless with only increased discharge. Some patients can cause hemorrhage or scrotal vein wall necrosis rupture bleeding due to deep ulcers. 3.Ophthalmia About 50% of patients are involved, both eyes can be involved. Ocular lesions can appear months or even years after the onset of the disease, and its manifestations are blurred vision, vision loss, eye congestion, eye pain, photophobia and tearing, foreign body sensation, mosquitoes and headache. It usually presents with a chronic, recurrent, progressive course. Eye involvement causes blindness in up to 25% of cases and is the leading cause of disability in this disease. The most common and severe ocular lesion is uveitis. Anterior uveitis, i.e., iridocyclitis, combined with pus in the anterior chamber is a typical characteristic sign of leukoaraiosis, and posterior uveitis and retinal vasculitis are the main causes of blindness. Other manifestations of ocular involvement include keratitis, herpetic conjunctivitis, scleritis, choroiditis, retinitis, optic nerve papillitis, and fundus hemorrhage. In addition there may be lens hemorrhage or atrophy, glaucoma, and retinal detachment. The edema of the optic disc alone suggests cerebral venous thrombosis, and intracranial vascular lesions caused by leukoaraiosis can lead to visual field defects. 4, skin lesions, high incidence of skin lesions, up to 80% ~ 98%, a variety of manifestations, nodular erythema, herpes, papules, acne-like rash, erythema multiforme, annular erythema, necrotizing tuberculosis rash-like damage, herpetic necrotizing vasculitis, Sweet’s disease-like lesions, pyoderma, and so on. A patient may have one or more of these lesions. The skin signs with special diagnostic value are nodular erythema-like lesions and inflammatory reaction to tiny trauma (needle prick). 5, joint damage 25% to 60% of patients have joint symptoms. The manifestation is relatively mild limited, asymmetric arthritis. It mainly involves knee joints and other large joints, and HLA-B27 positive patients may have sacroiliac joint involvement, similar to the manifestation of ankylosing spondylitis. 6.Neurological damage, also known as neuroleukodystrophy, the incidence rate is about 5%~50%. Often appear months to years after the disease, a few (5%) may be the first symptom. Clinical manifestations vary according to the site of involvement. Involvement of the central nervous system is more common, including headache, dizziness, Horner’s syndrome, pseudobulbar palsy, respiratory disorders, epilepsy, ataxia, aseptic meningitis, optic papilloedema, hemiplegia, aphasia, paraplegia of different degrees, urinary incontinence, bilateral lower limb weakness, sensory disorders, impaired consciousness, and psychiatric abnormality, etc. Peripheral nerve involvement is less common. Peripheral nerve involvement is less common, manifesting as numbness and weakness of the limbs, peripheral-type sensory deficits, and so on. Neurological damage also has the tendency of alternating episodes and remission, and may have multiple site involvement at the same time. The prognosis of most patients is not good, especially the brainstem and spinal cord lesions are one of the main causes of disability and death in this disease. 7, digestive tract damage, also known as intestinal leukosis. The incidence rate is 10%~50%. The whole digestive tract from the mouth to the anus can be involved, and the ulcers can be single or multiple, with different depths, which can be seen in the lower esophagus, stomach, distal ileum, ileocecal part, ascending colon, but the ileocecal part is more common. Clinical manifestations may include epigastric fullness, belching, dysphagia, middle and lower abdominal distension, vague pain, paroxysmal colic, diarrhea, black stools, constipation and so on. In severe cases, there may be perforated ulcers and even death due to complications such as hemorrhage. Intestinal leukoaraiosis should be noted with inflammatory bowel disease and non-steroidal anti-inflammatory drugs caused by mucosal lesions to distinguish, right lower abdominal pain should be noted with appendicitis to distinguish, often with clinical cases of postoperative wound non-healing. 8, vascular damage The basic lesion of this disease is vasculitis, the whole body large and small blood vessels can be involved, about 10% to 20% of patients with large and medium-sized vasculitis, is the main cause of death and disability. When the arterial system is involved, the elastic fiber of the arterial wall is destroyed and the endothelial fiber of the arterial wall is proliferated, resulting in arterial stenosis, dilatation or aneurysm, and the corresponding clinical manifestations appear, such as dizziness, headache, syncope and pulselessness. Aneurysms on the aortic arch and its branches are at risk of rupture. Involvement of the venous system is more common than that of the arterial system. superficial or deep migratory thrombophlebitis and venous thrombosis, resulting in stenosis and embolization, occur in about 25% of patients. Involvement of the inferior vena cava and lower extremity veins is more common, and Budd-Chiari syndrome, ascites, and swelling of the lower extremities may occur. Obstruction of superior vena cava may have swelling of the jaw, neck, and elevated venous pressure in the upper extremities. 9.Lung damage The incidence of lung damage is low, about 5%~10%, but most of the disease is serious. Pulmonary vascular involvement can have pulmonary aneurysm formation, aneurysm rupture can form pulmonary vascular – bronchial fistula, resulting in intrapulmonary hemorrhage; pulmonary vein thrombosis can lead to pulmonary infarction; alveolar peripapillary inflammation can make the endothelial hyperplasia and fibrosis affecting the function of air exchange. When the lung is involved, the patient has cough, hemoptysis, chest pain, dyspnea and so on. Massive hemoptysis can cause death. 10.Other Renal damage is rare, there may be intermittent or persistent proteinuria or hematuria, renal hypertension, renal pathology may have IgA glomerular proliferative lesions or amyloidosis. Cardiac involvement is less common and may include myocardial infarction, valvular lesions, conduction system involvement, and pericarditis. There may be ependymal thrombosis in the cardiac chambers, and in a few patients, the heart shows dilatation-like changes, constrictive pericarditis-like manifestations, and cardiac lesions are associated with local vasculitis. The incidence of epididymitis is about 4%~10%, which is more specific. Acute onset, manifested as single or bilateral epididymis swelling pain and pressure, 1~2 weeks can be relieved, easy to recur. Pregnancy may aggravate the disease in most patients, and remission of uveitis has also been reported. There can be intrauterine fetal growth retardation, and most of the disease worsens after delivery. Nearly 10% of patients with fibromyalgia syndrome-like manifestations, more common in women. Diagnostic points] 1, the clinical manifestations of the disease course of the doctor observed and recorded recurrent oral ulcers, ophthalmia, genital ulcers, and characteristic skin damage, such as erythema nodosum, folliculitis, acne-like rash, in addition to the presence of macrovascular or neurological damage is highly suggestive of leukoencephalopathy diagnosis. 2.Laboratory examination There is no specific laboratory abnormality in this disease. In the active stage, there may be rapid blood sedimentation, C-reactive protein elevation; some patients are positive for cryoglobulin and platelet agglutination; HLA-B51 is a susceptible antigen, and its positivity rate in leukemia patients is 57%~88%, which is related to the eye and gastrointestinal tract lesions. 3.Pathergy test: A 20-gauge sterile needle was inserted obliquely into the middle of the flexed surface of the forearm about 0.5cm along the longitudinal direction and then withdrawn after a slight twist, and a small folliculitis-like red spot or pustular herpes-like change of a diameter of >2mm appeared locally in 24-48 hours as a positive test. This test has high specificity and correlates with disease activity, with a positive rate of about 60%~78%. Similar lesions after venipuncture or skin trauma are of equal value. 4.Special examination Neuroleukodystrophy often has increased cerebrospinal fluid pressure and mildly elevated white blood cell count. Brain CT and magnetic resonance (MRI) examination is helpful for brain, brainstem and spinal cord lesions. The sensitivity of MRI in the acute stage is as high as 96.5%, and it can find increased signals in the brainstem, paraventricular white matter and basal ganglia. MRI in the chronic stage should be noted to distinguish from multiple sclerosis.MRI can be used for the diagnosis of neuroleukodystrophy and the follow-up observation of the treatment effect. Barium gastrointestinal imaging and endoscopy, angiography, color Doppler can help to diagnose the site and scope of the lesion. Lung radiographs may show diffuse exudate or round nodular shadows of varying sizes unilaterally or bilaterally, and blurred shadows of increased density around the pulmonary hilum in the case of pulmonary infarction. High-resolution CT or pulmonary angiography and isotope lung ventilation/perfusion scanning are helpful in the diagnosis of lung lesions. 5, Diagnostic criteria This disease has no specific serologic and pathologic features, the diagnosis is mainly based on clinical symptoms, so attention should be paid to detailed history taking and typical clinical manifestations. Differential diagnosis The disease is easy to be misdiagnosed as other systemic diseases if one systemic symptom is the prominent manifestation of the disease. Joint symptoms as the main manifestation, should pay attention to and rheumatoid arthritis, Wright (Reiter) syndrome, ankylosing spondylitis; skin and mucous membrane damage should be with erythema multiforme, erythema nodosum, syphilis, Sweet’s disease, Stevens-Johnson syndrome, common acne, herpes simplex infections, tropical mouth sores (Sprue), systemic lupus erythematosus, cyclic granulocytopenia, AIDS (AIDS). Gastrointestinal involvement should be differentiated from Crohn’s disease and ulcerative colitis. Neurological damage and infectious, allergic cerebrospinal meningitis, cerebrospinal tumors, multiple sclerosis, psychosis; epididymitis and epididymal tuberculosis. Treatment options and principles] There is no recognized effective cure for this disease. A variety of drugs are effective, but most of them are easy to relapse after stopping. The purpose of treatment is to control the existing symptoms, prevent and control the damage of important organs, slow down the progress of the disease. 1, general treatment Acute active period, should be bed rest. During the interictal period, attention should be paid to the prevention of recurrence. For example, control the infection of mouth and throat, and avoid stimulating food. Complicated infection should be given antibiotic treatment. 2.Local treatment Oral ulcers can be localized with glucocorticoid cream, ice boron powder, tin-like powder, etc., genital ulcers with 1:5000 potassium permanganate wash with antibiotic ointment; ocular conjunctivitis, keratitis can be applied to corticosteroid ophthalmic ointment or eye drops, ocular uveitis must be applied to dilate the pupil in order to prevent the post-inflammatory adhesions, severe ophthalmitis can be injected with adrenal corticotropic hormone in the subglottic conjunctiva. 3, systemic treatment (1) non-steroidal anti-inflammatory drugs: anti-inflammatory and analgesic effect. For the relief of fever, skin nodules erythema, genital ulcer pain and arthritis symptoms have a certain efficacy, commonly used drugs are ibuprofen 0.4~0.63/d; naproxen, 0.2~0.42/d; diclofenac sodium, 25mg3/d, etc., or other non-steroidal drugs and COX-2 selective inhibitors (see rheumatoid arthritis treatment). (2)Colchicine: it can inhibit neutrophil chemotaxis, and has some therapeutic effects on arthropathy, erythema nodosum, oral and genital ulcers, and uveitis, with a common dosage of 0.5mg2~3/d. Attention should be paid to adverse reactions such as hepatic and renal damage, granulocytopenia, and so on. (3) Thalidomide (Thalidomide): used in the treatment of severe oral and genital ulcers. It is recommended to start with a small dose (50mg/d) and gradually increase it to 200mg/d, to be taken orally in divided doses. Adverse reactions include drowsiness, thirst, decreased blood cells, increased liver enzymes, microscopic hematuria and numbness of finger tips. Pregnancy is prohibited during drug administration to avoid causing fetal malformations (see Ankylosing Spondylitis Medications), and there is a side effect of causing neuraxial degeneration. Gradually reduce the dosage after improvement. (4) Glucocorticoid: can effectively control acute inflammation, commonly used for prednisone 40~60mg/d. Serious patients such as severe ophthalmitis, central nervous system lesions, severe vasculitis patients can be considered to use intravenous application of high-dose methylprednisolone shock, 1,000mg/d, 3~5 days for a course of treatment, and immunosuppressant combined effect is better, the application of glucocorticoid can not prevent the recurrence of simple. Glucocorticoids alone cannot prevent relapse. Long-term application of glucocorticoids has adverse effects (see Systemic Lupus Erythematosus Medications). (5) Immunosuppressants: these drugs should be used when important organs are damaged. They are often used in combination with adrenocorticotropic hormones. After the control of the active phase of the disease, small-dose glucocorticosteroids (10-15mg) taken orally every other day and combined with immunosuppressive drugs are effective measures to prevent relapse. The side effects of such drugs are large, and the time of administration should be closely monitored. ①Nitrogen mustard phenylbutyrate (Chlorambucil, CB1348): used for the treatment of retinal, central nervous system and vascular lesions. It should be used at 2mg 3/d for several months until the disease is stabilized and then tapered to a low maintenance dose. Discontinuation of the drug can be considered after six months of complete remission. However, eye damage should be considered for more than 2~3 years to avoid recurrence. During the use of the drug, regular ophthalmologic consultation and examination should be conducted. Side effects include secondary infections, menopause or sperm reduction, azoospermia in long-term use. ② Azathioprine: the effect is worse than azathioprine phenylbutyrate. The dosage is 2~2.5mg/kg/d. It can inhibit oral and ocular lesions and arthritis, but it is easy to relapse after stopping the drug. It can be used in combination with other immunosuppressants. During the application period, blood routine and liver function should be checked regularly. Methotrexate: 7.5~15mg per week, taken orally or by injection. It is used to treat lesions of the nervous system, skin and mucous membranes, and can be taken in small doses for a long time. Adverse reactions include bone marrow suppression, liver damage and gastrointestinal symptoms. Regular check of blood routine and liver function should be performed. ④ Cyclophosphamide (Cyclophosphamide): in acute central nervous system damage or pulmonary vasculitis, ophthalmia, combined with prednisone, can be taken orally or high-dose intravenous shock treatment (each dosage of 0.5 ~ 1.0/O body surface area, every 3 ~ 4 weeks). Patients are instructed to drink large amounts of water to avoid the occurrence of hemorrhagic cystitis. In addition, there may be gastrointestinal reactions and leukopenia (see Systemic Lupus Erythematosus Medications). ⑤ Cyclosporine: it is more effective for ocular leukoaraiosis with poor efficacy of colchicine or other immunosuppressants, and the dose is 3~5 mg/kg/d. It should be used for 4 weeks after the condition is stabilized, and then reduced by 0.5 mg/kg/d in every 8 weeks, and if the efficacy of the commonly used dose is not good, the dose can be increased to 7 mg/kg/d as appropriate, and the patient should pay attention to the monitoring of blood pressure and hepatic and renal functions when using it to avoid adverse reactions. Avoid adverse reactions. (6) Liuzasulfapyridine: 3~4g/d, can be used in intestinal leukodystrophy or arthritis, should pay attention to the adverse effects of the drug. (6) Others ①α interferon: it is effective in the treatment of oral damage, skin disease and joint symptoms, and can also be used in the acute treatment of eye lesions. ② TNF monoclonal antibody (Infliximab) for the treatment of recurrent uveitis has been reported, still need further clinical observation. (iii) Tretinoin preparations are definitely effective for oral ulcers, subcutaneous nodules, arthropathy, and ophthalmia. It is less effective for intestinal symptoms. ④ Antiplatelet aggregation drugs (aspirin, Pansentin) and antifibrin therapy (urokinase, streptokinase) can also be used in the treatment of thrombotic diseases, but should not be abruptly discontinued to avoid rebound. ⑤ If the patient has tuberculosis or a history of tuberculosis, PPD skin test is strongly positive (5Iu with blisters), anti-tuberculosis treatment (triple) can be tried for at least three months, and observe the efficacy. 4.Surgical treatment When severe intestinal leukoencephalopathy is complicated by intestinal perforation, surgical treatment is feasible, but the recurrence rate of intestinal leukoencephalopathy after surgery can be as high as 50%. Recurrence has nothing to do with the surgical method and primary site, so the choice of surgery should be careful. After surgery for vascular lesions, aneurysms can also form again at the postoperative anastomosis, so surgery is generally not recommended, and interventional therapy can reduce the complications of surgery. Eye blindness with persistent pain can be removed surgically. After surgery, immunosuppressive therapy should be continued to reduce recurrence. Prognosis: The disease is generally chronic and easy to treat. Remission and relapse can last for weeks or years, or even decades. Blindness, vena cava obstruction and paralysis may occur during the course of the disease. The disease may result in death due to central nervous system, cardiovascular system, gastrointestinal tract involvement or.