尖峰眼科分享之Wills之——视网膜色素变性遗传性脉络膜视网膜营养不良

尖峰眼科分享之Wills之——视网膜色素变性遗传性脉络膜视
网膜营养不良
第二十八节视网膜色素变性/遗传性脉络膜视网膜营养不良
一、视网膜色素变性
【症状】
夜视力下降，常见夜盲，周边视野缺失，疾病进展早期或晚期可出现中心视力下降。

晚期出现辨色困难。

【体征】
见图11.28.1。

【主要体征】
典型的表现为:玻璃体细胞(最常见的体征)，成簇的色素沿血管分布于整个周边视网膜，常排列为“骨细胞样”，可无骨细胞样外观;视网膜色素上皮脱色素或萎缩区，小动脉变细，晚期视盘呈蜡样苍白。

有进行性视野缺损，常呈环形暗点，逐渐进展，使中心视野变小。

视网膜电图(ERG)通常表现为中度至重度下降。

【其他体征】
局限性或扇形色素沉着簇，黄斑囊样水肿，视网膜前膜，后囊膜
下白内障。

【遗传方式】
1、常染色体隐性遗传最常见，年轻时即出现视力严重丧失和夜盲。

2、常染色体显性遗传严重程度最轻。

缓慢起病，多成年后出现，外显率各异，白内障出现晚，视力丧失较轻。

3、X-连锁隐性遗传最少见，最严重。

发病与常染色体隐性遗传相似，女性携带者眼底常呈椒盐样，视力严重丧失。

4、散发性。

二、可治疗的与遗传性视网膜色素变性有关的全身病
许多全身病和综合征与视网膜色素变性有关，下面是一系列此类综合征。

1、植烷酸蓄积症(Refsum病，又称多神经炎型遗传性运动失调病)
缺乏植烷酸α-羟化酶，常染色体隐性遗传性视网膜色素变性，通常无骨细胞，伴血清植烷酸水平增高。

可有小脑共济失调，周围神经病变，耳聋，皮肤干燥，嗅觉丧失，肝脏疾病，或心脏病。

治疗:低植烷酸、低叶绿醇饮食，即减少患者饮食中的奶制品，动物脂肪，绿叶蔬菜。

随访:每6个月复查1次血清植烷酸水平。

2、遗传性β—脂蛋白缺乏(Bassen-Kornzweig综合征)
常染色体隐性遗传性视网膜色素变性，通常无骨细胞，伴有脂肪耐受不良，腹泻，血液中出现皱缩的红细胞(棘红细胞)，嗅觉丧失，进行性眼球运动障碍，由于缺乏脂蛋白和脂溶性维生素A、D、E、K吸收不良引起的其他神经系统症状，诊断依据是血清β—脂蛋白缺乏。

治疗:
(1)水溶性维生素A10000~15000IU口服，日1次。

(2)维生素E 200~300IU/kg口服，日1次。

(3)维生素K 5mg口服，每周1次。

(4)限制食品中的脂肪的摄人，其摄入量占总摄入量的15%。

(5)每2年查1次血清中维生素A和E的含量，每年1次的视网膜
电图(ERG),暗适应试验。

(6)考虑在患者饮食中增加锌。

3、Kearns-Sayre综合征
视网膜色素细胞变性，呈椒盐样外观，小动脉正常，进行性眼球运动障碍，无复视，上睑下垂，身材矮小，心脏传导阻滞。

眼部体征出现在20岁以前。

由线粒体DNA遗传。

详见第十章第十节慢性进行性眼外肌麻痹。

治疗:请心脏病专家每年做1次心电图（ECG），患者可能需要起搏器。

【鉴别诊断】
参见相似的眼底表现和遗传性脉络膜视网膜营养不良以及以下引起夜盲症的其他病因。

【检查】
1、病史询问与前述疾病有关的内科疾病和眼科疾病病史。

2、用药史。

3、家族史用于诊断和遗传咨询。

4、散瞳检查眼底。

5、视野检查如Humphrey视野计。

6、视网膜电图(ERG) 用于鉴别静止性视杆-视锥细胞功能障碍与视网膜色素变性(为进展性疾病)。

暗适应检查。

7、眼底照相。

8、若诊断不确定，可做荧光密螺旋体抗体试验(FTA-ABS）。

9、若患者为男性，且遗传方式不确定，则检查其母亲的眼底及视网膜电图。

X-性连锁疾病的女性携带者的中周部视网膜常有异常的色素沉着，其暗适应视网膜电图异常。

10、若表现为神经系统异常，如共济失调、多神经病、耳聋或嗅觉丧失，需检测空腹(至少14h)血清植烷酸水平，以排除Refsum病。

11、若怀疑遗传性β—脂蛋白缺乏综合征，需检测血清胆固醇和甘油三酯水平(其水平降低)，进行血清蛋白和脂蛋白电泳(可检测到β—脂蛋白缺乏)及外周血涂片(可见棘红细胞)。

12、若怀疑Kearns-sayre综合征，患者需由心内科专家行一系列心电图检查，患者可死于完全性心脏传导阻滞。

【治疗】
梅毒患者的治疗参见第十二章第十二节梅毒，维生素A缺乏患者的治疗参见第十三章第七节维生素A缺乏症。

1、对于视网膜色素变性，目前无确定的治疗方法。

一项研究发现，服用棕榈酸维生素A 15000U，可减慢视网膜电图的下降。

这项非常有争议的治疗(对视力没有帮助)只适用于年龄超过21岁、非妊娠患者。

用药过程中需检测肝功和维生素A水平。

2、白内障手术可提高中心视力，口服乙酰唑胺（500mg/d）可治疗黄斑囊样水肿。

3、遗传咨询对所有的患者有益，使其掌握如何应对他们的视力障碍。

浅色的眼镜可使患者在户外感到舒适，并可使其获得较好的对比度增强。

配戴助视器和职业康复可对晚期病例有帮助。

三、与视网膜色素变性眼底表现相似的疾病
1、吩噻嗪中毒
（1）甲硫哒嗪（如硫醚嗪）①色素簇位于后极部和赤道部，视网膜脱色素区，视网膜水肿，视野异常(中心暗点和全面缩窄)，视网膜电图受抑制或熄灭;②症状和体征可发生于开始于吩噻嗪治疗数周内，特别是使用非常大的剂量时(>2000mg/d)。

通常情况下，剂量超过800mg/d，长期使用，才会产生中毒表现;③如果出现中毒表现，停药;④随访:每6个月1次。

(2)氯丙嗪（如Thorazine）①异常色素沉着:见于眼睑、角膜、结膜(特别是睑裂区内)、晶体前囊;②偶见:由甲硫哒嗪引起的视野和视网膜电图改变所对应的色素性视网膜病变;③通常，剂量(1200~2400) mg/d连续使用超过12个月，才会产生中毒表现;④如果出现中毒表现，停药;⑤随访;每6个月1次。

2、梅毒螺旋体抗体吸附荧光测定（FTA-ABS）阳性，视野不对称性，眼底表现异常，可有复发性葡萄膜炎病史，无视网膜色素变性家族史，通常视网膜电图保持在某种程度上。

3、先天性风疹椒盐样眼底可伴有小眼球、白内障、耳聋、先天性心脏病、或另一种全身疾病。

通常视网膜电图正常。

4、Bietti结晶样营养不良
(1)常染色体隐性遗传疾病。

(2)成分不明的结晶沉积在周边部角膜基质层和视网膜的各层。

(3)可造成脉络膜萎缩、夜视力下降、视力下降和视网膜电图低平。

5、视网膜脱离痊愈后如妊娠毒血症或原田病，病史具有诊断意义。

6、色素性静脉旁视网膜脉络膜萎缩静脉旁色素上皮变性和色素沉积，无明确的遗传方式。

视野和视网膜电图多样，通常正常。

可以是静止性的，无需长期随访。

7、严重眼钝挫伤后通常是由视网膜脱离自愈造成。

8、眼动脉阻塞后。

9、眼白化病携带者参见第十三章第八节白化病。

注：由吩噻嗪中毒、梅毒、先天性风疹引起的色素异常位于视网膜色素上皮水平，视网膜脱离痊愈后的色素异常位于视网膜内。

四、遗传性脉络膜视网膜营养不良和造成夜盲症的其他原因
1、回旋状脉络膜视网膜萎缩：常染色体隐性遗传。

夜盲症和周边视力下降通常见于10岁以前，随后出现进展性视野缩窄。

儿童时期中周部扇形的色素上皮和脉络膜毛细血管层萎缩互相融合，累及全眼底。

后囊下白内障、高度近视合并散光。

视野缩小，视网膜电图异常或记录不到。

血鸟氨酸水平为正常值的10-20倍，血赖氨酸水平下降。

如果鸟氨酸水平未见明显升高，考虑视网膜电图和眼底荧光血管造影检查。

治疗:
(1)降低饮食中的蛋白质摄入，以含多种必需氨基酸而无精氨酸的人工调味液替代，如精氨酸限制性饮食。

监测血氨水平。

(2)补充维生素B6(吡多醇):目前剂量不确定，可试从20mg/d开始口服，若无反应，增加剂量直到500mg/d。

监测血鸟氨酸水平，以确定补充维生素B6的剂量和蛋白质摄人量的控制水平。

最理想的血鸟氨
酸水平为0.15~0.2mmol/L。

注：只有少数病例对补充维生素B6有反应。

2、无脉络膜症
（1）男性，20岁之前出现夜盲症。

继之出现隐匿性的周边视力的丧失，晚期中心视力下降。

(2)男性:早期表现为眼底周边部散布色素颗粒及局灶性色素上皮萎缩。

晚期视网膜色素上皮和脉络膜毛细血管完全丧失。

无“骨细胞”样色素沉着。

病程后期可出现视网膜小动脉变细和视神经萎缩，视野缩窄，色觉正常，视网膜电图异常。

(3)女性携带者:小而方的视网膜内色素颗粒散布，下方的脉络膜萎缩。

主要见于视网膜中周部。

(4)治疗:本病目前尚无有效的治疗，配戴深色太阳镜可能改善症状。

(5)X-连锁隐性遗传，应做遗传咨询。

3、维生素A缺乏症显著的夜盲，周边视网膜深层可见大量的、小的、境界清楚的黄白色斑点，干眼和/或结膜Bitot斑(白色的角质化病变)。

常见于营养不良或肠切除术后，也可以是遗传性(家族性胡萝卜素血症)。

参见第十三章第七节维生素A缺乏症。

4、锌缺乏症可致暗适应异常。

锌是维生素A代谢必需的微量元素。

5、先天性静止性夜盲
(1)自出生就有夜盲，视野正常，眼底正常或不正常，不进展，倒错性瞳孔对光反射。

(2)先天性静止性夜盲的一个变异类型为Oguchi病，特征为Mizuo现象:光适应状态下眼底表现为反光，暗适应状态下表现为正常颜色(需要大约12h)。

见图11.28.2和图11.28.3。

6.欠矫的近视可能是夜视力差最常见的原因。

11.28 Retinitis Pigmentosa and Inherited Chorioretinal Dystrophies
Retinitis Pigmentosa
Symptoms
Decreased night vision (often night blindness) and loss of peripheral vision. Decrease in central vision can occur early or late in the disease process. Color vision is intact until late.
Signs
(See Figure 11.28.1.)
Critical. Classically, vitreous cells (most consistent sign), clumps of pigment dispersed throughout the peripheral retina in a perivascular pattern, often assuming a “bone spicule” arrangement (though bone spicules may be absent), areas of depigmentation or atrophy of the RPE, narrowing of arterioles, and, later, waxy optic disc pallor. Progressive visual field loss, usually a ring scotoma, which progresses to a small central field. ERG usually moderately to markedly reduced.
Other. Focal or sectoral pigment clumping, CME, epiretinal membrane, posterior subcapsular cataract.
Inheritance Patterns
Autosomal recessive (most common): Diminished vision (severe) and night blindness occur early in life.
Autosomal dominant (least severe): More gradual onset of RP, typically in adult life, variable penetrance, late onset of cataract. Visual loss less severe.
Treatable Systemic Diseases Associated With Hereditary Retinal DegenerationX-linked recessive (rarest and most severe):
Onset similar to autosomal recessive. Female carriers often have salt-and-pepper fundus. Visual loss is severe
Sporadic.
Refsum Disease (Phytanoyl-CoA hydroxylase deficiency)
Autosomal recessive RP (often without bone spicules) with increased serum phytanic acid level. May have cerebellar ataxia, peripheral neuropathy, deafness, dry skin, anosmia, liver disease, or cardiac abnormalities. Treat with low-phytanic acid, low-phytol diet (minimize the amount of milk products, animal fats, and green leafy vegetables). Check serum phytanic acid levels every 6 months.
Hereditary Abetalipoproteinemia (Bassen–Kornzweig syndrome)
Autosomal recessive RP (usually without bone spicules) with fat intolerance, diarrhea, crenated erythrocytes (acanthocytes), ataxia, progressive restriction of ocular motility, and other neurologic symptoms as a result of deficiency in lipoproteins and malabsorption of the fat-soluble vitamins (A, D, E, and K). Diagnosis based on serum apolipoprotein-B deficiency.
Treatment
•Water-miscible vitamin A, 10,000 to 15,000 IU p.o., q.d.
•Vitamin E, 200 to 300 IU/kg p.o. q.d.
•Vitamin K, 5 mg p.o. weekly.
•Restrict dietary fat to 15% of caloric intake.
•Biannual serum levels of vitamins A and E; yearly ERG, and dark adaptometry.
•Consider supplementing the patient's diet with zinc.
Kearns–Sayre Syndrome
Salt-and-pepper pigmentary degeneration of the retina with normal arterioles, progressive limitation of ocular movement
without diplopia, ptosis, short stature and, cardiac conduction defects. Ocular signs usually appear before age 20 years. Mitochondrial inheritance. See 10.12, Chronic Progressive External Ophthalmoplegia.
Treatment
Refer the patient to a cardiologist for yearly ECGs. Patients may need a pacemaker.
Differential Diagnosis
See Similar Fundus Appearance and Hereditary Chorioretinal Dystrophies and other Causes of Nyctalopia below.
Work-Up
•Medical and ocular history pertaining to the diseases discussed previously.
•Drug history.
•Family history: for diagnostic and counseling purposes.
•Ophthalmoscopic examination.
•Formal visual field testing (e.g., Humphrey).
•ERG, which may help distinguish stationary rod–cone dysfunction from RP (a progressive disease), and dark adaptation studies.
•Fundus photographs.
•FTA-ABS if the diagnosis is uncertain.
•If the patient is male and the type of inheritance is unknown, examine his mother and perform an ERG on her. Women carriers of X-linked disease often have abnormal pigmentation in the mid-periphery and abnormal results on dark-adapted ERGs.
•If neurologic abnormalities such as ataxia, polyneuropathy, deafness, or anosmia are present, obtain a fasting (at least 14 hours) serum phytanic acid level to rule out Refsum disease.
•If hereditary abetalipoproteinemia is suspected, obtain
serum cholesterol and triglyceride levels (levels are low), a serum protein and lipoprotein electrophoresis (lipoprotein deficiency is detected), and peripheral blood smears (acanthocytosis is seen).
•If Kearns–Sayre syndrome is suspected, the patient must be examined by a cardiologist with sequential ECGs; patients can die of complete heart block.
Treatment
For syphilis, see 12.12, Syphilis. For vitamin A deficiency, see 13.7, Vitamin A Deficiency.
No definitive treatment for RP is currently known. However, vitamin A palmitate, 15,000 IU, has been shown to slow reduction of ERG. This very controversial treatment (which showed no visual benefits) is recommended only for nonpregnant patients >21 years of age. Monitor liver function test results and vitamin A levels.
Cataract surgery may improve central visual acuity. Oral acetazolamide (500 mg/day) may be effective for CME.
All patients benefit from genetic counseling and instruction on how to deal with their visual handicaps. Tinted lenses may provide comfort outdoors and may provide better contrast enhancement. In advanced cases, low-vision aids and vocational rehabilitation are helpful.
Similar fundus appearance
Phenothiazine toxicity
o—Thioridazine (e.g., Mellaril)
Pigment clumps between the posterior pole and the equator, areas of retinal depigmentation, retinal edema, visual field abnormalities (central scotoma and general constriction), depressed or extinguished ERG. Symptoms and signs may occur within weeks of starting phenothiazine therapy, particularly if
very large doses (>2,000 mg/day) are taken. Usually, more than 800 mg/day chronically needed for toxicity. Discontinue if toxicity develops. Follow every 6 months.
o—Chlorpromazine (e.g., Thorazine)
Abnormal pigmentation of the eyelids, cornea, conjunctiva (especially within the palpebral fissure), and anterior lens capsule; anterior and posterior subcapsular cataract; rarely, a pigmentary retinopathy within the visual field and ERG changes described for thioridazine. Usually, 1,200–2,400 mg/day for longer than 12 months needed for toxicity. Discontinue if toxicity develops. Follow every 6 months.
Syphilis: Positive FTA-ABS, asymmetric visual fields, abnormal fundus appearance, may have a history of recurrent uveitis, no family history of RP; the ERG is usually preserved to some degree.
Congenital rubella: A salt-and-pepper fundus appearance may be accompanied by microphthalmos, cataract, deafness, a congenital heart abnormality, or another systemic abnormality. The ERG is usually normal.
Bietti crystalline dystrophy: Autosomal recessive condition characterized by crystals of unknown composition in the peripheral corneal stroma and in the retina at different layers. Can cause choroidal atrophy, decreased night vision, decreased visual acuity, and a flat ERG.
After resolution of an RD: e.g., toxemia of pregnancy or Harada disease. The history is diagnostic.
Pigmented paravenous retinochoroidal atrophy: Paravenous localization of RPE degeneration and pigment deposition. No definite hereditary pattern. Variable visual fields and ERG (usually normal).
After severe blunt trauma: Usually due to spontaneous
resolution of RD.
After ophthalmic artery occlusion.
Carriers of ocular albinism: See 13.8, Albinism.
Note：The pigment abnormalities are at the level of the RPE with phenothiazine toxicity, syphilis, and congenital rubella. With resolved RD, the pigment is intraretinal.
Hereditary Chorioretinal Dystrophies And Other Causes Of Nyctalopia (Night Blindness)
•Gyrate atrophy: Nyctalopia and decreased peripheral vision usually presenting in first decade of life, followed by progressive contriction of visual field. Scalloped RPE and choriocapillaris atrophy in the midperiphery during childhood that coalesces to involve the entire fundus, posterior subcap-sular cataract, high myopia with astigmatism. Constriction of visual fields and abnormal to nonrecordable ERG. Plasma ornithine level is 10 to 20 times normal; lysine is decreased. Consider ERG and IVFA if the ornithine level is not markedly increased. Autosomal recessive.
Treatment
•Reduce dietary protein consumption and substitute artificially flavored solutions of essential amino acids without arginine (i.e., arginine-restricted diet). Monitor serum ammonia levels.
•Supplemental vitamin B6 (pyridoxine). The dose is not currently established; can try 20 mg/day p.o. initially and increase up to 500 mg/day p.o., if there is no response. Follow serum ornithine levels to determine the amount of supplemental vitamin B6 and the degree to which dietary protein needs to be restricted. Serum ornithine levels between 0.15 and 0.2 mmol/L are optimal.
Note：Only a small percentage of patients are vitamin B6 responders.
•Choroideremia: Males present in the first to second decade of life with nyctalopia, followed by insidious loss of peripheral vision. Decreased central vision occurs late. In males, early findings include dispersed pigment granules in the periphery with focal areas of RPE atrophy. Late findings include total absence of RPE and choriocapillaris. No bone spicules. Retinal arteriolar narrowing and optic atrophy can occur late in the process; constriction of visual fields, normal color vision, markedly reduced ERG. Female carriers have small, scattered, square intraretinal pigment granules overlying choroidal atrophy, most marked in the mid-periphery. No effective treatment for this condition is currently available. Darkly tinted sunglasses may ameliorate symptoms. X-linked recessive. Consider genetic counseling.
•Vitamin A deficiency: Marked night blindness; numerous small, yellow–white, well-demarcated spots deep in the retina seen peripherally; dry eye and/or Bitôt spots (white keratinized lesions) on the conjunctiva. See 13.7, Vitamin A Deficiency.
•Zinc deficiency: May cause abnormal dark adaptation (zinc is needed for vitamin A metabolism).
•Congenital stationary night blindness: Night blindness from birth, normal visual fields, may have a normal or abnormal fundus, not progressive. Paradoxic pupillary response. One variant is Oguchi disease, characterized by the Mizuo phenomenon—the fundus has a tapetum appearance in the light-adapted state, but appears normally colored when dark-adapted (takes about 12 hours). See Figures 11.28.2 and 11.28.3.
•Undercorrected myopia: May be the most common cause of poor night vision.。