Transcript Cryptococcal meningitis隐脑

case report
昆明医学院第二附属医院皮肤科
2012 年3月14日
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• In-patient Case History
• Pathogenesis and clinical
manifestation
• Diagnosis
• Differential Diagnosis
• Treatment
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Gender:female
Date of birth: 1990-12-08
Nation:Han
Occupation: farmer
Native place: Yuxi city Chengjiang county
Yunnan province
• Chief complaint: anasarca with chest
discomfort and breathlessness for 3
months, fever and headache 1 month.
Present illness
• In 2011 October,the patient was in late trimester
of pregnancy. From that time, she presented
with swelling on bilateral lower extremities,
accompanied by chest discomfort
,breathlessness and erythematous rash on
fingers and toes. She presented at the local
hospital .Routine urine test reveals :protein
(+++),WBC+++,RBC+++, 24 hour urinary protein
4.1g/day , BUN 8.4mmol / L, creat 148umol / L,
mixed hyperlipidemia, complete blood count
reveals anemia.
Present illness
• Complements are decreased, ANA +, AntidsDNA +, Anti-Sm-Ab +.she underwent induced
abortion and had a stillbirth. She was then
diagnosed to have systemic lupus
erythematosus. Methylprednisolone 500mg/day(
period unknown) and cyclophosphamide was
given (daily dosage of 200mg-600mg / d,
duration and total dosage unknown). She also
had fever with cough during the treatment, Blood
cultures grew Cryptococcus laurentti.
Intravenous fluconazole was given as anti fungal
therapy. The patient improved after treatment
and was discharged.
Present illness
• While outpatient, she took fluconazole tablets
100mg / d for nearly 2 weeks and subsequently
was non compliant. In January 2012,the patient
experienced fronto-parietal headache after an
episode of common cold, which was persistent
and paroxysmal with vomitting and nausea. She
also had fever and a body temperature of 38.5
degrees Celsius with fluctuations. She was then
readmitted. Lumbar puncture was performed
and the cerebrospinal fluid examination revealed
an elevated white blood cell count and a
depressed CSF glucose level.
Present illness
• CSF chloride levels were significantly
lower than that of normal. The CSF
protein level was significantly elevated.
The local hospital considered the possible
diagnosis of tuberculous meningitis, and
rifampicin and pyrazinamide were started
as anti-tuberculosis treatment for 2 days
without improvement. She then requested
for a transfer to our hospital for further
treatment.
Present illness
• Between 2011 December - 2012 January,
patient had been using low to moderate
doses of prednisone tablets (15mg-50mg /
d). One week before admission to our
hospital, the prednisone was stopped. In
the course of illness, patient complained of
anorexia, insomnia. The history was
negative for syncope, psychiatric, bladder
or bowel abnormalities.
Past History
• Her past medical history was negative for
cardiopulmonary disorders, diabetes
trauma,and other chronic diseases,. There
was also no past surgical history. There
was no past history of blood transfusions.
She denies a history of hepatitis and
typhoid infection. There was no known
drug allergy. Her immunization history was
not known.
Personal History
• She was born in Yuxi city Chengjiang
county Yunnan province.
• She completed the sixth grade in primary
school.
• She denies smoking and drinking.
• There is a possible history of exposure to
pigeons in her living environment.
Menstrual and Marriage History
• She had menarche at the age of 13 with a
cycle length of 30 days and a period
lasting three days each time.
• The last menstrual period was 11 Jan
2012.
• She got married at 20.
• G1P0. A history of stillbirth.
Physical examination
• T 37 degrees C, BP150 / 98mmHg,
HR102bpm,Weight 47Kg. Ill looking / toxic
appearance, alert, oriented to time ,space and
person. She can carry out addition and
subtraction within 10. Short term 3 item recall
was intact. There was decreased hearing in the
left ear. There was neck stiffness, with
symmetrical pupils. Bilateral light reflex was
slightly sluggish. Pharynx examination revealed
reactive hyperaemia. Four areas of erosions
about 1 – 2 mm on the hard palate as well as
three papules measuring about 1 -2 mm on the
floor of the mouth were seen / observed .
Physical examination
• Bilateral lung respiratory sounds were slightly
coarse and there were no rhonchi nor rales. She
had a heart rate of 102 beats / min with no
cardiac murmur. The abdomen is soft, with mild
tenderness that is vaguely localised. Liver
percussion tenderness was negative. Bowel
sounds were normal. Neurological examination:
Signs of meningismus were positive. She had
bilateral hyperreflexic knee jerks as well ankle
clonus. Primitive reflexes were not present. All 4
limbs had muscle power of 4 with normal muscle
tone.
Specialist examination
• Tiny dark red macules were noticed on the
tips of all the toes on both feet
Laboratory and imaging
examination
Table 1 Imaging examination
Table 1 Imaging examination
Table 1 Imaging examination
The final diagnosis
• 1.Cryptococcal meningitis
• 2.Systemic lupus erythematosus
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Pathogenesis and clinical
manifestation
• Cryptococcal infection commonly occur in
immuno-compromised patients. SLE patients
have existing abnormal humoral immunity and
cell mediated immunity. The complement levels
are decreased, the T lymphocyte counts are
reduced with other abnormalities, especially
during active SLE flares. Corticosteroids（皮质
激素） and immunosuppressive agents（免疫抑
制剂）are typically used in the treatment of SLE,
especially during the acute flares.
Pathogenesis and clinical
manifestation
• Glucocorticoids（糖皮质激素） can
weaken the inflammatory reaction，impair
lymphocytic function，resulting in cell
mediated immunity dysfunction. It can also
reduce humoral immunity and
complements.
Pathogenesis and clinical
manifestation
• Clinically，SLE complicated with cryptococcal
infection can present as a subacute or chronic
illness. When cryptococcal (cryptococcus
neoformans ) dissemination occurs, the
organism has a special affinity for the CNS. It is
the most common cause of mycotic meningitis.
There may be restlessness[‘restlisnis]烦躁不安 ,
hallucinations[hə,lu:si’neiʃən] 幻觉, depression,
severe headache, vertigo眩晕, nausea恶心 and
vomiting, nuchal rigidity颈强直, epileptiform
[,epi‘leptifɔ:m] seizures['si:ʒə]癫痫样发作, and
symptoms of intraocular hypertension.
Pathogenesis and clinical
manifestation
• Other organs, such as the liver, skin, spleen, as well
as the lymph nodes, may be involved. Disseminated
cryptococcosis can present in many organ systems;
hepatitis[,hepə‘taitis] 肝炎,
osteomyelitis[’ɔstiəu,maiə‘laitis] 骨骼系统, prostatitis前
列腺炎 pyelonephritis[,paiələuni’fraitis,]肾盂肾炎,
peritonitis[,peritə‘naitis] 腹膜炎, and skin involvement
have all been reported as initial manifestations of
disease. The incidence of skin involvement in cases of
cryptococcosis is between 10% and 15%, although it
is lower in the HIV infection population. Cutaneous
lesions may precede overt systemic disease by 2 to 8
months.
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Diagnosis
• The diagnosis is based mainly on clinical manifestation,
signs and laboratory examinations. Microbiological tests
are diagnostic.
• 1 cerebrospinal fluid (脑脊液 CSF)routine
examination :
CSF is usually clear. May be cloudy when (浑浊) there is
a large amount of cryptococcus ; the pressure is usually
elevated (300mmH20-900mmH20); leukocyte count（
白细胞计数）is usually increased (90%); the total protein
is increased (＜2g/L); both glucose and chloride(氯化物)
levels are decreased. The glucose levels are usually
significantly decreased (0).
Diagnosis
• CT and MRI:
• CT and MRI are not specific. Occasionally,
cryptococcal infection may present as an
intracranial space-occupying lesion.
• Possible changes on chest X-ray :
• hilar lymphadenopathy (肺门淋巴结肿大)
、patch /miliary infiltration 、cavitation
and pleural effusion (胸膜渗出).
Diagnosis
• Microbiological examination:
• (1)
• A: CSF smear and staining using
China/India ink : bright cryptococcus can
be found using Light Microscopy.Direct
microscopic examination of India ink
preparations of cerebrospinal fluid (CSF)
has not been fully satisfactory in making a
rapid diagnosis of cryptococcal meningitis
because its sensitivity in known cases is
53 to 56% even with serial examinations.
• B:microscopic
examination of
centrifuged
cerebrospinal fluid
sediment : microscopic
examination of
centrifuged and stained
CSF sediments results
in a higher sensitivity
(80%) for Cryptococcus
than the India ink test. It
also needs serial
examinations.
Diagnosis
• (2) CSF cytologically(脑脊液细胞学)
examination: the sensitivity is beteewn 84％-100
％. 早期多呈混合细胞学反应或以淋巴细胞反应为
主的混合细胞学反应，少数可呈以嗜中性粒细胞
反应为主的混合细胞学反应，可见成堆出现的隐
球菌。脑脊液经细胞玻片离心后，对所收集物行
MGG染色，常可在脑脊液标本中直接发现隐球菌
，菌体圆形，直径5-20微米不等，常于菌体上长
出较小的芽孢而呈葫芦状或哑铃状，有时可见菌
体周围呈针刺样辐射。菌体数量多时常成堆，成
簇排列，为紫红色，无核，周边染色较深，由于
菌体荚膜不着色，故大小不等的菌体间保持等距
离分布。
• 菌体数量少，单个散在分布时不易与小淋巴细胞
鉴别。首次检出阳性率为84％．阿利新兰染色对
于隐球菌是特染，荚膜被染成深蓝色，菌体呈淡
蓝色，而周围的炎性细胞不着色，因此染色对比
清晰，当隐球菌数目少时更容易观察，检出阳性
率在80％左右。
Diagnosis
• (3) fungal culture: the CSF fungal culture
was positive for cryptococcus(gold
standard). Although the the sensitivity is
＞90%.It is hard to make early diagnosis
because the method needs a long time (58days) and there may be false negatives.
目前已明确，黑素是新型隐球菌产生的一
种重要的毒性因子。利用产黑素培养基可
快速鉴定新型隐球菌，国内报道最快者在
1h 内即产生黑素。
• (4) detection of cryptococcal antigen:
• The latex agglutination test（乳胶凝集试验）
has been shown to be useful in the early
detection of CSF(99％)and serum (8o％
)cryptococcal capsular polysaccharide
antigen(隐球菌荚膜多糖抗原).When the titer＞
1:8 has diagnosis significance.
• (5) animal inoculation.： It is hard to make
early diagnosis because the method needs a
long time .
Diagnosis
Diagnosis
• 4 Gene Diagnosis: PCR
• PCR技术已经发展成为一种较为成熟而又
敏感快速的临床诊断方法，被公认为诊断
的发展方向。不论在阳性检出率，还是临
床符合率，均明显优于直接涂片墨汁染色
和真菌培养，但存在一定的假阳性
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Differential Diagnosis
一、结核性脑膜炎(tuberculous meningitis，
TBM)
TBM简称结脑，是由结核杆菌（Mycobacterium
tuberculosis，TB）侵入蛛网膜下腔，引起的软脑
膜、蛛网膜，进而累及脑实质和脑血管的病变。为全
身播散性粟粒性结核（miliary tuberculosis）的一
部分，也可继发于肺、淋巴结、骨骼或泌尿系统等结
核病灶引起的菌血症（bacteremia）。此外，TB还
可以从颅骨或脊椎的的结核病灶直接破溃入颅内或椎
管内引起TBM。
• TBM多见于儿童，但目前约半数以上的患
者为成年人。TBM是发展中国家最常见的
亚急性脑膜炎（Subacute meningitis）
• TBM 的诊断标准:
• ①既往有结核病史；
• ②呈急性或亚急性起病，伴有低热、盗汗、消
瘦及急性脑膜炎的症状和体征；
• ③CSF 中的葡萄糖、氯化物降低和细胞计数
、蛋白质升高；
• ④CSF 结核分枝杆菌培养阳性， 或CSF 涂片
抗酸染色（acid-fast stain）阳性或CSF 结核
分枝杆菌PCR 检测结果呈阳性；
⑤有神经系统外结核病灶证据；
⑥经抗结核治疗好转或痊愈。并排除其他病原
体引起的脑膜炎。
Differential Diagnosis
• Cryptococcal meningitis（CM）隐脑与TBM的不同
之处：
• ①起病比TBM更慢，病程比TBM更长，有时症状可
自行缓解，结核性脑膜炎症状出现快，而且重；
• ②一般以头痛为首发症状，颅内压增高（
increased intracranial pressure）常较显著，头
痛剧烈而发热不明显，而TBM发热出现较早；
• ③脑脊液检查常呈“三高一低”，即压力高、
蛋白高、以淋巴细胞增高为主的细胞数多
，糖减低，值得注意的突出特点为脑脊液
中糖含量明显降低，往往是愈后不良的标
志，可能与大量隐球菌造成糖大量酵解有
关系；
• ④脑ＣＴ及ＭＲＩ检查所见多为脑积水、
脑萎缩及灶性密度增高，一般缺乏特异性
，但TBM脑积水的发生率高、程度重。且
在发病早期即可出现。
• 2007年国内有报道对327例TBM和96例CM
进行临床分析显示：96例CM病人中，有46
例(占48%)有鸽类或家禽接触史。TBM的
CSF微量蛋白升高明显高于CM，TBM氯化
物降低明显高于CM，且有统计学意义。
CM的CSF压力升高比TBM明显，且有统计
学意义。
Differential Diagnosis
• 总之，CM与TBM在症状、脑脊液检查、ＣＴ 及ＭＲ
Ｉ检查方面非常相似，诊断极易发生混淆, CM 的误
诊率在70% 以上。多数CM 被误诊为TBM 而进行抗
结核治疗。由于糖皮质激素（glucocorticoids）与脱
水剂（osmotic diuretic）的应用, 患者的颅内高压表
现可暂时得到缓解, 医师往往误认为抗结核治疗有效
致使诊断进一步延误。二者的鉴别需依据相应的症状
特点，结合ＰＰＤ试验、抗结核治疗效果等多方面来
考虑。确诊要靠病原学证据，脑脊液墨汁染色或培养
找到隐球菌。1次阴性不能否定诊断，多次检查后可
提高阳性率。
Differential Diagnosis
•
二、红斑狼疮性脑病（lupus erythematosus
encephalopaathy，LEE）
LEE是系统性红斑狼疮（systemic lupus erythematosus，SLE）侵犯中枢神经系统常见的表现。
LEE 的主要病理基础是广泛的微血栓（microthrombus）和血管炎（vasculitis）所致大脑半球及
脑干组织的变性、水肿、软化, 甚至坏死, 主要引起
小动脉和毛细血管的反应性增生性改变, 导致脑皮
质、脑白质以及脑干多发性微梗死、较大梗死、颅
内出血( 脑出血、蛛网膜下腔出血或硬膜下出血)
及脱髓鞘改变、脑萎缩等为主要表现。
临床表现包括癫痫（epilepsy）、脑血管
意外（cerebrovascular accident）、颅
神经病变、颅内压增高及脑膜炎等神经症
状，可出现精神异常、意识障碍等。
• LEE 目前的诊断标准为SLE患者出现不同
的神经精神异常，并附加以下任何一项即
可诊断:①脑电图（electroencephalogram
）异常;②脑脊液异常;③排除精神病、高血
压、颅内感染、尿毒症脑病及激素等药物
治疗过程中出现的神经精神异常等原因。
• LEE的CSF检查常发现CSF压力升高, 白细
胞增高, 以淋巴细胞增高为主, 蛋白定量增
高, 糖及氯化物正常, 脑脊液白蛋白/血清白
蛋白比率上升。
• CT 及MR I是本病诊断的重要依据。弥漫型
系统性红斑狼疮脑病影像学表现多正常或
轻度损害。局灶型多有大片脑梗死（
cerebral infarction）、脑出血等局灶性损
害,CT表现为局限性低密度灶( 梗死)或高密
度灶( 出血);MRI 异常占74%表现为基底核
区、尾状核头部及内囊区单发或与弥漫性
病变并存的局灶性异常信号。
Differential Diagnosis
• 3．脑肿瘤（cerebral tumor）：隐脑颅内
压增高明显, 眼底较多出现视乳头水肿（
papilledema）, 故需与脑肿瘤鉴别。脑肿瘤
起病较隐脑缓慢, 颅内压增高显著, 而隐脑
常以发热、食欲不振等全身症状起病, 有明
显的脑膜刺激征, 脑脊液呈炎性改变, 而脑
肿瘤脑脊液细胞大都正常。对可疑脑肿瘤
者行CT脑扫描, 磁共振检查可确诊。
Differential Diagnosis
• 4．癌性脑膜炎（neoplastic meningitis）癌
性脑膜炎是颅内肿瘤的一个特殊类型, 其发
病率占全身癌转移患者的5%-8%。
• 病因：主要是全身其他部位癌通过血行扩
散, 局部直接侵犯或颅内手术时肿瘤细胞污
染软脑膜发生弥漫性蛛网膜下腔浸润所致
。
• 临床表现：患者因癌细胞浸润形成局限性
瘤结节或广泛性软脑膜癌病使脑脊液回流
受阻形成脑积水,引起颅压升高产生相应脑
神经及脊神经根受损症状和体征,故其临床
表现复杂多样且无特异性, 多以头痛、呕
吐等颅高压表现为首发症状, 部分患者可
以出现癫痫和意识及智力的改变, 神经系
统症状和体征没有特异性表现, 而且影像
学不一定都有典型的表现, 如果通过脑膜
病理活检或脑脊液中发现恶性肿瘤细胞,
说明脑膜已广泛转移, 也可以作出明确的
诊断。
• 检查：以影像学和脑脊液脱落细胞学检查为诊
断的主要手段, 影像学中癌性脑膜炎患者CT检
查可见脑膜增厚及脑室扩大, 增强或MRI可见
脑池室管膜、脑膜或脊膜有线形、薄片样或结
节样异常信号灶。脑脊液脱落细胞学检查前三
次的阳性率可达到80% ~ 90%,成为诊断该病
的一个常规检查。
• 其它疾病：有化脓性脑膜炎、病毒性脑膜炎、
脑脓肿、脑血管病、脑炎、等亦需与隐脑鉴别
, 除根据详细病史、症状和体征外, 作有关辅
助检查可助鉴别。
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Treatment
• The misdiagnosis rate of cryptococcal
meningitis is high. The keys to reduce mortality
are raising vigilance, early diagnosis, rational
use of antifungal drugs, effectively lowering the
intracranial pressure,and prevent recurrence.
Treatment
• The antifungal drugs are the main drugs to
control cryptococcal meningitis. At present,
the drugs commonly used are polyenes(多烯
类)as:amphotericin B(两性霉素B）、AM
Bison（两性霉素B脂质体）azolederivative（
吡咯类）as:fluconazole（氟康唑）、
Itraconazole（伊曲康唑）、voriconazole（伏
立康唑）et.al and nucleoside analogue（核苷
类似物）as：flucytosine(氟胞嘧啶)；
Acrylamide（丙烯酰胺类）as：Terbinafine（
特比奈芬）。
Treatment
• We advise that the use of antifungal drug
should in accordance with stage and drug
combination .that is two stage of induction
treatment and maintenance treatment.the
induction treatment is commonly last 8
to12 weeks, use the amphotericin B
combine with flucytosine(or
azolederivative) in order to make the
cryptococcus turn to negative in
cerebrospinal fluid quickly.
Treatment
• As the cryptococcus turn to negative in
cerebrospinal fluid,the pation can take the
oral azole derivatives for 3 to 4 months so
as to prevent the recurrence. In add ition,
Continuous intrathecal administration(椎管
内持续给药)and intrathecal injection of
ampho B can enhance the drug
concentration in the CSF and maintain a
stable and effective drug level for
treatment of cryptococcal meningitis.
Treatment
• The classical treatment is combination
therapy of amphotericin B/Lipo-AMB
(0.7mg/kg.d)and flucytosine(100mg/kg.d)
intravenously infusion, and then followed
by the maintenance therapy of oral
fluconazole. The induction treatment last 2
weeks, and then followed by the
maintenance therapy of fluconazole
(400mg/d)orally administration for at least
10 weeks. After 2 weeks of induction
treatment, perform lumbar puncture to
ascertain that the CSF is now negative for
cryptococcus.
Treatment
• If CSF is still positive at 2 weeks,we
should prolong induction treatment. Due to
the high toxicity and difficult administration
,intrathecal administration(椎管内持续给药
)and intrathecal injection is only used in
patients with systemic anti fungal therapy
failure.
谢 谢！