Case Discussion

A 22-year-old lady, an aboriginal Taiwanese, was admitted because of rapidly deteriorated consciousness in three days with intermittent fever. This 22-year-old kindergarten teacher, living in Taipei county, is a patient of systemic lupus erythromatosus (SLE) diagnosed at anonther hospital three years ago, with the initial presentation of spontaneous gum bleeding, high fever, malar rash, and discoid rash over trunk and both thighs. Positive antinuclear antibody (ANA) and decreased serum complement level were noted. Her presentation met the revised American Rheumatology Association (ARA) criteria for SLE. She took prednisolone of 15 mg/day ever since with only a few episodes of arthritis over ankle, knee, wrist, distal, middle interphalengeal and metacarpophalengeal joints intervening. No other events of disease flaring-up were noted, prednisone was therefore tapered to 10 mg/day. She ever experienced an episode of bacterial meningitis in this early January. The clinical presentation included fever, nausea/vomiting and neck stiffness. The cerebrospinal fluid (CSF) examination revealed polymorphonuclear cells predominant pleocytosis, decreased glucose level and elevated protein level. She was put on ampicillin plus ceftriaxone and then shifted to vancomycin plus ciprofloxacin because of beta-lactam related leukopenia. She was discharged later without major neurological sequelae. One episode of URI-like symptoms (rhinorrhea, mild cough, and sore throat) developed about one week before this admission. Three days later, her consciousness became drowsy and decreased physical activities were also noted. One episode of spontaneous epistaxis took place in the next day. She was brought to a LMD, where local treatment was applied and epistaxis stopped. However, persistent high fever with more deteriorated consciousness occurred in the morning of 2/10 (one day before admission). Several episodes of misnaming and decreased movement of her right limbs were noted by her mother later. No headache, nausea or vomiting was found. She was sent to our ER for help. On physical examination, the temperature was 39℃, the pulse rate was 120/min and the respiratory rate was 20/min. The blood pressure was 94/60 mmHg. The patient was drowsy but arousable (E3M5V3) and appeared acutely ill. Plenty of erythematous, discoid maculopapular lesion was noted over malar area. The pharyngeal wall was injected with whitish coating over left pillar. The neck was mildly stiff (chin to chest 3 fingerbreadth) and the carotid pulses were ++, without bruits. Grade I goiter was palpated. There was no lymphadenopathy, ecchymosis or petechiae. The lungs were clear and the heart sounds were normal. Abdominal examination was normal; the liver and spleen were not palpable. There was a few erythematous discoid maculopapular lesion of size 1×1 cm over medial side of bilateral thighs; no cyanosis, no clubbing or peripheral edema was present. Rectal examination revealed normal sphincter tone. On neurological exam, though the patient was arousable and could responded by murmuring, she could not fully follow our verbal order. Her vision appeared to be preserved, with full extraocular movements. The pupils were isocoric and reactive; there was a questionable right ptosis. The nasolabial fold was symmetric and the tongue was not deviated. The remaining cranial nerves were intact. Her muscle power test was impeded by her deeply-drowsy consciousness; the deep-tendon-reflex was symmetric, though the lower extremities showed diminished response (1+/1+), as compared with upper ones (2+/2+). Laboratory data at ER showed: hemogram WBC: 3680, Hb: 8.8, PLT: 129k; biochemistry: BUN/Cre: 15/0.9, Na: 141, K: 6.0 (H2+), Ca:1.9. Brain CT scan was performed before lumbar puncture and did not show any hemorrhage or any hypodense lesion. CSF study later at ER disclosed (Cell count 11, L/N: 7/4, RBC (-), Sugar: <30, Pandy’s test (+), Nonne-Apelt’s test (+)). The high fever persisted and she still remained drowsy. <Lab data> Hemogram   WBC Hb PLT Seg Band Meta My CRP 2/10(ER) 3680 8.8 129k 88.4%         2/14 3430 8.9 103k 85.8%         2/16 5310 11.0 162k 77%       5.03 2/19 7350 8.5 150k 64% 1% 6% 4%   2/24 9190 9.9 205k 67% 3% 4% 3% <0.01 CSF studies   Pressure (mmH2O) Character Cell (L/N) Pandy N-Apelt Sugar (serum) Protein (mg) Culture 2/10 150/110 Clear, 11(7/4) + ++ <30( only routine) nil Nil 2/14 84/80 Clear 0 + + 66(125) 144 No growth 2/24 54/10 Clear, 2(2/0) + + 74(130) 67 No growth Biochemistry   AST/ALT rGT/ALP Bil (T/D) BUN creatinine Na K Cl Ca 2/10       15 0.9 141 6.0 (H2+) - 1.9 2/12       13 1.0 141 4.1 107 1.44 2/14 105/49 438/233 0.4/0.2 9.3 0.8 141 4.0 111 1.77 2/16 46/36 544/252   11.4 0.8 140 4.3 111 1.95 2/19 45/37 536/311 0.4/0.2 15.5 0.6 133 4.5 -- 1.97 2/24 72/72 1108/688 0.5/0.2 20.8 0.7 136 4.4 -- 2.19 2/29 29/46 800/482 0.5/0.2 25.6 0.6 135 4.0 -- 2.29 3/4 20/37 408/284 0.4/0.2 16.5 0.6 137 3.9 -- -- ECG: normal sinus rhythm. No ST-T changes Coagulation profile PT: 13.8/12.3 PTT: 49.6/39.4 FDP: 10-20 D-D dimmer: 2.01 3P: negative dRVVT: negative, antiphospholipid antibody: negative anticardiolipin antibody: negative Serology:   C3 C4 Anti-dsDNA 2/12 28.7 <6 492 2/25 38 <6   3/4 61.4 6.8 419 EEG: Diffuse slow wave. Thyroid function: free T4: 0.59; TSH: 0.705 Hepatitis profile: Anti-HBs Ab: +; HBeAg: negative; Anti-HCV Ab: negative Viral isolation of Herpes simplex and enterovirus: negative Enterovirus antibody type 70 (paired serum): negative HTLV-1 antibody (paired serum): negative <Course and treatment > She was put on intravenous Amoxicillin/clavulanate (Augmentin) and fluconazole (Diflucan) at first for suspected tosillopharyngitis. But the clinical condition did not improve. The CSF examination revealed lymphocyte predominant pleocytosis and decreased glucose level. The antibiotics was therefore shifted to ciprofloxacin and vancomycin. Solu-medrol, 80 mg/day, was also used at the same time. The clinical condition did not improved. Repeated lumbar puncture disclosed cell-protein dissociation. The dosage of solu-medrol was increased to 160 mg/day under the impression of high activity of SLE. Brain MRI (T2WI) disclosed abnormally high signal along periventricular system and multiple lesions at brain stem and pons. But there was no meningeal enhancement. Viral encephalitis was suspected by neurologist and neuroradiologist. Acyclovir was added therefore. However, her consciousness had improved 2 days before the use of acyclovir. As the consciousness became more clear on the 5th day, asymmetric paraparesis (right lower extremity: 2/5, left lower extremity: 3/5) and bilateral positive Babinski’s sign developed. Areflexia over bilateral lower limbs was also noted. Severe parasthesia (numbness and severe pain with light touch) over right leg and foot was complained. Severe wasting of bilateral calf muscle (within 10 days) was also noted. No sphincter dysfunction developed. Neurophysiologic studies including nerve conduction velocity (NCV), F-wave and H-reflex documented polyradiculoneuropathy with severe axonal degeneration. The patient became quite clear in about 7 days. All antimicrobial agents were discontinued, as the CSF showed no evidence of infection, except high protein content. MRI follow-up on the 14th day disclosed complete resolution of previously high-signal area, but the patient’s paraparesis improved slowly. She was finally diagnosed to have neuropsychiatric lupus with the involvement of peripheral nervous system (axonal, motor type). But the contribution of other unknown viral infection could not be totally excluded. 請參考腦部MRI圖

繼續教育考題

1. (D)	In encountering a SLE patient with oral steroid therapy presenting as consciousness disturbance (as our patient), what should we take into consideration? Which of the following is the least likely ?
	A	CNS infection;
	B	Metabolic or drug effect;
	C	CNS lupus;
	D	Brain tumor
	E	Cerebral vascular accidents
2. (C)	Which further laboratory or imaging study would you like to arrange for this patient after thorough history-taking, physical examination, baseline hemogram and biochemistry? a. EEG b. CSF studies c. Brain CT scan d. Cerebral angiography e. PET scan
	A	a, b, c, d;
	B	c, d, e;
	C	a, b, c;
	D	b, d, e;
	E	b, c, d
3. (B)	In the light of CNS infection in an SLE patient, which specific pathogen should we think of, based on her clinical presentation, underlying disease, and initial CSF data, in addition to common pathogens ?
	A	Cryptococcus neoformens;
	B	Mycobacterium tuberculosis;
	C	Listeria monocytogenes;
	D	Legionella pneumophila;
	E	Herpes simplex virus
4. (E)	What are the possible causes of Cell-protein dissociation of our patient’s CSF studies? a. Bacterial meningitis b. TB meningitis c. Viral meningitis or meningoencephalitis d. CNS lupus e. Myelitis f. Severe polyradiculoneuropathy
	A	c, e, f;
	B	b, e;
	C	c, e;
	D	c, f;
	E	d, f
5. (C)	After examining her MRI film, what action would you take next ? (The patient has been put on Ciprofloxacin + Vancomycin for 2 days) a. Shift to more aggressive abx: Imepenam and Cilastatin + Teicoplanin + Amphotericin B b. Increase dose of Solu-medrol c. Add acyclovir d. Arrange cerebral angiography e. Consult neurosurgeon for emergent operation
	A	a, b, c;
	B	b, d, e;
	C	b, c;
	D	d, e;
	E	a, c
6. (A)	The most important and clinically available markers of SLE activity are a. C3; b. C4; c. Anti-dsDNA d. Leukocyte count e. Antinuclear antibody (ANA)
	A	a, b, c;
	B	b, d, e;
	C	b, c, d;
	D	d, e;
	E	a, d
7. (A)	Which agents do not belong to beta-lactam antibiotics (and may be used in patients with allergy or severe drug reactions to beta-lactam antibiotics)? a. Ciprofloxacin b. Vancomycin c. Ceftriaxone d. Ampicillin e. Imipenem
	A	a, b;
	B	c, d, e;
	C	b, c, d;
	D	d, e;
	D	a, d
8. (E)	Which manifestations may suggest bacterial meningitis?
	A	Fever with severe headache;
	B	Neck stiffness
	C	Fever associated with consciousness change or seizures
	D	Turbid cerebrospinal fluid
	E	All of above
9. (A)	Which agent is the most suitable empirical therapy for sporadic (i.e. not epidemic) viral encephalitis?
	A	acyclovir
	B	ganciclovir
	C	famciclovir
	D	wait for the results of brain MRI
	E	wait for the results of viral isolation from cerebrospinal fluid
10. (E)	What is the impact of SLE on pregnancy?
	A	Increase incidence of spontaneous abortion
	B	Increase incidence of fetal death in utero
	C	Increase incidence of prematurity
	D	Lupus activity may exacerbate during the third trimester or peripartum period
	E	All of above

病案分析及試題解說

此病患為一系統性紅斑性狼瘡 (systemic lupus erythematosus¸SLE) 的患者¸此自體免 疫疾病 (autoimmune disease) 原本就會影響T淋巴球的功能¸再加上長期使用類固醇¸使得其 T淋巴球功能更是雪上加霜¸導致細胞性免疫的功能嚴重缺損。所以¸若在此時出現了發燒及中 樞神經功能障礙¸首先必須考慮的鑑別診斷¸除了一般會想到的狼瘡中樞神經侵犯 (現今主流 的講法為Neuropsychiatric lupus, NPLE) 所導致的血管病變 (vasculopathy)，或自體免疫 抗體對神經元攻擊造成功能缺損以外¸還要考慮到與細胞性免疫缺損有關的各種中樞神經感染 ¸例如¸結核性腦膜炎 (Tuberculous meningitis)¸隱球菌腦膜炎 (Cryptococcal meningitis)¸ 以及少見的李斯特菌 (Listeria monocytogenes) 感染等。當然¸即使是正常免疫功能的人都 可能發生的細菌性腦膜炎及病毒性腦炎也得小心考慮。因此¸儘速安排腦部電腦斷層檢查 (Brain CT scan) 及脊髓液檢查 (lumbar puncture with cerebrospinal fluid analysis) 是必要的。 Neuropsychiatric lupus, NPLE的病人有將近六成會以癲癇的發作來表現，因此腦波圖（EEG） 的檢查也有其必要性，雖然大部份時候結果多半是diffuse slow wave or diffuse cortical dysfunction，但卻也常可以檢測到沒有臨床表現的癲癇活性，而且在治療過籌中的腦波追蹤 ，也可以讓我們多一項簡單， 不昂貴，非侵襲性的療效指標。雖然說，NPLE 的肇因可能是來 自狼瘡血管病變，但是這些病灶絕大多數是位在小血管，而且在過去腦部病理解剖的案例中並 沒有發現因發炎而血管阻塞，造成類似腦梗塞的證據。目前的說法以比較偏向是局部血管病變 造成permeability的增加所引起的，因此血管攝影的考慮比起MRI就應該是在其後了。當然， 如果該病人有抗磷脂症候群(Antiphospholipid syndrome)，則大血管栓塞的機率就會提高， 但這些懷疑都可以先由各種不同sequence的MRI來加以過濾，血管攝影的角色應該擺在用來確 定MRI上高度懷疑大血管或靜脈竇有栓塞的病人。正子放射攝影術(PET)一則昂貴，二則其結果 和臨床的結合，仍在爭議中，所以目前並不適合常規地使用於臨床上。 另外我們發現這個病人的脊髓液有一個有趣的發現，在第二次的檢驗中發現細胞數已降為零， 但蛋白量仍然驚人的高 (cell-protein dissociation)。過去的研究告訴我們，因細菌感染引起 的脊髓液變化，應該是以蛋白質和葡萄糖先恢復正常，細胞數則較緩，因此後來我們可以比較大 膽的排除我細菌感染的可能，而根據此病人快速的臨床症狀進展，TB meningitis的考量似乎較 小。另外文獻中的統計，病毒引起的中樞神經感染，極少會使脊髓液中的蛋白量大於100 mg/dl。 而被證實會造成這種脊髓液變化的疾病中(CNS lupus, myelitis, and polyradiculoneuropathy)， 依據病人神經學上的表現，並沒有Myelitis相符的神經學症狀。因此僅CNS lupus 和polyradiculoneuropathy較能解釋病人的神經學症狀和脊髓液檢查結果。