Presentation of Case
The 85-year-old man had been in his usual state of health until two months before this presentation, when worsening headaches occurred. He used to have chronic, generalized headaches for months, for which he was seen at an outside clinic for parenteral analgesics about three times in one month. Two months before this evaluation, the pain became more severe, with an explosive character, and was localized at the right occipital region. He needed administration of parenteral analgesic as frequent as 3 times in one week. The headache and eye pain were not worsened by Valsalva maneuver. The pain was not related to posture. Ptosis of the right upper eye developed, along with double vision. There were no red eyes, increased lacrimation, nausea, vomiting, hemiplegia or other neurological deficits. The patient had no history of fever, night sweats, chest pain, dysuria, diarrhea, rashes, muscle or joint aches, and weight loss, nor could he recall any trauma.
Two days before this admission, he had decreased visual acuity in the right eye and right eye pain. He was seen at an ophthalmology clinic, where fluorometholon 1 gtt OU BID and sulfamethoxazole 1 gtt OU QID were administered without benefit. He sought attention at 新北市立聯合醫院三重院區 on 2014/7/7, where computed tomography (CT) of the brain revealed no hemorrhage, mass, or other intracranial abnormalities. He was referred to the neurology clinic at this hospital on the next day. A review of the CT of the brain revealed a hyperdense lesion at the right cavernous sinus (Figure 1). Magnetic resonance imaging (MRI) of the brain revealed focal infiltration extending from the right anterior cavernous sinus to the optic apex (Figure 2). Neurological examination revealed right CN III, IV, VI palsy with decreased visual acuity. He was admitted.
He live in New Taipei city with his wife and children. He ran a grocery store and had retired for more than 10 years. He had a fall 40 years ago, which resulted in paraplegia but he could still walk for 100 meters with a quadricane. The family had noticed him with cognitive impairment and easy forgetfulness for 1-2 years. He received a diagnosis of coronary artery disease (CAD), 2-V-D (LAD and LCx), for which he had undergone percutaneous occlusive balloon angioplasty with stenting; diabetes mellitus for which he was receiving oral hypoglycemic agent for 40 years, with added-on insulin replacement four years earlier (2014/07/10, HbA1C 7.3%); dyslipidemia; chronic kidney disease (CKD), stage 4; gouty arthritis; old ischemic stroke without sequelae; and vascular dementia. His medications included aspirin, bisoprolol fumarate, isosorbide-5-mononitrate, furosemide, atorvastatin, Insulin glargine, linagliptin, and glimepiride. He neither drank nor smoked. He took Chinese medicine sometimes for constipation.
Treatment Course
On examination, the body temperature was 36°C; the other vital signs and oxygen saturation were normal. Ophthalmologic examination revealed absent light reflex, ptosis and total ophthalmoplegia at all direction of the right eye. The visual acuity of the right eye was impaired and he could not see hand moving and light just in front of him. The corneal reflex is intact in both eyes and the sensory of the face was symmetrically intact. A diagnosis of right orbital apex syndrome was made. Endoscopic endonasal examination revealed bilateral paranasal sinusitis.
The hematocrit, hemoglobin level, white-cell count and platelet count were normal, as were blood levels of electrolytes, liver function test and coagulation tests. BUN was 36.6 mg/dl and creatinine, 2.4 mg/dl; and tests of autoimmune markers revealed negative ANA and anti-ENA.
A lumbar puncture revealed an opening pressure of 13.5 cm of water. Analysis of a cerebrospinal fluid specimen revealed no white or red cells, with normal glucose and elevated total protein level (83 mg/dl). The IgG index was 0.689 (normal value, 0.23-0.64) . Gram and acid-fast staining revealed no organisms. The India ink smear and a test for cyptococcal antigen were negative. A chest radiograph showed clear lungs and no evidence of mediastinal lymphadenopathy.
Augmentin was started. On the third morning of admission, he had sudden onset of seizure-like movement of the left upper limb , followed by altered mental status with agitation and disorientation. A fever (38.4C) was noted and the blood pressure dropped to 81/59 with tachycardia (HR 108). The laboratory investigations revealed lactic acidosis (4.25 mg/dL) and elevated C-reactive protein (4.9 mg/L). The vital signs became stable and his consciousness returned to E4V5M6 after hydration and infusion of a low-dose inotropic agent.
The electroencephalography (EEG) did not show epileptic discharge. There was mild to moderate diffuse cortical dysfunction especially at the right hemisphere. Meropenam and teicoplanin were given. Blood cultures on the day of shock grew Enterobacter cloacae. The lumbar puncture was repeated and only elevated total protein (57.9 mg/dl) was noted.
A diagnosis of fungal sinusitis was made and amphotericin B was infused. He underwent FESS (functional endoscopic sinus surgery) on the 14th hospital day to reveal mucopus and much debris in bilateral maxillary and sphenoid sinus. The pathology revealed findings suggestive of aspergillosis by PAS and GMS (Figure 3). As a result, amphotericin B was changed to voriconazole.
討論
Orbital apex syndrome/Cavernous sinus syndrome/Orbital pseudotumor/ Tolosa-Hunt syndrome
一開始病人以頭痛、複視和視力模糊為主要表現，神經學檢查發現右側第二、三、四、六對腦神經受損，腦部電腦斷層和核磁共振發現右側海綿竇和右眼窩頂部(orbital apex)有異常浸潤 ; 眼窩頂部的解剖構造從frontal view和lateral view看如(Figure 4)和(Figure 5) ; 從lateral view來看，海綿竇就緊連在眼窩頂部之後(Figure 5) ; 海綿竇中有第三、四、六對腦神經通過(Figure 6)，神經學檢查和影像檢查的結果是符合的。
如果第三、四、六對腦神經受損而視神經正常，我們可以為病人下海綿竇症候群(cavernous sinus syndrome)的診斷；若連視神經也遭到波及像這位病人，我們可以下眼窩頂部症候群(orbital apex syndrome)的診斷。任何的病理變化，包含inflammatory、neoplastic、infectious、iatrogenic/traumatic，或是vascular (Table 1)，都可以導致orbital apex syndrome或cavernous sinus syndrome。
病人沒有trauma 或是surgical history ; 腦部核磁共振及血管攝影(magnetic resonance angiogram : MRA)沒有看到腫瘤 (最容易侵犯眼眶的腫瘤包括腦膜瘤、腦下腺瘤、腫瘤轉移，尤其是攝護腺癌、乳癌、黑色素皮膚癌)或其他血管病變諸如carotid cavernous aneurysm、carotid cavernous fistula或是cavernous sinus thrombosis。接下來要排除感染，除了基本的血液培養和腰椎穿刺，已發現鼻竇炎就要做切片及培養，看胸部X光片做抗酸性染色排除結核，驗VDRL排除梅毒；若排除感染，就剩下發炎性疾病了: giant cell arteritis、葛瑞夫茲氏眼病變(Graves’ ophthalmopathy) ；相關的血清抗體也要檢查 : 像是這個病人的ANA和Anti-ENA是陰性的。若以上檢驗都是陰性，最好再抽ANCA，因為granulomatosis with polyangiitis (GPA)和eosinophilic granulomatosis with polyangiitis (EGPA) 都有可能侵犯海綿竇周圍；若懷疑類肉瘤病 (sarcoidosis)，可以驗ACE (angiotensin converting enzyme)。如果做了以上仔細的檢查檢驗都找不到原因，那我們只好說病人有“Orbital pseudotumor”或稱“Idiopathic orbital inflammatory syndrome”，如果很不幸伴隨腦神經的病變，那就可以下“Tolosa-Hunt syndrome”的診斷。這些發炎性疾病包含Tolosa-Hunt syndrome的治療以類固醇為主。
在使用類固醇治療temporal arteritis、Tolosa-Hunt syndrome、sarcoidosis 或其他systemic inflammatory disease造成orbital apex syndrome之前；務必要排除感染，尤其是fungal infection。不能因為使用類固醇治療後症狀改善就確認病人不是感染或腫瘤，因淋巴瘤或是感染造成的發炎也會對類固醇有反應。
Fungal rhinosinusitis
鼻竇的構造異常使分泌物不易排出或是鼻黏膜受損容易造成fungal colonization，例如有鼻息肉(nasal polyp)或慢性鼻竇炎，不過只有colonization通常不會造成什麼症狀也不具有臨床意義。
鼻竇的黴菌感染並不常見，通常發生在免疫系統低下的人；在健康人身上發生的鼻竇黴菌感染通常是non-invasive，不過也有一些病例報告指出找不出免疫系統異常的人發生invasive fungal rhinosinusitis。因為治療和預後差別很大，所以區分invasive和non-invasive fungal rhinosinusitis是很重要的。Non-invasive只侷限在鼻竇，而invasive則會破壞鄰近的組織包含眼眶甚至腦部。
Non-invasive fungal rhinosinusitis包含allergic fungal sinusitis 和sinus mycetoma/ball。對環境空氣中的黴菌(通常是dematiaceous species)過敏造成allergic fungal sinusitis (AFS)，大部分這樣的病人有過敏性鼻炎的病史。除了開刀清除致敏的黴菌，術後再加上內科治療(類固醇、抗黴菌治劑、免疫療法)，否則容易復發。Fungal ball 發生在構造異常被阻塞的鼻竇。Aspergillus fumigatus 或是dematiaceous fungi的菌絲糾結成菌球，解決之道是開刀取出菌球以及打通阻塞，開刀後很少復發，內科治療則沒有角色。
Invasive fungal rhinosinusitis又分成acute和chronic：前者病程小於四週，發生在嚴重免疫低下的病患，像是血液惡性腫瘤、接受化學治療導致中性球低下、接受移植(幹細胞或是實體器官)、後天免疫缺乏症候群。Aspergillus species 或是 Mucorales的菌絲侵犯血管造成梗塞，通常是直接侵犯破壞鄰近骨頭組織，但也可以是以黴菌血症的方式導致多重器官的侵犯，死亡率高；後者發生在老年人、糖尿病患或使用低劑量類固醇(一日小於10 mg)的患者，致病菌有Aspergillus、Bipolaris、Curvularia、 Alternaria spp、Pseudallescheria boydii，一開始只有慢性鼻竇炎的症狀，兩三個月後出現併發症例如眼眶甚至腦部的侵犯。
回過頭來看我們的病人，病人老年有糖尿病，雖然血糖控制並不特別差(HbA1C 7.3%)，但是他有nasal polyp，構造上的異常導致黴菌容易移生在鼻竇。病人頭痛已經多年，在頭痛加劇後的兩個月出現複視視力模糊而得到診斷，我們可以更早得到正確的診斷嗎？
社區常見的老年人和糖尿病患，廣義來說也是免疫系統低下的宿主，這些病人有頭痛臉頰痛的主訴我們要把fungal rhinosinusitis 放到我們的鑑別診斷中，如果無法做第一時間做影像學檢查，也應及早安排耳鼻喉科檢查。確切的診斷仰賴切片，有一半以上的病人可以在顯微鏡下找到菌絲，但有時候需要重複切片才能取得致病原，這對抗生素的選擇是重要的。
治療前先以電腦斷層或核磁共振評估侵犯範圍，除了內科治療，外科清創很重要，甚至需要重複清創。如果能改善宿主的免疫問題，當然能提高治療成功率，高壓氧的角色目前未明。抗生素的選擇，不論是acute或chronic invasive fungal rhinosinusitis，在一開始還不知道致病菌的時候，先使用lipid formulations of amphotericin B 5 mg/kg/day IV，如果切片及培養的結果確定是Aspergillus species，則改用voriconazole 6 mg/kg IV q12h for two doses, then 4 mg/kg IV q12h, oral step-down therapy, using 200 mg twice daily，過程中要檢查trough serum levels，suppressive therapy 則要持續三到六個月，若治療時間不夠長容易復發；宿主的免疫問題如果無法解決(例如移植後須免疫抑制劑的病人)，甚至得終身用藥。
雖然說invasive fungal rhinosinusitis大多發生在免疫異常的宿主，但是參考文獻 3 收了十七名 1995 至 2010 年case reports 中orbital aspergillosis的病患，這些人都沒有免疫低下的病史(除了八名 70歲 以上的老人)，全數病患的最初表現就是單側頭痛或是後眼窩痛，疼痛後的一至六個月開始有視力模糊或複視，自症狀開始到診斷的時間二至十個月，治療之後五人活下來，其他人則在疼痛開始的二至十六個月死亡，這當中八名病人一開始被當成temporal arteritis 以類固醇治療，在這之中只有一人存活。
Figure 1至Figure 6 請點此連結
Table 1 Pathological process lead to orbital apex syndrome/cavernous sinus syndrome
Inflammatory |
1. Sarcoidosis
2. Systemic lupus erythematosus
3. Churg–Strauss syndrome (eosinophilic granulomatosis with polyangiitis (EGPA))
4. Wegener granulomatosis (granulomatosis with polyangiitis (GPA))
5. THS (Tolosa-Hunt syndrome)
6. Giant cell arteritis
7. Orbital inflammatory pseudotumor
8. Thyroid orbitopathy |
Infectious |
1. Fungi: Aspergillosis, Mucormycosis
2. Bacteria: Streptococcus spp., Staphylococcus spp., Actinomyces spp.,Gram-negative bacilli, anaerobes, Mycobacterium tuberculosis
3. Spirochetes: Treponema pallidum
4. Viruses: Herpes zoster |
Neoplastic |
1. Head and neck tumors: nasopharyngeal carcinoma,
adenoid cystic carcinoma, squamous cell carcinoma
2. Neural tumors: neurofibroma, meningioma, ciliary
neurinoma, schwannoma
3. Metastatic lesions: lung, breast, renal cell, malignant
melanoma
4. Hematologic: Burkitt lymphoma, non-Hodgkin lymphoma, leukemia
5. Perineural invasion of cutaneous malignancy |
Iatrogenic/traumatic |
A. Iatrogenic
1. Sinonasal surgery
2. Orbital/facial surgery
B. Traumatic
1. Penetrating injury
2. Nonpenetrating injury
3. Orbital apex fracture
4. Retained foreign body |
Vascular |
1. Carotid cavernous aneurysm
2. Carotid cavernous fistula
3. Cavernous sinus thrombosis
4. Sickle cell anemia |
Other |
Mucocele |
參考文獻
- Orbital apex syndrome; Current Opinion in Ophthalmology2004, 15:490–498
- Aspergillus Infection of the Orbital Apex Masquerading as Tolosa-Hunt Syndrome
ARCH OPHTHALMOL / VOL 125, APR 2007
- Orbital aspergillosis in immunocompetent patients Br J Ophthalmol 2014;0:1–6
- Localised invasive sino-orbital aspergillosis: characteristic features Br J Ophthalmol 2004;88:681–687
- Orbital Apex syndrome (uptodate)
- Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis.
N Engl J Med. 2002;347(6):408.
- Case 18-2015: A 41-Year-Old Woman with Decreased Vision in the Left Eye and Diplopia N Engl J Med 2015;372:2337-45
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Case Discussion
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