| Abstract|| |
A 57 year-old man presented six months after undergoing renal transplantation with the orbital apex syndrome comprising of retro-orbital pain, visual loss and complete ophthalmoplegia. Pathological examination from the granulomatous-like mass in the apex of the right orbit showed branching hyphae with the characteristic appearance of aspergillus. The differential diagnosis of such a lesion in an immunocompromised patient is discussed.
Keywords: Aspergillosis, Amphotericin-B, Ophthalmoplegia, Orbital apex, Renal transplant.
|How to cite this article:|
Bohlega SA. Clinical Approach to Ophthalmoplegia in Renal Transplant Recipients Differential Diagnosis and Case Illustration. Saudi J Kidney Dis Transpl 1998;9:27-32
|How to cite this URL:|
Bohlega SA. Clinical Approach to Ophthalmoplegia in Renal Transplant Recipients Differential Diagnosis and Case Illustration. Saudi J Kidney Dis Transpl [serial online] 1998 [cited 2020 Jul 5];9:27-32. Available from: http://www.sjkdt.org/text.asp?1998/9/1/27/39298
| Introduction|| |
In immunocompromised patients, the differential diagnosis of lesions in the region of the orbital apex, the parasellar region or the superior orbital fissure is wide and includes neoplastic, infectious, inflammatory, vascular and traumatic disorders , . The most important factor influencing survival in such patients is early diagnosis , . The orbital apex syndrome involves the optic nerve and structures in the apex of the orbit, including the nerves to the extra-ocular muscles and the first division of the trigeminal nerve. It is usually associated with proptosis but if the responsible lesion is contiguous with the cavernous sinus, proptosis may be absent. Thus, the presence of proptosis often suggests either a mass behind the globe or blockage of the orbit's venous system , . The clinical distinction between the orbital apex and superior orbital fissure is more academic than pragmatic , . Lesions involving this area affect one or more structures of the orbital apex (the second, third and fourth cranial nerves as well as the first division of the fifth cranial nerve and the sympathetic and parasympathetic enervation to the eye). Because of the richness of the vascular supply to this region, systemic diseases, metastatic lesions and vascular anomalies may lead to orbital apex syndrome  . The typical presentation of a patient with the orbital apex syndrome can be visualized by the following case illustration.
A 57 year-old Saudi male who had end-stage renal disease due to polycystic kidneys received a kidney transplant from a living nonrelated donor in India. He was maintained on prednisone 10 mg, azathioprine 50 mg and cyclosporin 50 mg daily. Six months after the transplant, he presented to us with constant right-sided headache with occasional exacerbation. On examination, he had absent light perception and pupillary reflex in the right eye. The right optic disc was swollen with mildly engorged, veins. External ocular movement was restricted to about 10 degrees in the right eye. The pin prick perception was reduced in the distribution of the first division of the trigeminal nerve of the right eye. The left eye was normal. Multiple, dark brownish, smooth lesions were present on the skin of the face, consistent with Kaposi's sarcoma.
The white cell count, hemoglobin, serum electrolytes, urea and creatinine were normal. Cyclosporin level was low at 133 ng/ml (normal therapeutic range 400-800). A chest radiograph showed scattered fibronodular infiltrates consistent with pulmonary Kaposi's sarcoma. A CT scan [Figure - 1] and MRI of the orbits revealed a right sphenoid sinus mass, eroding the bony wall and extending to the upper right nasopharynx, ethmoid, orbital apex and right anterior cavernous sinus.
Transnasal ethmoidal sinus biopsy showed some bony fragments and non-specific inflammatory cells. A=CT guided fine needle aspiration and biopsy demonstrated numerous hyphae in a background devoid of inflammatory cell response [Figure - 2]. The hyphae demonstrated "dichotomous branching". A presumptive diagnosis of aspergillosis was made on the basis of these characteristic features. The minimum inhibitory concentration to amphotericin-B was 16 mg/L. The CD4 count was 0.75 x109/L, CD8 count 0.32 xlO9 /L; HIV antibodies were negative. The patient received intravenous amphotericin-B at a dose of 0.5 mg/kg on day 1 and, thereafter, 1.0 mg/kg daily. The cyclosporin level was maintained at about 150 mg/ml. Over 10 days, the serum creatinine rose from 95 to 243 micromol/L and the patient became anuric. Amphotericin was discontinued and replaced with itraconazole and flucytosine until the renal function returned to normal. Subsequently, liposomal amphotericin-B (Ambisome), at a dose of 2 mg/kg, was administered intravenously daily and a total dose of 2 gm was given over the next two weeks. The serum creatinine remained normal throughout, and the urine output was normal. The headache became more tolerable and the ptosis and medial rectus palsy in the right eye showed partial recovery; however, his vision was not restored. Repeat CT scan did not demonstrate any change. The patient refused surgery to debulk the lesion; he also refused to discontinue his immunosuppressive agents and discharged himself against medical advice. He was readmitted to the emergency room four months later with fever, drowsiness, left hemoplegia, proptotic congested right eye with no ocular movement, disseminated cutaneous, gastric and pulmonary Kaposi's sarcoma and oro-esophageal candidiasis. All immunosuppressive agents were stopped; he lost consciousness after three days and died two days later.
| Differential Diagnosis and Discussion|| |
The presentation including recent clinical history of periorbital and temporal pain, preceding visual deterioration, and involvement of two cranial nerves suggest a destructive process in the posterior orbit. The appearance of a swollen optic disc and early blindness points to direct compression or invasion by the lesion rather than vascular occlusion. Periorbital, frontal and temporal pain has been described in patients with inflammatory disease of the orbit. Usually, the more anterior lesions involve the optic nerve early while the posterior ones involve the first division of the trigeminal nerve , . The first division is also affected in anterior cavernous sinus lesions, so the clinical findings suggested a lesion in a more posterior part of the parasellar region or anterior cavernous sinus  . The CT and MRI scans demonstrated that the posterior ethmoid and sphenoid sinus were also involved , .
The differential diagnosis of painful ophthalmoplegia associated with a cranioorbital lesion is wide and the clinical presentation depends on the location of the lesion rather than its nature [Table - 1]  . The clinical differentiation between an inflammatory process and a neoplasm can be very difficult, but the rapid progression and the presence of pain are suggestive of the former. Also, inflammatory lesions improve after systemic steroid therapy whereas a neoplasm rarely responds to such treatment 
The neoplasms that may occur in this region include pituitary adenoma, craniopharyngioma, meningioma, sarcoma, giant cell tumor, multiple myeloma, lymphoma, leukemia, direct spread from an adjacent structure such as a nasopharyngeal tumor and, less frequently, a metastatic tumor. In the patient described, the rapid progression from the orbital apex to the cavernous sinus suggested an inflammatory process  ; at least 50% of all cases of orbital diseases are caused by inflammation. The most common orbital inflammatory disease is thyroid ophthalmopathy  . Other causes include granulomatous reaction to a foreign body, sarcoidosis, tuberculosis, syphilis or Wegeners granuloma, or infection by parasites, bacteria or fungi and viruses such as Herpes zoster  . The occurrence of repeated episodes of orbital pain due to neural involvement is called idiopathic painful ophthalmoplegia or the Tolosa-Hunt syndrome in which there are nonspecific inflammatory changes in the cavernous sinus. By definition, this condition should be diagnosed only after all other causes have been excluded.
An infection progressing over several weeks in the orbit of a patient with reduced immunity is very likely to be of mycotic nature. Rhino-orbital mucormycosis is one such opportunistic infection. The infection usually originates in one of the sinuses in debilitated, diabetic patients, spreading to the orbit and causing ophthalmoplegia and decreased vision  . Progression through the cavernous sinus into the brain may also occur, a complication which is frequently fatal  . Conjuctival edema and occlusion of the central retinal artery are often seen, and black eschar of the nasopharyngeal mucosa may be observed as a result of arterial occlusion. Our patient was not extremely sick, acidosis was not present and there was no evidence of central retinal or intracranial artery occlusion.
Another fungal infection which is a frequent pathogen in the orbital apex syndrome is aspergillosis , . Aspergillus is an organism found in soil. The fungus may reside in anaerobic paranasal sinuses and occasionally causes a sclerosinggranulomatous infection which may be located to the sinuses or invade adjacent structures and destroy the bone  . In our patient, the right-sided headache, maximally localized between the eye and ear with occasional acute exacerbation indicated the presence of an inflammatory condition in the region of the sphenoid sinus  .
Another form of sinus aspergillosis is characterized by rapid invasion of adjacent structures. This form is more common in immunocompromised and debilitated patients, especially those with hematologic malignancies  . It may originate in the lungs with hematogenous spread  . In patients with hematological malignancy, aspergillosis is related to immunosuppressive chemotherapy, prolonged use of broad spectrum antibiotics or protracted and prolonged neutropenia  . Many of the symptoms of aspergillosis are caused by either direct invasion of the tissue or to infiltration of blood vessels with resulting necrotizing angitis and thrombosis  . The diagnosis of aspergillosis is relatively difficult  . In view of the evasive nature of the disease it is always prudent to keep this diagnosis in mind  , especially in post-transplant patients and patients with hematological malignancies and severe weight loss. An opacity in the sphenoid sinus, orbital extension, involvement of the cavernous sinus and destruction of bone, strongly suggest a diagnosis of aspergillosis  . Despite the difficulty in diagnosing this condition, early recognition is essential since intracranial or CNS invasion implies a very poor prognosis, regardless of whether the disease originated in the sinus or the lungs  . The mortality rate of this infection is high, approaching 28% if the disease is limited to the orbit, but 80% if there is CNS involvement  . The CT and MRI features of invasive orbital fungal diseases are crucial to ruling out other differential diagnoses. In general, MRI is better than CT in differentiating paranasal inflammatory disease, invasive fungal infections and neoplasm  . On MRI, normal signal intensity on TI weighted images and very decreased signal intensity, similar to air, on T2 weighted images, are characteristic of invasive fungal infection  ; these findings may be due to ferromagnetic elements within the structure of the fungus. In T2 weighted images, inflammation causes a high-intensity signal, whereas most tumors result in an intermediate signal  .
Invasive fungal orbital disease enhances with gadolinium. Thus, an MR] with contrast is of great value and is superior to CT in demonstrating orbital and cavernous sinus infection and thrombosis, internal carotid narrowing and occlusion and intracerebral involvement  .
The only way to establish a definite diagnosis is by biopsy for which a few operative approaches are available  . The first is a lateral orbitotomy with direct visualization of lesion. The second is a craniotomy with simultaneous access to the orbit, optic canal and cavernous sinus. The third is a CT= guided needle biopsy. Direct visualization enables the surgeon to obtain a diagnostic specimen from the lesion and to do additional debunking if needed. If aspergillosis is the working diagnosis, a more aggressive approach should be adopted. Craniotomy gives access to all the structures involved and enables the surgeon to perform extensive debridement of all infected tissue. A simple biopsy followed by a course of chemotherapy alone is unsatisfactory and is usually associated with a poor prognosis, as occurred in our patient.
| Treatment|| |
The action of amphotericin B is through permeability changes in sterol-containing membranes causing damage to fungi and in mammals, producing renal failure  . An additional confounding factor is that the penetration of amphotericin B into brain tissue is relatively poor. The use of liposomal amphotericin-B (Ambisome) seems promising in such cases  . Ambisome is a preparation of amphotericin B which has decreased toxicity for the mammalian host cell, but retains anti-fungal activity because of its intraphagocyte accumulation and subsequent lysosomal fusion with fungal material  . It appears to reach a higher concentration in the brain tissue than conventional amphotericin B  .
In summary, central nervous system infection occurs in 5-10% of renal transplant recipients. The mortality rate is excessive and around half of the patients may die as a result of these infections , . This excessive mortality results at least in part, from the delay in diagnosis caused by the subtlety of clinical presentation, to a large number of potential pathogens, and infections with more than one agent  .
As seen as in our patient, during the first six months after transplantation, the recipient is at greatest risk of life-threatening opportunistic infection  and, therefore, an aggressive approach based upon CT, MRI  and pathological diagnosis can be very rewarding.
| Acknowledgment|| |
We would like to extend our gratitude to Mrs. Yvonne Lock for her excellent secretarial assistance in the preparation of the manuscript.
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Saeed A Bohlega
Department of Neuroscience, King Faisal Specialist Hospital and Research Center, P.O. Box 3354, Riyadh 11211
[Figure - 1], [Figure - 2]
[Table - 1]