Now You See It…

SURVEY OF OPHTHALMOLOGY

VOLUME 53  NUMBER 2  MARCH–APRIL 2008

CLINICAL CHALLENGES PETER SAVINO AND HELEN DANESH-MEYER, EDITORS

Now You See It. Sagun Pendse, MD,1 Jurij R. Bilyk, MD,1 Christopher Olivia, MD,2 and Vale´rie Biousse, MD3 1

Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania; 2Cooper University Hospital, Cooper Health System, Camden, New Jersey; and 3Departments of Ophthalmology and Neurology, Emory University, Atlanta, Georgia, USA

(In keeping with the format of a clinical pathologic conference, the abstract and key words appear at the end of the article.)

Comments

Case Report. A 19-year-old, obese (BMI 42.3) woman initially presented to a neurologist reporting severe, constant, dull aching frontal headache that radiated to the retro-orbital region for 2 months. She also reported intermittent blurry vision in both eyes and the appearance of wavy lines in her vision. All of her symptoms worsened with any change in posture. There was nothing that alleviated her symptoms. Her past medical history was significant for a seizure disorder treated with topiramate. She was on no other medications. Her review of symptoms was negative; specifically, she denied fever, chills, nausea, vomiting, neck stiffness, weakness, and numbness. Vision was 20/20 in her right eye (OD), and 20/25 in her left eye (OS). Pupils were normal, ocular motility was full, and intraocular pressure was 12 mm Hg OU. The anterior segment was normal by slit-lamp examination. She had chronically swollen optic disks bilaterally without spontaneous venous pulsations (photos not available). Humphrey visual fields are shown in Fig. 1. How would you work up this patient?

Comments by Dr. Vale´rie Biousse This young patient likely has raised intracranial pressure (ICP), which is suggested by the presence of chronic headaches and bilateral optic nerve head edema. Her visual acuity is normal and Humphrey visual fields show enlarged blind spots with nasal depression in the left eye, suggesting papilledema. She is otherwise healthy, but obese, and has no associated symptoms and signs to suggest an underlying intracranial process. Therefore, idiopathic intracranial hypertension (IIH) is the most likely cause of raised ICP in this patient. However, IIH is a diagnosis of exclusion.10,11 She needs a magnetic resonance imaging (MRI) of the brain to rule-out an intracranial process and cerebral venous thrombosis, and a lumbar puncture with cerebrospinal fluid (CSF) opening pressure to confirm the intracranial hypertension and rule-out a meningeal process. It is essential to definitely rule-out cerebral venous thrombosis, which can mimic IIH.6,10,11 This can often be accomplished with just a good conventional MRI if there are interpreters with the 177

Ó 2008 by Elsevier Inc. All rights reserved.

0039-6257/08/$--see front matter doi:10.1016/j.survophthal.2007.12.008

178

Surv Ophthalmol 53 (2) March--April 2008

Fig. 1.

Humphrey visual fields show enlarged blind spots OU and nasal steps OS.

appropriate expertise. Otherwise, magnetic resonance venography (MRV) or a CT-venogram should be obtained in addition to MRI. Once the diagnosis of IIH is confirmed, careful interview of the patient should look for factors associated with IIH, such as weight fluctuation, recent weight gain, certain medications, and vitamin A use.10 I always specifically look for anemia, which is associated with a worse visual prognosis and may need to be aggressively treated if present,8 as well as sleep apnea, which is common in obese patients with IIH.14

Case Report (Continued) An MRI of the brain was performed along with an MRV (Fig. 2). A lumbar puncture was performed and revealed an elevated opening pressure (45 cm H2O), but the CSF was otherwise normal. How should this patient be treated?

Fig. 2.

PENDSE ET AL

Comments (Continued) Comments by Dr. Biousse The work-up confirmed the diagnosis of IIH. She is obese and does not have any of the other factors or disorders associated with IIH. There is no clinical trial evaluating the treatment of IIH, and the goals of the management are to alleviate symptoms and protect against progressive visual dysfunction (the major morbidity of IIH). Therefore, treatment includes 1) correction of any associated factor (such as obesity), and 2) decreasing ICP. Weight loss should be recommended and monitored. The lumbar puncture, which is part of the work-up, is often the most efficient immediate treatment. Indeed, it usually results in immediate improvement of headaches and papilledema. Acetazolamide is usually empirically prescribed in order to reduce CSF production. Usual doses are between 1 and 2

Initial MRI and MRV of the brain demonstrating no mass lesions and no venous sinus thrombosis.

179

NOW YOU SEE IT.

grams orally, per day. Careful follow-up with repeated Humphrey visual fields is necessary. If symptoms and signs improve, acetazolamide is usually continued for a few months until papilledema and headaches resolve. If visual function deteriorates, repeat lumbar puncture may be necessary and surgical treatment should be considered to prevent further visual loss.10

Case Report (Continued) Weight loss was recommended and she was started on acetazolamide 250 mg four times a day. Her neurologist noted improvement of her symptoms and resolving disk edema, and tapered the acetazolamide. She did not follow up with her ophthalmologist and did not have any repeat visual fields. Nine months later while on acetazolamide 250 mg twice daily, she developed recurrent symptoms identical to her initial presentation. Acetazolamide was increased to 500 mg four times daily without resolution of symptoms. She had two therapeutic lumbar punctures done by her neurologist with temporary improvement in symptoms. Four months after the recurrence of her symptoms her mother returned home to find the patient hysterical. The patient was screaming that she could not see anything. She was taken by ambulance to an emergency room were she was sedated and intubated because she was combative and could not be examined. Dilated fundus examination showed diffuse retinal hemorrhages and retinal whitening bilaterally, suggestive of bilateral combined central retinal vein and artery occlusion. On her fourth hospital day a repeat MRI and MRV were obtained (Fig. 3). What has happened to this patient and what should be done at this time?

Comments (Continued) Comments by Dr. Biousse The new MRI and MRV (Fig. 3) show thrombosis of the superior sagittal sinus and right transverse sinus. The clot appears as a hypersignal on the T1-weighted sagittal image, suggesting recent thrombus. As emphasized previously, cerebral venous thrombosis often presents with isolated raised ICP that may mimic IIH.6,7 However, the venous sinuses appeared normal on her initial MRI, suggesting new onset thrombosis.7 This patient, who was initially diagnosed with IIH, developed cerebral venous thrombosis 13 months later. The diagnosis of cerebral venous thrombosis was made four months after she experienced recurrent symptoms of raised ICP, and after she received two repeat lumbar

punctures. This case emphasizes the importance of repeating brain imaging in patients complaining of persistent headaches after lumbar puncture. Such cases are exceedingly rare but have been observed. A few hypotheses can be formulated to explain this sequence of events: 1. Although it is possible that this patient may have had cerebral venous thrombosis as the cause of raised ICP from the beginning and not IIH, this is very unlikely. Indeed, the time interval of 13 months between the onset of raised ICP and the diagnosis of cerebral venous thrombosis, and the fact that the initial MRI and MRV appeared normal are against this hypothesis. However, it has been emphasized that the diagnosis of cerebral venous thrombosis can be difficult on MRI.7,12,13 Furthermore, some authors have suggested that, in some patients with underlying hypercoagulable states, IIH may result from chronic thrombosis of the venous sinuses resulting in impaired CSF resorption at the level of the arachnoid granulations.17 In some cases, thrombosis in evolution may be missed on initial imaging. 2. Cerebral venous thrombosis complicating dural puncture (mostly after epidural or spinal anesthesia, but also after diagnostic lumbar puncture) has been reported in a few patients.1,2,15,16 This hypothesis should be considered in this patient who received repeated therapeutic lumbar punctures. It has been suggested that the decrease in CSF pressure secondary to dural puncture induces venous dilation and stasis as well as traumatic damage to the fragile venous endothelial wall, which may precipitate venous thrombosis. Venous thrombosis is often multifactorial and in most cases reported after dural puncture, other factors were present (particularly oral contraceptives), congenital or acquired thrombophilia, and the postpartum state.1 Therefore, a complete coagulation work-up should be obtained in this patient. 3. Diuretics can rarely precipitate cerebral venous thrombosis in the setting of dehydration-induced hyperviscosity. However, this is mostly observed in young children or during severe dehydration. To my knowledge no case of cerebral venous thrombosis has been reported as a complication of acetazolamide.

Case Report (Continued) During her hospitalization the patient developed acute renal failure, respiratory failure, liver failure, thrombocytopenia, and anemia. Work-up confirmed

180

Surv Ophthalmol 53 (2) March--April 2008

PENDSE ET AL

Fig. 3. Repeat MRI and MRV of the brain done one year later demonstrating large venous sinus thrombosis extending from the superior sagittal sinus to the right transverse sinus.

the diagnosis of catastrophic antiphospholipid syndrome (CAPS) leading to venous sinus thrombosis and multiple organ failure. Lupus anticoagulant was positive (positive hex phase, and dilute

Russell viper venom), but anticardiolipin antibodies were not detected; other serologic tests for systemic lupus erythematosus were negative (ANA, dsDNA). She was anticoagulated and did not have subsequent

181

NOW YOU SEE IT.

thrombotic events. Six months later, vision was bare light perception in both eyes.

systemic steroids or other immune modulators, plasmapheresis, and anticoagulation. Unfortunately, there is no definitive therapy or cure and the mortality is higher than 50%.8

Discussion In our review of the literature we found this patient to be unique. There were no other reports of patients with cerebral venous sinus thrombosis that previously had symptoms, papilledema, and a negative imaging by MRI and MRV. Given the similarities in the demographics and co-morbidities in patients with these two disease entities this may not be an uncommon occurrence. Sussman et al studied 38 patients with IIH; 18 had imaging with three demonstrating sinus thrombosis. They found a hypercoagulable state to be much more prevalent in the PTC population than in age-matched healthy obese patients. Antiphospholipid syndrome (APS) was the most common cause of hypercoaguable state, present in 31% of their patients. The authors recommended hypercoaguability work-up in all patients with IIH.10 Antiphospholipid antibodies are present in up to 5% of healthy controls. Anti-cardiolipin antibody and the lupus anticoagulant are types of antiphospholipid antibodies. APS requires at least one clinical criterion (vascular occlusion or pregnancy complication in the presence of an antiphospholipid antibody) for diagnosis. It is the most common cause of acquired thrombophilia. Primary APS occurs without any other recognizable disease, whereas secondary APS occurs in the presense of systemic disease, typically autoimmune in nature. CAPS is a severe form of APS with particularly high morbidity and mortality.4,5 Only 1% of patients with APS go on to develop CAPS. The diagnosis of CAPS is made when there is arterial or venous thrombosis in three or more organs in less than one week in the presence of antiphospholipid antibody. In the ‘‘CAPS Registry’’ at least 55% of patients had an identifiable trigger factor. Infections were the most common trigger, but surgical procedures (including minor diagnostic procedures) and the use of medications (including diuretics) are also important precipitating factors.9 Our patient was on acetozolamide therapy and underwent several lumbar punctures. Renal manifestations are seen in 70% of patients. Cardiopulmonary complications (ARDS in approximately 18.5%) are the most common cause of mortality.3 Other abdominal organs, such as the adrenal glands, spleen, intestines, and pancreas, are also frequently affected. Three percent of patients with CAPS have cerebral venous sinus thrombosis.6 CAPS can be treated with

References 1. Aidi S, Chaunu MP, Biousse V, et al: Changing pattern of headache pointing to cerebral venous thrombosis after lumbar puncture and intravenous high-dose corticosteroids. Headache 39:559--64, 1999 2. Albucher JF, Vuillemin-Azaı¨s C, Manelfe C, et al: Cerebral thrombophlebitis in three patients with probable multiple sclerosis. Role of lumbar puncture or intravenous corticosteroid treatment. Cerebrovasc Dis 9:298--303, 1999 3. Asherson RA: Acute respiratory distress syndrome and other unusual manifestations of the catastrophic antiphospholipid (Asherson’s) syndrome. Isr Med Assoc J 6:360--3, 2004 4. Asherson RA, Cervera R: Catastrophic antiphospholipid syndrome. Curr Rheumatol Rep 5:395--400, 2003 5. Asherson RA, Cervera R, Piette JC, et al: Catastrophic antiphospholipid syndrome. Clinical and laboratory features of 50 patients. Medicine (Baltimore) 77:195--207, 1998 6. Biousse V, Ameri A, Bousser MG: Isolated intracranial hypertension as the only sign of cerebral venous thrombosis. Neurology 53:1537--42, 1999 7. Biousse V, Bousser MG: Cerebral venous thrombosis. The Neurologist 5:326--49, 1999 8. Biousse V, Rucker JC, Vignal C, et al: Anemia and papilledema. Am J Ophthalmol 135:437--46, 2003 9. Cervera R, Gomez-Puerta JA, Espinosa G, et al: ‘‘CAPS Registry’’: a review of 200 patients from the International Registry of patients with catastrophic antiphospholipid syndrome (CAPS) [abstract]. Ann Rheum Dis 62(Suppl): 88, 2003 10. Friedman DI, Jacobson DM: Idiopathic intracranial hypertension. J Neuroophthalmol 24:138--45, 2004 11. Friedman DI, Jacobson DM: Diagnostic criteria for idiopathic intracranial hypertension. Neurology 59:1492--5, 2002 12. Hinman JM, Provenzale JM: Hypointense thrombus on T2-weighted MR imaging: a potential pitfall in the diagnosis of dural sinus thrombosis. Eur J Radiol 41:147--52, 2002 13. Idbaih A, Boukobza M, Crassard I, et al: MRI of clot in cerebral venous thrombosis: high diagnostic value of susceptibility-weighted images. Stroke 37:991--5, 2006 14. Lee AG, Golnik K, Kardon R, et al: Sleep apnea and intracranial hypertension in men. Ophthalmology 109: 482--5, 2002 15. Milhaud D, Heroum C, Charif M, et al: Dural puncture and corticotherapy as risks factors for cerebral venous sinus thrombosis. Eur J Neurol 7:123--4, 2000 16. Mouraux A, Gille M, Dorban S, et al: Cortical venous thrombosis after lumbar puncture. J Neurol 249:1313--5, 2002 17. Sussman J, Leach M, Greaves M, et al: Potentially prothrombotic abnormalities of coagulation in benign intracranial hypertension. J Neurol Neurosurg Psychiatry 62:229--33, 1997 This study was supported in part by a departmental grant (Department of Ophthalmology) from Research to Prevent Blindness, Inc, New York, New York, and by core grant P30-EY06360 (Department of Ophthalmology) from the National Institute of Health, Bethesda, Maryland. The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Reprint address: Sagun Pendse, MD, Wills Eye Hospital, Thomas Jefferson University, 900 Walnut St, Philadelphia, PA 19107.

182

Surv Ophthalmol 53 (2) March--April 2008

PENDSE ET AL

Abstract. A patient experienced recurrent postural headache, transient visual obscurations, and papilledema. The patient initially presented with papilledema without cerebral venous sinus thrombosis (pseudotumor cerebri, idiopathic intracranial hypertension). One year later she had the similar symptoms and a recurrence of papilledema but now had obvious venous sinus thrombosis. (Surv Ophthalmol 53:177--182, 2008. Ó 2008 Elsevier Inc. All rights reserved.) Key words. antiphospholipid syndrome  catastrophic antiphospholipid syndrome  cerebral venous sinus thrombosis  idiopathic intracranial hypertension  pseudotumor cerebri