A neurologist referred a 28-year-old woman in her 28th week of pregnancy to my clinic on June 2, 1989. She gave a history that on May 30, 1989, she suddenly developed a black spot in front of the lower, inner quadrant of her right eye at about 1 PM. She had noted periodic imbalance over the previous 2 months. On June 2, ophthalmic evaluation showed 20/20 visual acuity in both eyes. Fundus examination showed a superotemporal retinal infarct secondary to superior temporal BRAO in the right eye (Fig. 15.1a) and visual field defect (Fig. 15.1b). Vasculitis was seen at the site of occlusion of the involved BRAO (see arrow in Fig. 15.1a). The anterior segment and vitreous in the right eye showed no abnormality. Carotid duplex scan was normal, antinuclear antibody titer was elevated at 1:160 (speckled pattern), and the erythrocyte sedimentation rate was 42 mm/h.

On June 11, the patient developed slurred speech and personality changes. Later the same day, she had difficulty sitting and walking, with a tendency to fall to the left. She was admitted by the neurologist to a local hospital and had computed tomogram (CT) scan of the brain, electrocardiogram, screening blood work (including antinuclear and cardiolipin antibody titers), blood cultures, visual evoked potentials, and deep-venous Doppler sonograms of the lower extremities, and all were normal. The erythrocyte sedimentation was 50 mm/h, and contrast echocardiography revealed a right-to-left shunt with Valsalva maneuver, consistent with a patent foramen ovale. She was treated with intravenous heparin and improved slightly, although her dysarthria persisted. She was discharged on June 18 taking subcutaneous heparin (5,000 units every 12 h).

Over the next 48 h, her speech deteriorated and she developed decreased interest in her environment, perioral numbness, and unsteady gait with falling to the right. She was readmitted to the hospital and given intravenous heparin. T2-weighted magnetic resonance imaging of the brain performed on June 22 showed multifocal areas of increased signal intensity in the deep white matter, anterior corpus callosum, and brain stem.

One week later, she was transferred to the neurology department of the University of Iowa Hospitals and Clinics for further care. On arrival, her vital signs were normal. She had a systolic murmur in the heart. She had a flat affect, and she was dysarthric. There was a retinal infarct in the superior temporal sector of her right fundus, as before. Her gait was broad based and ataxic. She had bilateral Babinski’s signs. After admission, intravenous heparin was continued. Her mentation worsened; she became disoriented, responded minimally to questions, and had little interest in her environment. No new lateralizing signs developed. A repeat carotid duplex scan was normal. Repeat contrast echocardiography showed a right-to-left shunt. Thyroid studies and C-reactive protein and double-stranded deoxyribonucleicacid antibody titers were normal. Blood cultures were negative. Somatosensory evoked potentials and brain stem auditory evoked potentials were normal. An electroencephalogram showed diffuse slowing. Formal neurobehavior testing showed moderate to severe impairments in virtually all assessed aspects of cognitive function including attention, memory, behavioral organization, praxis, and language. She also showed perseverative tendencies and poor awareness of her condition. These findings were believed to be consistent with multifocal brain dysfunction. A CT scan of the brain without contrast done on July 1 was normal. Anticoagulants were stopped, and cerebrospinal fluid (CSF) examination revealed a protein concentration of 207 mg/dl with a glucose concentration of 55 mg/dl (serum glucose concentration 89 mg/dl), 2 white blood cells/mm³, a normal myelin-basic protein concentration and IgG index, and absent oligoclonal bands. Another CT scan without contrast done on July 5 showed small areas of hypodensity in the genu of the corpus callosum and the periventricular white matter. Four days later, she delivered a healthy infant boy. A cerebral arteriogram done 4 days after the delivery was normal. A second CSF examination showed a protein concentration of 144 mg/dl, a glucose concentration of 59 mg/dl, 1 white blood cell/mm³, and a normal immunoelectrophoresis pattern.

Ophthalmic evaluation on July 17 showed visual acuity of 20/20 and normal intraocular pressure in both eyes, and the fundus demonstrated multiple branch retinal arteriolar occlusions in the left eye and a cotton-wool spot (Fig. 15.2a). Fluorescein fundus angiography showed occlusion of three retinal arterioles during the transit phase (Fig. 15.2b) and, during the late phase, showed mild staining of the wall of occluded arterioles (Fig. 15.2c). There was marked resolution of the previously noted retinal infarct in the right eye (Fig. 15.3). Visual field plotting revealed corresponding field defects in both eyes. The anterior segment and vitreous in both eyes showed no abnormality. Audiometry demonstrated mild bilateral sensorineural hearing loss. Serum complement levels were mildly elevated (C3 196 mg/dl [normal range 70–176 mg/dl] and C4 45 mg/dl [normal range 16–45 mg/dl]).

After delivery, the patient’s mental status, dysarthria, and ataxia gradually improved, although she remained amnestic for many of the events of the past month. She was discharged taking warfarin on July 25. Ultrafast (cine) CT scan of the heart done as an outpatient was normal. Six weeks after her discharge, her examination was remarkable only for persistent visual field deficits in both eyes; her mental status, speech, coordination, and gait were normal. She took warfarin for 8 months without further episodes. She then took 325 mg aspirin per day, and 11 months after the onset of initial problem, a hypercoagulability profile including partial thromboplastin time; thrombin time; fibrinogen, antithrombin III, protein C, protein S, and plasminogen concentrations; platelet count; and platelet aggregation studies was normal.

In summary, the clinical features of this syndrome affecting arteriolar vascular distributions may be categorized within the triad of encephalopathy, retinopathy, and hearing loss. This patient had all the typical clinical features of this syndrome. She is a woman within the age range, of 18–40 years. She had an encephalopathy manifested by personality change, dementia, ataxia, long-tract signs, and dysarthria. She had multifocal branch retinal arteriolar occlusions with associated retinal infarcts and scotomas. She had bilateral sensorineural hearing loss detected by audiometry. She had a marked elevation of the CSF protein concentration without a marked pleocytosis. Her MRI showed multifocal areas of increased signal intensity in the cerebral white matter on T2-weighted images. Her cerebral arteriogram was normal. Her EEG showed diffuse slowing. She had a moderately elevated ESR, but there was no other evidence for vasculitis. This patient was shown to have a patent foramen ovale, but all the clinical findings fit Susac’s syndrome.

A 42-year-old female physician was seen in my clinic from July 27, 1992, to September 1998. She developed multiple episodes of BRAO, in one or the other or both eyes from time to time, from August 1991 till September 1994. Figures 15.4, 15.5, 15.6, 15.7, and 15.8 show fundus photographic and fluorescein fundus angiographic findings in July 1992 (Fig. 15.4a, b), September 1992 (Figs. 15.5a, b and 15.6a–c), November 1993 (Fig. 15.7a, b), and September 1994 (Fig. 15.8), involving one or the other eye. During these episodes, on many occasions, the vitreous showed some cells in the involved eye. The eyes progressively developed multiple scotomas and peripheral visual field defects, sparing central fixation so that the visual acuity was 20/15 in both eyes all along (Figs. 15.9 and 15.10). I treated her with corticosteroids from September 1992, starting with a high dose and then tapering it down, but whenever the dose was small, there was a recurrence, and each time she had to start all over again with a high dose. She was on corticosteroids till July 1995, with no recurrence after that. Thus, this lady had recurrent episodes of BRAO in both eyes for about 3 years, and it seems corticosteroids helped each time a new episode developed.

She had a history of hearing loss in the right ear, paresthesia of upper extremities, and migraine since the spring of 1990. On November 17, 1992, at supper time, she developed mental confusion, speech problems, and balance difficulty, with ringing in the ears and hearing problem; her mental and hearing problems, although better when seen on January 13, 1993, were not back to normal. She was fully investigated by the neurology department by various hematological evaluations, including ANA, erythrocyte sedimentation rate, and C-reactive protein evaluations and MRI, cerebral angiography, CSF examination, and other evaluations; none showed any abnormality, except that she had peripheral neuropathy.

Fluorescein fundus angiography in both the above cases with Susac’s syndrome shows that it provides much more useful information about the various BRAO than ophthalmoscopy, and also it shows evidence of vasculitis by the presence of fluorescein staining or leakage.

Hyperlipidemia causes atherosclerosis. Atherosclerosis is the most common cause of cardiovascular disease. This is discussed at length in Chap. 13 dealing with central retinal artery occlusion.

The association of carotid artery disease with BRAO is well known. Embolism is the most common cause of BRAO. Atherosclerotic lesions of the common and/or internal carotid artery are well-established causes of BRAO. There are many reports of the association of BRAO with carotid artery disease in the literature.

A variety of cardiac conditions have been reported associated with BRAO, due to embolism from the heart. These include various cardiac valvular lesions [3, 29–34], patent foramen ovale [3, 33, 35, 36], atrial fibrillation [33], and a retained left atrial catheter 21 years after operation [37].

The association of diabetes and arterial hypertension has been reported with BRAO [3, 33].

There are reports of BRAO developing following invasive cardiovascular procedures, such as coronary atherectomy [38] and intervention [39] and cardiac catheterization [40].

There are anecdotal case reports of the association of BRAO with a variety of vasculitides, including the following: toxoplasmic chorioretinitis [41–47], cytomegalovirus retinitis [48–51], acute multifocal inner retinitis [52], idiopathic retinal vasculitis [47], Behçet’s disease [48, 53, 54], cat-scratch disease [47, 55–57], Takayasu’s arteritis [58–60], aortoarteritis [61], vaccination [62, 63], varicella zoster virus [64], Crohn’s disease [47, 65], Churg-Strauss syndrome [66], lupus [67], rheumatoid arthritis [68], rickettsia infection [47, 69], West Nile virus [47], dengue fever [70], Lyme disease [71], ocular tuberculosis [47], pseudotumor cerebri [72], and candida endophthalmitis [73]. Fineman et al. [74] reported BRAO in giant cell arteritis, but that is in fact cilioretinal artery occlusion due to occlusion of the posterior ciliary artery by giant cell arteritis and not true BRAO because, as mentioned above, the so-called branch retinal arteries are in fact arterioles and giant cell arteritis does not involve arterioles.

There are several reports suggesting that thrombophilia plays a role in the development of BRAO. The various thrombophilic factors reported include antiphospholipid syndrome [75–78], factor V Leiden mutation and antiphospholipid antibody syndrome [77], protein C deficiency [5], protein S deficiency [79], hyperhomocysteinemia [80], and methylenetetrahydrofolate reductase [81].

BRAO has been reported in association with acute myelogenous leukemia [82] and non-Hodgkin’s large cell lymphoma [83].

There are reports of development of BRAO following non-ocular surgery, due to embolism from other regions, such as coronary angiography [84, 85], after carotid artery surgery [86], thyroid artery interventional embolization [87], embolization of arteriovenous malformation [88, 89], embolization of an intracranial meningioma [90], embolization of a maxillary sinus tumor [91], cosmetic facial filler injections [92] and septoplasty [93], and operative complications of optic nerve sheath decompression [94].

Development of BRAO has been reported following intranasal anesthetic injection [95].

Intravitreal injection of anti-VEGF drugs is commonly used for macular edema due to various causes, for neovascular age-related macular degeneration, and for ocular neovascularization. One report mentions development of BRAO following this injection for ischemic central retinal vein occlusion [96].

Several reports based on one or a few cases of BRAO have noted it in association with some other conditions. These include pregnancy [97, 98], migraine [10, 99, 100], prepapillary arterial loop [101, 102], photocoagulation of a peripapillary choroidal neovascular membrane [103] and of an arterial macroaneurysm [104], diathermy of a persistent hyaloid artery [105], removal of an intraocular foreign body from the optic nerve head [106], with interferon [107], with high-dose carmustine and cisplatin therapy [108], epipapillary isolated astrocytoma [109], hereditary hemorrhagic telangiectasia [110], rupture of retinal arteriolar macroaneurysm on the optic disc [111], and Gaucher disease [112].

The above list of causes for BRAO covers all age groups. I further analyzed the causes according to age groups into the following two groups: (1) CRAO in children (the United Nations Convention on the Rights of the Child defines a child as “a human being below the age of 18 years”) and (2) young persons, defined as aged between 18 and 44 years.