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Chapter 207 – Most Urgent Neuro-Pathologies

Chapter 207 – Most Urgent Neuro-Pathologies

 

PETER A. QUIROS

 

INTRODUCTION

Neuro-ophthalmic emergencies are few and far between. Although their incidence is much lower than other ophthalmic emergencies, such as retinal detachment or ruptured globe,[1] [2] their outcomes carry a much higher morbidity and even mortality. The ocular manifestations of neuro-ophthalmic emergencies are but portents of more dangerous central nervous system or systemic pathology. The vision-threatening and potentially life-threatening nature of these disorders requires prompt recognition and diagnosis on the physician’s part. A delay of even a few hours could result in a dire outcome. Therefore, the clinician must be familiar with the manifestations of these disease entities and initiate appropriate testing and treatment without delay.

In essence, there are five neuro-ophthalmic emergencies. These are:

• Giant cell arteritis (GCA)

• Orbital apex syndrome

• Intracranial aneurysm

• Cavernous sinus thrombosis

• Pituitary apoplexy

These may be grouped together by initial symptoms into three categories for ease of diagnosis: (1) entities resulting in vision loss—GCA, (2) those causing ophthalmoplegia—cavernous sinus thrombosis and intracranial aneurysm, and (3) those causing both vision loss and ophthalmoplegia—orbital apex syndrome and pituitary apoplexy.

EPIDEMIOLOGY AND PATHOGENESIS

Giant Cell Arteritis

The incidence of GCA (in the United States) is approximately 1 in 150,000 per annum in patients over 60 years of age.[3] The incidence increases sharply with age and can be as high as 44 per 100,000 for patients in their nineties.[4] The disease has a slight predilection for women over men. Caucasians are affected much more often than African–Americans and Hispanics.[2] [4] [5] The mean age of onset is in the seventh decade.[6]

GCA is a systemic disease that affects primarily small-to-medium–sized arteries, particularly the temporal, ophthalmic, and short posterior ciliary arteries. [7] Segments of these latter vessels become occluded, which leads to choroidal ischemia or ischemic optic neuropathy.[8] The arterial thrombosis of GCA may be demonstrated by delayed choroidal and disc filling on fluorescein angiography.[9]

Aneurysm

The incidence of intracranial saccular aneurysms is approximately 9 per 100,000. The incidence of rupture increases with age, peaking during the sixth and seventh decades. They are somewhat more frequent in women.[10] The vast majority of intracranial aneurysms arise from the carotid artery’s main trunk (40%), at the level of the posterior communicating artery (PCOM), the ophthalmic artery, and the cavernous sinus.[11] [12] Rupture of PCOM aneurysms has been reported as high as 85%.[13] In addition, the PCOM is by far the most frequent location to cause a third cranial nerve palsy prior to rupture.[14]

PCOM aneurysms generally cause pupil-involving third nerve palsies. These occur either due to subarachnoid hemorrhage or by external compression of the third nerve due to aneurysmal expansion prior to rupture.[15]

Cavernous Sinus Thrombosis

The incidence of this rare disorder has not been estimated. It may be classified as septic or aseptic, the latter being the rarer of the two forms. The mortality from septic cavernous sinus thrombosis was nearly 100% in the pre-antibiotic era. Now the mortality rate is lower but remains at about 30%. [16]

Most septic thromboses of the cavernous sinus arise from the facial, sphenoid or ethmoid sinus, and dental infections. Acute infections of these areas usually are caused by gram-positive bacteria, whereas chronic infections are more often associated with gram-negative bacteria and fungi. Interestingly enough, otitis media and orbital cellulites rarely lead to cavernous sinus thrombosis.

Aseptic thrombosis of the cavernous sinus is associated with conditions that lead to venous thrombosis. These may include polycythemias, sickle cell disease (vasculidities), trauma, neurosurgery, pregnancy, and oral contraceptive use.

Orbital Apex Syndrome

Less than 1% of all orbital cellulites result in an orbital apex syndrome.[17] However, over 50% of these occur in patients with diabetes mellitus.[18] In these patients, rhinocerebral mucormycosis is far and away the most frequent cause of orbital apex syndrome.

Even though ketoacidosis is not always present,[19] it is the most important risk factor.[20] Studies have demonstrated a lack of inhibitory activity against Rhizopus in serum from ketoacidotic patients. It appears that this inhibitory activity is restored upon correction of the acidosis.

Pituitary Apoplexy

This life-threatening condition is rare and its incidence is difficult to establish. It is thought to occur in 0.6–9.1% of all surgically managed cases of pituitary adenoma.[21]

The age range is broad, ranging from the first to the ninth decade. [22] One study estimates the peak incidence during the fifth decade.[23] There appears to be no sex predominance.

Pituitary apoplexy occurs with sudden enlargement of a tumorous pituitary gland, usually adenoma. The sudden enlargement damages surrounding structures such as the optic chiasm and the hypothalamus. Rapid expansion into the cavernous sinus is also not uncommon. The expansion may be caused by hemorrhage or infarction. Precipitating factors include reduced blood flow as in hypotension, stimulation of the gland in increased estrogen states such as pregnancy, anticoagulation, and increased blood flow.[23]

 

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OCULAR MANIFESTATIONS

Giant Cell Arteritis

Sudden visual loss is by far the most common manifestation of GCA, occurring in approximately 50% of these patients.[24] The vision loss occurs overwhelmingly as a result of arteritic anterior ischemic optic neuropathy. The permanent vision loss often is preceded by transient loss of vision, such as amaurosis fugax.[25]

Other causes of vision loss also associated with GCA, although occurring less frequently, include central retinal artery occlusion, choroidal ischemia, and posterior ischemic optic neuropathy. The elderly patient with central retinal artery occlusion who has no history of valvular disorders or visible emboli should be suspected of having GCA.[26]

Even though vision loss is the primary ophthalmic problem found in GCA, patients may also experience diplopia. This problem may occur due to infarction of the extraocular muscles, their associated cranial nerves, or the brainstem nuclei. In fact, GCA may cause a greater stroke syndrome.

Aneurysm

Ophthalmic manifestations are determined by the position of the aneurysm. These may range from vision loss due to ophthalmic artery aneurysms, cortical blindness resulting from basilar aneurysms, or ophthalmoplegia due to aneurysms of the circle of Willis or the cavernous sinus. The most common manifestation, however, is ophthalmoplegia.

Patients will have complete unilateral ptosis. Upon lifting the lid, the examiner will find an abducted eye that cannot adduct, infraduct, or supraduct. These patients usually have 1–2?mm of proptosis, also. This phenomenon is thought to result from laxity of the palsied musculature and not from aneurysmal displacement.

All non-diabetic patients with third cranial nerve palsies should raise suspicion of intracranial aneurysm.

Cavernous Sinus Thrombosis

Patients with septic cavernous sinus thrombosis will manifest a host of ocular abnormalities. Those with infections entering the cavernous sinus anteriorly usually will have eye pain, orbital congestion, proptosis, adnexal edema, ptosis, and ophthalmoplegia. The ophthalmoplegia may involve the third, fourth, and sixth cranial nerves. In addition, there may also be involvement of the first and second branches of the trigeminal nerve.

Symptoms are initially unilateral but often become bilateral as the infection and thrombosis spread to the contralateral side through the circular sinus. This sinus connects the right and left cavernous sinuses posteriorly. In addition, these patients are usually febrile. Nausea, vomiting, and somnolence are not uncommon.

Orbital Apex Syndrome

Patients with an orbital apex syndrome will have complete ophthalmoplegia, ptosis, decreased corneal sensation, and vision loss. Unlike cavernous sinus thrombosis, the vision loss is present early. Patients usually develop optic nerve signs, such as a relative afferent pupillary defect. Early on, there is little adnexal edema and orbital congestion. These develop as the disease progresses. Proptosis is often present, but patients do not always complain of pain.

Eschars rarely are seen initially but usually develop around the orbit if the disease goes untreated ( Fig. 207-1 ).

Pituitary Apoplexy

Patients usually suffer painful ophthalmoplegia and vision loss. Damage to the visual pathways occurs most frequently at the level of the chiasm. Therefore, visual field defects are common. Vision loss is variable, however, and may not always produce a

 

 

 

 

Figure 207-1 A, Patient with Mucormycosis of the right orbit, resulting in an orbital apex syndrome. B, Axial view from orbital MRI demonstrating mucormycosis of the Ethmoid sinuses with extension into orbit.

relative afferent pupillary defect. The degree of ophthalmoplegia may also be variable and asymmetrical, depending on the extent of involvement of each cavernous sinus.

DIAGNOSIS AND ANCILLARY TESTING

Giant Cell Arteritis

The diagnosis of temporal arteritis is based on clinical signs and symptoms. Laboratory findings are helpful, and temporal artery biopsy is the confirmatory gold standard.

Elderly patients with vision loss and/or transient vision loss usually have a positive review of systems. Therefore, a thorough review of systems for GCA should be elicited. A diagnosis can be arrived at with great certainty if several systems are positive for symptoms.[27]

Most patients will complain of headache, usually unilateral. In addition, there is usually scalp tenderness, as well as tenderness over the affected artery. Jaw claudication is often present. Whereas its absence does not rule out GCA, this sign is nearly pathognomonic of GCA, because it is seen rarely in other disorders. Finally, myalgias, fatigue, weight loss, and decreased appetite are seen frequently. Positive findings in three or more systems in the elderly patient should raise a high level of suspicion.

Laboratory testing usually consists of erythrocyte sedimentation rate (ESR), C-reactive protein level, and complete blood count. The ESR and C-reactive protein level usually are elevated markedly. The ESR should be adjusted for age and gender. The upper limit of normal is considered age divided by 2 in men and age plus 10 divided by 2 in women.[28]

 

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Figure 207-2 A, Digital subtraction angiogram (DSA) of PCOM aneurysm resulting in third nerve palsy. B, DSA of the same aneurysm after endovascular coiling.

The complete blood count often will reveal a normocytic anemia as well as a thrombocytosis.[29]

Temporal artery biopsy is the gold standard for diagnosis. A 2?cm segment of temporal artery should be obtained and several sections sampled, because “skip lesions” may occur. That is, sections of affected artery may be interspersed with non-affected sections. A single negative biopsy meeting the above criteria is usually enough to rule out GCA. However, despite low statistical yield, [30] if suspicion is high a second biopsy may be performed, given that a missed diagnosis results in dire consequences.

Aneurysm

Frontal head pain is usually present in both ruptured and unruptured aneurysms. In an unruptured aneurysm, it is referred pain from the adjacent tentorium. Like the eye and forehead, the tentorium is supplied by the first branch of the trigeminal nerve. A pupil-involving oculomotor nerve palsy is nearly invariably present. If such is the case, the aneurysm should be detectable by magnetic resonance (MR) angiography or spiral computed tomography (CT) angiography.[31] These modalities, however, may miss up to 10% of intracranial aneurysms.[32] Therefore, digital subtraction cerebral angiography remains the gold standard. A saccular aneurysm of 4?mm or greater usually is seen at the junction of the internal carotid and the posterior communicating arteries ( Fig. 207-2 ).

Cavernous Sinus Thrombosis and Orbital Apex Syndrome

Apart from the ocular signs that distinguish these two entities, neuroimaging is necessary to make the diagnosis. Orbital CT without contrast and magnetic resonance imaging (MRI) scanning with fat suppression will locate the site of involvement. In the case of orbital MRI, fat suppression is necessary in order to see involved orbital structures. The “noise” created by the fat may mask inflammation otherwise. Sinus disease is nearly always present.[33] In fact, orbital apex syndrome rarely occurs without adjacent ethmoid sinusitis. Sphenoid and maxillary sinus disease is also common. In either case, scans should be ordered with coronal and axial views that extend as far back as the posterior and inferior cavernous sinus.

Pituitary Apoplexy

In addition to ocular manifestations, most patients exhibit meningeal irritation. Following the apoplexy, hypofunction of the gland is common.[34] Patients may, therefore, exhibit irregular menses, decreased libido, hyponatremia, hypothyroidism, or hypercortisolism.

MRI is the gold standard for neuroimaging, because it will delineate both the tumor and any hemorrhage ( Fig. 207-3 ). It is much more sensitive than CT scanning.[35]

DIFFERENTIAL DIAGNOSIS

Giant Cell Arteritis

The differential of GCA is extensive. GCA is confused often with nonarteritic anterior ischemic optic neuropathy. These patients tend to be younger, have less severe vision loss, and have a negative review of systems, as well as normal laboratory test results.

The differential may also include:

• Inflammatory optic neuritis: patients usually in their twenties and thirties, have pain with eye movements, optic nerve swelling, and a negative review of systems

• Compressive tumor: very slowly progressive vision loss, negative review of systems

• Diabetic papillophlebitis: younger diabetic patients, optic nerve swelling with hemorrhages, negative review of systems, mildly elevated ESR

• Central retinal artery or vein occlusion

Aneurysm

If angiography findings are negative, the following entities may produce a similar clinical picture:

• Microvascular or ischemic lesions: patients usually diabetic; pupil nearly always spared

• Epidural or subdural hematoma: a history of trauma in most cases, mental status changes common

• Meningitis or encephalitis: fever and nuchal rigidity, often accompanied by mental status changes and seizures

• Hypertensive crisis: flame-shaped retinal hemorrhages usually present, as well as optic nerve edema

• Migraine: a relapsing and remitting course often accompanied by nausea, photophobia, visual auras, and transient hemiplegia, ophthalmoplegia, or ataxia

 

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Figure 207-3 A, Axial MRI view of enlarged apoplectic pituitary gland involving chiasm. B, Sagittal MRI view from the same patient.

Cavernous Sinus Thrombosis and Orbital Apex Syndrome

These entities have similar differential diagnoses, because most problems arise from adjacent structures.

• Tolosa–Hunt syndrome: otherwise healthy patients, severe pain, vision loss rare, inflammatory “pseudotumor” seen on neuroimaging

• Arteriovenous fistula: often with antecedent trauma, bruit may be auscultated, arterialized conjunctival vessels

• Thyroid eye disease: rarely seen without lid retraction and lid lag, positive forced ductions, thickened extraocular muscles on CT scan with little to no sinus disease

Pituitary Apoplexy

Intracranial aneurysm, both expanding and ruptured, should be considered if MRI scanning fails to reveal pituitary hemorrhage. An MR angiogram should then be undertaken.

 

 

 

 

Figure 207-4 A, Temporal artery biopsy positive for giant cell arteritis. Note destruction of elastic lamina and complete luminal occlusion. B, Normal temporal artery specimen.

PATHOLOGY

Giant Cell Arteritis

Biopsy specimens will reveal an overwhelming inflammatory mononuclear cellular infiltrate. There is destruction of the internal elastic lamina and necrosis of the media is seen often. Vessel lumens often are completely occluded. Multinucleated giant cells may be present ( Fig. 207-4 ).

Aneurysm

Histologically aneurysmal vessels exhibit markedly thinned media and adventitia. There is generalized disruption of the internal elastic lamina, with areas of thinning, fragmentation, and even absence. Some investigators have found a deficiency or defect in type III collagen formation, as well as a decrease in the type III–to–type I collagen ratio.[36]

Cavernous Sinus Thrombosis and Orbital Apex Syndrome

Sinus specimens often will reveal infectious organisms. Bacterial gram stains should be performed to ascertain the presence of gram-positive or gram-negative bacteria, or both. In addition, India ink and special stains for fungi should be performed to evaluate for mucormycosis. Nonseptate, large, branching hyphae that stain easily with H&E is indicative of Mucor and Rhizopus species.

Pituitary Apoplexy

This condition is marked by pituitary hemorrhage, often accompanied by necrosis, and thrombosis. Most specimens have a

 

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high degree of necrosis, making cell type identification difficult. One study, however, found null cells to be the most frequent (61%), followed by somatotroph (17%), corticotroph (11%), lactotroph (5.5%), and gonadotroph (5.5%). [37]

TREATMENT

Giant Cell Arteritis

The well-accepted management for GCA is systemic corticosteroids. Generally, the ophthalmic literature favors higher doses than the rheumatological literature. There is no clear agreement on starting dosage.[38] Neuro-ophthalmologists usually start at dosages of 80–100?mg of oral methylprednisolone. Rheumatologists start at lower dosages of 60–40?mg. Some even advocate initial intravenous steroid therapy. A recent retrospective series indicated increased likelihood of improvement in vision in those managed with intravenous steroids.[39]

ESR is followed every 4–6 weeks, and the steroid therapy is titrated accordingly. There is general consensus that the duration of therapy should be for many months, often extending up to 1 to 2 years.

Aneurysm

Management of unruptured intracranial aneurysms depends, in part, on their size and position, as well as the age and health of the patient. Unruptured aneurysms may be managed via a direct or “open” surgical approach or with an endovascular approach.

The direct surgical approach aims at applying metal clips at the base of the aneurysm in order to close it off. This approach is quite successful but incurs the risks associated with open craniotomy. Damage to adjacent structures (oculomotor nerve) may occur.

The endovascular approach uses catheters to introduce balloons or thromboembolic coils into the aneurysm, thereby mechanically occluding it or thrombosing it. This approach carries a lower mortality and morbidity but can be complicated by incomplete closure of the aneurysm or displacement of the endovascular balloon, as well as rupture due to penetration of the thin aneurysm wall.

Cavernous Sinus Thrombosis and Orbital Apex Syndrome

Septic thrombosis of the cavernous sinus is usually managed with a combination of antibiotics and anticoagulation. Corticosteroids may also play a role in reducing inflammation. If sinus disease is present, débridement of the sinuses should also take place. If there is clinical evidence or suspicion of Mucor, treatment with amphotericin B should be initiated. Correction of underlying metabolic acidosis greatly increases survival.[17]

Orbital apex syndrome is managed in much the same way, except that in cases of Mucor, sinus exenteration as well as orbital exenteration may be necessary in order to improve survival.

Aseptic thrombosis of the cavernous sinus is managed primarily by managing the underlying condition. Adjuvant anticoagulation may stop the spread of thrombosis.[40]

Pituitary Apoplexy

Most patients are managed with decompression of the sella transsphenoidally. In general, these patients have a neuro-ophthalmic abnormality prompting surgery. Some groups advocate the use of bromocriptine in cases with little or no neuro-ophthalmic deficit.

Supplementation of pituitary hormones is often necessary for prolonged periods after the apoplectic event.

COURSE AND OUTCOMES

Giant Cell Arteritis

The primary goal of therapy is to avert vision loss in the fellow eye. Restoration of vision in the affected eye is rare. However, if left untreated, nearly 90% of patients will suffer vision loss in the fellow eye.[41]

Aneurysm

The results of surgery on unruptured aneurysms are excellent. Mortality rates with these procedures are as low as 1–5%.[42] Morbidity is somewhat higher at 10–15%, which usually manifests in the form of incomplete recovery of oculomotor nerve function or aberrant regeneration.

Cavernous Sinus Thrombosis

The mortality rate for patients with septic cavernous sinus thrombosis is about 30%.[16] Morbidity is very high. Nearly all survivors have some neurological deficit. These usually are due to damage to the cranial nerves of the cavernous sinus. Therefore, ophthalmoplegias, sensory neuropathies, and even retinal vein or artery occlusions may be seen.

Aseptic thrombosis has a much lower mortality than septic thrombosis. Morbidity, nonetheless, remains high, with damage to the intracavernous cranial nerves common.

Orbital Apex Syndrome

The mortality from Mucor-induced orbital apex syndrome is reported between 46% and 52%,[43] despite amphotericin B therapy. Morbidity remains high, because many patients require exenteration of the sinuses and orbit. Permanent neurological deficits are common.

Pituitary Apoplexy

Surgical decompression of the sella appears to have good neuro-ophthalmic outcomes. Improvements in visual acuity, field deficits, and ophthalmoplegia were reported as high as 76%–91%.[37] Endocrine abnormalities, however, remained high, with 43–58% requiring some form of hormonal supplementation. Mortality with surgical management remained low.

 

 

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