What Is the Definition of Papilledema?
The term papilledema is frequently applied to optic disc swelling from any cause, but it should be used clinically only for disc swelling that results from increased intracranial pressure. The main reason for applying the term judiciously is that to most neuro-ophthalmologists papilledema implies an etiology, and thus inappropriate or unnecessary testing could result from miscommunication between providers.
Other forms of optic disc swelling due to local or systemic etiologies should be named according to their presumed etiology (e.g., optic neuritis, anterior ischemic optic neuropathy, etc). It is usually not possible to determine the etiology of disc swelling from the ophthalmoscopic appearance of the disc alone. The history and neuro-ophthalmologic examination, especially the visual fields, are necessary to reach an etiologic diagnosis. It is also important to note that optic disc swelling may not develop if optic atrophy is present. For example, in patients with prior “bow-tie atrophy” of the optic nerve from a suprasellar mass, disc swelling may affect only the superior and inferior aspects of the nerve (“twin peaks papilledema”) (Ing, 1996).
The symptoms associated with optic disc swelling depend on the underlying etiology. In general, swollen optic discs from any cause may be associated with transient visual obscurations (see Chapter 8) (Sadun, 1984). These are typically unilateral or bilateral dimming or blacking out of vision that usually lasts seconds and may be precipitated by changes in posture (e.g., bending or straightening).
What Are the Features that Distinguish Real Papilledema from Pseudopapilledema?
True disc swelling must be distinguished from pseudopapilledema (e.g., anomalously elevated discs caused by optic nerve head drusen) (Kurz-Levin, 1999). Pseudopapilledema is a relatively common finding, and optic disc drusen are among the most frequent etiologies. Drusen of the disc may be obvious, tiny, or buried. Other disc anomalies that may be mistaken for papilledema include small, “crowded” hyperopic discs and tilted or anomalous discs. With pseudopapilledema the peripapillary nerve fiber layer is normal, venous pulsations are usually present, there is no vascular engorgement or hemorrhages, there are no cotton-wool spots, and the discs do not leak dye on fluorescein angiography Myelinated nerve fibers may occasionally resemble disc swelling but are characterized by a white feathery nerve fiber layer appearance. Hyaloid traction on the optic disc and epipapillary glial tissue may occasionally also be mistaken for disc swelling. Ophthalmoscopic criteria that might distinguish pseudopapilledema from true papilledema include the following (Glaser, 1990):
1. An absent central cup with a small disc diameter
2. Vessels arising from the central apex of the disc
3. Anomalous branching of vessels (e.g., bifurcations, trifurcations) with increased number of disc vessels
4. Visible “glow” of drusen seen with disc transillumination
5. Irregular optic disc margins with derangement of peripapillary retinal pigment epithelium
6. Absence of superficial capillary telangiectasia on the optic disc head
7. No hemorrhages (although subretinal hemorrhages may occur with disc drusen)
8. No exudates or cotton-wool spots
What Evaluation Is Necessary for Optic Disc Drusen?
Most cases of pseudopapilledema can be diagnosed clinically and simply documented photographically. In difficult cases, further testing may be useful in the diagnosis of drusen. Disc drusen may show autofluorescence noted prior to injection of fluorescein angiography dye. Although generally not required for the diagnosis, computed tomography (CT) imaging may demonstrate the calcified drusen in the optic nerve. Buried drusen may also be visible on orbital ultrasound.
Kurz-Levin and Landau retrospectively reviewed 142 patients (261 eyes) with suspected optic disc drusen (Kurz-Levin, 1999). Evaluations included B-scan echography, orbital CT scan, and/or preinjection control photography for autofluorescence. Thirty-six of the 261 eyes were evaluated using all three techniques, and drusen of the optic nerve head were diagnosed in 21 eyes. B-scan ultrasonography was positive in all 21 eyes. Nine cases had positive CT scans findings, and 10 had positive preinjection control photographs. In 82 eyes with suspected buried drusen of the optic nerve head, B-scan echography showed drusen in 39 eyes, compared with 15 eyes in which drusen were shown using preinjection control photography. No drusen were seen on preinjection control photography or CT scan that were missed on B-scan echography. The authors concluded that drusen of the optic nerve head are diagnosed most reliably using B-scan echography compared with both preinjection control photography and CT scans. Preinjection control photography is usually positive when there are visible drusen of the optic disc, and therefore its clinical use is limited. Likewise, CT scan is an expensive and less sensitive test for the detection of buried drusen of the optic nerve head. We recommend B-scan ultrasonography for the detection of buried drusen as the initial diagnostic study (class III, level C).
Is the Disc Swelling Caused by Optic Neuropathy or Papilledema?
Disc swelling due to raised intracranial pressure (i.e., papilledema) is usually bilateral and symmetric in both eyes. Unilateral disc swelling is most commonly caused by local pathology within the optic nerve or orbit. Unilateral papilledema, however, can occur, although most of these cases are actually bilateral but asymmetric disc swelling (Chari, 1991; Huna-Baron, 2001; Killer, 2001; Lepore, 1992; Strominger, 1992; To, 1990). If one optic nerve is atrophic, it may not swell, and unilateral disc swelling may occur from increased intracranial pressure in these cases (e.g., Foster Kennedy syndrome). These optic neuropathies are discussed in Chapters 1 through 6. Processes causing optic neuropathies associated with disc swelling are usually unilateral, but may be bilateral, and are listed in Table 7–1. Other processes that may mimic papilledema and that may present with bilateral optic disc swelling with little or no visual acuity impairment, color vision loss, or visual field defects and normal intracranial pressure are listed in Table 7–2.
Certain inflammatory or infectious processes, such as syphilis, sarcoidosis, HIV-associated meningoradiculitis, and viral meningoencephalitis that affect the meninges may cause optic disc swelling due to perineuritis (Hykin, 1991; Nakamura, 1999; Prevett, 1997). Cat-scratch disease and Lyme disease may also cause bilateral disc edema with normal visual fields and vision (Bafna, 1996; Fedorowski, 1996, Rothermel, 2001).
What Are the Clinical Features of Papilledema?
The clinical features and stages of papilledema are outlined in Tables 7–3 and 7–4. The Frisen papilledema grading scale is listed in Table 7–5. Features helpful in differentiating true optic disc edema from pseudo-disc edema (e.g., buried disc drusen) are outlined in Table 7–6.
Infectious (e.g., infectious optic neuritis, meningitis, neuroretinitis, uveitis associated disc edema, cat-scratch disease, Lyme disease)
Demyelinating (e.g., multiple sclerosis)
Inflammatory (e.g., systemic lupus erythematosus, sarcoidosis) (Sherman, 1999)
Vascular conditions, including arteritic and nonarteritic anterior ischemic optic neuropathy, disc swelling in diabetics (diabetic papillopathy), central retinal vein occlusion, and carotid-cavernous sinus fistula
Infiltrative (e.g., carcinomatous meningitis, sarcoid)
Compressive (e.g., neoplastic thyroid ophthalmopathy)
Hereditary (e.g., Leber’s hereditary optic neuropathy) Traumatic (rare)
Paraneoplastic optic neuropathy
Mechanical (e.g., hypotony)
Chronic respiratory disease (O’Halloran, 1999)
Hypertensive optic neuropathy and retinopathy (Lee, 2002a; Wall, 1995a)
Blood dyscrasias (e.g., anemia, polycythemia, dysproteinemia)
Cyanotic congenital heart disease: disc swelling may be due to decreased arterial oxygen saturation and polycythemia
Sleep apnea: probably by a mechanism similar to that in congenital cyanotic heart disease (Purvin, 2000)
Spinal cord tumors (often with myelopathy: e.g., back pain, leg weakness, sensory changes, bladder involvement, etc.)
Acute inflammatory demyelinating polyradiculoneuropathy (AIDP or Guillain-Barre syndrome) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (Morrison, 1999)
POEMS (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes)
Crow-Fukase syndrome (peripheral polyneuropathy, organomegaly, lymphadenopathy, Castleman’s disease, endocrinopathy, gammopathy, or myeloma and skin changes (Boiling, 1990; Wong, 1998)
Hypoparathyroidism (primary or surgically induced) (McLean, 1998)
Uremia—these patients may have normal or increased intracranial pressure
Hypoxemia and anemia
Diabetic papillopathy (see Chapter 4)
What Studies Should Be Performed to Investigate the Patient with Papilledema?
All patients with papilledema require a thorough neurologic and neuro-ophthalmologic history and physical examination. In general, the syndromes causing increased intracranial pressure are listed in Table 7–7.
Usually bilateral but may be unilateral or asymmetric (Killer, 2001)
Usually preserved visual acuity and color vision early
May have transient visual loss lasting seconds (obscurations of vision)
Visual field defects
Enlarged blind spot
Eventual peripheral constriction, especially nasally
No afferent pupillary defect unless severe and asymmetric disc edema
Early disc capillary dilation, dye leakage, and microaneurysm formation
Late leakage of dye beyond disc margins
May be normal in early papilledema
Echography may show increased diameter of optic nerve with fluid in the optic nerve sheath
Minimal disc hyperemia with capillary dilation
Early opacification of nerve fiber layer (peripapillary retina loses its superficial linear and curvilinear light reflex and appears red without luster)
Early swelling of disc
Absence of venous pulsations
Peripapillary retinal nerve fiber layer hemorrhage
Fully developed papilledema
Engorged and tortuous retinal veins
May have splinter hemorrhages at or adjacent to the disc margin
Disc surface grossly elevated
Surface vessels become obscured by now opaque nerve fiber layer
May have cotton wool spots
Pa ton’s lines (circumferential retinal folds) or choroidal folds
May have exudates (e.g., macular star or hemistar)
May have hemorrhages or fluid in the macula that may decrease vision
In acute cases (e.g., subarachnoid hemorrhage), subhyaloid hemorrhages may occur that may break into vitreous (Terson’s syndrome)
Rarely macular or peripapillary subretinal neovascularization
Hemorrhages and exudates slowly resolve
Central cup, which is initially retained even in severe cases, ultimately becomes obliterated
Initial disc hyperemia changes to a milky gray
Small hard exudates that are refractile and drusen-like may appear on disc surface
Visual field loss including nerve fiber layer defects may develop
Optociliary “shunt” (collaterals) vessels may develop
Atrophic papilledema (pale disc edema)
Optic disc pallor with nerve fiber bundle visual field defects
Retinal vessels become narrow and sheathed
Occasional pigmentary changes or choroidal folds in macula
Selective loss of peripheral axons while sparing central axons (usually preservation of good central visual acuity)
In all patients with bilateral optic disc swelling, the blood pressure should be checked to evaluate for possible malignant hypertension. Blood dyscrasia should be considered if there are other suggestive retinal vascular findings (e.g., incomplete or complete central retinal vein occlusion with optic disc edema). Neuroimaging is required in all patients (class II, level B).
CT imaging is the preferred study in evaluating acute vascular processes (e.g., subarachnoid, epidural, subdural, or intracerebral hemorrhage, acute infarction) or in acute head trauma (e.g., rule out fracture, acute bleed). CT scan may be used in patients with contraindications to magnetic resonance imaging (MRI) (e.g., pacemakers, metallic clips in head, metallic foreign bodies), and obese or claustrophobic patients. Otherwise, MRI is the modality of choice in papilledema. MR angiography or MR venography may be useful for suspected arterial disease or venous obstruction. If neuroimaging shows no structural lesion or hydrocephalus, then lumbar puncture is warranted. Studies should include an accurate opening pressure, cerebrospinal fluid (CSF) cell count and differential, glucose, protein, cytology, Venereal Disease Research Laboratory (VDRL) test, and appropriate studies for microbial agents.
Stage 0: Normal optic disc
Obscuration of the nasal border of the disc
No elevation of the disc borders
Disruption of the normal radial nerve fiber layer (NFL) arrangement with grayish opacity accentuating nerve fiber bundles
Normal temporal disc margin
Subtle grayish halo with temporal gap
Obscuration of all borders
Elevation of nasal border
Complete peripapillary halo
Obscuration of all borders
Elevation of all borders
Increased diameter of the optic nerve head
Obscuration of one or more segments of major blood vessels leaving the disc
Peripapillary halo—irregular outer fringe with finger-like extensions
Elevation of entire nerve head
Obscuration of all borders
Total obscuration on the disc of a segment of a major blood vessel
Dome-shaped protrusions representing anterior expansion of the optic nerve head
Peripapillary halo is narrow and smoothly demarcated
Total obscuration of a segment of a major blood vessel may or may be present
Obliteration of the optic cup
Source: Reprinted from Friedman, 2001, with permission from Elsevier Science.
Optic Disc Edema
Disc vasculature obscured
Disc margin vasculature clear
Elevation of peripapillary NFL
Elevation confined to disc
Obscured peripapillary NFL
Sharp peripapillary NFL
No venous congestion
Exudates/cotton wool spots
No exudates/cotton wool spots
Loss of cup late
Small cupless disc
Normal disc vessels
Anomalous disc vessels
No circumpapillary light reflex
Crescent circumpapillary light reflex
Absent venous pulsations
With or without spontaneous venous pulsations
NFL, nerve fiber layer.
Idiopathic pseudotumor cerebri syndrome (idiopathic intracranial hypertension) with papilledema or without papilledema
Shunt failure in patient with hydrocephalus (ventriculomegaly may be absent)
Mass lesions—tumor, hemorrhage, large infarction, abscess
Arteriovenous malformations with high blood flow overloading venous return
Intracranial or extracranial venous obstruction
Secondary pseudotumor cerebri syndrome due to certain systemic diseases, drugs, or pregnancy
Source: J.J. Corbett, personal communication.
Patients with a history of a ventriculoperitoneal shunt for hydrocephalus may develop papilledema, visual loss, or signs of a dorsal midbrain syndrome (see Chapter 14) due to shunt failure. Usually CT or MRI reveals recurrence of the hydrocephalus. Shunt malfunction may occur without ventriculomegaly, perhaps due to poor ventricular compliance and “stiff ventricles” (Katz, 1994; Lee, 1996; Newman, 1994a). Thus shunt revision is indicted when there are signs or symptoms of increased intracranial pressure, even if ventriculomegaly is absent, to prevent deterioration of visual function and potentially irreversible visual loss.
What Is the Pseudotumor Cerebri Syndrome?
Pseudotumor cerebri is a diagnosis of exclusion. The modified Dandy criteria include (1) normal neuroimaging studies (usually MRI); (2) normal CSF contents; (3) elevated opening pressure; and (4) signs and symptoms related only to increased intracranial pressure (e.g., headache, papilledema, nonlocalizing sixth nerve palsy). Pseudotumor cerebri (PTC) is usually idiopathic but may be due to certain systemic diseases, drugs, pregnancy, and intracranial or extracranial venous obstruction.
Obstruction or impairment of intracranial venous drainage may result in cerebral edema with increased intracranial pressure and papilledema. Tumors that occlude the posterior portion of the superior sagittal sinus or other cerebral venous sinuses may cause increased intracranial pressure. Septic or aseptic thrombosis or ligation of the cavernous sinus, lateral sinus, sigmoid sinus, or superior sagittal sinus may mimic PTC (gelebisoy, 1999; Couban, 1991; Cremer, 1996; Daif, 1995; Gironeil, 1997; Horton, 1992; Kim, 2000; Lam, 1992; Van den Brink, 1996). A patient with neurofibromatosis type 2 developed papilledema from obstruction of cerebrospinal outflow at the arachnoid granulations by diffuse convexity meningiomatosis (Thomas, 1999). Kieper et al noted that 5 of 107 patients who underwent suboccipital craniotomy or translabyrinthine craniectomy developed PTC (Kieper, 1999). In each patient, the transverse sinus on the treated side was thrombosed, and patency of the contralateral sinus was confirmed on MRI. PTC has also been described after arteriovenous malformation embolization (Kollar, 1999). Sluggish flow in a venous varix after embolization, resulting in thrombosis that was propagated to vein of Galen, was the proposed mechanism. Ligation of one or both jugular veins (e.g., radical neck dissection), thrombosis of a central intravenous catheter in the chest or neck, subclavian vein catheterization and arteriovenous fistula, the superior vena cava syndrome, or a glomus jugular tumor impairing venous drainage may also cause increased intracranial pressure. Osteopetrosis causing obstruction of venous outflow at the jugular foramen has also been reported (Ageli, 1994; Kiers, 1991; Lam, 1992; Siatkowski, 1999). Venous sinus thrombosis may be the mechanism for PTC reported in several conditions including systemic lupus erythematosus, essential thrombocythemia, protein S deficiency, antithrombin III deficiency, the antiphospholipid antibody syndrome, activated protein C resistance, paroxysmal nocturnal hemoglobinuria, Behcet’s disease, meningeal sarcoidosis, lymphoma, hypervitaminosis A, mastoiditis, and trichinosis (Akova, 1993; Biousse, 1999; Daif, 1995; Farah, 1998; Gironeil, 1997; Hauser, 1996; Leker, 1998; Mokri, 1993; Pelton, 1999; Provenzale, 1998). In fact, elevated intracranial venous pressure is thought by some authors to be the universal mechanism of PTC of varying etiologies, including idiopathic PTC (Cremer, 1996; Karahalios, 1996; King, 1995). Higgins et al presented a case of PTC thought secondary to bilateral transverse sinus stenosis discovered on venography that was treated successfully by inserting a self-expanding stent across the stenosis in the right transverse sinus (Higgins, 2002). These authors suggest that the transverse sinus pathology was not thrombosis but an idiopathic narrowing of the transverse sinus bilaterally.
Biousse et al noted that central venous thrombosis (CVT) can present with all the classic criteria for idiopathic pseudotumor cerebri, including normal CT imaging and CSF contents (Biousse, 1999). Of 160 consecutive patients with CVT, 59 patients (37%) presented with isolated intracranial hypertension. Neuroimaging revealed involvement of more than one venous sinus in 35 patients (59%); CT imaging was normal in 27 of 50 patients (54%). The superior sagittal sinus was involved in 32 patients (54%) (isolated in 7) and the lateral sinus in 47 (80%) (isolated in 17). The straight sinus was thrombosed in eight patients, cortical veins were involved in two patients, and deep cerebral veins in three, always in association with thrombosis in the superior sagittal sinus or lateral sinuses. Lumbar puncture was performed in 44 patients and showed elevated opening pressure in 25 of 32 (78%) and abnormal CSF contents in 11 (25%). Etiologic risk factors included local causes (7), surgery (1), inflammatory disease (18), infection (2), cancer (1), postpartum (1), coagulopathies (11), and oral contraception (7). The cause was unknown in 11 cases (19%). Anticoagulants were used in 41 of 59 patients (69%), steroids or acetazolamide in 26 (44%), therapeutic lumbar puncture in 44 (75%), and surgical shunt in 1. Three patients had optic atrophy with severe visual loss, one died from carcinomatous meningitis, and 55 (93%) had complete recovery (although visual field testing was not systematically performed). The authors emphasized that MRI and MR venography should be considered in presumed isolated intracranial hypertension.
Among the 59 patients with isolated increased intracranial hypertension, 33 (56%) were female, but the authors did not record the patients’ weights. They note, however, that being a young, obese woman does not protect a patient from developing CVT, and therefore should not be used on an individual basis to rule out CVT. When MRI is not available, the authors suggest that conventional angiography be performed and, indeed, in another prospective study of 24 patients with apparently idiopathic PTC, angiography disclosed CVT in six patients (Tehindrazanarivelo, 1992). Increased blood flow and venous hypertension have also been implicated as the mechanism of papilledema noted in some patients with cerebral arteriovenous malformations (AVMs), especially dural AVMs and fistulas (Adelman, 1998; gelebisoy, 1999; Chimowitz, 1990; Cockerell, .1993; Cognard, 1998; David, 1995; Martin, 1998; Rosenfield, 1991). Thus, we consider MR venography (and, in selected cases, MR angiography or even formal angiography) to investigate the possibility of venous sinus occlusion in patients with PTC, especially in patients with features not typical for idiopathic PTC (e.g., in thin patients, men, the elderly) (class III, level C). However, we found MR venography to be normal in 22 consecutive obese females with idiopathic PTC (Lee and Brazis, 2000).
King et al found that when transducer-measured intracranial venous pressure is high in patients with idiopathic PTC, reduction of CSF pressure by removal of CSF predictably lowers the venous sinus pressure (King, 2002). This study indicates that the increased venous pressure in idiopathic PTC patients is caused by the elevated intracranial pressure and not the reverse. According to Corbett and Digre, “The chicken is the CSF pressure elevation and the egg is the venous sinus pressure elevation” (Corbett, 2002).
The idiopathic narrowing of the venous sinuses bilaterally noted in the case of PTC described by Higgins et al may conceivably have been transverse sinus compression from increased intracranial pressure (Higgins, 2002). Thus, venous occlusive disease and elevated venous pressure may well not be the mechanism of PTC in most idiopathic cases.
Many systemic diseases, drugs, vitamin deficiencies and excesses, pregnancy, and hereditary conditions have been associated with the pseudotumor cerebri syndrome (secondary pseudotumor cerebri). These reported etiologies are listed in Table 7–8. In general, many of these reported associations may be coincidental and anecdotal. Of those listed in Table 7–8, the etiologies most firmly associated with pseudotumor cerebri include drugs and systemic diseases (Ireland, 1990).
The drugs or drug conditions associated with pseudotumor cerebri are hypervitaminosis A, steroid withdrawal, anabolic steroids, lithium, nalidixic acid, the insecticide chlordecone (Kepone), isoretinoin, ketoprofen (Orudis) or indomethacin in Bartter’s syndrome, thyroid replacement in hypothyroid children, danazol, all-frans-retinoic acid (ATRA) or tretinoin, cyclosporine, exogenous growth hormone, and probably tetracycline and minocycline.
The systemic diseases or syndromes associated with pseudotumor cerebri are Behcet’s syndrome, renal failure, Addison’s disease, hypoparathyroidism, systemic lupus erythematosus, and sarcoidosis (most of these likely cause pseudotumor cerebri syndrome by venous sinus obstruction or impairment of venous sinus drainage).
Hypervitaminosis A (Alemayehu, 1995; Donahue, 2000; Moskowitz, 1993; Scott, 1997; Sharieff, 1996; Sirdofsky, 1994)
Excessive carrot intake to maintain weight loss likely exacerbated papilledema in one patient with PTC, due to high vitamin A levels (Donahue, 2000)
Hypovitaminosis A (Panozzo, 1998)
Vitamin D-deficient rickets (Alpan, 1991)
Multiple vitamin deficiencies (Scott, 1997; Van Gelder, 1991)
Drugs and other exogenous agents
Nalidixic acid (Mukherjee, 1990; Scott, 1997)
Tetracycline (Cuddihy, 1994; Gardner, 1995; Scott, 1997)
Minocycline (Chiu, 1998; Donnet, 1992; Lewis, 1997; Moskowitz, 1993; Torres, 1997)
Ofloxacin (Getenet, 1993)
Ciprofloxacin (Winrow, 1990)
Amiodarone (Ahmad, 1996; Borruat, 1993)
Lithium (Ames, 1994; Dommisse, 1991; Levine, 1990)
Cytosine arabinoside (Sacchi, 1999)
Leuprorelin acetate (Arber, 1990)
Indomethacin in Barrier’s syndrome
Ketoprofen in Bartter’s syndrome
Insecticide exposure: lindane, chlordecone (Kepone) (Verderber, 1991)
Steroids, including topical steroid and anabolic steroids (Scott, 1997)
Steroid withdrawal (Liu, 1994; Scott, 1997)
Oxytocin (Mayer-Hubner, 1996)
Growth hormone (Blethen, 1995; Francois, 1997; Koller, 1997; Malozowski, 1995; Maneatis, 2000; Rogers, 1999)
Beta-human chorionic gonadotropin (Haller, 1993)
Depo-Provera (depot medroxyprogesterone)
L-thyroxine therapy for juvenile hypothyroidism (Campos, 1995; Misra, 1992; Raghavan, 1997)
Endocrine and metabolic dysfunction and pregnancy
Pregnancy (including ectopic pregnancy) and postpartum (Daif, 1995; Koppel, 1990; McDonnell, 1997; Shapiro, 1995)
Hypothyroidism (Adams, 1994)
Addison’s disease and crisis (Alexandrakis, 1993; Condulis, 1997; Leggio, 1995)
Hypoparathyroidism and pseudohypoparathyroidism (Mada Mohan, 1993)
Cushing’s disease and post-pituitary surgery for Cushing’s disease (Parfitt, 1994)
Polycystic ovaries (Au Eong, 1997)
Catch-up growth following severe nonorganic (physical and emotional abuse including food deprivation) failure to thrive (Alison, 1997)
Familial hypomagnesemia-hypercalcuria (Gregoric, 2000)
Rickets (Salaria, 2001)
Systemic illnesses (including some causing venous occlusion)
Systemic lupus erythematosus (Chaves-Carballo, 1999; Chevalier, 1992; Daif, 1995; Green, 1995; Horoshovski, 1995; Scott, 1997; Vachvanichsanong, 1992)
Behçet’s syndrome (Bosch, 1995; Daif, 1995; Farah, 1998; Kansu, 1991)
Cystic fibrosis (Bikangaga, 1996; Lucidi, 1993; Nasr, 1995; Scott, 1997)
Antiphospholipid antibody syndrome (Daif, 1995; Leker, 1998; Mokri, 1993; Orefice, 1995)
Hematologic abnormalities and malignancies
Iron-deficiency anemia (Scott, 1997; Tugal, 1994)
Pernicious anemia and other megaloblastic anemias (Van Gelder, 1991)
Thrombocythemia and thrombocytosis (Sussman, 1997; Tehindrazanarivelo, 1990)
Abnormal fibrinogen or increased serum fibrinogen (Sussman, 1997)
Leukemia (Guymer, 1993; Saitoh, 2000)
Myeloma (Wasan, 1992)
Protein S deficiency (Daif, 1995)
Activated protein C resistance (Provenzale, 1998)
Antithrombin III deficiency (Daif, 1995; Sussman, 1997)
Anticardiolipin antibodies (Kesler, 2000)
Hemophilia A (factor VIII deficiency) (Jacome, 2001)
Multicentric angiofollicular lymph node hyperplasia (Feigert, 1990)
Paroxysmal nocturnal hemoglobinuria (Hauser, 1996)
Polycythemia (Sussman, 1997)
Chronic respiratory insufficiency and the Pickwickian syndrome (Wolin, 1995)
Sleep apnea (Lee, 2002b)
Chronic renal failure and uremia (Chang, 1992; Guy, 1990; Scott, 1997)
Renal or bone marrow transplantation (Avery, 1991, Katz, 1997; Obeid, 1997; Sheth, 1994)
Infections and inflammatory diseases
HIV infection and AIDS (Gross, 1991; Javeed, 1995; Schwarz, 1995; Travero, 1993)
Lyme disease (Kan, 1998; Scott, 1997)
Typhoid fever (Moodley, 1990; Vargas, 1990)
Familial Mediterranean fever (Gokalp, 1992)
Otitis media (Scott, 1997)
Acute purulent sinusitis (Kumar, 1999)
Neurosarcoidosis (Akova, 1993; Pelton, 1999; Redwood, 1990)
Tolosa-Hunt syndrome (Nezu, 1995)
Mucopolysaccharidoses (Sheridan, 1994)
After occipitocervical arthrodesis and immobilization in a halo vest (Daftari, 1995)
Chiari I malformation (Milhorat, 1999)
Guillain-Barre syndrome (Weiss, 1991)
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (Fantin, 1993; Kaufman, 1998; Midroni, 1996)
Multiple sclerosis (Newman, 1994b)
Crohn’s disease (Scott, 1997)
Peripheral nerve sheath tumor of thigh (Hills, 1998)
Familial pseudotumor cerebri (possible autosomal recessive or dominant transmission) (Fujiwara, 1997; Kharode, 1992; Santinelli, 1998)
Homozygous twins (Fujiwara, 1997)
What Is Idiopathic Pseudotumor Cerebri?
Idiopathic PTC (idiopathic intracranial hypertension) is a disease typically of obese women in the childbearing years (Arseni, 1992; Corbett, 1982; Ireland, 1990; Jain, 1992; Kesler, 2001a; Radhakrishnan, 1994; Soler, 1998; Walker, 2001; Wall, 1991). Approximately 10 to 15% of cases are male (Digre, 1988), and, when it occurs in children, there is usually no gender preference (Balcar, 1999; Cinciripini, 1999; Lessell, 1992; Scott, 1997), although in some series girls outnumber boys (Gordon, 1997). Children with PTC, especially younger children, are less likely to be obese than adults with PTC (Balcar, 1999; Cinciripini, 1999; Scott, 1997). Even though men with PTC are less likely to be obese than woman, they tend to be more obese than controls (Digre, 1988). In a study from Israel, 18 of 134 patients with idiopathic PTC were men and 25% of the men were significantly overweight, as compared to 78% of the women (Kesler, 2001b). The occurrence of PTC in a man, especially a thin man, should raise the possibility of venous occlusive disease or a secondary PTC syndrome. African-American men appear to be at greater risk of visual loss. The incidence of idiopathic PTC is approximately 1 or 2 per 100,000, with a higher incidence in obese women between the ages of 15 and 44 years (4 to 21 per 100,000) (Kesler, 2001a; Radhakrishnan, 1993a,b). Table 7–9 lists the diagnostic criteria for idiopathic PTC.
What Are the Risk Factors and Clinical Characteristics of Idiopathic PTC?
The most important risk factors for the development of idiopathic PTC include female sex, obesity, and recent weight gain (Giuseffi, 1991; Ireland, 1990). Several conditions previously associated with idiopathic PTC are no more common in PTC than in controls. In a retrospective case-control study of 40 patients with idiopathic PTC and 39 age- and sex-matched controls, all forms of menstrual abnormalities, incidence of pregnancy, antibiotic use, and oral contraceptive use were equal in both groups (Ireland, 1990). In another study comparing 50 PTC patients with 100 age-matched controls, iron deficiency anemia, thyroid dysfunction, pregnancy, antibiotic intake, and the use of oral contraceptives were no more common in PTC patients than in controls (Giuseffi, 1991).
Increased intracranial pressure must be documented in an alert and oriented patient without localizing neurologic findings (except for cranial nerve VI palsy)
Spinal fluid pressures between 200 and 250 mm H20 may occur normally in obese patients, and when elevated spinal fluid pressure is suspected, confirmation requires values greater than 250 mm H20 (Corbett, 1983)
The cerebrospinal fluid should have normal contents (including protein and glucose) with no cytologic abnormalities; occasionally the cerebrospinal fluid protein level may be low
Neuroimaging (MR imaging with and without contrast and possibly MR venography) should be normal with no evidence of hydrocephalus, mass lesion, meningeal enhancement, or venous occlusive disease; neuroimaging may often show the following, which may be helpful in establishing the diagnosis of PTC (percentages from Brodsky and Vaphiades, 1998):
Flattening of the posterior sclera (80% of patients)
Distention of perioptic subarachnoid space (50% of patients)
Enhancement (with gadolinium) of the prelaminar optic nerve (45% of patients)
Empty sella (70% of patients)
Intraocular protrusion of the prelaminar optic nerve (30% of patients)
Vertical tortuosity of the orbital optic nerve (40% of patients) (Brodsky, 1998; Gibby, 1993; Jacobson, 1990; Manfre, 1995)
No secondary cause (secondary PTC) is evident
The reason that obesity predisposes to PTC is unclear. Central obesity may raise intraabdominal pressure, which increases pleural pressure and cardiac filling pressure, including central venous pressure, leading to increased intracranial venous pressure and increased intracranial pressure (Sugerman, 1997). As noted above, elevated intracranial venous pressure is thought by some authors to be the universal mechanism of PTC of various etiologies, including idiopathic PTC. However, the study of King et al cited above indicates that the increased venous pressure in idiopathic PTC patients is caused by the elevated intracranial pressure and not the reverse (King, 2002). Idiopathic PTC may share a common pathogenesis with orthostatic edema, a condition in which there is evidence of dependent edema after prolonged standing (Friedman, 1998b). Seventy-seven percent of PTC patients had evidence of peripheral edema and 80% had significant orthostatic retention of sodium and water. Excretions of a standard saline load and of a tap water load were significantly impaired in the upright posture in the PTC patients with orthostatic edema compared to lean and obese but otherwise normal subjects. Orthostatic retention of water and sodium and consequent edema is similar in patients with idiopathic PTC and orthostatic edema. This suggests that these two disorders may have a common pathogenesis.
Elevated vitamin A levels have been noted in patients with idiopathic PTC (Jacobson, 1999). Serum retinol concentrations were significantly higher in patients with idiopathic PTC compared to controls (Selhorst, 2000), even after adjusting for age and body mass index. Patients may ingest an abnormally large amount of vitamin A, metabolize it abnormally, or be unusually sensitive to its effects. Alternatively, elevated levels of serum retinol may reflect an epiphenomenon of another variable not measured or a nonspecific effect of elevated retinol binding capacity (Jacobson, 1999).
Endocrinologic abnormalities may be more common in men with PTC (Lee, 2002c). In a study of eight men with PTC, two had abnormal estradiol levels, four had abnormal follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, and seven had low testosterone levels (Lee, 2002c).
What Are the Symptoms of PTC?
The most common symptoms of PTC include headache, transient obscurations of vision, pulsatile tinnitus, and diplopia (Giuseffi, 1991; Ireland, 1990; Wall, 1991). In a prospective study of 50 idiopathic PTC patients (92% women; mean age, 32 years; 92% obese), symptoms included headache (94%), transient visual obscurations (68%), intracranial noises (58%), sustained visual loss (26%), photopsia (54%), diplopia (38%), and retrobulbar pain (44%) (Wall, 1991). The headaches in patients with PTC may be constant or intermittent, and in 93% of patients they are reported to be the most severe headache ever (Wall, 1990). The headache may often be pulsatile, be of gradually increasing intensity during the day, awaken the patient at night, be precipitated by changes in posture, and be transiently relieved by lumbar puncture (Wall, 1990). Pain in a cervical nerve root distribution (possibly from a dilated nerve root sleeve) or retro-ocular pain with eye movement, uncommon with other headache disorders, may help to differentiate this headache syndrome (Wall, 1990). There is no clear correlation between the height of CSF pressure and the severity of the headache. Transient visual obscurations last seconds, may be unilateral or bilateral, and related to changes in posture. They do not correlate with the degree of intracranial hypertension or the extent of disc swelling, and are not considered to be harbingers of permanent visual loss (Corbett, 1982; Giuseffi, 1991). Intracranial noises are common with PTC and are perhaps due to transmission of intensified vascular pulsations via CSF under high pressure to the walls of the venous sinuses (Sismanis, 1990). The pulsatile tinnitus may be audible to others (Biousse, 1998). In fact, PTC without papilledema has been reported in patients with pulsatile tinnitus (Felton, 1995; Wang, 1996). Diplopia is often mild and usually due to a sixth cranial nerve palsy, presumably a nonlocalizing sign of raised intracranial pressure.
In a study of 101 patients with PTC, other minor symptoms included neck stiffness in 31 patients, distal extremity paresthesias in 31, tinnitus in 27, joint pains in 13, low back pain in 13, and gait instability in 4 (Round, 1988). These minor symptoms resolved promptly upon lowering of the intracranial pressure. Stiff neck and strabismus may be the most common presenting symptoms in children with PTC (Cinciripini, 1999). Sleep-related breathing problems are common in PTC patients and may be a risk factor (Marcus, 2001). Patients with idiopathic PTC are significantly more affected by hardships associated with health problems than age- and weight-matched controls and have higher levels of depression and anxiety (Kleinschmidt, 2000). Other rare and exceptional clinical abnormalities that have been described in patients with PTC are listed in Table 7–10.
Fourth cranial nerve palsy (Lee, 1995; Speer, 1999)
Third cranial nerve palsy
Sixth cranial nerve palsy (unilateral) without papilledema (Krishna, 1998)
Bilateral sixth and fourth cranial nerve palsies (Patton, 2000)
Complete external ophthalmoplegia (Friedman, 1998a)
Bilateral total internal and external ophthalmoplegia
Internuclear ophthalmoplegia with vertical gaze paresis with or without ptosis (Friedman, 1997, 1998a)
Vertical gaze palsy (Friedman, 1998a)
Divergence insufficiency (Jacobson, 2000)
Sensory exotropia or comitant esotropia in children (Cinciripini, 1999)
Ptosis (Friedman, 1998a)
Lid retraction (Friedman, 1998a)
Trigeminal neuropathy (Davenport, 1994)
Unilateral or bilateral facial nerve palsy (Bakshi, 1992; Capobianco, 1997; Selky, 1994a)
Hemifacial spasm (Mayer, 1996; Selky, 1994a)
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