Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

52.Morrow MJ, Sharpe JA. Retinotopic and directional deficits of smooth pursuit initiation after posterior cerebral hemispheric lesions. Neurology 1993;43: 595–603.

55.Sharpe JA. Neuroanatomy and neurophsiology of smooth pursuit: lesion

studies. Brain Cognition 2008;68:241– 254.

69.Hain TC, Spindler J. Head-shaking nystagmus. In: Sharpe JA, Barber HO (eds) The Vestibulo-Ocular Reflex and Vertigo. New York: Raven, 1993:217– 228.

Key references

73.Buttner-Ennever JA, Buttner U, Cohen B. Vertical gaze paralysis and the rostral interstitial nucleus of the medial longitudinal fasciculus. Brain 1982;105: 125–149.

Clinical background

Key symptoms and signs

The signs and symptoms of increased intracranial pressure (ICP) are headache, subjective pulse-synchronous bruit, and papilledema (Box 39.1). Papilledema can cause fleeting visual obscurations in one or both eyes. Occasional diplopia is attributed to presumed sixth-nerve compression. Visual field loss and decreased acuity are unusual early in the course of disease, but may become devastating over time.

Historical development

Helmholtz’s 1851 invention of the ophthalmoscope allowed visualization of the optic nerves, and of their dramatic engorgement with the swelling of papilledema that accompanied the increased ICP of brain tumors. The development of the first effective neurosurgical procedures by Harvey Cushing around 1910, which allowed life-saving treatment by urgent removal or decompression of such tumors, made recognition of papilledema and its connection to brain tumors critically important.1 It was an association, which when recognized and acted upon, might save a patient’s life. For that reason it became a highpriority sign in the routine medical examination, so that papilledema, or any optic disc edema, needed to be quickly categorized as “brain tumor” or “otherwise.” The “otherwise” became known as pseudotumor cerebri (PTC), a brain tumor-mimicking form of papilledema. The most common cause before 1950 was bacterial meningitis, a nonsurgical cause of increased ICP, as shown by the early work of Paton and Holmes.2 A frequent cause of meningitis, with an associated element of adjacent venous thrombosis, in that preantibiotic era, was mastoiditis. An infection of the mastoid air spaces in the petrous bone, it might start as a routine nasopharyngitis, extend to the eustachian tube and inner ear, then a petrous bone infection with mastoiditis. The sequential adjacent meningitis and lateral sinus thrombosis became recognized as “otitic hydrocephalus”.3

Deborah M Grzybowski and Martin Lubow

All of this changed after World War II with the availability of penicillin. Bacterial meningitis and otitic hydrocephalus became unusual, but the appearance of a patient with papilledema still required a determination of brain tumor versus pseudotumor as the first diagnostic step. Despite the availability of cerebral angiography and ventriculography, many patients had exploratory craniotomies as the last step in ruling out a brain tumor and in establishing their diagnoses as pseudotumor. It was not until the evolution of neuroimaging to modern computed tomography and magnetic resonance techniques that this became unnecessary. Until then all increased ICP, meaning all papilledema, was regarded, and needed to be so regarded, as due to brain tumor.

Nomenclature for PTC syndromes is varied. “Benign intracranial hypertension” is flawed, in that the disorder is anything but benign. We prefer “idiopathic pseudotumor cerebri” or iPTC for cases where the etiology is unclear, although in deference to common use, we will use the term “idiopathic intracranial hypertension” (IIH) in this chapter. “Secondary PTC” is used when there is a detectable etiology, e.g., cerebral venous thrombosis or use of tetracycline, doxycycline, minocycline, or retinoids (Box 39.2).

Epidemiology

IIH is a disease that most frequently affects obese women of child-bearing age.4–7 The incidence of IIH in the general population is 1 : 100 000; however, the incidence rises to 19.3 : 100 000 in women aged 20–44 who are at least 20% over ideal body weight.8,9 The incidence of IIH appears to be rising dramatically, and the Centers for Disease Control recently released statistics indicating that the rate of obesity in the USA has doubled in the past decade.10

Genetics

Rare, but verified, examples of a mother with known IIH, and her son with the same diagnosis,11 a father with a daughter,12 and dizygotic twin brothers,13 are consistent with a genetic link. Twins have been reported, both heterozygous

Box 39.1  Key symptoms and signs of increased intracranial pressure in idiopathic pseudotumor cerebri

•Increased intracranial pressure (over 250 mm H2O)

•Headache

•Papilledema

•Pulsatile bruit (noise)

•Transient visual obscurations

•Obesity

•Child-bearing age

•Female

•Diplopia (uncommon)

•Visual field loss (uncommon)

and homozygous, e.g., homozygous twin sisters with similar onset of symptoms in both.14,15

Diagnostic workup

IIH is diagnosed when the following are all true:

1.Symptoms and signs all attributable to increased ICP or papilledema

2.No medications known to elevate ICP (see Box 39.2)

3.Normal neurological examination except for papilledema and possibly evidence of sixth-nerve dysfunction

4.Normal magnetic resonance imaging and magnetic resonance venography

5.Elevated ICP recorded during lumbar puncture in the standard lateral decubitus position (cerebrospinal fluid

(CSF) opening pressure greater than 250 mm H2O; pressures of 200–250 mm H2O should remain suspect)

6.Normal CSF composition.

Treatment

Normalizing and maintaining the CSF pressure can be challenging. Fluid removal is often temporary, and shunting to another location is invasive and often impermanent. Medical treatment can decrease fluid formation, but does so incompletely and with side-effects that can be unpleasant and sometimes dangerous.

Most patients are managed with medical treatment to lower the CSF pressure. The typical treatment progression for IIH is shown in Box 39.3. Carbonic anhydrase inhibitors (CAIs), usually acetazolamide, are used to impair CSF formation and can improve symptoms of headache and visual obscurations in most patients. Despite unpleasant sensory disturbances (tingling fingers and toes, and taste distortions), malaise, diuresis, and even the risks of abreaction (sulfa allergies and aplastic anemia), the CAIs are the most common form of medical treatment. The effect of CAIs on CSF outflow is unknown; however, receptors for CAIs have been identified in the arachnoid membrane, suggesting a role in modulating CSF outflow.

More effective agents than CAIs are not known. Furosemide has been tried and adds little beyond the risk of potas-

Clinical background

Box 39.2  Secondary causes of pseudotumor cerebri

•Head trauma (including posttraumatic brain injury)

•Underlying disease: liver or kidney failure

•Sleep apnea

•Venous thrombosis (cerebral blood clots)

•Stroke (subarachnoid hemorrhage)

•Cystinosis

Drugs

•Accutane (isotretinoin)

•Tetracycline

•Growth hormone

•Corticosteroids

•Tetracyclines

•ATRA (acute promyelocytic leukemia)

•Vitamin A (hypervitaminosis A; retinoids)

•Amiodarone

•Nitrofurantoin

•Nalidixic acid

•Sulfa antibacterials

•Leuprorelin (luteinizing hormone-releasing hormone analog)

•Lithium

•Levonorgestrel (Norplant)

•Steroid withdrawal

Underlying infectious diseases

•Meningitis (bacterial or viral)

•Lyme disease

•Human immunodeficiency virus (HIV)

•Poliomyelitis

•Coxsackie B viral encephalitis

•Guillain–Barré syndrome

•Infectious mononucleosis

•Syphilis

•Malaria

Box 39.3  Typical treatment progression for

idiopathic pseudotumor cerebri

1.Carbonic anhydrase inhibitors (CAIs)

2.Other pharmaceuticals

a.Lasix (furosemide)

b.Beta-blockers (propranolol)

c.Octreotide (somatostatin)

3.Surgery

a.Optic nerve sheath fenestration

b.Neurosurgical shunts

i.Lumboperitoneal (LP) shunt

ii.Ventriculoperitoneal (VP) shunt

iii.Cisterna magnum shunt

c.Cortical venous stents

sium imbalance. Somatostatin analogs may be encouraging, demonstrated by our clinical experience with octreotide (not published),16 but remain at the research level.

Shunting procedures include lumbar peritoneal shunts, ventriculoperiotoneal shunts, and optic nerve sheath fenestration. These procedures have significant limitations. They

each need a patent opening to allow persistent drainage of CSF from the subarachnoid or intraventricular space into the peritoneal cavity or orbit. A critical limitation in both is failure to work consistently and predictably over the years.

A controversial alternative to surgery of the intracranial or orbital subarachnoid space for lowering ICP is cortical venous sinus stenting.17–21

Prognosis and complications

Patients with IIH are carefully followed with perimetry and fundoscopy in order to detect visual field deterioration (which may be asymptomatic until late) and worsening papilledema. Retinal nerve fiber layer analysis by optical coherence tomography is a promising complement to the clinical examination.

Pathophysiology

Normal CSF homeostasis relies on a careful balance between CSF production and absorption. Alterations in the rate of CSF formation, absorption, or outflow resistance can lead to a buildup of ICP, causing multiple neurological deficits.

While the mechanisms explaining secondary PTCs remain obscure, their clarification is a worthwhile objective. Neurophysiologists and neuroscience-oriented physicians are quick to presume that such agents somehow impair CSF outflow by damage to outflow channels. Likely that is true, but except for seeing red blood cells in the subarachnoid space and in the arachnoid villi after intracranial hemorrhage, we don’t know what happens, or how it happens, at the molecular level of the CSF outflow pathways.

Isolating the “distilled” group of patients labeled as IIH now permits us to focus on their common findings and characterize them in a way that should help our clinical perspective, while recognizing that later information will regroup them more accurately. The following factors should be considered in any discussion of pathogenesis:

1.Genetics

2.Obesity

3.Retinoids

4.Hydrocephalus

5.Models.

A simplified model circuit shows the movement of CSF in Figure 39.1.22–24 Basic fluid mechanics shows that the driving force for fluid movement is a pressure difference.25 This implies that a pressure gradient must occur prior to any movement of CSF. Any of the fluid reservoirs shown in Figure 39.1 may be affected by changes in pressure gradients and the resultant fluid redistribution. The subarachnoid space (SAS) acts like a variable fluid capacitor, taking up excess CSF when needed or giving it up if necessary. The ability of the SAS to do so is affected by age and other factors that stiffen the arachnoid trabeculae. The vasculature responds to changes by dilation or constriction (autoregulation), with a redistribution of fluid, and a rebalance of pressure gradients, which leads us to mechanistic theories.

Foramen

of Monro

Cortical subarachnoid space

Arachnoid membrane

point of pressure gradient

Cerebral microvasculature

Jugular foramen

Figure 39.1  Model circuit of fluid movement between cerebrospinal fluid and vasculature.

Mechanistic theories

CSF homeostasis and raised ICP in IIH have long puzzled investigators.24,26 CSF formation rates range from approximately 0.3 to 0.4 ml/min.27–29 Based on this, the entire CSF volume turns over 3–4 times daily.

In a seemingly healthy patient, with all other variables unchanged, CSF pressure rise must be due to either increased CSF production or decreased CSF outflow. Increased CSF production is possible, but much less likely than decreased outflow. Several studies have shown that the rate of CSF production is either normal or slightly decreased, therefore hypersecretion of CSF as a mechanism is unlikely.30,31 Further evidence against excessive CSF production as the mechanism of IIH lies in clinical experience, such as with choriod plexus papilloma, a condition with excessive CSF production, which does not clinically produce anything similar to IIH.32

Theories explaining decreased outflow relate to slowed egress through the membrane system that includes the arachnoid membrane and arachnoid granulations (AGs),24,33–36 or increased backpressure in the cortical venous system, similar to that seen in secondary PTC due to venous thrombosis.

Vitamin A connection

Because of clinical experience with vitamin A toxicity, recent attention has focused on retinoid metabolism and transport with interesting, but still inconclusive, results. The association between secondary PTC and vitamin A has been recognized in cases of excessive dietary intake of vitamin A (hypervitaminosis A), the most prominent example of which is the well-documented vitamin A toxicity resulting from the ingestion of polar bear liver by arctic explorers and Eskimos.37 It has since been demonstrated that bear and seal livers contain extremely high concentrations of vitamin A and can produce rapid vitamin A toxicity when consumed even in

moderate doses.38 Secondary PTC has also been reported in association with natural and synthetic retinoid-based medications, often used in dermatology in the treatment of acne (for review, see Friedman39). The secondary association between vitamin A and PTC in these cases is so strong that it has recently led to the investigation of serum and CSF levels of retinol and serum retinol-binding protein (RBP) levels in IIH patients without excessive vitamin A intake or supplementation.40–42

Several studies have examined the levels of retinol in the serum and CSF of patients with and without PTC and found conflicting results, most likely due to differences in study design and/or sample handling. Jacobson et al40 examined only the serum levels of retinol and retinyl ester in patients with and without PTC. Selhorst et al43 compared both serum retinol and serum RBP levels in patients with and without PTC. More recently studies have focused on CSF retinol levels. Tabassi et al41 measured both serum and CSF retinol in 20 patients with PTC and 20 ageand body mass indexmatched control patients. These studies have led to the hypothesis that perhaps patients with IIH are predisposed to vitamin A intoxication, even at normal intake levels.

Warner et al have recently reported on CSF retinol and RBP levels in several patient groups, including those with IIH.42 In this study, the authors found that patients with IIH had significantly elevated CSF retinol levels in addition to significantly reduced CSF RBP levels compared to control patients. This led to a significantly increased CSF retinol : RBP ratio in patients with IIH. The results of this study led the authors to hypothesize that these decreased levels of CSF RBP coupled with increased CSF retinol might lead to elevated circulating levels of free, unbound retinol that could potentially be toxic to the arachnoid villi and granulations.

Important too is the 2005 review article by Helen Everts et al44 in which they demonstrate (in rats) immunolocalization of RA biosynthesis systems to the selected tissue sites where their effects are required. The focal paracrine nature of these retinoid functions obviates the need for endocrinetype systemic circulation of retinoids or their transporters beyond the initial retinol stage. In IIH patients the tissues will be normal, but the signal transduction pathway will be abnormal and cause overproduction of RA, measurable in their CSF but probably not in their serum.45

No one has been able to develop an adequate demonstration of a consistent abnormality, nor to offer an adequate hypothesis to explain the role of retinoids and increased CSF pressure. This is especially troublesome in view of known examples of vitamin A toxicity, and in view of long-standing animal work in other species showing that hypervitaminosis A causes decreased CSF pressure.46

Vitamin A and adipocytes

Two proteins for vitamin A transport in blood and brain are transthyretin (TTR) and RBP. TTR is a critical transport protein for thyroxine and retinol. It is also an important metabolic modulator and has been linked to obesity. It is expressed in liver, and synthesized and secreted by the choroid plexus into CSF.

Studies in rats show that adipocytes synthesize RBP and store RBP and retinoids.47 Cellular RBP (CRBP) gene expression is regulated dynamically in adipocytes by retinol uptake,

Pathophysiology

intracellular transport, and metabolism. Another rat study showed that adipocytes are dynamically involved in retinoid storage and metabolism, and synthesis and secretion of RBP.48 This may be significant for those IIH patients who characteristically have a body mass index greater than 30. Increased numbers of adipocytes, which regulate vitamin A metabolism by altering gene expression, are critical in IIH. A Medical Research Council study was conducted in 1942 to determine time of vitamin A depletion in human volunteers. They found it very difficult to deplete vitamin A; in some cases it took over 2 years, the length of their study.49

The increased levels of adipocytes in obese IIH patients can dynamically regulate vitamin A metabolism by altering gene expression, and must be considered as a possible mechanism for IIH. Retinoic acids (RAs) have the ability to alter gene transcription via their receptors, which have been identified in arachnoid tissues in our unpublished data. Increases in the plasma concentration of RA isomers have been shown to upregulate expression of their receptors, suggesting that the metabolism of vitamin A can be altered or self-regulated in humans.50 Elevated RA levels may also act directly via dynamic vitamin A-related transcriptional changes to alter CSF pressure. These transcriptional changes lead to decreased cellular viability, proliferation, cellular remodeling, adhesiveness, and a resultant decrease in membrane permeability which also contributes to elevated CSF pressure.

Vitamin A animal models

Studies on hypoand hypervitaminosis A in animal models, including rodents, cattle, and goats, have investigated the effects of vitamin A on CSF formation and clearance rates as well as on biochemical composition of the dura mater and arachnoid villi. Several groups have investigated the association between altered vitamin A status and morphological changes in the AGs associated with changes in ICP.

Hypovitaminosis A

Increased ICP has been found in hypovitaminotic A calves46 and in rat.51 The effects of vitamin A deficiency on the formation and absorption of CSF by adult goats were reported by Frier et al.52 Unlike the results previously reported for developing calves, deficient adult goats exhibited no change in CSF formation rate or ICP; however CSF outflow resistance was elevated compared to control animals. The authors conclude that adult ruminates may require a deficiency of a longer duration to produce similar effects as in younger, developing animals.

Hayes et al53 reported the first detailed analysis of arachnoid morphology in hypovitaminotic calves and rats. They used histology with electron microscopy to examine the AGs of deficient animals. The authors of this study report that the AGs of deficient animals were larger and more readily visible, and in some cases so large that portions of the brain had herniated through the dura mater and into the dural sinus lumen. Ultrastructural analysis of the AGs revealed an overall thickening of the dura mater and subarachnoid trabeculae. The fibrous capsule and interstitial arachnoid cells appeared fibrotic, with increased collagen fibrils, tonofilaments, and glycogen granules. The general thickening of these tissues led these authors to speculate that ICP increases might be due

to an overall decrease in the subarachnoid CSF space and an increased resistance to CSF outflow.

Hypervitaminosis A

Similar studies by Hurt et al on the rates of CSF formation and absorption have been performed in calves with vitamin A toxicity. They reported on the rates of CSF formation and absorption in hypervitaminosis A and found the calves had significantly decreased ICP and a decreased rate of CSF production.54

Frier et al55 noted that the hypervitaminosis A toxicity reported by Hurt et al54 was quite severe and that several animals died from the toxicity. They repeated the test in calves using mild vitamin A toxicity, and found decreased ICP. Increased CSF formation rate and increased bulk absorption of CSF were attributed to decreased resistance to CSF outflow.

Frier et al55 studied the effects of vitamin A toxicity in adult goats. They compared the effects of vitamin A toxicity in the developing calf and found decreased ICP and increased CSF formation rate.

Finally, Gorgacz et al56 provided a morphologic assessment of the AGs in calves with hypervitaminosis A, similar to the analysis of Hayes57 for vitamin A deficiency. This study reported that the AGs in bovine vitamin A toxicity were significantly reduced in size with overall thinning of the cellular membranes, including a thinner fibrous capsule surrounding the granulations. In addition, the height of choroid plexus epithelial cells in hypervitaminotic calves was reduced.

Taken together, these studies on the effects of vitamin A status on CSF homeostasis in animal models initially seem to agree. They indicate that vitamin A deficiency is associated with increased ICP and is likely due to decreased absorption of CSF from increased resistance to CSF outflow. In these animal models, hypervitaminosis A is associated with a significantly reduced ICP and a decreased resistance to CSF absorption. On the other hand, production rates of CSF vary with age and species.

Vitamin A animal model conclusions

The results of animal studies are in direct contrast with human vitamin A status, where vitamin A toxicity is closely associated with increased ICP and a secondary PTC condition. It is not clear if these differences relate to fundamental differences in the transport and metabolism of vitamin A between humans and animals, variation in the degree of toxicity/deficiency, or distinctions between developing and fully mature subjects. The important points to remember from this critical analysis of animal models are:

1.There is a link between vitamin A levels and ICP

2.Vitamin A levels effect structural and morphological changes in the arachnoid tissues, as shown in animals

3.Animal models are not adequate to study human IIH.

Other mechanisms

Recent work with calcium-regulating target genes has shown that alpha-klotho, with its link to fibroblast growth factor-2, is critical to membrane regulation of calcium homeostasis and thereby CSF formation in the choroid plexus and in

302

membranes generally.58,59 Interestingly there is also a link to retinoids via nuclear receptors and particularly peroxisome proliferator-activated receptor-γ.60

We have recently published a pathogenetic hypothesis for IIH45 which is based on: (1) the recognition of multigenerational familial disease patterns, which confirm the hereditary nature of IIH; and (2) the demonstration of retinaldehyde, an intermediate metabolite in the retinoid pathway, as an important regulator of adipogenesis, fat storage, and insulin resistance. We hypothesize that IIH is a familial disease. It is caused by a highly conserved, tightly controlled genetic variant of the enzyme systems controlling the regulation of the retinoid intermediate metabolite retinaldehyde, and its major oxidation product, RA. We point specifically to a deficit of retinaldehyde due to inefficient enzymatic regulation, and a resultant increase in available RA in the central nervous system (CNS) due to the same inefficient enzymatic regulation and inefficient RA degradation (Figure 39.2). The decrease in retinaldehyde is known to cause obesity and insulin resistance. The increase in RA is the cause of impaired CSF outflow and thereby idiopathic increased intracranial pressure (IICP) via impaired transport of CSF through the arachnoid membrane outflow channels. Of special interest is the necessary role of estrogen in the induction of RA expression, as demonstrated, and more recently reviewed, by Li et al.61 It suggests an explanation for the sex and the age preference of the IIH syndrome, with its onset in teenage girls, and it offers the possibility of medical treatment based on manipulation of estrogen hormone suppression and even ovarian cycle alteration to diminish the excess RA production which we hypothesize to be the cause of the IICP in these patients. These combined elements are the hallmarks of the syndrome we recognize as IIH. Localizing the metabolic defect and the enzyme variant offers the possibility of treatment and even possibly the cure of this familial syndrome. Initial treatment of IIH by diet modifications to bypass defective pathways, such as reduced retinoid intake and increased Raldh inhibitors such as citral, may be effective.45

CSF outflow models

Structure and function

The AGs, described by Pacchioni in 1705 as “peculiar wartlike excrescences” were functionally investigated by Key and Retzius in 1876.56,57,62,63 They injected Berlin blue-stained gelatin into the spinal subarachnoid space (SAS) of human cadavers “at fairly low pressures (60 mmHg)” and saw the blue pass through the AGs (“die Arachnoidenzotten”) into the cerebral sinus, but also into the lymphatic vessels of the frontal sinus and the nasal mucous membrane (Figure 39.3). Theirs was the first modern indication of a dual CSF drainage system in humans, demonstrating both AG and basal lymphatic outflow pathways.

Weed, working with Cushing at the beginnings of neurosurgery, used what he considered to be more informative markers, Prussian blue and ferrocyanide solutions, and again verified the AG pathway into the venous sinus.64,65 He dismissed the basal lymphatic outflow as insignificant, and emphasized that CSF was absorbed across the arachnoid villi and into the venous system.

A

B

Figure 39.3  (A) Cerebrospinal fluid outflow pathway marked with Berlin blue-stained gelatin by Key and Retzius in 1875. (B) Close-up of filled subarachnoid space, arachnoid membrane, and granulations, and the superior sagittal sinus. (Courtesy of the Johns Hopkins Rare Book Collection.)

Most studies thereafter dealt with the issue of open versus closed (valved) channel mechanisms of CSF outflow through the arachnoid membrane. The open-channel theory was first proposed by Davson et al in 197366 and followed by others67,68 until the electron microscope became commercially available around 1965, when numerous studies hypothesized a mechanism which utilizes valve-like structures, or closed channels.69–73 Tripathi also detailed the analogy between outflow of aqueous humor and CSF.72

Ultrastructural perspectives have also shown that human AGs are different from those of other species.74 Human AGs demonstrate a cap cell layer contacting or extending through the dura in places to provide a direct contact with the venous lumen. This combination of special anatomy, cap cells, and their location further suggests a special function in their role for CSF outflow in humans.75–81

More recently, research attention has returned to the basal lymphatic pathway shown earlier by Key and Retzius in 1875.82–84 A major component via olfactory fibers through the cribriform plate has been suggested, but the microanatomy remains to be clarified. It is likely that it will turn out to be a variant of the arachnoid sleeve structure shown along the spinal nerves, where an arachnoid sheath surrounds the exiting nerve with an adjacent lymphatic channel available for passage of exiting CSF (Figure 39.4).85–91

The optic nerve remains a special physiological entity due to its location, its origin (white-matter tract of the CNS surrounded by CSF along its length), and the opposing pressures induced by the CSF from the subarachnoid space and intraocular pressures. Animal work has suggested that the optic nerve offers a similar pathway to adjacent lymphatics, but clinical experience demonstrates that this is not true in humans. Indeed, the cul-de-sac nature of the duralarachnoid sleeve on the optic nerve terminating as it does at the globe is the very reason for chronic increased ICP in PTC causing nerve compression blindness. Some have claimed otherwise, but have not explained common clinical experience.92,93

D

SAS

VR

DR

A

Figure 39.4  (A) Schematic drawing of the spinal cerebrospinal fluid outflow pathway (arrows) along the ventral and dorsal root (VR, DR) seen from the subarachnoid space. The dura (D) is held by tenting sutures to visualize the outflow area, which, due to bulges and trabeculae of the external arachnoid layers, has a reticular appearance (magnified inset). (B) Schematic drawing of the horizontal cutting plane of (A). The median outflow area toward the endoneurium between dorsal root (DR) and ventral root (VR) can be differentiated from two lateral outflow areas of the subarachnoid space (SAS). In these areas the outer arachnoid layer forms several bulges and excavations (EC). The external arachnoid layer (AB) builds the border to the dura mater (D, white area), which becomes thinner in the distal area. Lymph vessels (L) can be found in the connective tissue around the dura mater, predominantly near spinal ganglia (G). (Modified from Voelz K, et al. A ferritin tracer study of compensatory spinal CSF outflow pathways in kaolin-induced hydrocephalus. Acta Neuropathol 2007;113:569–575.)

Studies have shown that arachnoid villi are present in the optic nerve sheaths of both humans and primates.94,95 This is an area of controversy because it disputes clinical findings. Optic nerve surgery for PTC seems to demonstrate that the optic nerve sheaths retain CSF under increased pressure. Though villi are present, perhaps they are unable to drain at increased pressure. These seemingly confounding ideas will be explored further in the discussion of human models.

Development of arachnoid villi

Controversies over the time of appearance of arachnoid villi seem misplaced, in that their function is the issue of interest and need not depend on their enlargement or visibility as AGs later in life. Nevertheless, Le Gros Clark96 concluded his 1920 studies with the opinion that the villi were present at birth and at times in the fetus. Visible granulations appeared variably from 4 to 18 months, when the fontanels closed. Since then Turner97 showed arachnoid villi in developing human embryos at 12 weeks’ gestation, and in term fetuses,

Figure 39.5  Comparison of average cerebrospinal fluid outflow resistance in physiologically perfused human arachnoid granulations in arachnoid membrane (AG/AM) and arachnoid membrane with no visible granulations (AM). Perfusion pressure was 5 mmHg (physiologic). The values are within the range of previously reported human arachnoid membrane resistance values.

and in 92 other human subjects. These data suggest the potential for CSF outflow function through these structures before birth.

Human CSF outflow model

Models for human CSF outflow in vitro and ex vivo have been developed and used to verify arachnoid membrane functional characteristics.98–101 They have shown unidirectionality of flow across the arachnoid membrane, and fluid transport via transcellular (vacuoles) and paracellular (vesicles) pathways,97,98 both mimicking physiologic CSF passage. These findings are in agreement with earlier electron microscopic ultrastructural studies.72,81,102

Of special interest is our demonstration that our ex vivo perfusion model of the human arachnoid membrane alone, without visible granulations, has the capability of permitting the passage of five times the volume of outflow than the AG perfusion model (Figure 39.5; unpublished data).

Our ex vivo model shows that resistance to outflow at 15 mmHg is greater than at 5 mmHg. This might explain the disparity that is suggested with increased pressure and failure of the outflow mechanism in the optic nerve. Figure 39.6 (unpublished data) shows the increase in resistance by human arachnoid membrane with increasing pressure. We must keep in mind that the arachnoid membrane in the ex vivo model is not an exact model of in vivo functionality.

When verified by others, this CSF outflow resistance data would suggest the need to reconsider the relative distribution between the venous and the lymphatic contributions in selected age groups. The developmental status of the membrane surface used, as manifested by age and by morphology, will be important for the study of infantile hydrocephalus where, despite increase in the CSF pressure gradient (versus systemic venous and lymphatic pressures), the CSF outflow mechanism has failed.

Increased cerebral venous sinus pressure

Others have speculated that CSF absorption is decreased by increased cerebral venous pressure which decreases the

Figure 39.6  Comparison of average cerebrospinal fluid outflow resistance in physiologically perfused human arachnoid granulations in arachnoid membrane (AG/AM) and arachnoid membrane with no visible granulations (AM) at physiologic pressure (5 mmHg) and increased intracranial pressure (15 mmHg).

Key references

driving force for CSF outflow.17,18,103 Numerous studies have reported controversial results for use of stents in PTC patients.18,104 Conflicting results may be attributed to uncontrolled variables and differences in patient selection criteria.

King et al showed by manometry that removal of CSF in PTC patients produced a drop in proximal transverse sinus pressure. This indicates that venous outflow obstruction is reversible by reducing ICP, from which it follows that the stenosis is the effect and not the cause.105 Three case reports by Rohr et al also indicate that the venous sinus obstruction is secondary to increased ICP.106

It has always been presumed, and more recently recognized, that increased ICP greater than cerebral venous pressure would collapse the low-pressure cerebral venous sinuses, and that a drop in that elevated ICP should allow those low-pressure veins to reopen, and to drain properly. This drop in pressure also affects the arachnoid membrane resistance to outflow, thereby allowing normal CSF outflow to resume through normalized arachnoid membrane. Removal of CSF can, at times, relieve IIH in a similar manner.

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29.Rubin RC, Henderson ES, Ommaya AK, et al. The production of cerebrospinal fluid in man and its modification by acetazolamide. J Neurosurg 1966;25: 430–436.

38.Rodahl K, Moore T. The vitamin A content and toxicity of bear and seal liver. Biochem J 1943;37:166–168.

42.Warner JE, Larson AJ, Bhosale P, et al. Retinol-binding protein and retinol analysis in cerebrospinal fluid and serum of patients with and without idiopathic intracranial hypertension. J Neuroophthalmol 2007;27:258–262.

45.Grzybowksi, Lubow in press

46.Calhoun MC, Hurt HD, Eaton HD,

et al. Rates of formation and absorption of cerebrospinal fluid in bovine hypovitaminosis A. J Dairy Sci 1967;50: 1489–1494.

53.Hayes KC, McCombs HL, Faherty TP. The fine structure of vitamin A deficiency. II. Arachnoid granulations

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62.Key G, Retzius A. Studien in der Anatomie des Nervensystems und des Bindesgewebe. Stockholm: Samson and Wallin, 1876.

65.Weed LH. The absorption of the cerebrospinal fluid into the venous system. Am J Anat 1923;31:191–221.

71.Shabo AL, Maxwell DS. The subarachnoid space following the introduction of a foreign protein: an electron microscopic study with peroxidase. J Neuropathol Exp Neurol 1971;30:506–524.

72.Tripathi RC. The functional morphology of the outflow systems of ocular and cerebrospinal fluids. Exp Eye Res 1977;25(Suppl.):65–116.

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in human arachnoid villi. Neurosurgery 1988;22:633–641.

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Clinical background

Giant cell arteritis (GCA) is a serious and relatively common systemic vasculitis that occurs in adults older than 50 years. The key symptoms and signs of GCA include both systemic and neuro-ophthalmic manifestations (Table 40.1).1–3 Systemic manifestations may involve a long prodromal period of multiple symptoms including weight loss, fatigue, fever, and malaise. Generalized muscle pain, claudication of the jaw or tongue, or localized scalp or temporal pain, swelling, and tenderness are also commonly observed in this disease. Ischemic manifestations from vascular compromise include blindness, stroke, aortitis with aneurysm, myocardial ischemia, and bowel infarction.4 Neuro-ophthalmic manifestations include arteritic anterior ischemic optic neuropathy, posterior optic neuropathy, choroidal ischemia, diplopia, retinal arterial occlusions, and ocular ischemic syndromes, occuring in up to 70% of patients.5–8 It is estimated that 15–20% of patients with GCA suffer permanent and potentially bilateral visual loss from ischemic infarction of the optic nerve.

Although the original descriptions of GCA are attributed to Hutchinison in 1890, initial references to this disease were first noted in ancient Egypt.9,10 The hallmark granulomatous inflammation with giant cells was described in 1932 by Horton. Use of the terms temporal or cranial arteritis is commonly found in the literature but may preclude the understanding that GCA is a systemic, not localized, disease.

Epidemiology of GCA depends on geography; it is a rare disease in Japan, and the incidence in Europe increases in association with higher latitudes. Recent literature suggests that prior reports of a lower prevalence among Hispanic and Black individuals was underestimated, perhaps because of ascertainment bias.11–13 In western countries the frequency is commonly defined at about 20 per 100 000 individuals older than age 50. However, for reasons that remain obscure, this increases over time, reaching a peak at between 70 and 80 years of age and women are twice as likely to be affected as compared to men. The cyclical increase in incidence of GCA every 7 years in the large epidemiologic Minnesota study, as well as other associations between onset of GCA and epidemics of specific bacterial or viral infections, suggests an environmental or infectious impact on disease prev- alence.14–16 Genetically there is an association between GCA

Giant cell arteritis

Lynn K Gordon

and HLA-DRB1*04.17–19 Other associations have been reported between genetic polymorphisms in multiple genes and susceptibility to GCA or its complications. These genes include matrix metalloproteinase 9 (MMP 9),20 platelet glyco­protein receptor IIIA,21 interferon-γ (IFN-γ),22 and the interleukin (IL)-10 and IL-6 promoters.23–25

Diagnostic evaluation of patients with suspected GCA is challenging as there are no specific laboratory examinations. On physical examination, a palpable, tender, enlarged temporal artery may be identified and the abnormal portion should be biopsied for histopathologic analysis (Figure 40.1). Histology, when positive, can be diagnostic but the characteristic giant cells identified at the junction of the intima and media are only observed in about half of the cases; the remaining positive biopsy specimens demonstrate a nonspecific mixed inflammatory response and may show disruption of the internal elastic lamina (Figure 40.2).26–28 One potential challenge is that the lesions are not continuous and may only involve a portion of the artery, therefore a long segment of artery (greater than 15 mm) must be carefully evaluated in its entirety, and sometimes multiple biopsies increase the diagnostic yield.28

Some patients with suspected GCA do not have a positive biopsy and then the diagnosis is based on the clinical history, physical examination, and nonspecific laboratory diagnostic indicators of inflammation. Laboratory findings include elevations in the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and platelet counts.29,30 Although these are not specific for GCA, the sensitivity of an elevated ESR and CRP in a patient suspected of having GCA is greater than 99%, and the positive likelihood value of thrombocytosis alone is high in patients with other signs and symptoms referable to GCA.31 However, it is also important to note that a normal ESR does not exclude GCA as a diagnosis and may occur in more than 15% of affected individuals. Recent improvements in imaging techniques have been applied to the diagnosis of GCA with varying results. Color duplex ultrasonography, high-resolution magnetic resonance imaging, and positron emission tomography imaging have all been reported as helpful in the diagnosis, yet the accuracy remains controversial and thus these are not routinely performed for GCA diagnosis.32–34

The differential diagnosis of GCA is dependent on the presenting symptoms and signs. If one considers only the ophthalmologic presentations, then there are three main