Available online at www.sciencedirect.com Phytochemistry 69 (2008) 1469–1495 Cordyceps – A traditional Chinese medicine and another fungal therapeutic biofactory? R. Russell M. Paterson * Institute for Biotechnology and Bioengineering (IBB), Centre of Biological Engineering, Campus de Gualtar, University of Minho, 4710-057 Braga, Portugal Received 17 December 2007; received in revised form 17 January 2008
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Neurostation.netPseudotumor Cerebri: Brief Review of Clinical
Syndrome and Imaging Findings
SUMMARY: PTC is a clinical entity of uncertain etiology characterized by intracranial hypertension. The
syndrome classically manifests with headaches and visual changes in women with obesity. Tradition-ally, imaging ruled out secondary causes of elevated CSF pressure but now may reveal findingsfrequently seen in patients with PTC, including the following: flattening of the globe, an empty sella,an enlarged ONS, protrusion and enhancement of the optic nerve head, and increased tortuosity of theoptic nerve. Novel imaging methods, including MR venography, have additionally identified sinovenousstenosis as a potential indicator of PTC.
ABBREVIATIONS: BMI ⫽ body-mass index; CN ⫽ cranial nerve; HIV ⫽ human immunodeficiency
virus; ICP ⫽ intracranial pressure; IIH ⫽ idiopathic intracranial hypertension; ISF ⫽ interstitial fluid;
MRI ⫽ MR imaging; ONS ⫽ optic nerve sheath; ONSF ⫽ optic nerve sheath fenestration; IOP ⫽
intraocular pressure; PCOS ⫽ polycystic ovary syndrome; PTC ⫽ pseudotumor cerebri syndrome
Several formalized criteria for IIH exist in the literature and known and putative etiologies. In the history of this condi- are subject to extensive debate. The Modified Dandy Criteria tion, the name given to the clinical syndrome referred to as first incorporated the use of CT in the diagnosis of IIH, pri- PTC or more commonly IIH has varied widely and been the marily as a means of excluding occult causes of intracranial subject of much contention.1 Heinrich Quincke, an early pio- hypertension previously missed in the era before diagnostic neer in the use of lumbar puncture, reported the first recorded imaging.9 Friedman and Jacobson7 updated these criteria (Ta- cases of intracranial hypertension of unknown cause in what ble 2) to reflect the advances of MR imaging and the charac- he described as "meningitis serosa" in 1893; at that time, he terization of other etiologies of intracranial hypertension such posited that inadequate CSF resorption was responsible for as venous thrombosis.
the syndrome, a theory that is still entertained by some re- Additional caveats have been proposed as conditions in the searchers.2 The term "PTC" was coined in 1904 by Nonne to diagnosis of IIH: excluding patients who have intracranial si- describe a condition characterized by symptoms associated nus venous thrombosis, a systemic condition associated with with intracranial tumors with an unusual course of remission elevated right heart pressure, or those who have been exposed and subsequently termed "benign intracranial hypertension" to medications or toxins associated with increased intracranial by Foley in 1955.1 hypertension such as those mentioned in Table 1.4,5 The absence of a clear identifiable etiology for a clinical syndrome characterized by elevated ICP exists in nearly 90% of cases, and this ambiguity inevitably has led to the replace- The precise etiology of IIH, as the name suggests, is largely ment of the misnomer "benign" intracranial hypertension unknown, despite much clinical investigation and basic sci- with IIH in light of the incidence of vision loss resulting from ence research. Theories generally fall under 5 different pro- this condition.3 Despite numerous revisions during the past posed mechanisms resulting in elevated intracranial hyperten- century, these definitions remain inadequate and limited in sion as outlined in Table 3 and discussed at greater length in that some cases of IIH have identifiable etiology, such as dural the article by Walker.10 Older theories, including those of venous stenosis, which has been implicated in 14%–90% of Quincke, suggest a disturbance of CSF homeostasis, either im- patients with IIH.4-6 For this reason, certain authors proposed pairment of reabsorption or excess production of CSF.1,11 the use of PTC as a catchment for both categories: purely IIH Many researchers cite case studies showing CSF collections as and that due to secondary causes of intracranial hypertension proof of this theory of disordered CSF hydrodynamics.12 Crit- such as venous stenosis.5 We prefer the more encompassingterm "PTC" to reflect diagnostic limitations in elucidating ics of this traditional hypothesis point to the intermittent suc- potential secondary causes of IIH, such as those listed in Table cess of lumbar puncture, which, from a physiologic stand- 1.7,8 Another argument proposes a classification of isolated point, should alleviate the symptoms due to excess CSF and, in intracranial hypertension as being either idiopathic or addition, the lack of expansion of ventricles, which would oc- cur if CSF volume was increased as in the case of meningitis-induced hydrocephalus.10 Many cases of PTC may not, in fact, be idiopathic but From the Department of Radiology, George Washington University Hospital, Washington, rather secondary to venous thrombosis, which many argue is frequently missed if MR venography is not used to evaluate Please address correspondence to Lucien M. Levy, Department of Radiology, GeorgeWashington University Hospital, 900 23rd Street N.W., Washington, DC 20037; e-mail: patients with suspected PTC.13 As a result, 1 author proposed classifying benign intracranial hypertension as either idio-pathic (also called PTC) or venogenic, if caused by thrombo- Indicates open access to non-subscribers at www.ajnr.org sis, vasculitis, extrinsic venous compression, or intraluminal Degnan 兩 AJNR 32 兩 Dec 2011 兩 www.ajnr.org Table 1: Confounding conditions that may present as similar to IIHa
Table 2: Criteria for diagnosing IIHa
Medical disorders 1) If symptoms are present, they may only reflect those of generalized intracranial hypertension or papilledema 2) If signs are present, they may reflect only those of generalized Chronic obstructive pulmonary disease intracranial hypertension or papilledema Right heart failure with pulmonary hypertension 3) Documented elevated ICP measured in the lateral decubitus position Obstructive sleep apnea (findings of assessment of ICP by lumbar puncture are considered Pickwickian syndrome abnormal if above 20 cm H O in normal-weight individuals and 25 mm Polycystic ovary syndrome H O in obese individuals20); MRI abnormal if above 20 cm H O in normal- Systemic lupus erythematosus weight individuals and 25 mm H O in obese individuals20) 4) Normal CSF composition Severe iron deficiency anemia 5) No evidence of hydrocephalus, mass, structural, or vascular lesion on MRI or contrast-enhanced CT for typical patients and on MRI and MR Tetracycline and related compounds (minocycline, doxycycline) venography for all others Vitamin A (at doses ⬎25 000 IU daily) and related compounds 6) No other cause of intracranial hypertension identified (isotretinoin 关Accutane兴, vitamin supplements, excessive intake a Adapted from Friedman and Jacobson.7 of liver, all-trans retinoic acid) Anabolic steroidsCorticosteroid withdrawal following prolonged administration aches occur in nearly all (90%–94%) patients with PTC—they Growth hormone administration in deficient patients are characteristically pressurelike, throbbing, and usually un- remitting and occur with retro-ocular pain and may be ac- companied by nausea.19,20 Vision loss is the most feared se- Oral contraceptive useLevonorgestrel implant system quela of PTC, but most vision loss in this syndrome is transient in nature and occurs in approximately 68%– 85% of pa- tients.19-22 This vision loss less frequently takes the form of impairments in the visual field, with the typical impairment Obstruction to venous drainage presenting as tunnel vision.19 Transient ischemia of the optic Cerebral venous sinus thrombosis nerve due to pressure is thought to explain the transient vision Jugular vein thrombosisSuperior vena cava syndrome changes.22 Pulse-synchronous tinnitus is another commonly Jugular vein ligation following bilateral radical neck dissection reported symptom of PTC (58% of patients) and is often de- Increased right heart pressure scribed as a unilateral "whooshing" sound by patients and may be exacerbated by positional changes and relieved by jugular Compression by tumor process (eg, meningioma) compression.3,19,22 Other common symptoms include pho- topsia (54%) and eye pain (44%).22 More severe symptoms are HIV infection, borreliosisPostvaricella infection in children less frequently encountered, yet diplopia (38%) and vision loss (30%) occur in a significant number of patients.22 Adapted from Friedman and Jacobson,7 Szitkar,8 Wall,22 and Alperin et al.79 Ophthalmologic signs of PTC consist of diminished visual A newer theory stemming from observations of sinus acuity, visual field losses on formalized testing in nearly all thrombosis producing a clinical presentation similar to IIH patients, and, most strikingly, papilledema on funduscopic ex- suggests that most cases of IIH are due to venous outflow amination in 40% of patients.19,22 Visual loss is directly corre- obstruction, which can also take the form of stenosis in the lated with the extent of disc edema, which is thought to result absence of thrombosis.14 The observation of stenotic trans- from elevated IOP referred from elevated CSF pressure.23 An- verse sinuses in ⬎90% of patients with IIH in 1 study gives atomic connections between the cranial fossa and orbit are credence to this thinking.6 There is clinical evidence to sup- thought to explain why ICP directly correlates with IOP.24 port the idea that impaired venous outflow leads to increased Absence of papilledema has been reported in many popula- total blood flow.6 Even if it is assumed that venous stenosisexists in PTC, there is controversy as to whether venous ste- tions of patients with IIH, but its absence may be more sug- nosis and elevated venous pressure are due to elevated ICP or gestive of an alternative etiology for headache and vision constitute the proximal cause of PTC.14-16 The first explana- loss.19 Other funduscopic findings that may be seen in PTC are tion is an application of the Monroe-Kellie doctrine: Expan- choroidal folds, parallel striae of alternating yellow crests, and sion of the brain within a fixed space will lead to the compres- darker troughs; choroidal folds compromise vision and can be sion of venous sinuses, assuming that these are compressible seen with elevated ICP, even when papilledema has re- structures, to vent CSF during systole when ICP increases.17 solved.25,26 Cranial nerve palsies, usually of the abducens One cadaveric study suggested that the stenosis of the trans- nerve (CN VI), may occur as well in as many as 10%–20% of verse sinus observed in IIH might be due to the presence of a patients.27 Rarely, facial nerve (CN VII) palsies may be associ- large septum within the venous sinus.18 ated with IIH; all of these CN palsies are thought to occur as aresult of direct compression due to elevated ICP.22 PTC is a rare condition, occurring in the general population PTC classically presents with headache and, frequently, vision with an incidence of 0.9 cases per 100,000 population in 2 changes in women with obesity of childbearing age.19 Head- epidemiologic studies in the United States.28,29 PTC demon- AJNR Am J Neuroradiol 32:1986 –93 兩 Dec 2011 兩 www.ajnr.org it is uncertain whether the exact mechanism of this increased Table 3: Putative theories to explain elevated ICP in PTCa
risk is related to a prothrombotic state, enhanced estrogenic- Proximal Etiology ity, inflammatory cytokine expression, endocrinologic dys- Increased interstitial fluid (ISF) Increased cerebral volume function, or some other yet-to-be-ascertained mechanism.
While more common in reproductive-age women, PTC Increased blood volume may occur as a slightly different clinical entity in other popu- Increased tissue volumeIncreased CSF production rate Increased CSF volume lations.4 These older patients are more likely to be men, pres- Increased CSF outflow resistance ent with different symptoms (fewer headaches, more visual Loss of cerebral autoregulation Increased cerebral arterial pressure changes), and have identifiable etiologies for elevated ICP, Increased cerebral venous pressure Increased venous blood volume and which arguably disqualify these patients from fitting the crite- ria for IIH on further clinical investigation.4 Men with PTC are Reduced CSF outflow and increased less likely to be obese (25% versus 75% of women) and are at a twice greater risk of vision loss than women with PTC.39,40 (Adapted from Walker.10) PTC is rare within the pediatric population and generally strates a strong female predominance, with a female/male ra- occurs with greater frequency in postpubertal females, obesity becoming a significant risk factor with older age.41 PTC occur- Reported risk factors for the development of PTC, includ- ring in prepubertal children generally lacks any sex predilec- ing those discussed here, mostly originated from case reports, tion or association with obesity and is thought to have less risk whereas very few controlled studies of PTC risk factors exist in of permanent vision loss.42 the literature.20 As a result, some of these risk factors may beconfounded by their coexistence in the at-risk population; for Management and Outcomes
example, PCOS occurs more frequently in reproductive-age IIH and PTC were typically thought of as self-limiting condi- women with obesity, yet 1 study posited an association be- tions with little risk of major sequelae, which, in part, explains tween PCOS and PTC while failing to control for the increased the historical name "benign intracranial hypertension"; how- incidence of PCOS in women with obesity, who are already at ever, severe deficits of visual acuity may occur in as many as increased risk of PTC.30 one-quarter of patients without treatment.29 Recently, some Classically, PTC is more commonly observed in overweight racial disparities in outcome have been noted, in which black women of reproductive age.24 The incidence of PTC in women patients are more than 3 times as likely to have severe visual who are between 20 and 44 years of age and 20% above ideal loss, even with equivalent access to treatment; severe visual body weight increases to 19.3 cases per 100,000 population; loss was present in 23% of black patients versus 7% of non- the odds ratio of PTC increases from 6.5 for a BMI of 25–29 to black patients.43 Patients with PTC also appear to have depres- 26.0 for a BMI of ⬎35.28,31 Obesity has long been associated sion and anxiety to a greater extent than weight-matched con- with the development of PTC.10,31,32 One mechanistic theory trols and healthy controls.44 Health-related quality-of-life proposes that obesity predisposes patients to having elevated scores are also affected in PTC, with patients reporting signif- intrabdominal pressure, elevated intrathoracic pressure, and icantly lower general health than controls and patients with thus elevated central venous pressure as the final common other neuro-ophthalmologic conditions.31 pathway leading to IIH.32 Randhawa and Van Stavern26 point Restoration of visual acuity and resolution of papilledema out that this explanation fails to elucidate a female predomi- constitute the primary goals of management in PTC and the nance. A recent study counters this theory of increased central benchmark of relative success of a treatment technique. The venous pressure by discovering lower body (gynecoid) obesity fact that most cases of PTC spontaneously resolve and that as a risk factor for IIH, which may suggest that increased es- most treatment studies lack control groups limits our inter- trogenicity, rather than elevated intrabdominal pressure, is the pretation of outcome measures reported for many treatment inciting element by which obesity propagates IIH.33 modalities.45 Conservative measures are typically recom- In keeping with enhanced estrogenicity in the obese, others mended in patients without vision changes as the predomi- propose endocrinologic dysregulation leading to a prothrom- nant presentation and consist of weight loss and medication.20 botic state in obesity and, similarly, in pregnancy, as the path- These conservative approaches may take time to take effect; as way that promotes PTC.34 Other studies note increased leptin a result, frequent follow-up, including formal visual field test- levels in obese patients with IIH compared with both obese ing at intervals of 1 month, 3 months, and then every 3– 6 and nonobese controls,35 while another group did not find months, is advisable.20 significant differences between leptin levels of patients and Weight loss is thought to address 1 of the fundamental risk controls.36 A recent study found similar CSF leptin levels in factors for recurrence of PTC and may reduce the risk of PTC patients with PTC but noted significantly increased CSF levels and concomitant vision impairment through reductions of of the inflammatory cytokine CCL2.37 Still another divergent central venous pressure or a tentative endocrinologic mecha- explanation for obesity in PTC is that intracranial hyperten- nism.32 Gastric bypass surgery was associated with remittance sion leads to hyperphagia; according to this theory, obesity is of symptoms in all but 1 of 19 patients with a history PTC in 1 the result rather than the proximal cause of PTC.38 However, if study; notably, symptoms only recurred in the 2 patients who PTC was the cause of obesity, one would expect more women regained weight following surgery. Another case report dem- to present with symptoms of increased ICP before weight gain onstrated a reduction of dural venous sinus pressure in 2 pa- under this theory. Thus, while obesity is long-established as a tients following bariatric surgery.46,47 substantial risk factor for the development of PTC in women, Medications to treat and prevent recurrence of PTC typi- Degnan 兩 AJNR 32 兩 Dec 2011 兩 www.ajnr.org Table 4: Imaging Findings in PTC
Agid et al, 200666 Yuh et al, 200064 Partially empty sella/decreased pituitary height Agid et al, 200666 Yuh et al, 200064 Brodsky and Vaphiades, 199862 Flattened posterior globe/sclera Agid et al, 200666 Brodsky and Vaphiades, 199862 Jinkins et al, 199671 Enlarged ONS (perioptic subarachnoid space) Agid et al, 200666 Brodsky and Vaphiades, 199862 Increased tortuosity of optic nerve Agid et al, 200666 Brodsky and Vaphiades, 199862 Enhancement of optic nerve Agid et al, 200666 Brodsky and Vaphiades, 199862 Intraocular protrusion of optic nerve head Agid et al, 200666 Brodsky and Vaphiades, 199862 Slitlike ventricles Agid et al, 200666 cally have activity against carbonic anhydrase, which has been which ONSF relieves symptoms.51 While some studies have found to decrease the rate of CSF production, and thus address alleged that the incidence of serious complications from ONSF 1 of the proposed mechanisms of PTC.22 Acetazolamide is is as low as 1%, ONSF may result in worsening vision, infec- historically the most commonly used medication to treat PTC, tion, oculomotor dysfunction (albeit generally temporary), but topiramate has been shown to have equal effect as a result and death (in 1 older study).20,22,52 Following ONSF, visual of partial carbonic anhydrase⫺inhibition activity augmented acuity stabilized or improved in 94% of eyes and deteriorated by beneficial analgesic action against headaches and weight in 6% of eyes in 2 studies.52,53 ONSF in the pediatric popula- loss as a fortuitous side effect.15,26,48 Corticosteroids may re- tion improved visual acuity in two-thirds of patients, and vi- sult in temporary remission of PTC, but the risks of chronic sion worsened in 17% of patients.54 steroid use in already obese patients preclude their use. Some Some groups propose the use of venous sinus stent place- clinicians advocate the use of corticosteroids in patients with ment to treat IIH on the basis of several imaging studies show- severe headache, acute papilledema, and very high CSF ing stenosis of the cerebral venous sinuses and the presump- tion that venous outflow obstruction constitutes the Therapeutic lumbar puncture is another common treat- underlying etiology of most cases of IIH.24,55 One group at the ment method and addresses the issue of elevated CSF pressure University of Cambridge reported success with 5 of 12 patients directly by reducing it immediately; 1 older study suggests that rendered asymptomatic and 4 of 8 patients demonstrating res- the effects are short-lived, with a return to initial pressure olution of papilledema after venous sinus stent placement.55 within just ⬎1 an hour.50 There is little published evidence Conversely, another group cited 3 cases of restenosis to coun- comparing lumbar puncture with medication or other treat- ter the belief that stent placement is a universally applicable ment modalities.
procedure in IIH; they argued that stenosis in IIH may be the More aggressive measures for preventing sequelae of PTC result of the elevated ICP itself and not the cause of the in- are traditionally reserved for 2 groups of patients: those who creased ICP.56 Another researcher alleges that restenosis fol- continue to experience vision loss despite conservative man- lowing stent placement is the result of failure to support all of agement and those who initially present with rapid vision loss.
the compliant portions of the venous sinus.57 Notably, the Lumboperitoneal shunt surgery is a method in which the ele- retrospective nonrandomized noncontrolled nature of these vated CSF pressure is referred to the peritoneal cavity; this studies substantially limits objective assessment of the relative situation places the patient at risk of serious complications, success of any of these treatment attempts.
ranging from shunt obstruction and shunt-related meningitisor abdominal infection to tonsillar herniation and death.20 Shunt failure occurs in roughly one-half of patients, and ap- Historically, imaging of patients with PTC served the purpose proximately one-tenth of patients have worsening vision fol- of excluding other pathology responsible for symptoms of in- lowing shunt surgery for IIH. As a result, shunt placement creased ICP.58 Some of the earliest radiologic investigations of necessitates frequent neurologic follow-up.22,49 PTC demonstrated evidence of decreased ventricle size and Many ophthalmologists advocate ONSF (also called de- sella turcica demineralization, thought to be a late manifesta- compression) as an alternative surgical approach associated tion of increased ICP, on plain film skull x-ray examination.59 with fewer complications and improved outcomes in the man- The concept of decreased ventricle size as a sign of PTC agement of refractory PTC.20,51 In this approach, the surgeon emerged from these early studies.11,45 Early CT studies enabled cuts slits in the ONS behind the globe to allow CSF to leak clinicians to evaluate intracranial masses before lumbar punc- from the subarachnoid space.22,49 Postoperative MR imaging ture.58 Said and Rosman cautioned against using CT alone, showing fluid collections adjacent to the site of fenestration which has the potential of missing important pathology that supports CSF extravasation into the orbit as the mechanism by may explain increased ICP, especially in evaluating pediatric AJNR Am J Neuroradiol 32:1986 –93 兩 Dec 2011 兩 www.ajnr.org
Fig 1. This 31-year-old woman presenting with headache is found to have an empty sella
Fig 2. A narrowed right transverse sinus is noted in this 32-year-old woman, seen on MR
on sagittal T1-weighted MR imaging.
venography, in addition to ONS enlargement and a partially empty sella on axial MRimaging.
patients.60 The advent of MR imaging advanced the imagingparadigm in PTC from simply using imaging to rule out other subject to interpretation.66-68 Globe flattening may be ex- processes (eg, space-occupying lesions) to detecting signs plained by the direct correlation between elevated ICP and thought to indicate PTC itself.
IOP via the transmission of elevated CSF pressure through thesubarachnoid space, extending through the ONS to the poste- rior globe.24 One possible confounding explanation for poste- The American College of Radiologists, in their most recent rior sclera flattening is its detection in the context of ocular appropriateness criteria, recommended the use of fat-sup- hypotony; however, this condition is more rare, and this neu- pressed contrast-enhanced MR imaging of the brain for the roimaging finding is more likely to be indicative of intracranial evaluation of any disorder involving vision changes.61 Several neuroimaging findings have been put forth as signs support- Intraocular protrusion (Fig 3) is thought to occur in a man- ing intracranial hypertension or even more specifically PTC.
ner similar to posterior globe flattening and is another sign Estimates of the occurrence, sensitivity, specificity, and rele- associated with PTC.70,71 The optic nerve head is considered vance of these imaging signs vary widely in the published lit- by some to be the most vulnerable site; thus, this finding on erature and clinical practice and are summarized in Table 4.
MR imaging may well correspond to the presence of visual These vast ranges of reported statistics and anecdotes most symptoms, in light of its absence in patients with PTC lacking likely result from the varying effort in detecting particular visual symptoms.70 This finding has also been reported in pe- signs at the expense of potentially ignoring other findings and diatric patients as well.72 technical differences (particularly in MR venography).
ONS enlargement (Fig 4A, -B) appears as a widened ring of The "empty sella" sign (Fig 1) is associated with the long- CSF around an optic nerve, which may appear compressed on standing effects of increased ICP and is thought to result from coronal images, and as widened CSF signal intensity on either a downward herniation of an arachnocele through the dia- side of the optic nerve on axial images.62 Studies of the effec- phragma sella.45,62 It was 1 of the first signs noted on plain film tiveness of ONSF emphasize the importance of this imaging x-ray examination and subsequently on early MR imaging finding.73 ONS enlargement on T2-weighted MR imaging re- studies.59,63 The term "empty sella" should be reserved for solves in patients in whom ONSF is successful, while those studies in which the pituitary gland is not visible, and these patients who remain symptomatic still have enlarged ONSs.73 cases tend to be later manifestations of increased ICP.64 Thereis a wide spectrum of pituitary height changes; thus, manycases of empty sella may, in fact, be better described as a par-tially empty sella or a compressed pituitary gland. The widerange of sensitivities and specificities reported reflects thisambiguity.
Transverse sinus narrowing (Fig 2) can be seen best on MR venography as well as on sagittal and axial MR imaging and isthought to represent the effect of increased ICP.15 A small orabsent bony groove in the occiput in conjunction with thecompressible nature of the transverse sinus makes this struc-ture vulnerable to tapering with increased ICP.65 This partic-ular imaging finding is more frequently noticed on MR venog-raphy studies, which are discussed at more length below.6 Posterior globe flattening is considered by some authors to Fig 3. Protrusion of the right optic nerve head and horizontal tortuosity of the optic nerve
be the sine qua non neuroimaging sign of PTC and can be seen are seen in this 21-year-old woman on axial T2-weighted MR imaging. Clinically, the on both CT and MR imaging but may be a more subtle finding patient presented with headaches, vision changes, and papilledema noted on examination.
Degnan 兩 AJNR 32 兩 Dec 2011 兩 www.ajnr.org
Fig 4. A, The ONS is widened with expanded CSF hyperintensity surrounding the optic nerve, seen on axial T2-weighted MR imaging in conjunction with posterior flattening of the globes.
ONS widening is thought to coincide with papilledema, which is seen in this 27-year-old woman who presented with headaches. B, Coronal T2-weighted MR imaging in a 55-year-old
woman with headache demonstrates increased peri-ONS space marked by hyperintense signal intensity surrounding the optic nerve.
Widening of the optic nerve has also been observed in child- fied venous stenoses in 90% of patients with IIH with a re- hood IIH.72 This association of ONS enlargement in PTC is ported sensitivity and specificity of 93%. These findings have supported by the converse association of the decreased diam- similarly been replicated in the CT venography literature.77 eter of the ONS in patients with CSF hypovolemia.74 Further advancements in MR venography may demonstrate Optic nerve tortuosity (Fig 3) has been associated with in- stenosis of the venous sinuses to be an excellent indicator of creased ICP; the distal and proximal points of fixation of the the presence of elevated ICP.6 optic nerve enable it to kink freely in its course to the globe on Yet another hypothesized imaging indicator of IIH seen on protrusion of the intracranial contents under pressure.62 The MR venography is increased total blood flow.78 In support of sensitivity of observing optic nerve tortuosity in either the ver- this finding, Bateman78 noted a 46% increase in total blood tical or horizontal planes is dependent on section thickness.
flow in 5 patients with IIH and decreased blood flow in 7 Horizontal tortuosity is thought to be less frequently visual- patients, with secondary intracranial hypertension due to ized but more specific to intracranial hypertension.
thrombosis and arachnoid granulation in 1 patient. As with Enhancement of the optic nerve is thought to be reflective many research inquiries, this form of measurement is a rela- of the same pathology leading to papilledema. Increased pres- tive calculation of blood flow in patients compared with con- sure referred from the cranial fossa generates venous conges- trols and, as of yet, has no direct clinical application for eval- tion, capillary leakage, and possible breakdown of the blood- uating patients with suspected PTC.
retinal barrier.75 To evaluate for this finding, one must usecontrast.62 Other Imaging Methods
Slitlike ventricles appear to be a poor neuroimaging sign of MR imaging measurement of intracranial elastance and its PTC in light of the their infrequent occurrence.66 This finding correlation with ICP is another technique that may prove was first noted in older studies using ventriculography and fruitful in averting a more invasive measurement of ICP also in early CT studies, but it appears to be an insignificant through lumbar puncture.79 Unfortunately, this imaging tech- finding of little clinical use now.45,58,59 nique has only been studied in a limited population of healthycontrols and those with chronically elevated ICP, as well as in baboons; moreover, complex calculations to correlate the elas- Previously, it was thought that MR venography should be re- tance index with ICP preclude clinical use at present.79 If val- served for use in atypical (eg, male, normal weight) patients to idated, this method would greatly improve the feasibility of rule out sinovenous thrombosis.76 Now, many authors pro- repeated measurement of ICP as part of routine evaluation pose that any patient with suspected elevated intracranial hy- pertension undergo MR venography in addition to traditionalMR orbital imaging to evaluate venous thrombosis or stenosis Recommended Imaging Protocol
as the etiology of PTC symptoms.6,8,39,55 Newer imaging In evaluating patients with headache, clinicians frequently or- methods have enhanced detection of intracranial sinovenous der routine brain MR imaging studies; thus, the radiologist stenoses previously undetected due to artifactual flow voids in must be cognizant of possible indicators of PTC on axial T2- the transverse sinuses on traditional time-of-flight MR venog- weighted images as discussed in this article. If there is an ad- raphy.6 Higgins et al14 identified bilateral sinus flow gaps in ditional clinical or imaging indication to suggest a greater like- 65% of patients with IIH by using 3D contrast-enhanced lihood of PTC, we recommend the addition of coronal T2- venography. By using a novel MR venography method, auto- weighted imaging of the orbits to assess ONS widening and triggered elliptic centric⫺ordered imaging, Farb et al6 identi- MR venography to evaluate venous sinus thrombosis, sino- AJNR Am J Neuroradiol 32:1986 –93 兩 Dec 2011 兩 www.ajnr.org venous narrowing related to PTC, or congenital narrowing of 22. Wall M. Idiopathic intracranial hypertension. Neurol Clin 2010;28:593– 617
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European Journal of Neuroscience, Vol. 24, pp. 229–242, 2006 Progesterone reverses the spatial memoryenhancements initiated by tonic and cyclic oestrogentherapy in middle-aged ovariectomized female rats Heather A. Bimonte-Nelson,1 Kevin R. Francis,2 Claudia D. Umphlet2 and Ann-Charlotte Granholm21Department of Psychology, Arizona State University, PO Box 871104, Tempe, AZ 85287, USA2Department of Neuroscience and the Center on Ageing, Medical University of South Carolina, Charleston, SC 29425, USA