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Hypothesis: The pathogenesis of pseudotumor cerebri
Medical Hypotheses 6: 913-918, 1980
HYPOTHESIS: THE PATHOGENESIS OF PSEUDOTUMOR CEREBRI. D.A. Rottenberg, K.M. Foley and J.B. Posner. Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021. ABSTRACT
In susceptible individuals, one of a variety of known or unknown precipitants affects the arachnoid villi so as to produce a large increase in CSF outflow resistance, Ra. This increase in R, raises CSF pressure (CSFP), which rise provokes a redistribution of arteriovenous pressures across the cerebrovascular bed. The end result is a measurable increase in cerebral blood volume, compression of the ventricular system and compromise of the convexity subarachnoid space, which further increases CSF outflow resistance. Ultimately, a new steady state CSFP is attained. INTRODUCTION The pathogenesis of pseudotumor cerebri has challenged the ingenuity of two generations of neurologists and neurosurgeons (1,2), and the controversy continues, as witnessed by a recent exchange of letters in the Annals of Neurology (3,4). This communication briefly reviews several theoretical and clinical considerations which may illuminate the pathogenesis and natural history of this still mysterious, often chronic and not invariably benign condition (5). Pseudotumor cerebri refers to a syndrome of increased intracranial pressure (ICP) without localizing neurological signs or neuroradiologic evidence of an intracranial mass. Any hypothesis purporting to explain the pathogenesis of this disorder must account for the following observations: Chronic Pseudotumor. Pseudotumor cerebri is generally believed to be a self-limited disease in which CSF oressure (CSFP) returns to normal as clinical symptoms remit. However,'clinical‘imprbvement is not always accompanied by a reduction in CSFP; our own clinical data (5) suggest that there is a subgroup (of unknown size) of pseudotumor patients whose CSFP remains persistently elevated after neurological signs and symptoms (headache, papilledema, diplopia, etc.) have resolved. This subgroup has been previously recognized (6,7) but not specifically commented upon. The existence of such a subgroup implies that clinical symptoms may be independent of the absolute magnitude of CSFP and that chronically
raised ICP may be totally asymptomatic. We have observed a similar chronic, asymptomatic "pseudotumor syndrome" in patients who have undergone bilateral radical neck dissection for head-and-neck cancer. Absence of Hydrocephalus. Despite persistently elevated CSFP, most chronic pseudotumor patients do not become hydrocephalic. We have obtained serial CT scans on 4 asymptomatic pseudotumor patients with chronically increased ICP (280-400 mm CSF); in no case was there evidence of progressive ventricular enlargement. The chronicity of the disease in these 4 patients (4-15 years) and the lack of clinical progression suggest that whatever mechanism "resets" CSFP at a supranormal level does not necessarily predispose to the development of communicating hydrocephalus. Associated or Predisposing Conditions. Although pseudotumor cerebri may occur without obvious precipitants in the setting of general good health, its occasional relationship to drug administration and steroid withdrawal and its reported association with a variety of endocrine disorders (e.g., obesity, Addison's disease, Gushing's syndrome, hyper/hypoparathyroidism) suggest the existence of a final comnon pathogenetic pathway rather than a multitude of distinct pathogenetic mechanisms. HYPOTHESIS Chronically increased intracranial pressure necessarily implies (i) an increase in dural sinus venous pressure, Pd; (ii) an increase in CSF outflow resistance, R,; (iii) an increase in the rate of CSF formation, If, or (iv) some combination of above (8,9). [An intracranial mass lesion (e.g., tumor, clot or edema) does not, in and of itself, chronically increase ICP (lo).] One or more of these mechanisms must elevate CSFP in pseudotumor patients. We postulate the following pathogenesis for pseudotumor cerebri: In susceptible individuals, one of a variety of known (e.g., anemia, pregnancy, steroid withdrawal, etc.) or unknown precipitants affects the arachnoid villi so as to produce a large increase in Ra. This increase in R, raises CSFP, which rise provokes a redistribution of arteriovenous pressures across the cerebrovascular bed (ll), the end result of which is a measurable increase in cerebral blood volume (12). The net effect of this increase in cerebral blood volume is to compress the ventricular system and to compromise the convexity subarachnoid space, further increasing Ra. Ultimately, a new steady-state CSFP is attained. A similar mechanism is probably operative in patients who develop chronically increased ICP following radical neck dissection: Increased dural sinus venous pressure increases cerebral venous pressure, CSFP and cerebral blood volume (CBV). As noted above, in one subgroup of pseudotumor patients R, remains elevated long after the original precipitant has been removed: in such oatients. CSFP is effectively "reset" at a supranormal level,-and neurologic signs and symptoms resolve without specific therapy. As long as R, remains lower than the resistance to transependymal passage/absorption of CSF, periventricular lucencies and communicating hydrocephalus do not develop.
914
Although the issue remains controversial, we believe [with Johnston (13) and others (14)] that an increase in CSF outflow resistance and/or an increase in dural sinus venous pressure must be operative in the pathogenesis of pseudotumor cerebri. The patency of the convexity subarachnoid space in pseudotumor patients (15,16) [the primary increase in CSF outflow resistance occurs within the arachnoid villi,ot within the convexity subarachnoid space] precludes the development of transmural pressure gradients and progressive hydrocephalus (17). Furthermore, as long as the resistance to transependymal passage/absorption of CSF remains higher (as is the case in normals) than the resistance to CSF outflow through the arachnoid villi, transependymal bulk flow of CSF, periventricular leukoedema and hydrocephalus will not occur. In this connection, it is interesting to observe that periventricular lucencies do not develop in pseudotumor patients with papilledema and raised ICP, whereas such lucencies are characteristically observed in patients with acute, obstructive hydrocephalus (18,lg). Thus, in pseudotumor patients, the ventricular ependyma remains intact, significant transependymal passage/absorption of CSF does not occur, and the periventricular white matter does not become edematous or attenuated. DISCUSSION An alternative hypothesis is that the increased ICP of pseudotumor is caused by an increase in brain bulk consequent upon an increase in CBV or in brain water content (cerebral edema). We have already suggested that an increase in brain bulk does not increase ICP unless Pd, If or Ra are secondarily increased. Dandy (1) first proposed that an increase in CBV might be implicated in the pathogenesis of pseudotumor cerebri, and Raichle et al (12) reported a 33% increase in CBV in their pseudotumor patients; however, the latter authors considered that an increase in CBV was unlikely to account for the observed increase in CSFP. We believe that the increased CBV in pseudotumor patients is a result, not a cause, of increased ICP. Grubb et al (20) demonstrated an increase in CBV in adult rhesus monkeys following induced increases in CSFP. The question of increased brain water content in pseudotumor cerebri is more intriguing. Raichle et al (12) suggested that a 23% increase in the cerebral mean transit time for water in pseudotumor patients (130 set vs 106 set in normals) "suggests a 23% increase in tissue volume, which could be accounted for by a 4% increase in brain water content," assuming a normal average tissue water content of 79%. A 23% increase in tissue volume, when applied to a brain weighing 1400 g, increases intracranial volume by approximately 320 ml, which is more than twice the volume of intracranial blood and CSF (21)! Since the cerebral mea'n transit time for any substance‘is a function of its weighted mean transit times through gray and white matter, it is possible that the increase in cerebral mean transit time for water measured by Raichle et al represents a redistribution of cerebral blood flow, favoring white matter (longer mean transit time) over gray matter. What distinguishes patients with pseudotumor cerebri, some of whom present with mild to moderate ventricular dilatation (X,22,23), from pa915
tients with communicating hydrocephalus is the nature of their response to intracranial hypertension. Whether, in a given patient, intracranial hypertension gives rise to communicating hydrocephalus seems to depend upon (i) the magnitude and duration of increased ICP; (ii) the patency of the convexity subarachnoid space; (iii) the relative contributions of Pd and R, to measured increases in CSF pressure; (iv) the continued integrity of the choroid plexus and ventricular ependyma; (v) the presence or absence of cerebral edema; and (vi) the response of the cerebral vasculature to prolonged periods of intracranial hypertension. Sustained elevations of CSFP predispose to-- but do not always result in-- the development of hydrocephalus (24). Obliteration of the convexity subarachnoid space (17,25), sudden large increases in R, (26), diminished choroidal production of CSF (CSF stasis) (27), disruption of the ventricular ependyma and transependymal passage of CSF (28), chronic leukoedema (29) and hypertensive cerebrovascular disease (30) also predispose to hydrocephalus. Fishman (3) recently discussed the role of transcerebral mantle pressure gradients in the genesis of normal pressure hydrocephalus, referring to the experimental work of Hoff and Barber (31). The latter authors concluded that a pressure gradient across the cerebral mantle may contribute to ventricular dilatation in normal pressure hydrocephalus. This conclusion was based upon data from four severely head-injured patients, three of whom had required evacuation of a subdural hematoma, and applies, therefore, only to patients with post-traumatic hydrocephalus. It seems likely that the small (2-4 mm Hg) mean pressure gradients between the ventricular wall and cortical surface which Hoff and Barber measured in their head-injured patients, were a consequence of head injury (compartmentalization of the subarachnoid and subdural spaces in response to hemagenic lepto- and pachymeningitis) rather than a cause of hydrocephalus. CONCLUSIONS How then can our hypothesis be tested? The development of a largeanimal model of pseudotumor cerebri would be the logical first step. In calves, hypovitaminosis A is associated with increased CSFP and structural changes in the arachnoid villi (32). Thus, one might serially monitor CSFP, Pd' R , If% and CBV in laboratory animals after steroid withdrawal P33), selective nutritional deprivation or hormonal manipulation. Serial in vivo measurements of ventricular volume and brain water content, omaned from high-resolution CT brain scans (34,35), might resolve the longstanding argument about the role of interstitial brain edema. Only such a thoroughgo ng experimental approach will provide new insights into the pathogenesis of pseudotumor cerebri and allow for the rational development and application of effective treatment modalities. REFERENCES 1.
Dandy WE. Intracranial pressure w ithout brain tumor. Ann Surg 106 . 492, 1937. I.
2.
Symonds CP. Otitic hydrocephalus.
Brain 54: 55, 1931.
3.
Fishman RA. Pathophysiology 1979.
4.
Raichle ME. Reply to Fishman RA: Pathophysiology Ann Neurol 5: 496, 1979.
5.
Foley KM. Is benign intracranial Neurology 27: 388, 1977.
6.
Foley J. Benign forms of intracranial hypertension-"otitic" hydrocephalus. Brain 78: 1, 1955.
7.
Weisberg LA. Benign intracranial 1975.
8.
Marmarou A, Shulman K, Rosende RM. A nonlinear analysis of the cerebrospinal fluid system and intracranial dynamics. J Neurosurg 48: 332, 1978.
9.
Rottenberg DA, Posner JB. Intracranial pressure Control. p 89 in Anesthesia and Neurosurgery. (JE Cottrell, H Turndorf, eds) The C.V. Mosby Company, St. Louis, 1979.
of pseudotumor.
Ann Neurol 5: 496,
hypertension
hypertension.
10. Van Crevel H. Absence of papilloedema Neurol Neurosurg Psychiat 38: 931, 1975.
of pseudotumor.
a chronic disease? "Toxic" and
Medicine
54: 197,
in cerebral tumours. J
11.
Benabid AL, De Rougemont J, Barge M. Pression veineuse cerebrale, pression sinusale et pression intracranienne. Neuro-chirurgie 20: 623, 1974.
12.
Raichle ME, Grubb RL, Phelps ME, Gado MH, Caronna JJ. Cerebral hemodynamics and metabolism in pseudotumor cerebri. Ann Neurol 4: 104, 1978.
13.
Johnston I. The definition of a reduced CSF absorption syndrome: a reaprraisal of benign intracranial hypertension and related conditions. Med Hypotheses 1: 10, 1975.
14.
Mann JO, Johnson RN, Butler AB, Bass NH. Impairment of cerebrospinal fluid circulatory dynamics in pseudotumor cerebri and response to steroid treatment. Neurology 29: 550, 1979.
15.
Boddie HG, Banna M, Bradley WG. "Benign" intracranial hypertension: a survey of the clinical and radiological features, and long-term prognosis. Brain 97: 313, 1974.
16.
James AE, Harbert JC, Hoffer PB, Deland FH. CSF imaging in benign intracranial hypertension. J Neurol Neurosurg Psychiat 37: 1053, 1974.
17.
Guinane 1977.
18.
Weisberg L, Nice CN. Computed tomographic evaluation of increased intracranial pressure without localizing signs. Radiology 122: 133, 1977.
JE. Why does hydrocephalus progress? J Neural Sci 32: 1,
19.
Moseley IF, Radu EW. Factors influencing the development of periventricular lucencies in patients with raised intracranial pressure. Neuroradiology 17: 65, 1979.
20.
Grubb RL, Raichle ME, Phelps ME, Ratcheson RA. Effects of increased intracranial pressure on cerebral blood volume, blood flow and oxygen utilization in monkeys. J Neurosurg 43: 385, 1975.
21.
Fishman RA. Brain edema. New Eng J Med 293: 706, 1975.
22.
Johnston I, Paterson A. Benign intracranial hypertension: diagnosis and prognosis. Brain 97, 289, 1974.
23.
Bulens C, De Vries WAEJ, Van Crevel H. Benign intracranial hypertension. J Neurol Sci 40: 147, 1979.
24.
Morley JB, Reynolds EH. Papilloedema and the Landry-Guillain-Barre syndrome. Brain 89: 205, 1966.
25.
Deland FH, James AE,Jr., Ladd DJ, Konigsmark BW. Normal pressure hydrocephalus: a histologic study. Amer J Clin Path01 58: 58, 1972.
26.
Milhorat TH. Acute Hydrocephalus. N Eng J Med 283: 857, 1970.
27.
Lying-Tunell, U. Cerebrospinal fluid turnover and convexity block in mental impairment. Neurology 27: 460, 1977.
28.
Price DL, James AE Jr, Sperber E, Strecker E-P. Comnunicating hydrocephalus; cisternographic and neuropathologic studies. Arch Neurol 33: 15, 1976.
29.
Allen JC, Thaler HT, Deck MDF, Rottenberg DA. Leukoencephalopathy following high-dose intravenous methotrexate chemotherapy: quantitative assessment of white matter attenuation using computed tomography. Neuroradiology 16: 44, 1978.
30.
Koto A, Rosenberg G, Zingesser LH, Horoupian D, Katzman R. Syndrome of normal pressure hydrocephalus: possible relation to hypertensive and arteriosclerotic vasculopathy. J Neurol Neurosurg Psychiat 40: 73, 1977.
31.
Hoff J, Barber R. Transcerebral mantle pressure in normal pressure hydrocephalus. Arch Neurol 31: 101, 1974.
32.
Hayes KC, McCombs HL, Faherty TP. The fine structure of vitamin A deficiency II: arachnoid granulations and CSF pressure. Brain 94: 213, 1971.
33.
Johnston I, Gilday DL, Hendrick EB. Experimental effects of steroids and steroid withdrawal on cerebrospinal fluid absorption. J Neurosurg 42: 690, 1975.
34.
Rottenberg DA, Pentlow KS, Deck MDF, Allen JC. Determination of ventricular volume following metrizamide CT ventriculography. Neuroradiology 16: 136, 1978.
35.
Thaler HT, Ferber PW, Rottenberq DA. A statistical method for determining the proportions of gray matter, white matter, and CSF using computed tomography. Neuroradiology 16: 133, 1978.
HYPOTHESIS: THE PATHOGENESIS OF PSEUDOTUMOR CEREBRI. D.A. Rottenberg, K.M. Foley and J.B. Posner. Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021. ABSTRACT
In susceptible individuals, one of a variety of known or unknown precipitants affects the arachnoid villi so as to produce a large increase in CSF outflow resistance, Ra. This increase in R, raises CSF pressure (CSFP), which rise provokes a redistribution of arteriovenous pressures across the cerebrovascular bed. The end result is a measurable increase in cerebral blood volume, compression of the ventricular system and compromise of the convexity subarachnoid space, which further increases CSF outflow resistance. Ultimately, a new steady state CSFP is attained. INTRODUCTION The pathogenesis of pseudotumor cerebri has challenged the ingenuity of two generations of neurologists and neurosurgeons (1,2), and the controversy continues, as witnessed by a recent exchange of letters in the Annals of Neurology (3,4). This communication briefly reviews several theoretical and clinical considerations which may illuminate the pathogenesis and natural history of this still mysterious, often chronic and not invariably benign condition (5). Pseudotumor cerebri refers to a syndrome of increased intracranial pressure (ICP) without localizing neurological signs or neuroradiologic evidence of an intracranial mass. Any hypothesis purporting to explain the pathogenesis of this disorder must account for the following observations: Chronic Pseudotumor. Pseudotumor cerebri is generally believed to be a self-limited disease in which CSF oressure (CSFP) returns to normal as clinical symptoms remit. However,'clinical‘imprbvement is not always accompanied by a reduction in CSFP; our own clinical data (5) suggest that there is a subgroup (of unknown size) of pseudotumor patients whose CSFP remains persistently elevated after neurological signs and symptoms (headache, papilledema, diplopia, etc.) have resolved. This subgroup has been previously recognized (6,7) but not specifically commented upon. The existence of such a subgroup implies that clinical symptoms may be independent of the absolute magnitude of CSFP and that chronically
raised ICP may be totally asymptomatic. We have observed a similar chronic, asymptomatic "pseudotumor syndrome" in patients who have undergone bilateral radical neck dissection for head-and-neck cancer. Absence of Hydrocephalus. Despite persistently elevated CSFP, most chronic pseudotumor patients do not become hydrocephalic. We have obtained serial CT scans on 4 asymptomatic pseudotumor patients with chronically increased ICP (280-400 mm CSF); in no case was there evidence of progressive ventricular enlargement. The chronicity of the disease in these 4 patients (4-15 years) and the lack of clinical progression suggest that whatever mechanism "resets" CSFP at a supranormal level does not necessarily predispose to the development of communicating hydrocephalus. Associated or Predisposing Conditions. Although pseudotumor cerebri may occur without obvious precipitants in the setting of general good health, its occasional relationship to drug administration and steroid withdrawal and its reported association with a variety of endocrine disorders (e.g., obesity, Addison's disease, Gushing's syndrome, hyper/hypoparathyroidism) suggest the existence of a final comnon pathogenetic pathway rather than a multitude of distinct pathogenetic mechanisms. HYPOTHESIS Chronically increased intracranial pressure necessarily implies (i) an increase in dural sinus venous pressure, Pd; (ii) an increase in CSF outflow resistance, R,; (iii) an increase in the rate of CSF formation, If, or (iv) some combination of above (8,9). [An intracranial mass lesion (e.g., tumor, clot or edema) does not, in and of itself, chronically increase ICP (lo).] One or more of these mechanisms must elevate CSFP in pseudotumor patients. We postulate the following pathogenesis for pseudotumor cerebri: In susceptible individuals, one of a variety of known (e.g., anemia, pregnancy, steroid withdrawal, etc.) or unknown precipitants affects the arachnoid villi so as to produce a large increase in Ra. This increase in R, raises CSFP, which rise provokes a redistribution of arteriovenous pressures across the cerebrovascular bed (ll), the end result of which is a measurable increase in cerebral blood volume (12). The net effect of this increase in cerebral blood volume is to compress the ventricular system and to compromise the convexity subarachnoid space, further increasing Ra. Ultimately, a new steady-state CSFP is attained. A similar mechanism is probably operative in patients who develop chronically increased ICP following radical neck dissection: Increased dural sinus venous pressure increases cerebral venous pressure, CSFP and cerebral blood volume (CBV). As noted above, in one subgroup of pseudotumor patients R, remains elevated long after the original precipitant has been removed: in such oatients. CSFP is effectively "reset" at a supranormal level,-and neurologic signs and symptoms resolve without specific therapy. As long as R, remains lower than the resistance to transependymal passage/absorption of CSF, periventricular lucencies and communicating hydrocephalus do not develop.
914
Although the issue remains controversial, we believe [with Johnston (13) and others (14)] that an increase in CSF outflow resistance and/or an increase in dural sinus venous pressure must be operative in the pathogenesis of pseudotumor cerebri. The patency of the convexity subarachnoid space in pseudotumor patients (15,16) [the primary increase in CSF outflow resistance occurs within the arachnoid villi,ot within the convexity subarachnoid space] precludes the development of transmural pressure gradients and progressive hydrocephalus (17). Furthermore, as long as the resistance to transependymal passage/absorption of CSF remains higher (as is the case in normals) than the resistance to CSF outflow through the arachnoid villi, transependymal bulk flow of CSF, periventricular leukoedema and hydrocephalus will not occur. In this connection, it is interesting to observe that periventricular lucencies do not develop in pseudotumor patients with papilledema and raised ICP, whereas such lucencies are characteristically observed in patients with acute, obstructive hydrocephalus (18,lg). Thus, in pseudotumor patients, the ventricular ependyma remains intact, significant transependymal passage/absorption of CSF does not occur, and the periventricular white matter does not become edematous or attenuated. DISCUSSION An alternative hypothesis is that the increased ICP of pseudotumor is caused by an increase in brain bulk consequent upon an increase in CBV or in brain water content (cerebral edema). We have already suggested that an increase in brain bulk does not increase ICP unless Pd, If or Ra are secondarily increased. Dandy (1) first proposed that an increase in CBV might be implicated in the pathogenesis of pseudotumor cerebri, and Raichle et al (12) reported a 33% increase in CBV in their pseudotumor patients; however, the latter authors considered that an increase in CBV was unlikely to account for the observed increase in CSFP. We believe that the increased CBV in pseudotumor patients is a result, not a cause, of increased ICP. Grubb et al (20) demonstrated an increase in CBV in adult rhesus monkeys following induced increases in CSFP. The question of increased brain water content in pseudotumor cerebri is more intriguing. Raichle et al (12) suggested that a 23% increase in the cerebral mean transit time for water in pseudotumor patients (130 set vs 106 set in normals) "suggests a 23% increase in tissue volume, which could be accounted for by a 4% increase in brain water content," assuming a normal average tissue water content of 79%. A 23% increase in tissue volume, when applied to a brain weighing 1400 g, increases intracranial volume by approximately 320 ml, which is more than twice the volume of intracranial blood and CSF (21)! Since the cerebral mea'n transit time for any substance‘is a function of its weighted mean transit times through gray and white matter, it is possible that the increase in cerebral mean transit time for water measured by Raichle et al represents a redistribution of cerebral blood flow, favoring white matter (longer mean transit time) over gray matter. What distinguishes patients with pseudotumor cerebri, some of whom present with mild to moderate ventricular dilatation (X,22,23), from pa915
tients with communicating hydrocephalus is the nature of their response to intracranial hypertension. Whether, in a given patient, intracranial hypertension gives rise to communicating hydrocephalus seems to depend upon (i) the magnitude and duration of increased ICP; (ii) the patency of the convexity subarachnoid space; (iii) the relative contributions of Pd and R, to measured increases in CSF pressure; (iv) the continued integrity of the choroid plexus and ventricular ependyma; (v) the presence or absence of cerebral edema; and (vi) the response of the cerebral vasculature to prolonged periods of intracranial hypertension. Sustained elevations of CSFP predispose to-- but do not always result in-- the development of hydrocephalus (24). Obliteration of the convexity subarachnoid space (17,25), sudden large increases in R, (26), diminished choroidal production of CSF (CSF stasis) (27), disruption of the ventricular ependyma and transependymal passage of CSF (28), chronic leukoedema (29) and hypertensive cerebrovascular disease (30) also predispose to hydrocephalus. Fishman (3) recently discussed the role of transcerebral mantle pressure gradients in the genesis of normal pressure hydrocephalus, referring to the experimental work of Hoff and Barber (31). The latter authors concluded that a pressure gradient across the cerebral mantle may contribute to ventricular dilatation in normal pressure hydrocephalus. This conclusion was based upon data from four severely head-injured patients, three of whom had required evacuation of a subdural hematoma, and applies, therefore, only to patients with post-traumatic hydrocephalus. It seems likely that the small (2-4 mm Hg) mean pressure gradients between the ventricular wall and cortical surface which Hoff and Barber measured in their head-injured patients, were a consequence of head injury (compartmentalization of the subarachnoid and subdural spaces in response to hemagenic lepto- and pachymeningitis) rather than a cause of hydrocephalus. CONCLUSIONS How then can our hypothesis be tested? The development of a largeanimal model of pseudotumor cerebri would be the logical first step. In calves, hypovitaminosis A is associated with increased CSFP and structural changes in the arachnoid villi (32). Thus, one might serially monitor CSFP, Pd' R , If% and CBV in laboratory animals after steroid withdrawal P33), selective nutritional deprivation or hormonal manipulation. Serial in vivo measurements of ventricular volume and brain water content, omaned from high-resolution CT brain scans (34,35), might resolve the longstanding argument about the role of interstitial brain edema. Only such a thoroughgo ng experimental approach will provide new insights into the pathogenesis of pseudotumor cerebri and allow for the rational development and application of effective treatment modalities. REFERENCES 1.
Dandy WE. Intracranial pressure w ithout brain tumor. Ann Surg 106 . 492, 1937. I.
2.
Symonds CP. Otitic hydrocephalus.
Brain 54: 55, 1931.
3.
Fishman RA. Pathophysiology 1979.
4.
Raichle ME. Reply to Fishman RA: Pathophysiology Ann Neurol 5: 496, 1979.
5.
Foley KM. Is benign intracranial Neurology 27: 388, 1977.
6.
Foley J. Benign forms of intracranial hypertension-"otitic" hydrocephalus. Brain 78: 1, 1955.
7.
Weisberg LA. Benign intracranial 1975.
8.
Marmarou A, Shulman K, Rosende RM. A nonlinear analysis of the cerebrospinal fluid system and intracranial dynamics. J Neurosurg 48: 332, 1978.
9.
Rottenberg DA, Posner JB. Intracranial pressure Control. p 89 in Anesthesia and Neurosurgery. (JE Cottrell, H Turndorf, eds) The C.V. Mosby Company, St. Louis, 1979.
of pseudotumor.
Ann Neurol 5: 496,
hypertension
hypertension.
10. Van Crevel H. Absence of papilloedema Neurol Neurosurg Psychiat 38: 931, 1975.
of pseudotumor.
a chronic disease? "Toxic" and
Medicine
54: 197,
in cerebral tumours. J
11.
Benabid AL, De Rougemont J, Barge M. Pression veineuse cerebrale, pression sinusale et pression intracranienne. Neuro-chirurgie 20: 623, 1974.
12.
Raichle ME, Grubb RL, Phelps ME, Gado MH, Caronna JJ. Cerebral hemodynamics and metabolism in pseudotumor cerebri. Ann Neurol 4: 104, 1978.
13.
Johnston I. The definition of a reduced CSF absorption syndrome: a reaprraisal of benign intracranial hypertension and related conditions. Med Hypotheses 1: 10, 1975.
14.
Mann JO, Johnson RN, Butler AB, Bass NH. Impairment of cerebrospinal fluid circulatory dynamics in pseudotumor cerebri and response to steroid treatment. Neurology 29: 550, 1979.
15.
Boddie HG, Banna M, Bradley WG. "Benign" intracranial hypertension: a survey of the clinical and radiological features, and long-term prognosis. Brain 97: 313, 1974.
16.
James AE, Harbert JC, Hoffer PB, Deland FH. CSF imaging in benign intracranial hypertension. J Neurol Neurosurg Psychiat 37: 1053, 1974.
17.
Guinane 1977.
18.
Weisberg L, Nice CN. Computed tomographic evaluation of increased intracranial pressure without localizing signs. Radiology 122: 133, 1977.
JE. Why does hydrocephalus progress? J Neural Sci 32: 1,
19.
Moseley IF, Radu EW. Factors influencing the development of periventricular lucencies in patients with raised intracranial pressure. Neuroradiology 17: 65, 1979.
20.
Grubb RL, Raichle ME, Phelps ME, Ratcheson RA. Effects of increased intracranial pressure on cerebral blood volume, blood flow and oxygen utilization in monkeys. J Neurosurg 43: 385, 1975.
21.
Fishman RA. Brain edema. New Eng J Med 293: 706, 1975.
22.
Johnston I, Paterson A. Benign intracranial hypertension: diagnosis and prognosis. Brain 97, 289, 1974.
23.
Bulens C, De Vries WAEJ, Van Crevel H. Benign intracranial hypertension. J Neurol Sci 40: 147, 1979.
24.
Morley JB, Reynolds EH. Papilloedema and the Landry-Guillain-Barre syndrome. Brain 89: 205, 1966.
25.
Deland FH, James AE,Jr., Ladd DJ, Konigsmark BW. Normal pressure hydrocephalus: a histologic study. Amer J Clin Path01 58: 58, 1972.
26.
Milhorat TH. Acute Hydrocephalus. N Eng J Med 283: 857, 1970.
27.
Lying-Tunell, U. Cerebrospinal fluid turnover and convexity block in mental impairment. Neurology 27: 460, 1977.
28.
Price DL, James AE Jr, Sperber E, Strecker E-P. Comnunicating hydrocephalus; cisternographic and neuropathologic studies. Arch Neurol 33: 15, 1976.
29.
Allen JC, Thaler HT, Deck MDF, Rottenberg DA. Leukoencephalopathy following high-dose intravenous methotrexate chemotherapy: quantitative assessment of white matter attenuation using computed tomography. Neuroradiology 16: 44, 1978.
30.
Koto A, Rosenberg G, Zingesser LH, Horoupian D, Katzman R. Syndrome of normal pressure hydrocephalus: possible relation to hypertensive and arteriosclerotic vasculopathy. J Neurol Neurosurg Psychiat 40: 73, 1977.
31.
Hoff J, Barber R. Transcerebral mantle pressure in normal pressure hydrocephalus. Arch Neurol 31: 101, 1974.
32.
Hayes KC, McCombs HL, Faherty TP. The fine structure of vitamin A deficiency II: arachnoid granulations and CSF pressure. Brain 94: 213, 1971.
33.
Johnston I, Gilday DL, Hendrick EB. Experimental effects of steroids and steroid withdrawal on cerebrospinal fluid absorption. J Neurosurg 42: 690, 1975.
34.
Rottenberg DA, Pentlow KS, Deck MDF, Allen JC. Determination of ventricular volume following metrizamide CT ventriculography. Neuroradiology 16: 136, 1978.
35.
Thaler HT, Ferber PW, Rottenberq DA. A statistical method for determining the proportions of gray matter, white matter, and CSF using computed tomography. Neuroradiology 16: 133, 1978.