Article abstract
In two patients with benign intracranial hypertension, the regional cerebral blood volume was markedly elevated (mean of 85 percent) while regional cerebral blood flow was slightly reduced (mean of 10 percent). Reductionof cerebrospinal fluid pressure by removal of cerebrospinal fluid reduced the mean values of regional cerebral blood volume by 13 percent without significant change in regional cerebral blood flow. The abnormal regional volume and regional flow returned to normal concurrent with the clinical improvement. Venous engorgement and increased intracranial blood volume appear to play an important part in the pathophysiologyof increased intracranial pressure in benign intracranial hypertension. A unified concept of the pathogenesis of benign intracranial hypertension is proposed.
Increased cerebral blood volume in benign int racranial hypertension NINAN T. MATHEW, M.D., F.R.C.P.(C), JOHN STIRLING MEYER, M.D., and ERWIN 0. OTT, M.D.
atients with benign intracranial hyperP tension, sometimes termed pseudotumor cerebri ," present to the clinician with headache, papilledema, and "
increased intracranial pressure. Despite the presence of abnormally elevated intracranial pressure, patients appear relatively well and examination fails to show neurologic abnormalities other than papilledema. Other tests such as electroencephalogram, x-rays of the skull, arteriogram, and pneurnoencephalogram are normal except that the ventricles are small in size and no obstruction to the ventricles is demonstrable. The pathogenesis of this type of intracranial hypertension remains undefined and even the intracranial compartment that is expanded and at fault (brain, blood, or cerebrospinal fluid) is uncertain. Sahs and Joynt' reported intracellular and extracellular brain edema in their patients with benign intracranial hypertension who underwent cortical biopsies. Later it was shown by radioisotope cisternography in cases of benign intracranial hypertension that clearance of the From the Department of Neurology, Baylor College of Medicine and the Baylor-Methodist Center for Cerebrovascular Research, Houston, Texas. This work was supported by NlNDS grant NS 09287 and in part by grant RR 00350 from the General Clinical Research Center Branch, Division of Research Resources, National Institutesof Health. Dr. Ott was a Research Associate in the Department of Neurology, Baylor College of Medicine, and is presently in the Department of Neurology, University Clinic for Neurology and Psychiatry, Graz, Austria. Received for publication October 7, 1974. Reprint requests should be addressed to Dr. Ninan T. Mathew, Department of Neurology, Baylor College of Medicine, 1200 Moursund Avenue, Houston, TX 77025.
646 NEUROLOGY 25: 646-649, July 1975
isotope was delayed, presumably because of defective absorption of cerebrospinal fluid (CSF).213 Many years ago, Dandy4 predicted that increased cerebral blood volume (CBV) was the cause of the increased intracranial pressure in benign intracranial hypertension but actual measurements of CBV have not been made in this condition until recently by Raichle and associates. The purpose of the present communication is to report measurements of CBV and cerebral blood flow (CBF) before and after reduction of intracranial pressure in two cases of benign intracranial hypertension and the successful treatment of the condition with oral glycerol. Case 1 . A 23-year-old, obese woman complained of progressively severe headaches for 4 months, oligomenorrhea, and occasional episodes of diplopia. There was no history of otitis media, mastoiditis, or the use of oral contraceptives. Bilateral papilledema of 3 diopters without other neurologic signs was found. Apart from the headaches she was well. X-rays of the skull, electroencephalogram, brain scan, and bilateral carotid arteriograms were within normal limits and the jugular veins in the neck appeared normal in the angiogram. Lumbar CSF had a pressure of 380 mm CSF with no cells and a normal protein content. Pneumoencephalogram showed small ventricles without displacement or distortion and the subarachnoid spaces were normal. Regional cerebral blood volume ( C B V ) and regional cerebral blood flow (rCBF) were measured with the use of intra-arterial radioisotope technique6 with a gamma camera. Details of the technical aspects and reliability of gamma camera for measurement of rCBF after intracarotid injection of XE'33 were reported by Heiss, Prosenz, and R o s ~ u c z k yShort . ~ term
variations in C B F and interregional differences are accurately recorded by the gamma camera.10*'' With the intracarotid technique, gamma camera gives r CBF values comparable to those measurable by multiple probe system. l 2 Serial intracarotid injections of Xe133and T c ~ ~were " ' made to measure rCBF and regional transit time, respectively. In the calculation of regional ~ methods ~ , of transit time after intracarotid injection of T c ~ the Fazio, Fieschi, and Agnoli13 and 0ldendo1-f'~were adopted. Regional transit time was calculated as the interval between increment and decrement of the Tc99 curve at the mid point of the maximal vertical axis. Theoretical aspects of calculation of rCBV from transit time and rCBF are discussed by Fieschi and associates.ls The clearance of Xe'33 was monitored from the lateral surface of the head for 10 minutes and after that the clearance of Tc~~"'was recorded for 1 minute after its injection. The data were stored on a magnetic tape. A specially programmed computer analyzed the clearance curves of both radioisotopes and provided an automatic printout of rCBF expressed as rCBF for 10 minutes (ICBFio), flow in the gray matter, flow in the white matter, and I - C B V . ~Regional ~~ CBV was computed using rCBFio and the transit time of cerebral circulation obtained from injecting the nondiffusible Tcg9"'. Arterial blood pressure and arterial carbon dioxide pressure (PaCOz) were recorded during the procedure. After steady state measurement, a lumbar puncture was done and CSF pressure was lowered by removal of CSF and the measurements were repeated. The patient was placed on glycerol by mouth in a dosage of 1.5 gm per kilogram body weight administered in fruit juice in three divided doses daily. She was reexamined at intervals of 6 weeks over the ensuing 6 months. After 2 weeks of glycerol treatment the headaches lessened and at the end of the second month had disappeared completely. The papilledema gradually receded and was no longer present after 18 weeks. At the end of 6 months, the C B V , ICBF, and CSF pressure measurements were repeated. Since the signs and symptoms were completely reversed she was advised to reduce the dosage of glycerol to half the original. She continues to take this dosage of glycerol with no side effects and has been free of symptoms for 9 months.
Case 2. A 32-year-old, obese woman complained of headaches of increasing seventy that had begun after a severe upper
respiratory infection. She had been taking oral anovulating contraceptive pills (Ovral@ tablets, each containing 0.5 mg norgestrel with 0.05 mg ethinyl estradiol) for the preceding 3 years. Examination showed bilateral papilledema confirmed by fluorescence angiography of the retina. Lumbar puncture revealed a CSF pressure of 375 mrn with no cells and normal protein content. Brain scan and EEG tests were within normal limits and pneumoencephalogram showed small ventricles. Measurements of rCBV and rCBF were made before and after lowering CSF pressure by lumbar puncture. The patient then was placed on oral glycerol in a dosage of 1.5 gm per kilogram body weight and the oral contraceptive was stopped. By the end of 3 months her headaches had disappeared. The glycerol was discontinued for 2 weeks to check its effectiveness, and her headaches reappeared. Minimal blurring of the optic disks was still present at the end of 3 months but there was not significant papilledema. Regional CBV and rCBF measurements were repeated after 4% months when she was asymptomatic.
Results. Results of rCBV, rCBF, and CSF pressure measurements in the two cases are summarized in the table. Regional CBV and rCBF values were obtained from 16 regions of the right cerebral hemisphere in each case. The rCBV was diffusedly increased compared with normal values in both cases, with a mean increase of 85 percent (p C 0.001). Values for rCBFio were slightly lower than normal with a mean decrease of 10 percent (p < 0.05). The flow in the gray matter was reduced by 15 percent in case 2. After reduction of CSF pressure by lumbar puncture there was a small reduction (mean 13 percent) (p < 0.05) of rCBV but no significant change in C B F . However, when the measurements were repeated after the relief of symptoms of headache, disappearance of the papilledema, and reduction of CSF pressure, the C B V and rCBF were restored to normal levels. There were no side effects after prolonged use of glycerol.
Discussion. Foley' reported increased hemispheric cerebral blood flow in three patients with pseudotumor cerebri but did not measure CBV. The present
Table. Cerebral blood volume and flow in benign intracraniai hypertension in two patients
NEUROLOGY July 1975 647
Cerebral blood volume in benign intracranial hypertension measurement confirms that in the acute stages of benign intracranial hypertension, rCBV is grossly increased. Raichle and c o - w o r k e r ~ ,using ~ C1sO-labeled hemoglobin and x-ray fluorescence for measuring rCBV, presented findings similar to ours in cases of benign intracranial hypertension. Regional CBV values we obtained (normal 4.05 -t 0.81 ml per 100 gm) were slightly higher than that reported by Raichle and associatesS (normal 3.76 +- 0.61 ml per 100 gm) and Reivich and associates.” This may be because no correction was applied to the mean transit time to account for the fact that T c ~ ~is” ’a plasma tag. Sahs and Joynt’ reported dilation of the blood vessels with intracellular and extracellular brain edema in cortical biopsies of benign intracranial hypertension. The fact that rCBV was disproportionately higher than rCBF, which was slightly low in the present two cases, indicates that there was extreme dilation of the capacitance vessels, particularly the cerebral veins. It could be argued that the increased rCBV may be due to cerebral vasodilation as an attempt of the cerebral vasculature to keep CBF constant in the face of increased intracranial pressure (normal autoregulatory mechanism), a phenomenon described by Langfitt, Kassell, and Weinstein.’* Increase in CBV associated with a fall in CBF has been reported in the face of increasing intracranial pressure in experimental animals. This compensatory autoregulatory mechanism appears to have played only a minor role in the pathogenesis of increased intracranial pressure in the two cases reported here because reduction of CSF pressure by lumbar puncture to near normal levels resulted in only a small decrease (13 percent) in rCBV and no change in rCBF. Intracranial venous engorgement with increased CBV and subsequent brain edema accounts for at least part of the raised intracranial pressure in these patients. INTERFERENCE WITH CEREBRAL VENOUS OUTFLOW AND DISORDERS OF CEREBRAL VASCULAR DILATATION
111
121
131
141
INTRACRANIAL VENOUS SINUS OBSTRUCTION 181 Mastoiditis lbt Otitis, Sinusitis kl Trauma (dl B l o d Dyscrasias With Thrombosis (el Oral Contraceptives EXTRACRANIAL CEREERAL VENOUS OBSTRUCTION la1 Thrombosis M Superior Vena Cava lbl Block Dissstion of Neck kl Mediastinal Tumor CEREBRAL VENOUS STASIS Ial Oral Contraceptives tbl Endocrine Dysfunction As I n Pregnancy And Menarche CEREBRAL VASCULAR DILATATION DUE TO C07 RETENTION lal (bl Ll
Extreme Obesity. Pickwickian Syndrome Chronic Obstructive Pulmonary Disease Respiratory Paralysis
t
VASCULAR ENGORGEMENT AND INCREASED CEREBRAL BLOOD VOLUME
Cerebrovascular engorgement is a well-known outcome of obstruction to the major dual sinuses, both internal jugular veins, or the superior vena cava and these conditions have been reported to be associated with benign intracranial hypertension. 20,21 There are other cases of benign intracranial hypertension where there is no obvious obstruction to venous outflow, at least no obstruction demonstrable by angiography, as in the cases reported here. The estrogenic component of the oral contraceptive agents is known to cause “loss of tone” of smooth muscles of the vascular system, to interfere with the elastic tissue resulting in loss of elasticity, and to cause stasis of flow, particularly in the veins of the lower is ?possible that a similar mechanism e x t r e m i t i e ~ .It~ ~ ~~ producing venous stasis and increased CBV may be operating in patients who develop benign intracranial hypertension while taking oral contraceptives. Increased platelet adhesiveness associated with the use of oral contraceptives plus the cerebral venous stasis may result in thrombosis of major cerebral veins and in benign intracranial pressure as in one case we have seen previously. Some of the endocrine causes of benign intracranial h y p e r t e n s i o n , such as menstrual d y s f ~ n c t i o npregnancy,zs ,~~ and menarche,26also may be operating in a similar fashion, producing vasodilation due to imbalance in sex hormones. Salt retention and water, associated with the use of estrogenic hormones, may contribute to the development of benign intracranial hypertension. Brain edema is present in the acute stage of benign intracranial hypertension because the ventricles are reduced in size and have a “pinched” appearance. At operation, neurosurgeons find difficulty in locating the small ventricles with cannulas and the brain tends to bulge when the skull and dura are opened. Sahs and Joynt found
DISORDERED MEMBRANE TRANSPORT MECHANISMS
(a1 1bl lcl (dl lel
Obesity Pregnancy Menarche Addison’s Disease Hypoparathyroidism
BLOCKAGE BY INCREASED PROTEIN I N CSF lal Guillian Barre Syndrome lbl Spinal Cord Tumor
12) HYPERVITAMINOSIS A
DYSFUNCTION OF MICROTUBULAR SYSTEM OF ARACHNOID Vllll
13) TETRACYCLINE THERAPY
I
Its Withdrawal
141 POST IMECTIOUS STATE I
I
I
I
D BRAIN EDEMA
I
I
REDUCED CSF
Figure. Schematic outline of possible mechanisms in the pathogenesis of benign intracranial hypertension.
ABS/ORPT’oN I INCREASED INTRACRANIAL PRESSURE HEADACHE PAPI LLEOEMA IBIHl
648 NEUROLOGY July 1975
DYSFUNCTION O f THE ARACHNOID V I L L I
brain edema in cortical biopsies.’ The fact that oral glycerol effectively reduces intracranial pressure in these patients further confirms the presence of brain edema.27 Although the brain edema could be secondary to vascular engorgement, in some cases brain edema may be primarily due to interference with transport mechanisms of the cell membranes in the brain as a result of endocrinopathies, drug the rap^,'^^^^ hypervitaminosis A,30 and h y p o ~ a l c e m i a .In ~ ~ such cases, the venous distension may be an autoregulatory phenomenon in an attempt to maintain CBF constant. l 8 It is to be expected also that CSF absorption is delayed in these patients if there is venous congestion, since the CSF is absorbed into the dural venous system.*t3 Increased superior sagittal sinus pressure delays CSF absorption. Dysfunction of the arachnoid villi and its microtubular system by endocrinopathies and drug therapyz or their blockage by an abnormally high protein content of the CSF as has been reported in some cases of the Guillain-Barri syndrome32 also can produce benign intracranial hypertension, primarily by interfering with CSF absorption. Since there is increased CBV, brain edema and delayed CSF absorption, it appears to us that all three intracranial compartments may be involved in the production of increased intracranial pressure in benign intracranial hypertension, although the primary etiology may vary and varying degrees of the three factors may be involved. This concept has been illustrated diagrammaticallyin the figure. Since cerebral edema is more easily controlled by therapeutic measures than the other two factors, the logical treatment should be anti-cerebral edema measures. Dexamethasone, commonly used in brain edema caused by tumors, is undesirable in benign intracranial hypertension because of the side effects of prolonged use and because steroid therapy and its withdrawal itself may be a cause of benign intracranial hypertension. Mannitol and urea are available only for intravenous use and hence are not suitable for long-term therapy. Moreover, rebound phenomenon of intracranial pressure is commonly seen with these two drugs. Diuretics like furosemide, though effective, produce electrolyte and water imbalance on prolonged therapy. On the other hand, oral glycerol therapy is not associated with any adverse reactions. Although disappearance of papilledema and other clinical manifestations can occur spontaneously or after cessation of oral contraceptives, in our experience, oral glycerol therapy appears to be beneficial in hastening recovery in benign intracranial hypertension.
REFERENCES 1. Sahs AL, Joynt RJ: Brain swelling of unknown cause. Neurology
(Minneap) 6:791-803, 1956 2. Bercaw BL, Greer M: Transport of intrathecal ’3’1 Risa in benign intracranial hypertension. Neurology (Minneap) 20:787-790, 1970 3. Johnston I:ReducedCSF absorption syndrome. Reappraisalof benign intracranial hypertension and related conditions. Lancet 2:418420, 1973
4. Dandy WE: lntracranial pressure without brain tumor. Ann Surg 106:492-513, 1937 5. Raichle M, Gad0 M, Eichling J, et al: Cerebral hernodynamics and metabolism in pseudotumor cerebri. (Abstr) Neurology (Minneap) 24397, 1974 6. Lassen NA, lngvar D: The blood flow of cerebral cortex determined by radioactive Krypton. Experientia 17:42-43, 1961 7. Mathew NT, Meyer JS, Bell RL, et at: Regional cerebral blood flow and blood volume measured with the gamma camera. Neuroradiology 41133-140, 1972 8. Mathew NT, Meyer JS, Hartmann A: Diagnosis and treatment of factors complicating subarachnoid hemorrhage. Neuroradioiogy 6:237-245, 1974 9. Heiss WD. Prosenz P, Roszuczky A: Technical considerations in the use of a gamma camera, 1600 channel analyzer system for the measurementof regional cerebral Mood flow. J Nucl Med 13534-543, 1972 10.Heiss WD: Drug effects on regional cerebral blood flow in focal cerebrovascular disease. J Neurol Sci 19:461-482, 1973 11. Prosenr P,Heiss WD, Tschabitscher H, et el: The value of regional cerebral blood flow measurement compared to angiography in the assessment of obstructive neck vessel disease. Stroke 5:19-31,1974 12. Klassen AC, Kush GS, Resch JA, et al: Gamma camera evaluation of cerebral circulation using inhalation and intracarotid injection of ’33Xenon. In Ross Russell RW (Editor): Brain and Blood Flow. Proceedings of the Fourth lntemationalSymposium on the Regulation of Cerebral Blood Flow. London, Pitman Publishing Corporation. 1971, pp 42-47 13. Fazio C, Fieschi C, Agnoli A: Direct common carotid injection of radioisotopes for evaluation of cerebral circulatory disturbances. Neurology (Minneap) 13:561-574, 1963 14. Oldendorf WH: Radioisotope method for cerebral blood flow determination. In Wang Y. Padetti P (Editors): Radionuclide Applications in Neurology and Neurosurgery. Springfield, IL, Charles C Thomas, Publisher, 1970, p 27 15. Fieschi C, Agnoli A, Battistini N, et al: Relationships between cerebral transit time of nondiffusible indicators and cerebral blood flow: A comparative study with Krypton-85 and radioalbumin. Experientia 22:189-199, i966 16. Foley J: Benignformsof intracranial hypertension-“Toxic” and “otitic” hydrocephalus. Brain 78:1-41, 1955 17. Reivich M, Kuhl D, Nyary I, et al: Measurement of local cerebral blood volume in three dimensions in man. (Abstr) Neurology (Minneap) 24:389, 1974 18. Langfitt TW, Kassell NF, Weinstein JD: Cerebral blood flow with intracranial hypertension. Neurology (Minneap) 15761 -773, 1965 19. Nagai H, lkeyama A, Furuse M, et al: Effect of increased intracranial pressure on cerebral hsmodynamics: Observation of CBF, CBV, and POz. Eur Neurol 852-56, 1972 20. Greer M: Benign intracranial hypertension: 1. Mastoiditis and lateral sinus obstruction. Neurology (Minneap) 12:472-476. 1962 21. Hooper R: Hydrocephalus and obstruction of the superior vena cava in infancy: Clinical study of the relationship between cerebrospinal fluid pressure and venous pressure. Pediatrics 28:792-799, 1961 22. Goodrich SM, Wood JE: Peripheral venous distensibility and velocity of venous blood flow during pregnancy or during oral contraceptive therapy. Am J Obstet Gynecol 90:740-744. 1964 23. Wood JE: The Veins: Normal and Abnormal Function. Boston, Little, Brown and Company, 1965 24. Greer M: Benign intracranial hypertension: V. Menstrual dysfunction. Neurology (Minneap) 14:668-673, 1964 25. Greer M: Benign intracranial hypertension: 111. Pregnancy. Neurology (Minneap) 13:670-672, 1963 26. Greer M: Benign intracranial hypertension: IV: Menarche. Neurology (Minneap) 14569-573, 1964 27. Reinglass JL: Dose response curve of intravenous glycerol in the treatment of cerebral edema due to trauma. Neurology (Minneap) 24:743-747, 1974 28. Greer M: Benign intracranial hypertension: 11. Following corticosteroid therapy. Neurology (Minneap) 13:439-441, 1963 29. Koch-Weser J, Gilmore EB: Benign intracranial hypertension in an adult atter tetracycline therapy. JAMA 200:345-347. 1967 30. Feldman MH, Schlezinger NS: Benign intracranial hypertension associated with hypervitaminosis A. Arch Neurol22:l-7, 1970 31. Sugar 0:Central neurological complications of hypoparathyroidism. Arch Neurol Psychiatry 70336-107, 1953 32. Gardner WJ, Spitler DK, Whitten C: Increased intracranial pressure caused by increased protein content in the cerebrospinal fluid: Explanation of papilledema in certain cases of small intracranial and intraspinal tumors, and in Guillain-Bard Syndrome. N Engl J Med 250:932-936, 1954
NEUROLOGY July 1975 649
Increased cerebral blood volume in benign intracranial hypertension NINAN T. MATHEW, JOHN STIRLING MEYER and ERWIN O. OTT Neurology 1975;25;646 DOI 10.1212/WNL.25.7.646 This information is current as of July 1, 1975 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1975 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
In two patients with benign intracranial hypertension, the regional cerebral blood volume was markedly elevated (mean of 85 percent) while regional cerebral blood flow was slightly reduced (mean of 10 percent). Reductionof cerebrospinal fluid pressure by removal of cerebrospinal fluid reduced the mean values of regional cerebral blood volume by 13 percent without significant change in regional cerebral blood flow. The abnormal regional volume and regional flow returned to normal concurrent with the clinical improvement. Venous engorgement and increased intracranial blood volume appear to play an important part in the pathophysiologyof increased intracranial pressure in benign intracranial hypertension. A unified concept of the pathogenesis of benign intracranial hypertension is proposed.
Increased cerebral blood volume in benign int racranial hypertension NINAN T. MATHEW, M.D., F.R.C.P.(C), JOHN STIRLING MEYER, M.D., and ERWIN 0. OTT, M.D.
atients with benign intracranial hyperP tension, sometimes termed pseudotumor cerebri ," present to the clinician with headache, papilledema, and "
increased intracranial pressure. Despite the presence of abnormally elevated intracranial pressure, patients appear relatively well and examination fails to show neurologic abnormalities other than papilledema. Other tests such as electroencephalogram, x-rays of the skull, arteriogram, and pneurnoencephalogram are normal except that the ventricles are small in size and no obstruction to the ventricles is demonstrable. The pathogenesis of this type of intracranial hypertension remains undefined and even the intracranial compartment that is expanded and at fault (brain, blood, or cerebrospinal fluid) is uncertain. Sahs and Joynt' reported intracellular and extracellular brain edema in their patients with benign intracranial hypertension who underwent cortical biopsies. Later it was shown by radioisotope cisternography in cases of benign intracranial hypertension that clearance of the From the Department of Neurology, Baylor College of Medicine and the Baylor-Methodist Center for Cerebrovascular Research, Houston, Texas. This work was supported by NlNDS grant NS 09287 and in part by grant RR 00350 from the General Clinical Research Center Branch, Division of Research Resources, National Institutesof Health. Dr. Ott was a Research Associate in the Department of Neurology, Baylor College of Medicine, and is presently in the Department of Neurology, University Clinic for Neurology and Psychiatry, Graz, Austria. Received for publication October 7, 1974. Reprint requests should be addressed to Dr. Ninan T. Mathew, Department of Neurology, Baylor College of Medicine, 1200 Moursund Avenue, Houston, TX 77025.
646 NEUROLOGY 25: 646-649, July 1975
isotope was delayed, presumably because of defective absorption of cerebrospinal fluid (CSF).213 Many years ago, Dandy4 predicted that increased cerebral blood volume (CBV) was the cause of the increased intracranial pressure in benign intracranial hypertension but actual measurements of CBV have not been made in this condition until recently by Raichle and associates. The purpose of the present communication is to report measurements of CBV and cerebral blood flow (CBF) before and after reduction of intracranial pressure in two cases of benign intracranial hypertension and the successful treatment of the condition with oral glycerol. Case 1 . A 23-year-old, obese woman complained of progressively severe headaches for 4 months, oligomenorrhea, and occasional episodes of diplopia. There was no history of otitis media, mastoiditis, or the use of oral contraceptives. Bilateral papilledema of 3 diopters without other neurologic signs was found. Apart from the headaches she was well. X-rays of the skull, electroencephalogram, brain scan, and bilateral carotid arteriograms were within normal limits and the jugular veins in the neck appeared normal in the angiogram. Lumbar CSF had a pressure of 380 mm CSF with no cells and a normal protein content. Pneumoencephalogram showed small ventricles without displacement or distortion and the subarachnoid spaces were normal. Regional cerebral blood volume ( C B V ) and regional cerebral blood flow (rCBF) were measured with the use of intra-arterial radioisotope technique6 with a gamma camera. Details of the technical aspects and reliability of gamma camera for measurement of rCBF after intracarotid injection of XE'33 were reported by Heiss, Prosenz, and R o s ~ u c z k yShort . ~ term
variations in C B F and interregional differences are accurately recorded by the gamma camera.10*'' With the intracarotid technique, gamma camera gives r CBF values comparable to those measurable by multiple probe system. l 2 Serial intracarotid injections of Xe133and T c ~ ~were " ' made to measure rCBF and regional transit time, respectively. In the calculation of regional ~ methods ~ , of transit time after intracarotid injection of T c ~ the Fazio, Fieschi, and Agnoli13 and 0ldendo1-f'~were adopted. Regional transit time was calculated as the interval between increment and decrement of the Tc99 curve at the mid point of the maximal vertical axis. Theoretical aspects of calculation of rCBV from transit time and rCBF are discussed by Fieschi and associates.ls The clearance of Xe'33 was monitored from the lateral surface of the head for 10 minutes and after that the clearance of Tc~~"'was recorded for 1 minute after its injection. The data were stored on a magnetic tape. A specially programmed computer analyzed the clearance curves of both radioisotopes and provided an automatic printout of rCBF expressed as rCBF for 10 minutes (ICBFio), flow in the gray matter, flow in the white matter, and I - C B V . ~Regional ~~ CBV was computed using rCBFio and the transit time of cerebral circulation obtained from injecting the nondiffusible Tcg9"'. Arterial blood pressure and arterial carbon dioxide pressure (PaCOz) were recorded during the procedure. After steady state measurement, a lumbar puncture was done and CSF pressure was lowered by removal of CSF and the measurements were repeated. The patient was placed on glycerol by mouth in a dosage of 1.5 gm per kilogram body weight administered in fruit juice in three divided doses daily. She was reexamined at intervals of 6 weeks over the ensuing 6 months. After 2 weeks of glycerol treatment the headaches lessened and at the end of the second month had disappeared completely. The papilledema gradually receded and was no longer present after 18 weeks. At the end of 6 months, the C B V , ICBF, and CSF pressure measurements were repeated. Since the signs and symptoms were completely reversed she was advised to reduce the dosage of glycerol to half the original. She continues to take this dosage of glycerol with no side effects and has been free of symptoms for 9 months.
Case 2. A 32-year-old, obese woman complained of headaches of increasing seventy that had begun after a severe upper
respiratory infection. She had been taking oral anovulating contraceptive pills (Ovral@ tablets, each containing 0.5 mg norgestrel with 0.05 mg ethinyl estradiol) for the preceding 3 years. Examination showed bilateral papilledema confirmed by fluorescence angiography of the retina. Lumbar puncture revealed a CSF pressure of 375 mrn with no cells and normal protein content. Brain scan and EEG tests were within normal limits and pneumoencephalogram showed small ventricles. Measurements of rCBV and rCBF were made before and after lowering CSF pressure by lumbar puncture. The patient then was placed on oral glycerol in a dosage of 1.5 gm per kilogram body weight and the oral contraceptive was stopped. By the end of 3 months her headaches had disappeared. The glycerol was discontinued for 2 weeks to check its effectiveness, and her headaches reappeared. Minimal blurring of the optic disks was still present at the end of 3 months but there was not significant papilledema. Regional CBV and rCBF measurements were repeated after 4% months when she was asymptomatic.
Results. Results of rCBV, rCBF, and CSF pressure measurements in the two cases are summarized in the table. Regional CBV and rCBF values were obtained from 16 regions of the right cerebral hemisphere in each case. The rCBV was diffusedly increased compared with normal values in both cases, with a mean increase of 85 percent (p C 0.001). Values for rCBFio were slightly lower than normal with a mean decrease of 10 percent (p < 0.05). The flow in the gray matter was reduced by 15 percent in case 2. After reduction of CSF pressure by lumbar puncture there was a small reduction (mean 13 percent) (p < 0.05) of rCBV but no significant change in C B F . However, when the measurements were repeated after the relief of symptoms of headache, disappearance of the papilledema, and reduction of CSF pressure, the C B V and rCBF were restored to normal levels. There were no side effects after prolonged use of glycerol.
Discussion. Foley' reported increased hemispheric cerebral blood flow in three patients with pseudotumor cerebri but did not measure CBV. The present
Table. Cerebral blood volume and flow in benign intracraniai hypertension in two patients
NEUROLOGY July 1975 647
Cerebral blood volume in benign intracranial hypertension measurement confirms that in the acute stages of benign intracranial hypertension, rCBV is grossly increased. Raichle and c o - w o r k e r ~ ,using ~ C1sO-labeled hemoglobin and x-ray fluorescence for measuring rCBV, presented findings similar to ours in cases of benign intracranial hypertension. Regional CBV values we obtained (normal 4.05 -t 0.81 ml per 100 gm) were slightly higher than that reported by Raichle and associatesS (normal 3.76 +- 0.61 ml per 100 gm) and Reivich and associates.” This may be because no correction was applied to the mean transit time to account for the fact that T c ~ ~is” ’a plasma tag. Sahs and Joynt’ reported dilation of the blood vessels with intracellular and extracellular brain edema in cortical biopsies of benign intracranial hypertension. The fact that rCBV was disproportionately higher than rCBF, which was slightly low in the present two cases, indicates that there was extreme dilation of the capacitance vessels, particularly the cerebral veins. It could be argued that the increased rCBV may be due to cerebral vasodilation as an attempt of the cerebral vasculature to keep CBF constant in the face of increased intracranial pressure (normal autoregulatory mechanism), a phenomenon described by Langfitt, Kassell, and Weinstein.’* Increase in CBV associated with a fall in CBF has been reported in the face of increasing intracranial pressure in experimental animals. This compensatory autoregulatory mechanism appears to have played only a minor role in the pathogenesis of increased intracranial pressure in the two cases reported here because reduction of CSF pressure by lumbar puncture to near normal levels resulted in only a small decrease (13 percent) in rCBV and no change in rCBF. Intracranial venous engorgement with increased CBV and subsequent brain edema accounts for at least part of the raised intracranial pressure in these patients. INTERFERENCE WITH CEREBRAL VENOUS OUTFLOW AND DISORDERS OF CEREBRAL VASCULAR DILATATION
111
121
131
141
INTRACRANIAL VENOUS SINUS OBSTRUCTION 181 Mastoiditis lbt Otitis, Sinusitis kl Trauma (dl B l o d Dyscrasias With Thrombosis (el Oral Contraceptives EXTRACRANIAL CEREERAL VENOUS OBSTRUCTION la1 Thrombosis M Superior Vena Cava lbl Block Dissstion of Neck kl Mediastinal Tumor CEREBRAL VENOUS STASIS Ial Oral Contraceptives tbl Endocrine Dysfunction As I n Pregnancy And Menarche CEREBRAL VASCULAR DILATATION DUE TO C07 RETENTION lal (bl Ll
Extreme Obesity. Pickwickian Syndrome Chronic Obstructive Pulmonary Disease Respiratory Paralysis
t
VASCULAR ENGORGEMENT AND INCREASED CEREBRAL BLOOD VOLUME
Cerebrovascular engorgement is a well-known outcome of obstruction to the major dual sinuses, both internal jugular veins, or the superior vena cava and these conditions have been reported to be associated with benign intracranial hypertension. 20,21 There are other cases of benign intracranial hypertension where there is no obvious obstruction to venous outflow, at least no obstruction demonstrable by angiography, as in the cases reported here. The estrogenic component of the oral contraceptive agents is known to cause “loss of tone” of smooth muscles of the vascular system, to interfere with the elastic tissue resulting in loss of elasticity, and to cause stasis of flow, particularly in the veins of the lower is ?possible that a similar mechanism e x t r e m i t i e ~ .It~ ~ ~~ producing venous stasis and increased CBV may be operating in patients who develop benign intracranial hypertension while taking oral contraceptives. Increased platelet adhesiveness associated with the use of oral contraceptives plus the cerebral venous stasis may result in thrombosis of major cerebral veins and in benign intracranial pressure as in one case we have seen previously. Some of the endocrine causes of benign intracranial h y p e r t e n s i o n , such as menstrual d y s f ~ n c t i o npregnancy,zs ,~~ and menarche,26also may be operating in a similar fashion, producing vasodilation due to imbalance in sex hormones. Salt retention and water, associated with the use of estrogenic hormones, may contribute to the development of benign intracranial hypertension. Brain edema is present in the acute stage of benign intracranial hypertension because the ventricles are reduced in size and have a “pinched” appearance. At operation, neurosurgeons find difficulty in locating the small ventricles with cannulas and the brain tends to bulge when the skull and dura are opened. Sahs and Joynt found
DISORDERED MEMBRANE TRANSPORT MECHANISMS
(a1 1bl lcl (dl lel
Obesity Pregnancy Menarche Addison’s Disease Hypoparathyroidism
BLOCKAGE BY INCREASED PROTEIN I N CSF lal Guillian Barre Syndrome lbl Spinal Cord Tumor
12) HYPERVITAMINOSIS A
DYSFUNCTION OF MICROTUBULAR SYSTEM OF ARACHNOID Vllll
13) TETRACYCLINE THERAPY
I
Its Withdrawal
141 POST IMECTIOUS STATE I
I
I
I
D BRAIN EDEMA
I
I
REDUCED CSF
Figure. Schematic outline of possible mechanisms in the pathogenesis of benign intracranial hypertension.
ABS/ORPT’oN I INCREASED INTRACRANIAL PRESSURE HEADACHE PAPI LLEOEMA IBIHl
648 NEUROLOGY July 1975
DYSFUNCTION O f THE ARACHNOID V I L L I
brain edema in cortical biopsies.’ The fact that oral glycerol effectively reduces intracranial pressure in these patients further confirms the presence of brain edema.27 Although the brain edema could be secondary to vascular engorgement, in some cases brain edema may be primarily due to interference with transport mechanisms of the cell membranes in the brain as a result of endocrinopathies, drug the rap^,'^^^^ hypervitaminosis A,30 and h y p o ~ a l c e m i a .In ~ ~ such cases, the venous distension may be an autoregulatory phenomenon in an attempt to maintain CBF constant. l 8 It is to be expected also that CSF absorption is delayed in these patients if there is venous congestion, since the CSF is absorbed into the dural venous system.*t3 Increased superior sagittal sinus pressure delays CSF absorption. Dysfunction of the arachnoid villi and its microtubular system by endocrinopathies and drug therapyz or their blockage by an abnormally high protein content of the CSF as has been reported in some cases of the Guillain-Barri syndrome32 also can produce benign intracranial hypertension, primarily by interfering with CSF absorption. Since there is increased CBV, brain edema and delayed CSF absorption, it appears to us that all three intracranial compartments may be involved in the production of increased intracranial pressure in benign intracranial hypertension, although the primary etiology may vary and varying degrees of the three factors may be involved. This concept has been illustrated diagrammaticallyin the figure. Since cerebral edema is more easily controlled by therapeutic measures than the other two factors, the logical treatment should be anti-cerebral edema measures. Dexamethasone, commonly used in brain edema caused by tumors, is undesirable in benign intracranial hypertension because of the side effects of prolonged use and because steroid therapy and its withdrawal itself may be a cause of benign intracranial hypertension. Mannitol and urea are available only for intravenous use and hence are not suitable for long-term therapy. Moreover, rebound phenomenon of intracranial pressure is commonly seen with these two drugs. Diuretics like furosemide, though effective, produce electrolyte and water imbalance on prolonged therapy. On the other hand, oral glycerol therapy is not associated with any adverse reactions. Although disappearance of papilledema and other clinical manifestations can occur spontaneously or after cessation of oral contraceptives, in our experience, oral glycerol therapy appears to be beneficial in hastening recovery in benign intracranial hypertension.
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NEUROLOGY July 1975 649
Increased cerebral blood volume in benign intracranial hypertension NINAN T. MATHEW, JOHN STIRLING MEYER and ERWIN O. OTT Neurology 1975;25;646 DOI 10.1212/WNL.25.7.646 This information is current as of July 1, 1975 Updated Information & Services
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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1975 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
