Pseudotumor cerebri history and symptoms: Difference between revisions

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==Overview==
==Overview==


==History==
==History and Symptoms==
the important points in the history of a patient suspected for pseudotumor cerebri are:
 
=== History ===
* The important points in the history of a patient suspected for pseudotumor cerebri are:
 
===== Age and gender =====
===== Age and gender =====
Most of the [[Idiopathic intracranial hypertension|IIH]] cases happen in women in child bearing age<ref name="pmid1998880">{{cite journal |vauthors=Wall M, George D |title=Idiopathic intracranial hypertension. A prospective study of 50 patients |journal=Brain |volume=114 ( Pt 1A) |issue= |pages=155–80 |date=February 1991 |pmid=1998880 |doi= |url=}}</ref>, but it can also happens in children and old adult with male gender. In prepubertal age the gender is not an important [[risk factor]] and in old patients the percent of affected males was higher than females.<ref name="pmid9534686">{{cite journal |vauthors=Soler D, Cox T, Bullock P, Calver DM, Robinson RO |title=Diagnosis and management of benign intracranial hypertension |journal=Arch. Dis. Child. |volume=78 |issue=1 |pages=89–94 |date=January 1998 |pmid=9534686 |pmc=1717437 |doi= |url=}}</ref><ref name="pmid11937898">{{cite journal |vauthors=Bandyopadhyay S, Jacobson DM |title=Clinical features of late-onset pseudotumor cerebri fulfilling the modified dandy criteria |journal=J Neuroophthalmol |volume=22 |issue=1 |pages=9–11 |date=March 2002 |pmid=11937898 |doi= |url=}}</ref>
* Most of the [[Idiopathic intracranial hypertension|IIH]] cases happen in women in child bearing age<ref name="pmid1998880">{{cite journal |vauthors=Wall M, George D |title=Idiopathic intracranial hypertension. A prospective study of 50 patients |journal=Brain |volume=114 ( Pt 1A) |issue= |pages=155–80 |date=February 1991 |pmid=1998880 |doi= |url=}}</ref>, but it can also happens in children and old adult with male gender. In prepubertal age the gender is not an important [[risk factor]] and in old patients the percent of affected males was higher than females.<ref name="pmid9534686">{{cite journal |vauthors=Soler D, Cox T, Bullock P, Calver DM, Robinson RO |title=Diagnosis and management of benign intracranial hypertension |journal=Arch. Dis. Child. |volume=78 |issue=1 |pages=89–94 |date=January 1998 |pmid=9534686 |pmc=1717437 |doi= |url=}}</ref><ref name="pmid11937898">{{cite journal |vauthors=Bandyopadhyay S, Jacobson DM |title=Clinical features of late-onset pseudotumor cerebri fulfilling the modified dandy criteria |journal=J Neuroophthalmol |volume=22 |issue=1 |pages=9–11 |date=March 2002 |pmid=11937898 |doi= |url=}}</ref>


===== Obesity =====
===== Obesity =====
Some evidences suggest that [[obesity]] can increase intra abdominal and [[intracranial pressure]] and have a role in [[pathogenesis]] of [[Idiopathic intracranial hypertension|IIH]].<ref name="pmid2310315">{{cite journal |vauthors=Ireland B, Corbett JJ, Wallace RB |title=The search for causes of idiopathic intracranial hypertension. A preliminary case-control study |journal=Arch. Neurol. |volume=47 |issue=3 |pages=315–20 |date=March 1990 |pmid=2310315 |doi= |url=}}</ref>
* Some evidences suggest that [[obesity]] can increase intra abdominal and [[intracranial pressure]] and have a role in [[pathogenesis]] of [[Idiopathic intracranial hypertension|IIH]].<ref name="pmid2310315">{{cite journal |vauthors=Ireland B, Corbett JJ, Wallace RB |title=The search for causes of idiopathic intracranial hypertension. A preliminary case-control study |journal=Arch. Neurol. |volume=47 |issue=3 |pages=315–20 |date=March 1990 |pmid=2310315 |doi= |url=}}</ref>


===== Positive family history<ref name="pmid24756302">{{cite journal |vauthors=Wall M, Kupersmith MJ, Kieburtz KD, Corbett JJ, Feldon SE, Friedman DI, Katz DM, Keltner JL, Schron EB, McDermott MP |title=The idiopathic intracranial hypertension treatment trial: clinical profile at baseline |journal=JAMA Neurol |volume=71 |issue=6 |pages=693–701 |date=June 2014 |pmid=24756302 |pmc=4351808 |doi=10.1001/jamaneurol.2014.133 |url=}}</ref> =====
===== Positive family history<ref name="pmid24756302">{{cite journal |vauthors=Wall M, Kupersmith MJ, Kieburtz KD, Corbett JJ, Feldon SE, Friedman DI, Katz DM, Keltner JL, Schron EB, McDermott MP |title=The idiopathic intracranial hypertension treatment trial: clinical profile at baseline |journal=JAMA Neurol |volume=71 |issue=6 |pages=693–701 |date=June 2014 |pmid=24756302 |pmc=4351808 |doi=10.1001/jamaneurol.2014.133 |url=}}</ref> =====
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===Common Symptoms===
===Common Symptoms===
Common symptoms of pseudotumor cerebri include:
* Common symptoms of pseudotumor cerebri include:


==== Headache (84 to 92 percent): ====
==== Headache (84 to 92 percent): ====
[[Headache]] is the most common presenting [[symptom]] of pseudotumore cerebri<ref name="pmid1998880">{{cite journal |vauthors=Wall M, George D |title=Idiopathic intracranial hypertension. A prospective study of 50 patients |journal=Brain |volume=114 ( Pt 1A) |issue= |pages=155–80 |date=February 1991 |pmid=1998880 |doi= |url=}}</ref> and can be very variable in character. The [[headache]] can be lateralized, throbbing or pulsatile, intermittent or persistent and with or without [[nausea and vomiting]]. The [[headache]] can mimic [[migraine]] or [[Tension headache|tension headaches]] and can be exacerbate with change in posture. The [[Headache|headaches]] can follow a nerve root distribution ([[Trigeminal nerve|trigeminal]] or cervical nerve roots).<ref name="pmid2289234">{{cite journal |vauthors=Wall M |title=The headache profile of idiopathic intracranial hypertension |journal=Cephalalgia |volume=10 |issue=6 |pages=331–5 |date=December 1990 |pmid=2289234 |doi=10.1046/j.1468-2982.1990.1006331.x |url=}}</ref>
* [[Headache]] is the most common presenting [[symptom]] of pseudotumore cerebri<ref name="pmid1998880">{{cite journal |vauthors=Wall M, George D |title=Idiopathic intracranial hypertension. A prospective study of 50 patients |journal=Brain |volume=114 ( Pt 1A) |issue= |pages=155–80 |date=February 1991 |pmid=1998880 |doi= |url=}}</ref> and can be very variable in character. The [[headache]] can be lateralized, throbbing or pulsatile, intermittent or persistent and with or without [[nausea and vomiting]]. The [[headache]] can mimic [[migraine]] or [[Tension headache|tension headaches]] and can be exacerbate with change in posture. The [[Headache|headaches]] can follow a nerve root distribution ([[Trigeminal nerve|trigeminal]] or cervical nerve roots).<ref name="pmid2289234">{{cite journal |vauthors=Wall M |title=The headache profile of idiopathic intracranial hypertension |journal=Cephalalgia |volume=10 |issue=6 |pages=331–5 |date=December 1990 |pmid=2289234 |doi=10.1046/j.1468-2982.1990.1006331.x |url=}}</ref>


==== visual symptoms(68 to 72 percent): ====
==== visual symptoms(68 to 72 percent): ====
Transient visual obscuration can be rarely present in one group and frequently in another one. This [[symptom]] is unilateral or bilateral and can be provoked by change in position like standing up or bending over and also with [[valsalva maneuver]], bright light and eye movement.<ref name="pmid1998880">{{cite journal |vauthors=Wall M, George D |title=Idiopathic intracranial hypertension. A prospective study of 50 patients |journal=Brain |volume=114 ( Pt 1A) |issue= |pages=155–80 |date=February 1991 |pmid=1998880 |doi= |url=}}</ref><ref name="pmid1992368">{{cite journal |vauthors=Giuseffi V, Wall M, Siegel PZ, Rojas PB |title=Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): a case-control study |journal=Neurology |volume=41 |issue=2 ( Pt 1) |pages=239–44 |date=February 1991 |pmid=1992368 |doi= |url=}}</ref>
* Transient visual obscuration can be rarely present in one group and frequently in another one. This [[symptom]] is unilateral or bilateral and can be provoked by change in position like standing up or bending over and also with [[valsalva maneuver]], bright light and eye movement.<ref name="pmid1998880">{{cite journal |vauthors=Wall M, George D |title=Idiopathic intracranial hypertension. A prospective study of 50 patients |journal=Brain |volume=114 ( Pt 1A) |issue= |pages=155–80 |date=February 1991 |pmid=1998880 |doi= |url=}}</ref><ref name="pmid1992368">{{cite journal |vauthors=Giuseffi V, Wall M, Siegel PZ, Rojas PB |title=Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): a case-control study |journal=Neurology |volume=41 |issue=2 ( Pt 1) |pages=239–44 |date=February 1991 |pmid=1992368 |doi= |url=}}</ref>


==== Intracranial noises (pulsatile tinnitus) (52 to 60 percent): ====
==== Intracranial noises (pulsatile tinnitus) (52 to 60 percent): ====
Pulse synchronous [[tinnitus]] is very suggestive of [[Idiopathic intracranial hypertension|IIH]] especially when it happens during [[headache]] periods. The reason of this voice is believed to be the vascular pulsation transmitted by high pressure [[CSF]] to the venous sinuses.<ref name="pmid1992368">{{cite journal |vauthors=Giuseffi V, Wall M, Siegel PZ, Rojas PB |title=Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): a case-control study |journal=Neurology |volume=41 |issue=2 ( Pt 1) |pages=239–44 |date=February 1991 |pmid=1992368 |doi= |url=}}</ref><ref name="pmid2293699">{{cite journal |vauthors=Sismanis A, Butts FM, Hughes GB |title=Objective tinnitus in benign intracranial hypertension: an update |journal=Laryngoscope |volume=100 |issue=1 |pages=33–6 |date=January 1990 |pmid=2293699 |doi=10.1288/00005537-199001000-00008 |url=}}</ref>
* Pulse synchronous [[tinnitus]] is very suggestive of [[Idiopathic intracranial hypertension|IIH]] especially when it happens during [[headache]] periods. The reason of this voice is believed to be the vascular pulsation transmitted by high pressure [[CSF]] to the venous sinuses.<ref name="pmid1992368">{{cite journal |vauthors=Giuseffi V, Wall M, Siegel PZ, Rojas PB |title=Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): a case-control study |journal=Neurology |volume=41 |issue=2 ( Pt 1) |pages=239–44 |date=February 1991 |pmid=1992368 |doi= |url=}}</ref><ref name="pmid2293699">{{cite journal |vauthors=Sismanis A, Butts FM, Hughes GB |title=Objective tinnitus in benign intracranial hypertension: an update |journal=Laryngoscope |volume=100 |issue=1 |pages=33–6 |date=January 1990 |pmid=2293699 |doi=10.1288/00005537-199001000-00008 |url=}}</ref>


==== Photopsia (48 to 54 percent): ====
==== Photopsia (48 to 54 percent): ====
[[Photopsia|Photopsias]] which defines as seeing flashes of light or sparkles may also be present in the course of [[Idiopathic intracranial hypertension|IIH]] disease and can be exacerbate with change in position<ref name="pmid1992368">{{cite journal |vauthors=Giuseffi V, Wall M, Siegel PZ, Rojas PB |title=Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): a case-control study |journal=Neurology |volume=41 |issue=2 ( Pt 1) |pages=239–44 |date=February 1991 |pmid=1992368 |doi= |url=}}</ref>
* [[Photopsia|Photopsias]] which defines as seeing flashes of light or sparkles may also be present in the course of [[Idiopathic intracranial hypertension|IIH]] disease and can be exacerbate with change in position<ref name="pmid1992368">{{cite journal |vauthors=Giuseffi V, Wall M, Siegel PZ, Rojas PB |title=Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): a case-control study |journal=Neurology |volume=41 |issue=2 ( Pt 1) |pages=239–44 |date=February 1991 |pmid=1992368 |doi= |url=}}</ref>


==== Back pain (53 percent): ====
==== Back pain (53 percent): ====
These patients commonly report neck and back pain and stiffness.<ref name="pmid1998880">{{cite journal |vauthors=Wall M, George D |title=Idiopathic intracranial hypertension. A prospective study of 50 patients |journal=Brain |volume=114 ( Pt 1A) |issue= |pages=155–80 |date=February 1991 |pmid=1998880 |doi= |url=}}</ref><ref name="pmid1475750">{{cite journal |vauthors=Lessell S |title=Pediatric pseudotumor cerebri (idiopathic intracranial hypertension) |journal=Surv Ophthalmol |volume=37 |issue=3 |pages=155–66 |date=1992 |pmid=1475750 |doi= |url=}}</ref>
* These patients commonly report neck and back pain and stiffness.<ref name="pmid1998880">{{cite journal |vauthors=Wall M, George D |title=Idiopathic intracranial hypertension. A prospective study of 50 patients |journal=Brain |volume=114 ( Pt 1A) |issue= |pages=155–80 |date=February 1991 |pmid=1998880 |doi= |url=}}</ref><ref name="pmid1475750">{{cite journal |vauthors=Lessell S |title=Pediatric pseudotumor cerebri (idiopathic intracranial hypertension) |journal=Surv Ophthalmol |volume=37 |issue=3 |pages=155–66 |date=1992 |pmid=1475750 |doi= |url=}}</ref>


==== Retrobulbar pain (44 percent): ====
==== Retrobulbar pain (44 percent): ====
The most specific [[headache]] feature in [[Idiopathic intracranial hypertension|IIH]] patients is retrobulbar pain with eye movement or glob compression<ref name="pmid2289234">{{cite journal |vauthors=Wall M |title=The headache profile of idiopathic intracranial hypertension |journal=Cephalalgia |volume=10 |issue=6 |pages=331–5 |date=December 1990 |pmid=2289234 |doi=10.1046/j.1468-2982.1990.1006331.x |url=}}</ref>
* The most specific [[headache]] feature in [[Idiopathic intracranial hypertension|IIH]] patients is retrobulbar pain with eye movement or glob compression<ref name="pmid2289234">{{cite journal |vauthors=Wall M |title=The headache profile of idiopathic intracranial hypertension |journal=Cephalalgia |volume=10 |issue=6 |pages=331–5 |date=December 1990 |pmid=2289234 |doi=10.1046/j.1468-2982.1990.1006331.x |url=}}</ref>


==== Diplopia (18 to 38 percent): ====
==== Diplopia (18 to 38 percent): ====
Intermittent or continuous horizontal [[diplopia]] can occur in [[Idiopathic intracranial hypertension|IIH]] patients in the result of [[Sixth nerve palsy|abducens palsy]].<ref name="pmid1774176">{{cite journal |vauthors=Chari C, Rao NS |title=Benign intracranial hypertension--its unusual manifestations |journal=Headache |volume=31 |issue=9 |pages=599–600 |date=October 1991 |pmid=1774176 |doi= |url=}}</ref>
* Intermittent or continuous horizontal [[diplopia]] can occur in [[Idiopathic intracranial hypertension|IIH]] patients in the result of [[Sixth nerve palsy|abducens palsy]].<ref name="pmid1774176">{{cite journal |vauthors=Chari C, Rao NS |title=Benign intracranial hypertension--its unusual manifestations |journal=Headache |volume=31 |issue=9 |pages=599–600 |date=October 1991 |pmid=1774176 |doi= |url=}}</ref>


==== Sustained visual loss (26 to 32 percent)<ref name="pmid1998880">{{cite journal |vauthors=Wall M, George D |title=Idiopathic intracranial hypertension. A prospective study of 50 patients |journal=Brain |volume=114 ( Pt 1A) |issue= |pages=155–80 |date=February 1991 |pmid=1998880 |doi= |url=}}</ref> ====
==== Sustained visual loss (26 to 32 percent)<ref name="pmid1998880">{{cite journal |vauthors=Wall M, George D |title=Idiopathic intracranial hypertension. A prospective study of 50 patients |journal=Brain |volume=114 ( Pt 1A) |issue= |pages=155–80 |date=February 1991 |pmid=1998880 |doi= |url=}}</ref> ====

Latest revision as of 14:39, 29 November 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Overview

History and Symptoms

History

  • The important points in the history of a patient suspected for pseudotumor cerebri are:
Age and gender
  • Most of the IIH cases happen in women in child bearing age[1], but it can also happens in children and old adult with male gender. In prepubertal age the gender is not an important risk factor and in old patients the percent of affected males was higher than females.[2][3]
Obesity
Positive family history[5]
Medications
  • growth hormones: Development of IIH in result of GH therapy mostly happens in one year of medication initiation, but it can also develop after several years of treatment. with stopping the use of GH, symptoms of IIH will improve.[6][7]
Systemic illness
symptoms
  • Headache (84 to 92 percent):
  • visual symptoms(68 to 72 percent):
  • Intracranial noises (pulsatile tinnitus) (52 to 60 percent):
  • Photopsia (48 to 54 percent):
  • Back pain (53 percent):
  • Retrobulbar pain (44 percent):
  • Diplopia (18 to 38 percent):
  • Sustained visual loss (26 to 32 percent)[20]

Symptoms

Common Symptoms

  • Common symptoms of pseudotumor cerebri include:

Headache (84 to 92 percent):

visual symptoms(68 to 72 percent):

  • Transient visual obscuration can be rarely present in one group and frequently in another one. This symptom is unilateral or bilateral and can be provoked by change in position like standing up or bending over and also with valsalva maneuver, bright light and eye movement.[1][20]

Intracranial noises (pulsatile tinnitus) (52 to 60 percent):

  • Pulse synchronous tinnitus is very suggestive of IIH especially when it happens during headache periods. The reason of this voice is believed to be the vascular pulsation transmitted by high pressure CSF to the venous sinuses.[20][22]

Photopsia (48 to 54 percent):

  • Photopsias which defines as seeing flashes of light or sparkles may also be present in the course of IIH disease and can be exacerbate with change in position[20]

Back pain (53 percent):

  • These patients commonly report neck and back pain and stiffness.[1][9]

Retrobulbar pain (44 percent):

  • The most specific headache feature in IIH patients is retrobulbar pain with eye movement or glob compression[21]

Diplopia (18 to 38 percent):

Sustained visual loss (26 to 32 percent)[1]

References

  1. 1.0 1.1 1.2 1.3 1.4 Wall M, George D (February 1991). "Idiopathic intracranial hypertension. A prospective study of 50 patients". Brain. 114 ( Pt 1A): 155–80. PMID 1998880.
  2. Soler D, Cox T, Bullock P, Calver DM, Robinson RO (January 1998). "Diagnosis and management of benign intracranial hypertension". Arch. Dis. Child. 78 (1): 89–94. PMC 1717437. PMID 9534686.
  3. 3.0 3.1 Bandyopadhyay S, Jacobson DM (March 2002). "Clinical features of late-onset pseudotumor cerebri fulfilling the modified dandy criteria". J Neuroophthalmol. 22 (1): 9–11. PMID 11937898.
  4. Ireland B, Corbett JJ, Wallace RB (March 1990). "The search for causes of idiopathic intracranial hypertension. A preliminary case-control study". Arch. Neurol. 47 (3): 315–20. PMID 2310315.
  5. Wall M, Kupersmith MJ, Kieburtz KD, Corbett JJ, Feldon SE, Friedman DI, Katz DM, Keltner JL, Schron EB, McDermott MP (June 2014). "The idiopathic intracranial hypertension treatment trial: clinical profile at baseline". JAMA Neurol. 71 (6): 693–701. doi:10.1001/jamaneurol.2014.133. PMC 4351808. PMID 24756302.
  6. Rogers AH, Rogers GL, Bremer DL, McGregor ML (June 1999). "Pseudotumor cerebri in children receiving recombinant human growth hormone". Ophthalmology. 106 (6): 1186–9, discussion 1189–90. doi:10.1016/S0161-6420(99)90266-X. PMID 10366091.
  7. Vischi A, Guerriero S, Giancipoli G, Lorusso V, Sborgia G (2006). "Delayed onset of pseudotumor cerebri syndrome 7 years after starting human recombinant growth hormone treatment". Eur J Ophthalmol. 16 (1): 178–80. PMID 16496267.
  8. 8.0 8.1 8.2 Friedman DI (2005). "Medication-induced intracranial hypertension in dermatology". Am J Clin Dermatol. 6 (1): 29–37. PMID 15675888.
  9. 9.0 9.1 Lessell S (1992). "Pediatric pseudotumor cerebri (idiopathic intracranial hypertension)". Surv Ophthalmol. 37 (3): 155–66. PMID 1475750.
  10. Ames D, Wirshing WC, Cokely HT, Lo LL (August 1994). "The natural course of pseudotumor cerebri in lithium-treated patients". J Clin Psychopharmacol. 14 (4): 286–7. PMID 7962691.
  11. Scott IU, Siatkowski RM, Eneyni M, Brodsky MC, Lam BL (August 1997). "Idiopathic intracranial hypertension in children and adolescents". Am. J. Ophthalmol. 124 (2): 253–5. PMID 9262557.
  12. Mushet GR (April 1977). "Pseudotumor and nitrofurantoin therapy". Arch. Neurol. 34 (4): 257. PMID 843266.
  13. Alexandrakis G, Filatov V, Walsh T (November 1993). "Pseudotumor cerebri in a 12-year-old boy with Addison's disease". Am. J. Ophthalmol. 116 (5): 650–1. PMID 8238233.
  14. Sheldon RS, Becker WJ, Hanley DA, Culver RL (November 1987). "Hypoparathyroidism and pseudotumor cerebri: an infrequent clinical association". Can J Neurol Sci. 14 (4): 622–5. PMID 3690435.
  15. 15.0 15.1 Bruce BB, Kedar S, Van Stavern GP, Corbett JJ, Newman NJ, Biousse V (June 2010). "Atypical idiopathic intracranial hypertension: normal BMI and older patients". Neurology. 74 (22): 1827–32. doi:10.1212/WNL.0b013e3181e0f838. PMC 2882219. PMID 20513819.
  16. Dave S, Longmuir R, Shah VA, Wall M, Lee AG (2008). "Intracranial hypertension in systemic lupus erythematosus". Semin Ophthalmol. 23 (2): 127–33. doi:10.1080/08820530801888188. PMID 18320479.
  17. Celebisoy N, Seçil Y, Akyürekli O (December 2002). "Pseudotumor cerebri: etiological factors, presenting features and prognosis in the western part of Turkey". Acta Neurol. Scand. 106 (6): 367–70. PMID 12460143.
  18. 18.0 18.1 Glueck CJ, Iyengar S, Goldenberg N, Smith LS, Wang P (July 2003). "Idiopathic intracranial hypertension: associations with coagulation disorders and polycystic-ovary syndrome". J. Lab. Clin. Med. 142 (1): 35–45. doi:10.1016/S0022-2143(03)00069-6. PMID 12878984.
  19. Chang D, Nagamoto G, Smith WE (1992). "Benign intracranial hypertension and chronic renal failure". Cleve Clin J Med. 59 (4): 419–22. PMID 1525975.
  20. 20.0 20.1 20.2 20.3 Giuseffi V, Wall M, Siegel PZ, Rojas PB (February 1991). "Symptoms and disease associations in idiopathic intracranial hypertension (pseudotumor cerebri): a case-control study". Neurology. 41 (2 ( Pt 1)): 239–44. PMID 1992368.
  21. 21.0 21.1 Wall M (December 1990). "The headache profile of idiopathic intracranial hypertension". Cephalalgia. 10 (6): 331–5. doi:10.1046/j.1468-2982.1990.1006331.x. PMID 2289234.
  22. Sismanis A, Butts FM, Hughes GB (January 1990). "Objective tinnitus in benign intracranial hypertension: an update". Laryngoscope. 100 (1): 33–6. doi:10.1288/00005537-199001000-00008. PMID 2293699.
  23. Chari C, Rao NS (October 1991). "Benign intracranial hypertension--its unusual manifestations". Headache. 31 (9): 599–600. PMID 1774176.

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