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Pathophysiology of Idiopathic Intracranial Hypertension and the IIHTT

Pathophysiology of Idiopathic Intracranial Hypertension and the IIHTT Michael Wall, University of Iowa. Supported by NIH U10 EY017281. No Disclosures. Idiopathic Intracranial Hypertension Pseudotumor cerebri. Serous Meningitis (Quincke, 1897) Pseudotumor Cerebri (Nönne, 1904)

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Pathophysiology of Idiopathic Intracranial Hypertension and the IIHTT

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  1. Pathophysiology of Idiopathic Intracranial Hypertension and the IIHTT Michael Wall, University of Iowa Supported by NIH U10 EY017281 No Disclosures

  2. Idiopathic Intracranial Hypertension Pseudotumor cerebri • Serous Meningitis (Quincke, 1897) • Pseudotumor Cerebri (Nönne, 1904) • Otitic Hydrocephalus (Symonds, 1931) • Hypertensive Meningeal Hydrops (Davidoff, 1937) • Toxic Hydrocephalus (McAlpine, 1937) • Benign Intracranial Hypertension (Foley, 1955) • Idiopathic Intracranial Hypertension (Buchheit, 1969)

  3. The Elusive Cause of IIH • Genetics • Vitamin A hypothesis • IIHTT Metabolomics • Sex hormone studies • Obesity hormone studies • Absorbtion block or hyperproduction of CSF? • Spinal compliance, glymphatic circulation and aquaporin

  4. IIHTT Demographics; n = 165 • 161 women / 4 men (2.65%) were enrolled • Age 29.2 ± 7.5 with range of 18 – 53 years • 88% were obese; mean BMI was 39.9 • 5% identified family members with IIH Any hypotheses of IIH cause needs to explain these demographics.

  5. IIHTT GWAS • “Genetic Survey of Adult Onset Idiopathic Intracranial Hypertension” Kuehn et al. JNO (in press) • Analysis of chromosomal DNA from 95 IIH patients and 95 controls • Controls matched for sex, BMI, self-reported ethnicity, and distance to procurement site

  6. 3-D Outcome of Multi-Dimensional Scaling – Race A NA B W 0=Caucasian, 1=African-American, 2=Native American/Alaskan, 3=Asian, 4=Unknown, 5=Other / results similar to self report

  7. IIH GWAS – Manhattan plot p-values p = 5 x 10-8 p = 0.05 Loci possibly associated with IIH are designated by vertically stacked dots: see chr 5, 13, and 14.

  8. Genetics from the IIHTT • The locus on Chr 5 is near known genes for LINC00359 and FOXN3, respectively • Chr 13: LINC00359 is a species of long non-coding RNA involved in translational regulation of gene expression and may affect the activity of multiple genes. • Chr 14: FOXN3 has variants associated with altered fasting blood glucose and the regulation of glucose utilization by hepatocytes. Kuehn et al. JNO (in press)

  9. The genetics of IIH • 5% of cases in the IIHTT had family members with IIH (and there are many case reports) • 3 Chr regions (Chr 5, 13, 14) containing multiple SNPs, at significant p-values, were identified. • The GWAS from the IIHTT was limited by its modest size but suggested several variants and loci suggestive of an association with IIH and might be candidates for follow up.

  10. Vitamin A – Antarctic Expeditions Mawson

  11. death hepatotoxicity hemorrhage Vitamin A fractures Excess ↑ intracranial pressure osteoporosis alopecia desquamation erythema normal eczema night blindness Bitot’s spots dry eye Deficiency keratinization ianition death 10 100 1000 10,000 100,000 Vitamin A intake, μg/kg/day

  12. Vitamin A and IIHIIHTT Results No association with IIH Libien et al. J Neurol Sci 2017;372 78–84

  13. IIHTT Metabolomics With collaborators at Penn, the IIH Study Group are running blood samples for: • Metabolomics • Obesity hormones • Sex hormones • microRNA

  14. Sex Hormone Studies – Female • Most obvious culprit • But, no change in course of IIH with pregnancy or oral contraceptives • Reid and Thomson (1981) • 10 IIH patients at different disease stages and under different therapies • 10 age-matched obese “controls” that had been investigated for amenorrhea or Cushing’s syndrome • Basal and peak cortisol, GH, TSH, FSH, LH, and prolactin levels were normal except for high FSH levels in two patients.

  15. Sex Hormone Studies – female • Sørensen (1986) • 15 IIH patients (12 women and 3 men) • subnormal response of GH to insulin-induced hypoglycemia in four patients. • Other occasional abnormalities were: • low FSH in three women • high FSH in one man • high plasma estrone in two women and one man • Testosterone levels were normal in all men • plasma estrogen was normal in all. • CSF estrogen was normal.

  16. Sex Hormone Studies – female • Toscano (1991) • 5 patients with IIH and 12 controls (half women) • increased CSF estrone and decreased CSF androsteinedione were found in some IIH patients • Normal values found in plasma. In summary, these studies, with no consistent abnormalities, do not lead to any definitive conclusions about the role of female hormone levels in IIH pathogenesis.

  17. Sex Hormone Studies – male • Co-occurrence of PCOS and IIH (hyperandrogenemia) – no good case control study • The few FtM trangender case reports are not convincing since androgens also caused weight gain • Oral contraceptives substantially lower testosterone levels but do not appear to affect the course of IIH

  18. Obesity hormone studies • Leptin and Ghrelin levels in serum and CSF have not been conclusively shown to be different in IIH • The IIH study group is looking at a series of these obesity hormones – more to follow.

  19. IIH Pathophysiology:Absorbtion block or hypersecretion? Bercaw and Greer, Transport of intrathecal 131-I RISA in BIH. Neurology 1970;20:787-790.

  20. IIH Pathophysiology:Absorbtion block or hypersecretion? • CSF Infusion Studies • Formation rates decrease as ICP increases and eventually ceases around about 300 mm water Cutler et al. Brain 1968; 97:707-720

  21. IIH Pathophysiology:Absorbtion block or hypersecretion? CSF infusion studies in IIH • Martins AN, JNNP (1973) 36:313-318 • Johnston I. Lancet (1973) 2:418-420 • Sklar FH, Neurosurgery (1979) 5:208-216 • Janny P, Surg Neurol (1979) 5:208-216 • Søelberg P, ActaNeurolScand (1988) 77:164-172 • Guess HA, Comp Bio Res (1985) 18:184-192 • *Malm J, Neurology (1992) 42:851-858 Evidence overwhelmingly supports decrease in absorption in IIH not increased CSF formation

  22. Other mechanisms • Decreased spinal compliance • Glymphatic circulation • Aquaporin - choroid plexus aquaporin 1 and CSFPis increased in obese ratsbut not IIH NasalSeptum Lymphatic passage of CSF microfil to the ethmoid turbinates Johnston, Neuropathol. Appl. Neurobiol 29: 563, 2003.

  23. Causes of Weight Gain and IIH Many factors may appear to cause IIH but may just cause weight gain

  24. Conclusions • IIH remains idiopathic • Any hypothetical cause should explain • The strong preponderance for females • The strong association with obesity and weight gain • The change in phenotype with puberty

  25. Surgical IIHTT SIGHT

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