Sixth Annual Intensive Update in Neurology 09/15-16/2016

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The IIHTT: a Multicenter, Double-Blind, Randomized Clinical Trial Comparing

Acetazolamide and Placebo on Visual OutcomeOn Behalf of the NORDIC

IIH Study Group

Steven R. Hamilton

Swedish Medical Center

Supported by NIH U10 EY017281 No Disclosures

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Case Presentation

37-year-0ld obese woman with 2 weeks of constant bi-occipital headaches

2 days of greying out centrally and fullness of ears (like hearing seagulls)

220 pounds currently with 50 pound gain over last 6 years

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Neuro-ophthalmic Exam

Acuity 20/30 20/40

Color 10/10 10/10

Pupils Normal Normal

Motility Normal Normal

Fundus Grade 3 Grade 3

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Humphrey 24-2 Fields

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OCT scan

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Diagnostic Testing and Therapy

MRI and MRV of head were normal

CSF normal profile with OP = 57 CM

Started and maintained on 500 mg Diamox Sequel bid with regular follow up visits

Resolution of headaches, TVO, pulsatile tinnitus

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6 month FUV HVF

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6 Month FUV OCT

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Idiopathic Intracranial Hypertension Pseudotumor cerebri

VIII.

Ueber Meningitis serosa und

verwandte Zustände.

H. Quinckein Keil.

Zustande. Ztschr Nervenh 1897:9:149-168

About serous meningitis and

related conditions

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Entry CriteriaModified Dandy Criteria of IIH

symptoms and signs of increased ICP

otherwise normal neurologic exam

normal level of alertness

neurodiagnostics normal except elevated ICP

no other cause of increased ICP present

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Undiagnosed Papilledema in a Morbidly Obese Population: A Prospective Study

Krispel et al. JNO 2011

4 of 647 had subtle optic disc edema (3 had LP with mild elevation)All 4 had normal VFAverage BMI = 47

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IIH - Age at Diagnosis

Wall and George, Brain 1991

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IIH SymptomsA case control study

0

20

40

60

80

100

Headache TVO Tinnitu s Photopsia Eye Pain

Cases Controls

Giuseffi et al., Neurology 1991

Best symptom to differentiate

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Neuroimaging in IIH

Empty Sella Papilledema,

Flattened Globes

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Unfolded Optic Nerve Sheaths

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Lateral sinus stenosis

Sensitivity and specificity of 93% using ATECO MRVin prospective study of IIH.

Farb et al., Neurology 2003

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Mechanisms of Visual Loss in IIH

Axoplasmic flow stasis leading to axonal ischemia at the optic disc

spread of edema into macula (seen best with OCT)

transient hypotension – watershed infarct

choroidal folds (refractive)

elevated peripapillary retina (refractive)

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JAMA. 2014;311(16):1641-1651. doi:10.1001/jama.2014.3312

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Main entry criteria

Age 18 - 60 years

Meets modified Dandy criteria of IIH

Newly diagnosed (6 weeks or less)

Presence of papilledema

PMD -2 dB to -7 dB in the worst eye

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GWAS

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IIHTT

Secondary aim: GWAS to screenfor disease-causing mutations and IIH risk alleles – 154 subjects turned out to be an insufficient sample size to answer the question

Blood and CSF stored for futurestudies.

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LSU

USC

U IowaU Penn

FSU

Duke

Oregon HSU

U Minn

Swedish Neuroscience

U Oklahoma

UT San Antonio

Washington USt. Louis U

SUNY

U Miami

tOSU

NYEE Yale

Hotel Dieu Hosp

U Utah

U Alabama

Mass EEI

U I Peoria

Emory U

Beaumont Eye

Raleigh Neuro Asso

N J Med

WilmerUVA

Wake Forest

U Houston

Baltimore MC

Bethesda Neurology

Mount Sinai

Stony Brook U

Idiopathic Intracranial Hypertension Treatment Trial Sites

U Rochester

Houston Methodist

Cornell

Kentucky

Calgary

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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

-2 to -7 dB comprises about 1/3 of IIH patients

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IIHTT CONSORT Diagram

Acetazolamide Placebo

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Treatment Failures (n=7)

p = 0.06

All had high grade papilledema at baseline

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Symptoms at Baseline

84.2%

67.9%

52.7% 52.1% 51.5%47.9%

41.8%

32.1% 29.7%

19.8% 18.8% 17.6%

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0

10

20

30

40

50

60

70

80

0 - 0.75 1 - 1.75 2 - 2.75 3 - 3.75 4% P

art

icip

an

ts a

t ea

ch d

osa

ge

Dosage of Study Drug (g)

Placebo

Acetazolamide

Dosages of study medication at conclusion of study participation

3.5 g/d

2.5 g/d

Average AdherenceAcetazolamide: 89%Placebo:93%.

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Primary OutcomeVariable was PerimetricMean Deviation (PMD)

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Perimetric Mean Deviation (PMD) =Average loss per test location weighted for the central points

What is the perimetricmean deviation?

Average loss = -5.13 dB

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The prototype defect…

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Grades of visual loss in IIH

Grade I Grade II Grade III

Grade VGrade IV

Stages of progression

in IIH

Wall and George, Brain 1991

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Primary OutcomeChange in PMD in Worst Eye

Placebo + diet

Acetazolamide + diet

Multiple ImputationRx effect = 0.71 dB

p = 0.05

Last observation carried forward:

p = 0.007Effect 1.19 dB

Mediation analysis:ACZ effect independent

of weight loss

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PMD Effect SizeFrisén grade 3-5 baseline

Placebo Acetazolamide

Overall0.71 dB

Effect size = 2.27 dBp < 0.001

Mean PMD at baseline was 3.5 dB

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0 1 2 3 4 5 6

-2.0

-1.5

-1.0

-0.5

0.0

Month

M

ean

Cha

nge

in F

rise

n G

rade

(W

orst

Eye

)

0 1 2 3 4 5 6

-2.0

-1.5

-1.0

-0.5

0.0

Month

M

ean

Cha

nge

in F

rise

n G

rade

(W

orst

Eye

)

Change in Papilledema GradeWorst Eye

0 5

p < 0.001

2 431

Grades of Papilledema

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Weight Loss – Target 6%

Effect size -8.93 lbs.

p < 0.001

Mediation analysis showed ACZ effect was independent of weight loss

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Improvement in CSF Pressure from Baseline

Effect size -59.9 mm H2OCI: -96.4 to -23.4 mmH2O

p = 0.002

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Vitamin A Results

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Laboratory Values

Sodium, CBC with diff, LFTs, RFTs – unchanged

Chloride increased and CO2 decreased with ACZ

Potassium:

Effect size = -0.23 meq/lp < 0.001

No K+ supplementation

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Study Limitations

Entry criteria of -2 to -7 dB limits generalization

Modest effect on mean deviation of 0.71 dB

19% withdrawal rate

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Longitudinal IIHTT (LiihTT)

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Surgical IIHTT (SiihTT)

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What have we learned?

Acetazolamide led to significantly improved:

Visual field functionPapilledema grade Quality of life measuresCSF pressure

The PMD effect was greatest with

high grade edema and was mostly in month 1

Acetazolamide led to a reduction in TFs (6 vs. 1)

Acetazolamide was well tolerated at high dosages

and was associated with improved QoL

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What have we learned?

Acetazolamide promotes weight loss and it effect on vision is independent of weight loss

Acetazolamide used alone does not require K+

Perimetry performance failures were not uncommon and need to be recognized

Study of pointwise change across the visual field shows generalized changes, most peripherally

ETDRS acuity was abnormal more than expected

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Future Issues to be Resolved

Long term management of PTC patients

The LIIHTT study

Optimal dosing of diamox

Need for a noninvasive means of assessing ICP

Optimal treatment for patients with PMD greater than -7 dB (medical, ONSF or shunting)

Possible role of bariatric surgery for these patients who cannot lose weight or get off Diamox

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