Surgical Idiopathic Intracranial Hypertension Treatment Trial

After signing the informed consent form, potential subjects will be assessed for eligibility,
including eliciting medical and neurologic history, measurement of best-corrected visual
acuity, visual field testing, ophthalmoscopy with optic disc edema grading, physical
examination, and Optical Coherence Tomography (OCT). Questionnaires will be completed. Blood
will be drawn for complete blood count (CBC), electrolytes, liver function tests, renal
function tests, amylase if not done as part of routine care within 4 weeks and a pregnancy
test will be performed (women of childbearing potential).

The Screening Visual Field will use a size III stimulus. Two visual field examinations using
a size V stimulus will need to be performed at either the Screening or Baseline Visits. The
size V fields will be sent to the Visual Field Reading Center (VFRC) to confirm eligibility
or determine that testing must be repeated for the subject.

Eligible individuals will be randomly assigned with equal allocation to one of 3 treatment
groups: (1) medical therapy, (2) medical therapy plus ONSF, or (3) medical therapy plus VPS.
Acetazolamide should be started on the day of randomization. Surgery should be performed as
soon as possible, ideally within 3 days of randomization, but not more than 7 days.

Medical therapy will consist of a low sodium weight loss diet and acetazolamide with or
without furosemide. Treatment will start with acetazolamide 2 grams per day, with the dose
increased as tolerated up to 4 grams per day. If there is no clinical improvement after 2
weeks of maximal dosage of acetazolamide, furosemide will be started at a dose of 40 mg per
day (along with potassium) and titrated up to 160-200 mg per day. Pharmacotherapy will be
tapered when there is improvement in the papilledema grade, substantial improvement in the
PMD and improvement in symptoms or when there is a safety concern.

The primary outcome is measured at the first of 6 months (26 weeks) or time of treatment
failure. During the randomized trial, follow-up visits will occur after weeks 4, 8, 16, and
26 (± 7 days). Safety visits will occur after weeks 1 and 2 (± 4 days). Additional office
visits may occur as needed. Phone contacts will occur after 12 and 20 weeks (±7 days).

After the 6-month primary outcome visit, subjects will transition to the Treatment Failure
Identification Phase for up to 3 years. Ongoing treatment will continue following the
guidelines for the first six months as long as treatment failure criteria are not met at
which time treatment will be at the discretion of the Site Investigator. Investigators are
urged to employ treatments from another arm of the study before other treatments under these
circumstances.

Inclusion Criteria:

- Subject Eligibility Criteria Inclusion Criteria

1. Diagnosis of IIH by modified Dandy criteria (Table 4)

2. Age 18 to <64 years at time of consent

3. Age 18 to <61 years at time of diagnosis (time of diagnosis is the time at which
the patient meets the modified Dandy criteria, usually after the lumbar puncture
results are reviewed)

4. Presence of bilateral papilledema

5. Lumbar puncture within 6 weeks of screening visit or completed as part of
screening: Opening CSF pressure >250 mmH2O or 200 to 250 mmH2O; and at least one
of the following:

- Pulse synchronous tinnitus

- Cranial nerve VI palsy

- Echography for disc drusen negative and no other disc anomalies mimicking
disc edema present

- Magnetic Resonance Venography (MRV) with lateral sinus collapse/stenosis,
partially empty sella turcica on coronal or sagittal views of MRI, and optic
nerve sheaths with filled out CSF spaces next to the globe on T2 weighted
axial MRI scans If the patient was treated with intracranial pressure
lowering agents (e.g., acetazolamide) prior to obtaining a lumbar puncture,
the agent(s) must be discontinued for at least 24 hours prior to performing
the diagnostic lumbar puncture.

6. At least one eye meeting all eligible eye inclusion criteria and no exclusion
criteria.

7. Able to provide informed consent

8. Investigator believes participant is a good candidate for the study, including
the probability of returning for follow-up.

- Eye-Level Eligibility Criteria Subjects must have at least one eye meeting all of the
inclusion criteria and none of the exclusion criteria.

If both eyes meet eligibility criteria at the baseline examination, both will be included
in the primary outcome analysis.

Inclusion

1. Visual field loss meeting the following criteria based on two full threshold 24-2 size
V tests reviewed by the VFRC:

- PMD from -6 decibel (dB) to -27 dB

- Reproducible visual loss present on automated perimetry including no more than
15% false positive response

2. Visual acuity better than 20/200 (39 or more letters correct)

Exclusion Criteria:

- Subject Exclusion Criteria Exclusion Criteria

1. Treatment of IIH within the past 3 months with either (1) the maximally tolerated
dosage of acetazolamide for at least one week or (2) more than one month of
acetazolamide with a cumulative dosage of more than 30 grams 'Maximally-tolerated
dose' is defined as dosage was reached where dosage could not be increased
further either because of side effects or because a daily total dosage of 4 grams
per day was reached.

If individual discontinued acetazolamide in the past due to side effects,
individual is only eligible if investigator believes that the individual is
likely to tolerate acetazolamide, as it will be prescribed in the study.

2. Treatment of IIH within the past 3 months with either (1) the maximally tolerated
dosage of methazolamide for at least one week or (2) more than one month of
methazolamide with a cumulative dosage of more than 3 grams 'Maximally-tolerated
dose' is defined as dosage was reached where dosage could not be increased
further either because of side effects or because a daily total dosage of 400 mg
per day was reached.

3. Treatment with topiramate within two months and average cumulative dosage for the
preceding month of more than 700 mg per week

4. Previous surgery for IIH, including ONSF, CSF shunting, subtemporal
decompression, or venous sinus stenting; gastric surgery for obesity is allowed

5. Abnormalities on neurologic examination except for papilledema and its related
visual loss or cranial nerve VI to VII paresis; if other abnormalities are
present, the patient will need to be discussed with the Study Director (SD) for
study entry.

6. Abnormal CT or MRI scan (intracranial mass, hydrocephalus, dural sinus thrombus,
or arteriovenous malformation) other than findings known to occur with increased
intracranial pressure. Abnormalities on MRI that are not known to cause increased
intracranial pressure are acceptable.

7. Abnormal CSF contents: increased cells: > 8 cells; elevated protein: > 45 mg%;
low glucose: < 30 mg% (If the lumbar puncture produces a cell count compatible
with a traumatic needle insertion, the patient does not need to be excluded if
the CSF white blood cell count (WBC) after correction is 8 cells/mm3 or less -
see Manual of Procedures (MOP) for calculation. If > 8 cells or > 45mg% in CSF
protein are documented in the CSF or calculated after conversion from a traumatic
lumbar puncture, the patient can be discussed with the Study Director for
possible inclusion.)

8. Abnormal blood work-up indicating a medical or systemic condition associated with
raised intracranial pressure

9. Diabetes mellitus with diabetic retinopathy

10. Ingestion of a drug or substance, or presence of a disorder, that has been
associated with increased intracranial pressure within 2 months of diagnosis,
such as lithium, vitamin A related products (e.g., Retin-A), or various cyclines
(see MOP for conditions and drugs)

11. Laboratory test results showing severe anemia, leukopenia or thrombocytopenia,
renal failure, or hepatic disease, based on the Site Investigator's judgment

12. Other condition requiring oral, I.V. or injectable steroids (nasal, inhaled, or
topical steroids are allowed since the systemic effects are small)

13. Presence of a medical condition that would contraindicate use of acetazolamide or
furosemide or significantly increase surgical risk

14. Pregnancy or unwillingness for a subject of childbearing potential to use
contraception during the first 6 months of the study Women of childbearing
potential must use an acceptable form of birth control during the first 6 months
of the study. Acceptable forms include oral contraceptives, transdermal
contraceptives, diaphragm, intrauterine devices (IUDs), condoms with spermicide,
documented surgical sterilization of either the subject or their partner, or
abstinence.

15. Presence of a physical, mental, or social condition likely to affect follow-up
(drug addiction, terminal illness, no telephone, homeless)

16. Anticipation of a move from the site area within six months and unwillingness to
return for follow-up at a SIGHT study site

17. Allergy to pupil dilating drops or narrow angles precluding safe dilation

18. Presence of a condition that contraindicates general anesthesia

19. Participation in an investigational trial within 30 days of enrollment that
involved treatment with any systemic drug therapy or therapy that affects the
eligible eye(s)

- Eye Level Exclusion Criteria Exclusion

1. Intraocular pressure currently >28 mm Hg or >30 mm Hg at any time in the past

2. Refractive error of more than -6.00 or more than +6.00 sphere or more than 3.00
cylinder with the following exceptions:

- Eyes with more than 6.00 D of myopia but less than 8.00 D of myopia are
eligible if: 1) there are no abnormalities on ophthalmoscopy related to
myopia that are associated with visual loss (such as staphyloma, retinal
thinning in the posterior pole, or more than mild optic disc tilt), and 2)
the individual will wear a contact lens for all perimetry examinations with
the appropriate correction.

- Eyes with more than 6.00 D of hyperopia but less than 8.00 D of hyperopia
are eligible if: 1) there is an unambiguous characteristic halo of
peripapillary edema as opposed to features of a small crowded disc or other
hyperopic change related to visual loss determined by the Site Investigator
or the Photographic Reading Center (PRC) Director (or his designate), and 2)
the individual will wear a contact lens for all perimetry examinations with
the appropriate correction (which can be corrected for perimetry or with the
patient's own contact lens with over correction by lens at the perimeter).

Note: Refractive error exclusion and exceptions refer to sphere not spherical
equivalent, with cylinder expressed in plus format.

3. Other disorders causing visual loss except for refractive error and amblyopia,
including cells in the vitreous or iritis

4. Large optic disc drusen on exam or known in previous history (small drusen of the
disc can occur with longstanding papilledema and are allowed if not so numerous
that investigator determines they are contributing to vision loss)