IdiopathicIntracranialHypertension

Dr.Mar'nSu+onBrownMD.FRCPC

Neuro-Ophthalmology,NeurologyDivofNeurology,IslandHealth

ClinicalAssistantProfessor,DivofNeurology,UBC

StrokeRapidAssessmentUnit-Nanaimo

PacificCoastEyeCentre

Outline

ModifiedDandyCriteria1

1.  Symptomsandsignsonlyreflectthoseofgeneralizedintracranialhypertensionorpapilledema.

2.  ElevatedICPmustbedocumented,measuredinthelateraldecubitusposiNon.

3.  NormalCSFcomposiNon.4.  Noevidenceofhydrocephalus,mass,structuralor

vascularlesiononstructuralneuroimagingfortypicalpaNents,andmagneNcresonanceimaging(MRI)andmagneNcresonancevenographyforallothers.

5.  NoothercauseofintracranialhypertensionidenNfied.

1.  Neurology2002;59:1492-5

ModifiedDandyCriteria1

1.  Symptomsandsigns…–  Headachemostcommon.EnlargedBlindSpotordiscbasefieldloss,TVO,

Diplopia(VIpalsy)Otherrarefindings(VIIpalsy)2.  ElevatedICP…

1.  ≤20Normal,<25Boarderline,≥25Elevated2.  Considerrepeatifhighindex

3.  NormalCSFcomposiNon–  Cells,Protein,Glucose.Othersdependingoncontext

4.  Noevidenceof…lesiononstructuralneuroimaging1.  Lookatthejugular.2.  ConsiderspinalimaginginMenoratypicalcases

5.  NoothercauseofintracranialhypertensionidenNfied1.  Butwhentostop?Idon’tusetheCriteriasuggestedinNeurology2013;81:1159-65forPseudotumorcerebri

Neurology2002;59:1492-5

Demographics

•  ClinicalProfile1– Young(mean29)– Women(97%Female)– Obese(meanBMI40)

•  Incidenceincreasing2,3inMinnesota

– 1/100k(1976-1990)– 1.8/100kin1990to2014.(actually2.4insecondhalfofstudy!)

1.  JAMANeruol2014;71:693-7012.  ArchNeurol1993;50:78-80.3.  Ophthal2017;124:697-700.

LPbyU/Sguidance

SecondaryDifferenNal

•  SinusThrombosis•  Druginduced,VitA,Steroids,Estrogen,Testosterone•  SpinalLesionsorTumor1

•  Jugularveintumororthrombosis•  LeptomeningealCancer3

•  PrimaryorSecondaryHyperaldosteronism•  Syphilis4•  IronDeficiency5•  SuperficialSiderosis

1.  JournalofNeuro-Ophthalmology2013;33:13–162.  Neuroophthalmology.2015Jul15;39:179-1823.  JournalofNeuro-Ophthalmology2011;31:339-41.

4.BMJCaseRep.2011;2011.5.ArchDisChild.2013;98:418.

AtypicalIIH•  NormalBMI1–  4%(18/407)NormalBMI– MedicaNoninduced(28vs7%):VitA,ProgesNns,Steroids

– Men(22vs7%)•  Age≥50–  5%(19/407)–  LowerBMI(33vs38)–  LessiniNalHeadache(36vs76%)

– Morevision(42vs21%)

1.  Neurology2010;74:1827-32.

and symptoms of increased intracranial pressure, 2) no localizingsigns except abducens nerve palsy, 3) CSF opening pressure !25cm with normal CSF composition, and 4) normal neuroimaging(ruling out venous sinus thrombosis).1

Although the patient database was created using a retrospec-tive chart review, all patients had been evaluated in a standard-ized fashion by experienced neuro-ophthalmologists, includingdocumentation of body habitus, blood pressure, and completeneuro-ophthalmic examination with formal visual fields, fundusphotography, review of neuroimaging tests, and recording of fac-tors associated with IIH. Demographic information regardingage, gender, and race were collected. Patients younger than 18years of age at diagnosis were excluded. Race was assessed by thejudgment of the examiner based on patient appearance. Medica-tion use (current and recent), the presence or absence of severalassociated factors (recent weight gain, known sleep apnea, ane-mia [hemoglobin !12 g/dL], systemic hypertension, endocrinedisorders, and pregnancy), symptoms (headache, tinnitus, diplo-pia, and transient visual obscuration), Snellen visual acuity, for-mal visual fields (static perimetry using a Humphrey automatedperimeter and kinetic perimetry using a Goldmann perimeter),and dilated ophthalmoscopic appearance were recorded. Medi-cations considered possibly contributing included vitamin Apreparations, minocycline, cyclosporine, doxycycline, tetracy-cline, depot progestins, and recent discontinuation of steroids.The contributing medications were grouped by their presence orabsence in each patient for analysis. Patients without knownheight or weight were excluded from analysis. BMI was calcu-lated for use in statistical analyses according to the World HealthOrganization BMI guidelines.2 Prediagnosis duration of symp-toms, CSF opening pressure, height, weight, medical treatments,surgical treatments, follow-up duration, and visual outcomewere also recorded.

Snellen visual acuity was converted to logMAR visual acuityfor analysis. Formal visual fields were systematically reviewed forall patients. All visual field defects, whether obtained with staticor kinetic perimetry, were graded on a 1 to 4 scale as 1) normal;2) enlargement of the blind spot; 3) nasal or temporal defect; or4) diffusely constricted, as previously published.3,4 In addition,mean deviations were recorded for those patients who under-went static automated perimetry. Papilledema was graded with

the Frisen staging scheme5 by systematic review of fundus pho-tography: stage 0 defines a normal optic nerve head and stage 5,severe papilledema. Severe visual loss in an eye was defined bythe United States criteria for legal blindness (best-corrected vi-sual acuity less than or equal to 20/200 or total central visualfield less than 20 degrees) and assessed at the last available visit.

All patients had definite IIH by the modified Dandy criteria,but 2 aspects of our population merit further mention. First,although all patients underwent a lumbar puncture that docu-mented elevation of CSF opening pressure, the specific value wassometimes unavailable: 3 (16%) of the patients with BMI !25,2 (11%) of the patients aged 50 or older, and 56 (15%) of theremainder of the cohort. Second, clinically appropriate neuroim-aging was performed on all patients to rule out cerebral venousthrombosis. However, as the patient population is representativeof an actual clinical practice, there were occasionally practicallimitations to obtaining ideal imaging studies, such as body hab-itus preventing entry into imaging gantries and changes in theclinical usage of MRI and magnetic resonance (MR) venographyover the study period.6 MRIs were all reviewed at the time ofdiagnosis and MR venography or CT venography was obtainedwhen there was a question regarding possible cerebral venousthrombosis. Those patients who could not have MRI had headCT with contrast, often accompanied by CT venography.

Data analysis. Two groups of patients were identified andanalyzed separately: 1) patients considered to be of normalweight by World Health Organization BMI guidelines (BMI!25), and 2) patients aged 50 years or older at the time ofdiagnosis. This age cutoff was identified using a data-driven ap-proach as the age approximately 2 standard deviations above themean age of all 721 patients with IIH in our database, includingpediatric cases (mean: 29 years, SD: 11 years, figure 1). For eachof these atypical patients, a control patient with IIH matched byrace, presence or absence of hypertension, and year of visit wasrandomly selected from the remaining cohort.

Statistical analysis was performed with R: A language andenvironment for statistical computing (R Foundation for Statis-tical Computing, http://www.R-project.org). Continuous andordinal variables were compared between groups using theMann-Whitney U test. Pearson "2 with Yates’ continuity correc-

Figure 1 Age distribution of 721 patients with idiopathic intracranial hypertension

1828 Neurology 74 June 1, 2010

tempted to identify new medication associationswith IIH through a case-control study between ouratypical patients with IIH and other patients withIIH, but we did not find any such association. How-ever, by only using other patients with IIH ratherthan normal persons as controls, our power to findsuch associations would have been reduced, becauseother patients with IIH, despite their more typicalfeatures, may also have had an unknown medicationor other risk factor that contributed to their develop-ment of IIH.

Patients 50 years or older also represented only asmall percentage of patients with IIH, but both olderand normal weight patients shared several character-istics. First, and most importantly, both groups ap-peared to have similar, if not, better visual outcomescompared with the typical patient with IIH. A previ-ous descriptive series of 14 patients with IIH aged44–88 years of age suggested that the visual progno-sis was generally good in older patients.16 This sameseries also suggested, as our study confirms, thatolder patients are less likely to have headache and arenot as obese as the typical IIH patient. Another de-scriptive series of 23 patients with IIH older than 40years found, as we did, that older patients with IIHhad fewer complaints of headache and were morelikely to complain of visual disturbances.17 Older pa-tients appeared more likely to have better visual out-comes based on a reduced rate of severe visual lossand better visual field parameters. Our older patientsalso received less surgical and less medical therapy(table 2), further suggesting that they had less pro-gressive visual loss and milder symptoms. These im-proved visual outcomes occurred despite an increasedfrequency of vision-related symptoms as their initial

complaint. This is in direct contrast to men withIIH, who more frequently had poorer visual out-comes in the setting of more frequent vision-relatedpresentations.3 The better visual outcomes amongolder patients with IIH may be related to their rela-tively mild, although persistent, papilledema seen atlast follow-up. Indeed, we also observed among pa-tients with normal BMI what might represent a sim-ilar trend toward milder, but persistent papilledemawith equal or better visual outcomes at last follow-up. It is worth noting that previous studies have notclearly supported a direct relationship between thedegree of papilledema and visual outcome, except forcases of severe or atrophic papilledema.18

Patients with normal BMI and older patientswere about 1.5 times more likely to be white. In thecase of the normal weight patients, this may repre-sent confounding related to differences in the base-line prevalence of obesity between whites (24%) andblacks (36%). Among women, those at highest riskfor IIH, the difference is even greater: 39% of blackwomen are obese, compared with only 22% of whitewomen.19 Similarly, confounding may be responsiblefor the higher proportion of white subjects seenamong our older patients with IIH because 16% ofblacks are 55 or older in the US population, com-pared with 24% of whites.20 These characteristics ofthe underlying population would tend to lead to anoverrepresentation of white subjects among bothnonobese and older patients. We also found trendstoward more frequent hypertension in both moreobese and older patients with IIH, but this is againlikely due to confounding, because these groups ofpatients would be expected to be at higher risk of

Figure 2 Body mass index distribution of 407 patients with idiopathic intracranial hypertension

1830 Neurology 74 June 1, 2010

IIHinMen

•  Caseseriesof66menvs721Women(9%)1– OSA24%vs4%(maybeasig.underesNmate)2

– Older37vs28– LessHeadache55%vs75%– MoreVisualDisturbance35%vs20%– MoreSevereVisionLoss2.1RR

1.  Neurology2009;72:304-9.2.  Neurology2009;72:300-1

FulminantIIH•  <4weeksbetweenonsetofiniNalsymptomsandsevere

visuallossorrapidworseningofvisuallossoverafewdays•  16cases

–  81%notedvisionlossonsetatNmeofheadache–  MeanOP54–  VisionProgression7-28daystomaxloss–  Aoemptedtreatments:Diamox1-2g/day,IVmethylpred(4),RepeatLP

(11),ONSF(5),LPShunt(9),VPShunt(2)–  MedianDelayfromNOevaluaNontoSxwas3days.–  50%remainedlegallyblind

•  CasestudyshowedT2lesionwiththeopNccanal1.  Neurology2007;68:229-2322.  NeuroOphthalmology2017;41:84-9.

Pathophysiology

•  ExcessiveCSFproducNon•  ImpairedCSFabsorpNon– ArachnoidgranulaNons–  IncreasedVenousPressure•  VenousStenosisorcompression•  ElevatedJugularpressure

•  QuesNons–  Isitbecauseofmyweight?–  IsitgeneNc?

Obesity•  ObesityClearlycommoninIIHbutisitCausal?•  IIHisuncommonintheObese.

–  Consentedandscreened606ObeseClinicpts.•  17withpossiblesymptomsordiscedema•  4withGradeIdiscedemaonexam,•  ONLY3(0.5%)hadLP;ICPof24,25,32.

–  1084paNents,532photographscreened•  4priordiagnosisofIIH•  3addiNonaldetected•  7/1084=0.65%

•  Vs.PopulaNonstudiesof2.4/100kor0.0024%–  ButwearenotscreeningthepopulaNonformildIIH!

1.  JNeuroophthlamol2011;31:310-5.2.  SurgObesRelatDis2013;9-77-82.3.  Ophthal2017;124:697-700.

GeneNcs

•  RarecasereportsofFamilialIIH1,2,3

•  Motherand4daughters

•  MonozygoNctwins1,2

•  RaritysuggestsliolegeneNcbasis

1.  JNeuroophthal2008;28:337-47.2.  EurNeurol1989;29:106-83.  JChildNeurol1992;7:196-8

4.Fujiwaraetal.JNNP1997;62:652-4.5.WorldNeurosurgery.March2017;e1-4

MedicalTherapy

•  PressurereducingmedicaNons– Acetazolamide(CarbonicAnhydraseinhibitor)–  Topiramate–  Furosemide

•  Lifestyle– WeightReducNon:Aslioleas6%1

•  WeightreducNon– Acetazolamide-7.5kginIIHTT!–  LiragluNdeInj(Sexenda)2

1.  Ophthalmology1998;105:2313-17.2.  ObesRev.2017Jan;18:86-98.

IIHTT

•  IIHTT-MulNCentreRandomizeddoubleblinded,placebo-controlledtrialfor6months

•  165paNents•  Mildvisualloss(-2to-7dB)•  LowsodiumweightreducNondietplus– Acetazolamide(n=86)upto4g/day– Placebo

•  98%F,66%White,Age29,BMI40,ICP34-5cm

1.JAMA2014;311:1641-51.

IIHTT-Outcome

•  6monthOutcome(RxvsPlacebo)–  ChangePerimetricMeanDeviaNon:1.43vs.0.71Plp=0.05

–  ChangePapilledema-1.31vs,-0.61p<0.001

–  ChangePMD(Grade3-5discedema)2.00vs-0.27p<0.001

Copyright 2014 American Medical Association. All rights reserved.

completed follow-up) and 1 in the placebo group (who com-pleted follow-up). Eight of the drug discontinuations were dueto adverse events, and the other 2 (both in the acetazolamidegroup) were due to pregnancy and the desire to become preg-nant.

Both treatment groups experienced improvement in PMDover time in the study eye (Figure 2), with the mean improve-ment in the acetazolamide group being significantly larger thanthat in the placebo group at month 6 (acetazolamide: 1.43 dB,from −3.53 dB at baseline to −2.10 dB at month 6; placebo: 0.71dB, from −3.53 dB at baseline to −2.82 dB at month 6; treat-ment effect, 0.71 dB; 95% CI, 0 to 1.43 dB; P = .050) (Table 2).Secondary analyses of the primary outcome variable using dif-ferent strategies for accommodating missing data yielded simi-lar results (Table 2). Perimetric mean deviation in the felloweye also improved with acetazolamide treatment at month 6(acetazolamide: 0.87 dB, from −2.28 dB to −1.41 dB; placebo:0.42 dB, from −2.28 dB to −1.86 dB; treatment effect, 0.44 dB;95% CI, 0.01 to 0.87 dB; P = .045) (Table 3). An analysis thatincluded all eyes that had a PMD between −2 dB and −7 dB atbaseline (165 study eyes and 96 fellow eyes) also yielded a sig-

nificant effect of acetazolamide at month 6 (acetazolamide: 1.47dB, from −3.33 dB to −1.86 dB; placebo: 0.81 dB, from −3.33 dBto −2.52 dB; treatment effect, 0.66 dB; 95% CI, 0.16 to 1.17 dB;P = .01).

The treatment effect on the primary outcome variable wassubstantially greater in participants with a baseline papill-edema grade of 3-5 (2.27 dB) than in those with a baseline pap-illedema grade of 1-2 (−0.67 dB) (eTable 3 in the Supplement).

There was significant improvement in Frisén papill-edema grade associated with acetazolamide treatment in thestudy eye and in the fellow eye for both the fundus photogra-phy and site investigator ratings (Table 3). Acetazolamide-treated participants also experienced significant improve-ment in quality-of-life measures, including the VFQ-25 totalscore (acetazolamide: 8.33, from 82.97 to 91.30; placebo: 1.98,from 82.97 to 84.95; treatment effect, 6.35; 95% CI, 2.22 to 10.47;P = .003) and its 10-item neuro-ophthalmic supplement (ac-etazolamide: 9.82, from 75.45 to 85.27; placebo: 1.59, from 75.45to 77.04; treatment effect, 8.23; 95% CI, 3.89 to 12.56; P < .001),as well as the 36-Item Short Form Health Survey Physical Com-ponent Summary and Mental Component Summary scores

Table 2. Treatment Effects on the Primary Outcome Variable, Change From Baseline to Month 6 in PerimetricMean Deviation (PMD) in the Study Eye

Adjusted Mean (SE), dBaTreatment Effect

(95% CI) P ValueAcetazolamide PlaceboMissing data accommodated with multiple imputation

Baseline tomonth 6

−3.53 (0.09) to −2.10 (0.24) −3.53 (0.09) to −2.82 (0.09to 0.28)

Change 1.43 (0.24) 0.71 (0.28) 0.71 (0 to 1.43) .050

Missing data accommodated with MMRM

Baseline tomonth 6

−3.53 (0.09) to −2.02 (0.24) −3.53 (0.09) to −2.89 (0.26)

Change 1.51 (0.24) 0.64 (0.26) 0.87 (0.19 to 1.56) .01

Missing data accommodated with multiple imputation except LOCF imputation used for treatment failures

Baseline tomonth 6

−3.53 (0.09) to −2.06 (0.29) −3.53 (0.09) to −3.25 (0.30)

Change 1.47 (0.29) 0.28 (0.30) 1.19 (0.34 to 2.05) .007

Abbreviations: LOCF, last observationcarried forward; MMRM, mixedmodel repeated measures.a Values are mean changes (in

decibels) from baseline to month 6in PMD in the study eye, adjustedfor center, baseline PMD in thestudy eye, and baseline papilledemagrade in the study eye.

Figure 2. Adjusted Mean Change in Perimetric Mean Deviation (PMD) Over Time by Treatment Group

1.5

2.0

1.0

0.5

0.0

–0.5

–1.0

Adju

sted

Mea

n Ch

ange

in P

MD

(Wor

st E

ye),

dB

Month0

8679

1

8273

2

7667

3

7660

4

6760

5 6

7059

Placebo

Acetazolamide

No. of patientsAcetazolamidePlacebo

Numbers of patients reflect thosecontributing PMD data in each groupat each time point.The adjustedmeans were obtained from ananalysis of covariance model thatincluded center, baseline papilledemagrade (study eye), and baseline PMDas covariates. Missing data wereaccommodated with multipleimputation. Bars around the adjustedgroup means indicate 95% CIs.Adjusted group means for eachtreatment group are slightly offsetaround each visit to avoid overlap.

Research Original Investigation Acetazolamide for Mild Visual Loss in Intracranial Hypertension

1646 JAMA April 23/30, 2014 Volume 311, Number 16 jama.com

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/jama/930003/ by a University of British Columbia User on 04/24/2017

1.JAMA2014;311:1641-51.

IIHTT-Outcome

•  6monthOutcome(RxvsPlacebo)–  ChangeVisualAcuity2.65vs.2.64p=0.99

–  ChangeinCSF(n=85)-11cmvs.-5cm

– WeightReducNon7.5kgvs3.45kg

1.JAMA2014;311:1641-51.

IIHTT-TolerabilityandAE1

– Dose:44%tolerated4g/dayofAcetazolamide•  11%couldn’ttolerateabove750mg/day•  11%stoppedAcetazolamidebeforeendofstudy

– 84%hadoneormoreAE– Common:Paresthesia49%,Dysgeusia15%,GIupset30%,faNgue17%

– AEweremorecommonatdose<2g/day

1.JNeuroOphthal2016;36:13-9.

IIHTT-TolerabilityandAE1•  9SAE(6Acetazolamidevs3placebo)

•  3/6possiblyorprobablyrelated•  RenalImpairmentat4g/day•  TransaminiNsat4g/day•  AllergicreacNonat2.5g/day

•  Comments–  ItreducesopNcdiscedemainmostpaNentsatmuchlowerdosesthan4g/day(11cmofICP)

–  PaNentswithoutvisionlossmaynotbemoNvatedto“tolerate”asmuchmedicaNon

–  SulfonamideanNbioNcsallergynotacontraindicaNon–  NosignificanthypokalemiaonAcetazolamidealone–  ConsiderTransaminasemonitoring:2asymptomaNcé

1.JNeuroOphthal2016;36:13-9.

Pregnancy

•  Acetazolamide(CategoryCFDAdrug)– LimbmalformaNonsinrodentsathighdoses– Sacrococcygealteratomain1case1

•  SurveyofNANOSsocietymembers(16%)2

– 65%disconNnue,10%dosageê,25%same

•  63/101pregnanciesonAcetazolamide2

– 50infirst13weeks– Noevidenceofincreasedrisk

1.JAMA1978;240:251-2.2.JNeuro-Ophthalmol2013;33:9-12

BariatricSurgery

•  MetaAnalysisof65cases1

– 100%papilledemaresoluNon– 90%HeadacheresoluNon– BMIreducNon17.5kg/m2

•  OtherObesitybenefits:DM22…

•  Longevity:163Gastricbypass,24%yr1,23%yr33•  Risks:Shortbowlsynd,NutriNonaldeficiencyrelatedneurologicaldisease4andlate–Osteoporosis5

1.  ManfieldJHetal.ObesSurg2017;27:513-21.2.  SurgEndosc.2010May;24(5):1005-103.  ObesSurg.2016Sep;26(9):2161-74.  JNeuroOphthal2016;36:78-84. 5.ObesSurg.2014Jun;24(6):877-84.

ONSF

•  2MetaAnalysis– VisualFields64-68%– Acuity59-67%–  Papilledema80-95%–  RepeatSurgery9-11%– Headache41%–  CheapestopNon

•  MayOnlyneedoneeye

–  ComplicaNon18-26%,MajorcomplicaNonrate1.5%1.  ActaNeurochir2016;159:33-492.  AJNR2015;36:1899-904.

CSFShunNng

•  2MetaAnalysis– VisualFields71%– Acuity54-67%– Papilledema70-91%– RepeatSurgery43%(2.78addiNonalsx/failure)– Headache80-96%– ComplicaNon33%,MajorcomplicaNonrate7.6%

1.  ActaNeurochir2016;159:33-492.  AJNR2015;36:1899-904.

VenousStenNng•  Metaanalysisof155cases•  Meanfollowup22months•  Primarytreatmentin80%ofthesecases•  4-10mmHgstenosisgradient•  Acuity65%•  Fields75%•  Headache77%•  Papilledema98%•  TxFailure8%•  ComplicaNonrate12%SeriouscomplicaNon4%

1.  ActaNeurochir2016;159:33-49

TreatmentDecisions

TheEnd