Comprehensive review of visual defects reported with topiramate

Figures & data

Table 1 TEAEs suggestive of retinal damage reported in approved indication studies

	Placebo N (%)	All TPM N (%)
Adjunctive epilepsy trials
DB phase: 100–400, 600–1,000 mg/day, 5–25 mg/kg/day	(N=570)	(N=1,099)
Patients with retinal damage TEAEs	0	5 (0.5)
Scotoma	0	1 (0.1)
Tunnel vision	0	1 (0.1)
VFD	0	3 (0.3)
OL phase	(N=264)a	(N=2,262)a
Patients with retinal damage TEAEs	0	12 (0.5)
Blindness	0	1 (<0.1)
Optic atrophy	0	4 (0.2)
Papillophlebitis	0	1 (<0.1)
Retinal hemorrhage	0	1 (<0.1)
Retinal vein occlusion	0	1 (<0.1)
VFD	0	4 (0.2)
Monotherapy epilepsy trials
DB phase: 50, 100, 200, 400,	–	(N=1,365)
500 mg/day
Patients with retinal damage TEAEs		10 (0.7)
Retinal hemorrhage		1 (0.1)
Scotoma		5 (0.4)
VFD		4 (0.3)
OL phase	–	(N=708)b
Patients with retinal damage TEAEs		5 (0.7)
Blindness		1 (0.1)
Macular degeneration		1 (0.1)
Retinal hemorrhage		1 (0.1)d
Scotoma		3 (0.4)
VFD		1 (0.1)
Migraine prophylaxis trials
DB phase: 50, 100, 200 mg/day, 2–3 mg/kg/day	(N=1,264)	(N=2,215)
Patients with retinal damage TEAEs	1 (0.1)	7 (0.3)
Retinal tear	1 (0.1)	0
Scotoma	0	1 (<0.1)
VFD	0	6 (0.3)
OL phase	(N=492)c	(N=2,258)c
Patients with retinal damage TEAEs	2 (0.4)	5 (0.2)
Blindness	0	1 (<0.1)
Retinal degeneration	0	1 (<0.1)
Retinal vein occlusion	0	1 (<0.1)d
Scotoma	0	1 (<0.1)
Tunnel vision	0	1 (<0.1)
VFD	2 (0.4)	0

Notes:

a Placebo group: patients who received placebo in DB phase but were switched to TPM during OL phase. TPM group: patients who received TPM during the DB phase and OL phase.

b All patients received TPM during the OL phase. TPM: patients who were randomized to an active control during DB phase.

c Placebo group: patients who received placebo in DB phase but were switched to TPM during OL phase. TPM group: patients who received TPM or an active comparator during the DB phase and who either remained on TPM or were switched from active control to TPM during the OL phase.

d Serious TEAEs.

Abbreviations: DB, double-blind; OL, open-label; TEAE, treatment-emergent adverse event; TPM, topiramate; VFD, visual field defect.

Table 2 TEAEs suggestive of retinal damage reported in investigational indication studies

	Placebo N (%)	All TPM N (%)
Bipolar disorder
DB phase: ≤200, >200–400, 500–600 mg/day	(N=630)	(N=892)
Patients with retinal damage TEAEs	0	2 (0.2)
Retinal degeneration	0	1 (0.1)
VFD	0	1 (0.1)
OL phase	(N=261)a	(N=436)a
Patients with retinal damage TEAEs	0	1 (0.2)
Vitreous hemorrhage	0	1 (0.2)
Binge eating disorder
DB phase: 200, 400 mg/day	(N=202)	TPM 400 mg/day
		(N=202)
Patients with retinal damage TEAEs	0	1 (0.5)
VFDs	0	1 (0.5)
Diabetic peripheral neuropathy
DB phase: 100, 200, 400 mg/day	(N=531)	(N=1,140)
Patients with retinal damage TEAEs	6 (1.1)	9 (0.8)
Optic atrophy	1 (0.2)	0
Optic nerve disorder	0	1 (0.1)
Retinal detachment	2 (0.4)	0
Retinal hemorrhage	2 (0.4)	1 (0.1)
Retinal infarction	0	1 (0.1)
Retinal tear	0	1 (0.1)
Retinopathy	0	2 (0.2)
Scotoma	0	1 (0.1)
Vitreous adhesions	0	1 (0.1)
Vitreous hemorrhage	2 (0.4)	0
VFD	0	1 (0.1)
OL phase	(N=357)b	(N=574)b
Patients with retinal damage TEAEs	6 (1.7)	7 (1.2)
Macular edema	1 (0.3)	0
Retinal detachment	1 (0.3)	1 (0.2)c
Retinal hemorrhage	2 (0.6)	1 (0.2)
Retinopathy	2 (0.6)	4 (0.7)
Tunnel vision	0	1 (0.2)
Obesity
DB phase: <100, 100–200, >200–400 mg/day	(N=1,373)	(N=3,164)
Patients with retinal damage TEAEs	5 (0.4)	9 (0.3)
Macular degeneration	1 (0.1)	0
Retinal disorder	1 (0.1)	0
Retinal hemorrhage	1 (0.1)	1 (<0.1)
Scotoma	0	1 (<0.1)
Tunnel vision	0	3 (0.1)
VFD	2 (0.1)	4 (0.1)

Notes:

a Placebo group: patients who received placebo in DB phase but were switched to TPM during OL phase. TPM group: patients who received TPM or an active comparator during the DB phase and who either remained on TPM or were switched from active control to TPM during the OL phase.

b Placebo group: patients who received placebo in DB phase but were switched to TPM during the OL phase. TPM group: patients who received TPM during the DB phase and OL phase.

c Serious TEAE.

Abbreviations: DB, double-blind; OL, open-label; TEAE, treatment-emergent adverse event; TPM, topiramate; VFDs, visual field defects.

Figure 1 Risk analysis for VFDs.

Notes: RR for VFDs between the topiramate group (all dose groups combined) and placebo group was not significant. 95% CI (0.78, 2.91).
Abbreviations: CI, confidence interval; RR, relative risk; VFDs, visual field defects.

Table 3 Patient demographics, seriousness, latency, and reversibility for patients of VFD reported with topiramate treatment

Characteristics	Number of patients N=96
Sex
Men	25
Women	66
Not reported	5
Age group (years)
≤17	8
18–35	26
36–50	30
51–64	13
≥65	5
Not reported	14
Indication (≥2 patients)
Epilepsy	24
Migraine prophylaxis	15
Migraine	12
Convulsion	5
Bipolar disorder	4
Headache	3
Neuralgia	3
Convulsion prophylaxis	2
Partial seizures	2
Unknown	11
Seriousness
Serious	64
Nonserious	32
Latencya
<7 days	8
1 week to 1 month	19
>1 month to 3 months	14
>3 months to 6 months	10
>6 months to 1 year	3
>1 year to 5 years	13
>5 years	2
Not reported	27
Reversibility
Reversible	36
Not reversible	20
Unknown	40

Note:

a Time course from the initial topiramate administration to the reported event of interest.

Abbreviation: VFD, visual field defect.

Table S1 MedDRA (version 14.0) preferred terms suggestive of retinal dysfunction or damage

Macular cyst	Macular ischemia
Macular degeneration	Venous stasis retinopathy
Age-related macular degeneration	Biopsy conjunctiva
Macular opacity	Biopsy conjunctiva abnormal
Maculopathy	Biopsy conjunctiva normal
Vitreous adhesions	Biopsy cornea
Pars plana cyst	Biopsy cornea abnormal
Retinal cyst	Biopsy cornea normal
Retinal degeneration	Biopsy retina
Retinal depigmentation	Biopsy retina abnormal
Retinal degeneration	Biopsy retina normal
Retinal deposits	Biopsy sclera
Retinal detachment	Biopsy sclera abnormal
Retinal dystrophy	Biopsy sclera normal
Retinal pallor	Fundoscopy
Retinal pigment epitheliopathy	Fundoscopy abnormal
Retinal pigmentation	Fundoscopy normal
Retinal scar	Gonioscopy
Retinal tear	Gonioscopy abnormal
Retinopathy solar	Gonioscopy normal
Retinoschisis congenital	Paracentesis eye
Retinal toxicity	Paracentesis eye abnormal
Macular hole	Paracentesis eye normal
Osteoporosis-pseudoglioma syndrome	Retinogram
Detachment of retinal pigment epithelium	Retinogram normal
Retinal pigment epithelial tear	Retinogram abnormal
Acquired pigmented retinopathy	Visual field tests
Laurence–Moon–Bardet–Biedl syndrome	Visual field tests abnormal
Macular pseudohole	Visual field tests normal
Retinoschisis	Optic nerve disorder
Subretinal fibrosis	Optic neuropathy
Macular scar	Toxic optic neuropathy
Retinal infiltrates	Visual pathway disorder
Chorioretinitis	Visual evoked potentials
Choroid tubercles	Visual evoked potentials abnormal
Choroiditis	Visual evoked potentials normal
Diabetic retinal edema	Blindness
Macular edema	Chorioretinal atrophy
Cystoid macular edema	Chorioretinal scar
Retinal edema	Chorioretinopathy
Retinal vasculitis	Choroidal detachment
Retinitis	Choroidal effusion
Retinitis viral	Choroidal hematoma
Toxocariasis	Choroidal hemorrhage
Vitreous abscess	Choroidal infarction
Vitritis	Choroidal neovascularization
Necrotizing retinitis	Choroidal sclerosis
Hemianopia	Exudative retinopathy
Hemianopia heteronymous	Optic atrophy
Hemianopia homonymous	Optic disc disorder
Scotoma	Optic disc drusen
Tunnel vision	Optic nerve cupping
Visual field defect	Papillophlebitis
Uhthoff ’s phenomenon	Retinal artery embolism
Macular vasospasm	Retinal artery occlusion
Optic ischemic neuropathy	Retinal artery thrombosis
Optic nerve infarction	Retinal disorder
Retinal artery spasm	Retinal exudates
Retinal artery stenosis	Retinal neovascularization
Retinal ischemia	Retinal vascular disorder
Retinal hemorrhage	Retinal vascular thrombosis
Retinal vein thrombosis	Retinopathy
Retinal vein occlusion	Venous stasis retinopathy
Retinal vascular occlusion	Vitreous hemorrhage
Retinal infarction