effects side ocular induced-Drug • PART7
Clinical significance
Gabapentin’s most common ocular side effect is a decrease in central vision. The effect may be zigzag lines, a crowding of central letters on Snellen testing or blurred vision. The median onset of these symptoms is 4 days. While Browne (1993) reported an incidence of nystagmus at 11% and diplopia at 6%, these figures in other trials are lower than this (Physicians’ Desk Reference 2006). Conjunctivitis occurs in 1.2% over placebo controls. All Ocular side effects are reversible. This drug may aggravate myasthenia with worsening of ptosis.
References and Further Reading
Boneva N, Brenner T, Argov Z. Gabapentin may be hazardous in myasthenia gravis. Muscle Nerve 23: 1204–1208, 2000.
Browne T. Efficacy and safety of gabapentin. In: New Trends in Epilepsy Management: the Role of Gabapentin, Chadwick D (ed), London, Royal Society of Medicine Service, pp 47–58, 1993.
Goa KL, Sorkin EM. Gabapentin. A review of its pharmacological properties and clinical potential in epilepsy. Drugs 46(3): 409–427, 1993.
Scheschonka A, Beuche W. Treatment of post-herpetic pain in myasthenia gravis: exacerbation of weakness due to gabapentin. Pain 104: 423–424, 2003.
Physicians’ Drug Reference, 60th edn, Thomson PDR, Montvale NJ, pp 2498–2503, 2006.
effect profile. In placebo-controlled clinical trials, two of its five most common side effects were ocular (Schachter 1992), with 22% of patients having diplopia and 15% having blurred vision compared to controls. Betts et al (1991) noted that less than 5% had nystagmus. Alkawi et al (2005) reported a case of downbeat nystagmus. Decreasing the dosage may significantly decrease ocular side effects. All ocular side effects appear to be reversible. There are cases of severe bilateral visual loss that returned fully when the drug is discontinued. There have been reports to the National Registry of ptosis, hallucinations and pigmentary retinal defects. These are too few to draw any correlation with lamotrignine.
References and Further Reading
Alkawi A, Kattah JC, Wyman K. Downbeat nystagmus as a result of lamotrigine toxicity. Epilepsy Res 63: 85–88, 2005.
Betts T, Goodwin G, Withers RM, Yuen AWC. Human safety of lamotrigine. Epilepsia 32(Suppl. 1): S17–S21, 1991.
Das KB, Harris C, Smyth DP, Cross JH. Unusual side effects of lamotrigine therapy. J Child Neurol 18: 479–480, 2003.
Goa KL, Ross SR, Chrisp P. Lamotrigine. Drugs 46: 152–176, 1993. Schachter SC. A multicenter, placebo-controlled evaluation of the
safety of lamotrigine (Lamictal®) as add-on therapy in outpatients with partial seizures. Presented at the 1992 Annual Meeting
of the American Epilepsy Society, Seattle, December 4–10, 1992.
Generic name: Lamotrigine.
Proprietary name: Lamictal.
Primary use
This is an antiepileptic drug believed to suppress seizures by inhibiting the release of excitatory neurotransmitters.
Ocular side effects
Systemic administration
Certain
1. Diplopia
2. Blurred vision
3. Nystagmus
4. Eyelids or conjunctiva
a.Conjunctivitis
b.Photosensitivity
Probable
1. Angioneurotic edema
2. Visual hallucinations
Possible
1.Eyelids or conjunctiva
a.Stevens-Johnson syndrome
b.Toxic epidermal necrolysis
Conditional/Unclassified
1. Visual field changes – primarily generalized constriction
2. Retinal pigmentary change
Clinical significance
Lamotrigine is mainly an add-on drug used when current antiepileptic drugs are ineffective, which confuses its adverse
Generic name: Vigabatrin.
Proprietary name: Orphan drug production.
Primary use
Antiepileptic drug effective for refractory epilepsy, generalized tonic-clonic seizures and infantile spasms.
Ocular side effects
Systemic administration
Certain
1. Decreased or blurred vision
2. Visual field defects – may be irreversible
a.Concentric peripheral constriction
b.Tunnel vision
c.Variable visual field defects
d.Scotoma
3. Retina
a.Peripheral atrophy
b.Nerve fiber layer loss (Fig. 7.2a)
c.Surface wrinkling retinopathy
d.Hypopigment spots
4. Contrast sensitivity – reduced
5. Optic atrophy
6. Color vision abnormalities
7. Electroretinography
a.Abnormal ERG
b.Abnormal EOG
Possible
1. Eyelids – angioneurotic edema
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Fig. 7.2a Vigabatrin-induced retinal nerve fiber layer loss. The black arrow indicates temporal disc pallor, the white arrow the demarcation between atrophic and non-affected nerve fiber layer and the black triangle shows the telltale change in superficial light reflex aligning along the course of the exposed small vessel of the atrophic macula. Photo courtesy of Buncic JR. Characteristic retinal atrophy with secondary ‘inverse’ optic atrophy identifies vigabatrin toxicity in children. Ophthalmology 111: 1935–1942, 2004.
Clinical significance
While vigabatrin has been available for almost two decades, the potential for ocular side effects make it one of the most controversial drugs with regard to ocular safety issues. Some countries have banned its use. This drug may be indispensable for adults with refractory epilepsy, but as many as 30–40% of patients develop significant ocular side effects. The incidence in children is less clear due, in part, to the variability of responses to testing methods in children.
Lawden’s recent editorial based on the work of Krauss et al (1998) and others showed that vigabatrin, not epilepsy or other nervous system diseases, causes these ocular changes (Lawden 2003). Visual field defects may occur after a few months to years after starting the drug. They are bilateral and range from a localized nasal defect of 30–400 in eccentricity and may extend to complete concentric contraction. In rare instances, central vision can be involved. Johnson et al (2000) deny reversibility of visual field loss; however, visual acuity, color vision and ERG amplitude loss may be reversible if recognized early in patients with minimal or no field loss. Best and Acheson (2005) studied patients on the drug alone or in combination with other antiepileptic agents for a minimum of 5 years. This was in patients who elected to continue the medication for good seizure control. All patients had unequivocal visual field defects. They found only one in 16 had progression, and the range of follow-up was 18–43 months. Arndt et al (1999) feel that visual field changes are enhanced if the patients are also on valproate. Graniewski-Wijnands and Van Der Torren (2002) showed some recovery of EOG and ERG, but no change in visual fields once the drug was discontinued.
The primary retinal effects are peripheral atrophy and nerve fiber bundles defects. Choi and Kim (2004) have shown retinal nerve fiber layer defects correlating with visual field constriction. Outer retinal dysfunction should be present if visual field changes are present. Banin et al (2003) suggest that vigabatrin not only impairs peripheral cones, but foveal cones based on electroretinographic amplitudes. In the main these changes are
irreversible; however there are rare reports of some reversibility (Fledelius 2003). Other retinal effects include abnormal macular light reflexes, surface wrinkling retinopathy and narrowing of the arterial tree.
The incidence of visual field defects varies from a 2% incidence at 6 months (Wilton et al 1999) to 10–20% or more. There is evidence to suggest that this is dose related, but the time of onset varies greatly. Some cases occur as soon as 1 month after starting the drug, and others have occurred after 6 or more years of treatment. The mechanism behind the visual field defects could be related to impairment of the highly GABA-ergic amacrine cells in the retina. Histopathological studies in animals show a microvacuolation in myelin sheaths of white matter when exposed to vigabatrin. How these alterations affect the visual field in patients receiving vigabatrin is not known. Frisén and Malmgren (2003), Viestenz et al (2003), Buncic et al (2004) and Rebolleda et al (2005) have described optic nerve pallor and atrophy secondary to vigabatrin. It is felt that there is a toxic effect on the axons of the retinal ganglion cells resulting in various degrees of optic atrophy. This atrophy occurs most frequently nasally.
The EOG is possibly a more sensitive and specific diagnostic tool than ERG for drug-related retinal effects. Wild et al feel ocular coherence tomography of the retinal nerve fiber layer thickness can efficiently identify this drug’s damage in adults and children unable to perform perimetry. It may also be helpful in cases where the question of toxic damage is equivocal.
Recommendations (modified from recommendations by the manufacturer, Hoechst Marion Roussel)
1. Baseline visual field – if patient has a cognitive age of 9 years or more, Goldmann or Humphrey fields. Below the age of 9, there is currently no reliable method available. Possibly, ERG has a role here.
2. Visual field testing every 6 months. If visual fields are abnormal this needs to be confirmed by retesting.
3. Question patients regularly for visual symptoms.
4. If there are any new visual symptoms, consider repeating the visual field testing. If defects are extensive, progressive and reproducible, the risk-benefit ratio needs to be revisited. If the drug is discontinued, this should be done over a 2- to 4-week period.
5. Electroretinography or visual evoked potential have been of minimal value to date, but may be of benefit as more data are accumulated.
References and Further Reading
Arndt CF, Derambure P, Defoort-Dhellemmes S, Hache JC. Outer retinal dysfunction in patients treated with vigabatrin. Neurology 52: 1205–1208, 1999.
Banin E, Shclev RS, Obolensky A, et al. Retinal function abnormalities in patients treated with vigabatrin. Arch Ophthalmol 121: 811–816, 2003.
Baulac M, Nordmann JP, Lanoe Y. Severe visual field constriction and side-effects of GABA-mimetic antiepileptic agents (letter). Lancet 352: 546, 1998.
Beck RW. Vigabatrin-associated retinal cone system dysfunction (letter). Neurology 51: 1778–1779, 1998.
Best JL, Acheson JF. The natural history of vigabatrin associated visual field defects in patients electing to continue their medication. Eye 19: 41–44, 2005.
Blackwell N, Hayllar J, Kelly G. Severe persistent visual field constriction associated with vigabatrin. Patients taking vigabatrin should have regular visual field testing (letter, comment). BMJ 314: 180–181, 1997.
Brigell MG. Vigabatrin-associated retinal cone system dysfunction (letter). Neurology 51: 1778–1779, 1998.
CNS the affecting Agents • 2 Section
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effects side ocular induced-Drug • 7 t Pa r
Buncic RJ, Westall CA, Panton CM, et al. Characteristic retinal atrophy with secondary ‘inverse’ optic atrophy identifies vigabatrin toxicity in children. Ophthalmology 111: 1935–1942, 2004.
Choi HJ, Kim DM. Visual field constriction associated with vigabatrin: retinal nerve fiber layer photographic correlation. J Neurol Neurosurg Psychiatry 75: 1395, 2004.
Eke T, et al. Severe persistent visual field constriction associated with vigabatrin. BMJ 314: 180–181, 1997.
Fledelius HC. Vigabatrin-associated visual field constriction in a longitudinal series. Reversibility suggested after drug withdrawal. Acta Ophthalmol Scand 81: 41–45, 2003.
Frisén L, Malmgren K. Characterization of vigabatrin-associated optic atrophy . Acta Ophthalmol Scand 81: 466–473, 2003.
Graniewski-Wijnands HS, Van Der Torren K. Electro-ophthalmological recovery after withdrawal from vigabatrin. Doc Ophthalmol 104: 189–194, 2002.
Harding GFA, et al. Severe persistent visual field constriction associated with vigabatrin. BMJ 316: 232–233, 1998.
Harding GFA, Robertson K, Spence EL, Holliday I. Vigabatrin; its effect on the electrophysiology of vision. Doc Ophthalmol 104: 213–229, 2002.
Johnson MA, Krauss GL, Miller NR, et al. Visual function loss from vigabatrin: effect of stopping the drug. Neurology 55: 40–45, 2000.
Koul R, Chacko A, Ganesh A, et al. Vigabatrin associated retinal dysfunction in children with epilepsy. Arch Dis Child 85: 469–473, 2001.
Krauss GL, et al. Vigabatrin-associated retinal cone system dysfunction. Neurology 50: 614–618, 1998.
Krauss GL, Johnson MA, Miller NR. Vigabatrin-associated retinal cone system dysfunction (reply). Neurology 51: 1779–1781, 1998.
Lawden MC. Vigabatrin, tiagabine, and visual fields. J Neurol Neurosurg Psychiatry 74: 286, 2003.
Lhatoo SD, Sander JW. Infantile spasms and vigabatrin. Visual field defects may be permanent (letter). BMJ 318: 57, 1999.
Mackenzie R, Klistorner A. Severe persistent visual field constriction associated with vigabatrin. Asymptomatic as well as symptomatic defects occur with vigabatrin (letter; comment). BMJ 314: 233, 1998.
Nousiainin I, Kalviainen R, Mantyjarvi M. Color vision in epilepsy patients treated with vigabatrin or carbamazepine monotherapy. Ophthalmology 107: 884–888, 2000.
Rao GP, Fat FA, Kyle G, et al. Study is needed of visual field defects associated with any long term antiepileptic drug (letter). BMJ 317: 206, 1998.
Rebolleda G, García Pérez JL, Muñoz Negrete FJ, Tang RA. Vigabatin toxicity in children. Ophthalmology 112: 1322–1323, 2005.
Roff Hilton EJ, Cubbidge RP, Hosking SL, et al. Patients treated with vigabatrin exhibit central visual function loss. Epilepsia 43: 1351–1359, 2002.
Roubertie A, Bellet H, Echenne B. Vigabatrin-associated retinal cone system dysfunction (letter). Neurology 51: 1779, 1998.
Ruether K, et al. Electrophysiologic evaluation of a patient with peripheral visual field contraction associated with vigabatrin. Arch Ophthalmol 116: 817–819, 1998.
Van Der Torren K, Graniewski-Wijnands HS, Polak BCP. Visual field and electrophysiological abnormalities due to vigabatrin. Doc Ophthalmol 104: 181–188, 2002.
Viestenz A, Viestenz A, Mardin CV. Vigabatrin-associated bilateral simple optic nerve atrophy with visual field constriction. A case report and a survey of the literature. [German]. Ophthalmologe 100: 402–405, 2003.
Wild JM, Robson CR, Jones AL, et al. Detecting vigabatrin toxicity by imaging of the retinal nerve fiber layer. Invest Ophthalmol Vis Sci 47: 917–924, 2006.
Wilson EA, Brodie MJ. Severe persistent visual field constriction associated with vigabatrin. Chronic refractory epilepsy may have role in causing these unusual lesions (letter; comment). BMJ 314: 1693–1695, 1997.
Wilton LV, Stephens MDB, Mann RD. Interim report of the incidence of visual field defects in patients on long term vigabatrin therapy. Pharmacoepidemiol Drug Safety 8: S9–S14, 1999.
Class: Anorexiants
Generic names: 1. Amfetamine; 2. dextroamfetamine sulfate (dexamphetamine); 3. methamfetamine hydrochloride.
Proprietary names: 1. Multi-ingredient preparation only; 2. Dexedrine, Dextrostat; 3. Desoxyn.
Street names: 1-3. Crank, Rx Diet Pills, speed, uppers, ups.
Primary use
These sympathomimetic amines are used in the management of exogenous obesity; amfetamine, dextroamfetamine and methamphetamine, and are also effective in narcolepsy and in the management of minimal brain dysfunction in children. They are also used off-label as recreational drugs.
Ocular side effects
Systemic administration
Certain
1. Decreased vision
2. Increase in critical flicker frequency
3. Visual hallucinations
4. Problems with color vision – objects have blue tinge (amfetamine)
5. Pupils (toxic states)
a.Mydriasis – may precipitate narrow-angle glaucoma
b.Decreased reaction to light
Possible
1. Ocular teratogenic effects (methamfetamine)
2. Oculogyric crisis (dextroamfetamine sulfate)
3. Eyelids and conjunctiva
a.Stevens-Johnson syndrome
b.Toxic epidermal necrolysis
Nasal application – methamphetamine
Certain
1. Decreased vision
2. Cornea
a.Keratitis
b.Ulceration 3. Conjunctivitis
Possible
1.Retina
a.Venous thrombosis
b.Intraretinal hemorrhages
c.Ischemic changes
d.Arterial narrowing
e.Vasculitis
f.Central or branch vein occlusion
2.Optic nerve
a.Ischemic changes
b.Optic atrophy
Clinical significance
Ocular side effects due to these sympathomimetic amines are seldom of consequence and are mainly seen in recreational use or overdose situations. Chuck et al (1996) describe recurrent corneal ulcers in a patient on chronic methamfetamine abuse, much like the ‘crack eye syndrome’ resulting from the smoked form of cocaine. This same ocular pattern is evident secondary to the smoked form of methamfetamine, ‘ice’. Several hours after methamfetamine was applied to the nose of a young female, she developed blurred vision and intraretinal hemorrhages. This was felt to be due to a sudden increase in blood pressure caused by the drug (Wallace et al 1992). Wijaya et al (1999) described a similar case of methamfetamine applied once nasally to a 35-year-old male with a unilateral acute loss of vision with resultant ischemic optic nerve and optic atrophy. Shaw et al (1985) described a patient who developed amaurosis fugax and retinal vasculitis 36 hours after
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