is a thickened appearance of the nerve fiber layer, termed “pseudo-edema”. This characteristic fundus appearance may be present prior to the onset of visual loss and can also be seen in about half of unaffected family members, many of whom never progress to visual loss. In about one-third of patients with symptomatic LHON, the disc has a completely normal appearance at the time of initial visual loss. Hence, a normal fundus appearance in no way rules out a diagnosis of LHON. In some cases, optic atrophy has already developed by the time the patient is evaluated.

LHON is a maternally inherited disorder due to a point mutation in the mitochondrial DNA complex I genes. Four mutations (11778, 3460, 14484 and 14459) are considered “primary” and account for approximately 95% of cases, with the 11778 mutation alone accounting for about 50%. A fifth, 15257, may be another primary LHON mutation but is also found in low frequency in control groups. Genetic testing is strongly recommended, not only for diagnostic confirmation, but also for prognostic value. In most patients with symptomatic LHON, visual loss is usually profound and permanent. Yet an occasional patient experiences some degree of spontaneous improvement and the likelihood of such recovery is related to the specific mutation. Only 4% of patients with the common 11778 mutation experience visual improvement, whereas the other mutations are associated with a higher percentage of spontaneous visual recovery. The onset of visual recovery, when it does occur, can be surprisingly delayed, occurring from three months to several years after initial visual loss.

There is currently no effective treatment for visual loss due to LHON. Exogenous factors such as systemic infection, nutritional deficiency, medications and exposure to toxins have been explored as possible triggers that may provoke the onset or increase the risk of phenotypic expression, but no definite causal relationship has been confirmed for any of these. Nonetheless, patients who harbor a LHON mutation are strongly advised to discontinue smoking, avoid exposure to solvents and other fumes and take daily vitamin supplements.

Genetic counselling is an important aspect of management in patients with LHON. Phenotypic penetrance of the LHON mutation is notably incomplete; many individuals carry the mutation but never suffer visual loss. Because all mitochondria are maternally inherited, men with the LHON mutation never pass on the disorder and male patients should be assured of this fact. However, all female relatives of a male proband are obligatory carriers, and will necessarily transmit the mutation to all their children. In addition to being carriers, 5 to 20% of females with a primary LHON mutation will eventually experience visual loss. In contrast, male carriers have a much greater lifetime risk of visual loss, ranging from 25 to 60%. The basis for this genderspecific susceptibility is unknown.

Since the availability of genetic testing for this disorder, our understanding of the clinical features has greatly expanded, including confirmed cases of LHON occurring in young children and in individuals over age 65 years. Atypical temporal patterns have also been described, including sudden bilateral blindness and protracted visual deterioration over years. These variations in the phenotype serve as reminders that LHON should be included in the differential diagnosis of any patient with an acute painless optic neuropathy, regardless of age and gender.

The clinical scenario: Acute monocular optic neuropathy with central visual loss in a young adult

The look-alikes: Idiopathic optic neuritis vs. Leber’s hereditary optic neuropathy

Tip: Absence of pain, male gender and normal MRI strongly suggest the possibility of Leber’s hereditary optic neuropathy.

Acute tonic pupil vs. pharmacologic mydriasis

Case: A 40-year-old oncology nurse accidently splashed disinfecting solution in his right eye while cleaning a countertop. He immediately experienced a burning sensation and copiously lavaged his eye.

140 Chapter 9: Neuro-ophthalmic look-alikes

Figure 9.2 Pupils of the above nurse with accidental chemical exposure to the right eye three days earlier. The right pupil is markedly dilated and unresponsive to light stimulation and near effort; the left pupil is normal in shape, size and reactivity.

Several days later, he noted photophobia, blurred vision and a dilated pupil on that side (Figure 9.2).

Examination three days later revealed normal visual acuities at distance, but near vision in his right eye was poor (about 20/200) and required a +3.00 lens to achieve 20/20. In room light, his right pupil measured 8 mm and appeared to be completely unreactive to direct and consensual light stimulation. The left pupil measured 4 mm and had a normal light reflex. When the patient was asked to focus on a near object, there was normal convergence and pupillary constriction on the left side but there was no change in the right pupil. Ocular motility and fundus appearance were normal bilaterally. The anterior chamber was quiet and intraocular pressures were normal.

What common mechanisms of injury could explain this patient’s pupillary dysfunction?

A dilated pupil that does not constrict to light stimulation or to near effort indicates impairment of the iris sphincter. Possible mechanisms include direct damage to the sphincter muscle, pharmacologic paralysis of sphincter activity or denervation. In this case, there was no history of ocular trauma or prior surgery and the iris appeared structurally intact. The accidental chemical exposure to the eye in question raised the possibility of pharmacologic pupillary dilation. It was assumed that the disinfecting solution must have contained a parasympatholytic (atropine-like) agent that blocked the postsynaptic

receptors on the sphincter muscle. Thus, a diagnosis of pharmacologic mydriasis was made. The patient was told that his pupil should soon return to normal. Three weeks later, however, his examination was unchanged and therefore the possibility of postganglionic parasympathetic denervation of the sphincter was entertained.

What examination finding can distinguish pharmacologic blockade from postganglionic denervation of the iris sphincter?

Sectoral palsy, visible as a demarcation between areas of functioning and non-functioning iris sphincter, rules out pharmacologic blockade and localizes the site of damage instead to the peripheral short ciliary nerves. This is because pharmacologic agents, e.g. atropine-like substances, act diffusely on the iris sphincter and cannot produce sectoral paralysis. Slit-lamp examination with high magnification showed that this patient’s right iris sphincter was not completely paralyzed. There was a small nasal segment (between the two and four o’clock segments) that demonstrated normal contractility (Figure 9.3). General medical and neurologic examinations were otherwise normal as were blood glucose, general chemistries, syphilis serology and an erythrocyte sedimentation rate. A diagnosis of acute, idiopathic tonic (Adie’s) pupil was made. The close temporal relationship between the onset of his tonic pupil and the chemical exposure turned out to be purely coincidental. At two-month followup, his right pupil was still dilated and poorly reactive to light but now demonstrated cholinergic supersensitivity and light-near dissociation.

Discussion: Acute postganglionic denervation of the iris sphincter (Adie’s tonic pupil) and ocular exposure to an atropine-like agent can both lead to a large pupil, on the order of 7–9 mm in room light, that is unresponsive to light and near stimulation. Over time, a denervated pupil often develops cholinergic supersensitivity, light-near dissociation, and tonicity, but these characteristic features of an Adie’s pupil are not present in the first week (see also

Chapter 11, Isolated unilateral mydriasis). Thus, in the acute state, the only examination feature that effectively distinguishes denervation injury and pharmacologic mydriasis is the presence of sectoral palsy of the iris sphincter. An acutely denervated pupil may appear to have no light reflex when observed with the unaided eye. However, under high magnification at the slit-lamp or by using a magnifying glass and a bright hand-held light source, sectoral sphincter palsy is almost always visible. Sectoral palsy is detected by carefully watching each clock-hour segment of the sphincter as the illuminator light is rapidly turned on and off. Paralyzed sectors of the sphincter have an absent or thinned pupillary ruff, and the contour of the pupillary margin appears flattened (Figure 9.4). In addition, the iris segment adjacent to the palsied sector makes a characteristic undulating movement when the light is turned on, termed stromal streaming, due to passive pulling of the stroma toward normally contracting segments of iris.

Sectoral sphincter palsy is highly suggestive of, but not limited to, peripheral nerve injury. Direct injury to the iris can result in similar focal paral-

ysis of the sphincter muscle. In such cases, however, there is usually a history of trauma, intraocular inflammation or ocular surgery, as well as visible evidence of damage to other anterior segment structures. When it is unclear if the site of injury is the muscle or the nerve, look for other signs of postganglionic nerve injury such as cholinergic supersensitivity, light-near dissociation and tonicity, which favor a diagnosis of tonic pupil.

Sectoral sphincter palsy persists in the chronic phase of an Adie’s pupil and remains an extremely valuable clinical feature. While clinicians often depend on the dilute pilocarpine test to confirm a diagnosis of Adie’s pupil, it is important to remember that the demonstration of cholinergic supersensitivity using dilute pilocarpine is neither completely sensitive nor specific. About 20% of patients with tonic pupils fail to demonstrate such enhanced sensitivity. More importantly, cholinergic supersensitivity is also present in some patients with disruption of the preganglionic parasympathetic impulses to the iris, i.e. a third nerve palsy. The diagnosis of an Adie’s pupil is most confidently based on a constellation of clinical findings, the