Leber Hereditary Optic Neuropathy (LHON) - EyeWiki Key Points

Disease Overview

• LHON is the most common inherited mitochondrial disorder
• Begins as unilateral progressive optic neuropathy, with sequential fellow eye involvement months or years later
• Males more commonly affected than females - some reported ratios as high as 9:1
• Age of onset typically 10-30 years; onset in the 7th or 8th decade has also been noted
• Visual loss usually progresses to worse than 20/200
• Visual loss rarely progresses to no light perception
• ICD-10: H47.2 | ICD-9: 377.16 | OMIM: 535000

Etiology

• These mutations affect respiratory chain complex I genes
• 90% of LHON patients harbor one of these three mutations

Heteroplasmy (important unique feature)

• 10-15% of LHON patients have a mixed population of normal and mutant mitochondria
• Those with mutation load < 60-75% may never develop visual loss
• The right and left eyes may have different amounts of affected mitochondrial DNA due to heteroplasmy

Pathophysiology

• Mitochondrial mutations cause defects in NADH-ubiquinone oxidoreductase chains
• Impairs glutamate transport; increases reactive oxygen species → retinal ganglion cell death, specifically in the papillomacular bundle (small calibre axons particularly vulnerable)
• In acute LHON: macular changes precede peripapillary RNFL swelling
• Acute thickening is followed by long-term thinning
• Process is thought to be due to a state of pseudohypoxia followed by compensatory response
• OCT-A findings: vascular dilation and tortuosity

Risk Factors

• Unknown why males preferentially affected (up to 80%); theory: susceptibility locus on Y chromosome
• Age and lifestyle choices alone do NOT increase LHON incidence
• Tobacco and alcohol may worsen disease severity once a person develops LHON (late-onset patients had higher cumulative consumption)

Diagnosis

History

• Unilateral, slowly progressive, painless visual blurring - second to fourth decade
• Average age of onset: 22-24 years (G11778A mutation); ~20 years (T14484C mutation)
• Often confused with optic neuritis - key difference is lack of pain
• Longest interval between first and second eye: 18 years
• "LHON Plus" disease: associated with dystonia, tremor, neuropathy, movement disorders, arrhythmias, Leigh syndrome

Physical Examination

• Visual acuity: mildly reduced early, may progress to counting fingers
• Afferent pupillary defect (APD) when disease is asymmetric
• Decreased red-green colour discrimination
• Central or cecocentral scotoma on visual fields
• Subclinical deficits in seemingly unaffected fellow eye on formal VF testing
• Reduced contrast sensitivity; subnormal electroretinograms
• Anterior segment: normal slit lamp
• Fundus: hyperemic, pseudo-edematous optic nerves with peripapillary telangiectasias
• Tortuous retinal arterioles
• No leakage on fluorescein angiogram (unlike inflammatory optic disc edema) - KEY distinguishing feature

Diagnostic Procedures

• Fluorescein angiogram: no dye leakage at optic nerve borders (rules out true edema)
• OCT: elevation early; atrophy in later phases
• MRI: recommended to rule out demyelinating disease and compressive lesions
  • LHON can show increased T2 signal in optic nerves, chiasm, and tracts
  • May show optic nerve enhancement AND chiasmal enlargement/enhancement - can mimic optic neuritis
  • These MRI findings should NOT dissuade physicians from including LHON in the differential
• Lab tests: B12, folate, RPR, FTA-ABS, ANA, Lyme titres, ACE, PPD to exclude other causes
• Genetic testing: targeted mutation analysis - 90% will have one of the three primary mutations; helps predict prognosis

Management

Medical Therapy

• No established treatment; management is primarily supportive
• Early visual aids and occupational therapy
• Antioxidants (vitamins B12, C, coenzyme-Q10, brimonidine, lutein) - minimal benefit
• Avoid tobacco and alcohol (increase oxidative stress)

Idebenone (RHODOS Trial - Key Trial)

• Short-chain synthetic benzoquinone
• Double-blind, randomized, placebo-controlled trial
• 85 patients; idebenone 300 mg TID for 24 weeks
• Did not reach primary endpoint (best recovery in VA)
• Post-hoc analysis: improvement in patients with discordant vision between eyes
• G11778A and G3460A mutations appeared to benefit more
• Well-tolerated; results promising but limited utility

Gene Therapy (Emerging)

• EPI-743: potentially more potent than idebenone; no clinical trials yet
• Allotopic expression and nuclear transfer techniques
• Phase 1 trial: intravitreal injection of genetically modified AAV vectors with ND4 gene in 15 patients with G11778A mutation - safe and well-tolerated, mild intraocular inflammation
• Another study of 5 patients (G11778A): similar safety results with some improvement in certain patients

Medical Follow-Up & Genetic Counselling

• Serial monitoring: VA, visual fields, contrast sensitivity, colour testing
• Early provision of low-vision aids
• Genetic counselling recommended for patients and maternal family members
• Male patients cannot transmit LHON to offspring (mitochondrial inheritance)
• Mother of affected individual likely harbours the mutation (may or may not have symptoms)
• Female patients transmit the mutation to ALL offspring
• Heteroplasmic females may transmit low mutation load - offspring may have low disease risk
• De novo mutations are rare but possible (even without maternal family history)

Horner Syndrome - Important Points Beyond Kanski

1. Neuroanatomy & Three-Neuron Arc (Detailed)

• 1st order (central): Hypothalamus → lateral tegmentum of brainstem → ciliospinal centre of Budge (C8-T2) in the spinal cord
• 2nd order (preganglionic): Exits C8-T2 → over the apex of the lung and subclavian artery → up to the superior cervical ganglion (at the level of C2-C3 vertebrae / carotid bifurcation)
• 3rd order (postganglionic): Travels along the internal carotid artery (ICA) into the cavernous sinus → joins the ophthalmic division of CN V → enters the orbit to supply the dilator pupillae, Müller's muscle (upper lid), inferior tarsal muscle (lower lid)

The sudomotor fibers for the face split at the carotid bifurcation: fibers for the medial forehead follow the ICA; fibers for the rest of the face follow the external carotid artery (ECA). This is why postganglionic (3rd order) lesions above the bifurcation often spare facial anhidrosis.

2. Complete Clinical Features (Beyond the Classic Triad)

• Localization in Clinical Neurology 8e, p. 498-499
• Adams & Victor's Principles of Neurology 12e

3. Dilatation Lag - The Most Important Diagnostic Sign

• Best clinical discriminator between Horner syndrome and physiologic anisocoria
• Anisocoria is greatest at 5 seconds after dimming lights, then reduces at 15 seconds
• Demonstrable in only ~50% of patients clinically
• The mechanism: normal pupil dilates via active sympathetic stimulation; Horner pupil dilates only passively via parasympathetic withdrawal (slower)
• Localization in Clinical Neurology 8e, p. 498

4. Anhidrosis - Localisation Clue

• Adams & Victor's Principles of Neurology 12e

5. Pharmacological Testing - Detailed Protocol

Step 1 - Confirm Horner (Apraclonidine or Cocaine)

• Alpha-2 agonist + weak alpha-1 agonist
• In Horner, the denervated dilator muscle develops adrenergic supersensitivity (takes 2-5 days to develop)
• Alpha-1 receptor supersensitivity causes the Horner pupil to dilate with apraclonidine (alpha-1 dominant effect)
• Normal pupil slightly constricts (alpha-2 effect predominates)
• Result: reversal of anisocoria = positive test
• Ptosis also reverses within 5 minutes (Mueller's muscle effect via conjunctival penetration)
• Important: May give false negatives in acute Horner (< 2-5 days old, before supersensitivity develops)

• Blocks norepinephrine reuptake → dilates normal pupil only
• Failure to dilate = Horner confirmed
• 1 drop in each eye; check at 45-60 minutes
• Limitation: controlled substance, causes positive urine drug screen

Step 2 - Localise (Hydroxyamphetamine 1%)

• Releases stored norepinephrine from intact postganglionic terminals
• 3rd-order lesion: postganglionic neuron damaged → no norepinephrine to release → pupil does NOT dilate
• 1st or 2nd-order lesion: postganglionic neuron intact → pupil dilates normally
• Sensitivity up to 93%, specificity 83% for 3rd-order lesion
• Must wait 48-72 hours after cocaine or apraclonidine before using hydroxyamphetamine (to avoid interference)
• Requires intact corneal epithelium; no prior eye drops (including anesthetic drops)
• Often unavailable even from compounding pharmacies

Most experts now recommend imaging the entire sympathetic pathway regardless of pharmacological test results, as false positives and negatives occur.

• Wills Eye Manual, pp. 640-641

6. Causes by Neuron Order

First-Order (Central) Causes:

• Stroke (Wallenberg lateral medullary syndrome - most classic), tumor, MS, neuromyelitis optica
• Syringomyelia, sarcoidosis, syphilis, poliomyelitis
• Anterior spinal artery thrombosis, giant cell arteritis (with ipsilateral INO)
• Diencephalomesencephalic junction lesions, hemorrhage, trauma
• Accompanying symptoms: hemisensory loss, dysarthria, dysphagia, ataxia, vertigo, nystagmus

Second-Order (Preganglionic) Causes:

• Pancoast tumor (apical lung cancer) - most common overall cause of Horner syndrome
• Aortic aneurysm (tertiary syphilis), mediastinal lymphadenopathy
• Thyroid adenoma, neurofibroma/schwannoma, neuroblastoma, chordoma
• Cervical rib, ruptured intervertebral disc, foraminal osteophyte
• Iatrogenic: chest drain, central line (subclavian/jugular catheterization), carotid endarterectomy, radical thyroid surgery, vagus nerve stimulator implantation, anterior cervical fusion (C3-C6)
• Herpes zoster (T3-T4 distribution), thoracic epidural analgesia
• In children: neuroblastoma is the key concern
• Arm or scapular pain + Horner = suspect Pancoast tumor
• Accompanying symptoms: arm pain, scapular pain, wasting of intrinsic hand muscles

Third-Order (Postganglionic) Causes:

• Carotid artery dissection - most urgent diagnosis to exclude; painful Horner
• Cluster headache, migraine, Raeder paratrigeminal syndrome
• Varicella zoster, otitis media, Tolosa-Hunt syndrome
• Cavernous sinus pathology (thrombosis, infection, aneurysm, tumor)
• Neck trauma/tumor/inflammation
• Accompanying symptoms: ipsilateral head/face/neck pain, pulsatile tinnitus, dysgeusia (foul taste), possible TIA/stroke signs
• Wills Eye Manual, p. 640; Neuroanatomy through Clinical Cases 3e; Localization in Clinical Neurology 8e

7. Bilateral Horner Syndrome

• Rare - usually seen in:
  • Autonomic neuropathies
  • High cervical cord transection
• Bilateral miosis may be detected by: pronounced dilation lag when light is withdrawn (pupils redilate slowly and remain small)
• Adams & Victor's Principles of Neurology 12e

8. Sympathetic Irritation Syndrome (Opposite of Horner)

• Stimulation/irritation of sympathetic fibers produces the opposite of Horner:
  • Lid retraction + pupil dilation + apparent proptosis
• This is the basis of the ciliospinal reflex: painful pinch to the neck (afferent: C2, C3) → pupillary dilation via cervical sympathetic efferents
• If ciliospinal reflex is absent on one side = Horner syndrome on that side
• Adams & Victor's Principles of Neurology 12e

9. Raeder Paratrigeminal Syndrome

• Postganglionic Horner + ipsilateral facial pain (trigeminal distribution) + variable CN III, IV, VI involvement
• Caused by lesion near the trigeminal ganglion / parasellar region / middle cranial fossa
• Must rule out: ICA aneurysm, parasellar tumour, middle fossa mass
• Medscape; Wills Eye Manual

10. Congenital Horner Syndrome

• Birth trauma (especially Klumpke's palsy - lower brachial plexus injury affecting C8-T1) is the most common cause
• Associated with heterochromia iridis (lighter ipsilateral iris) - only if onset before age 2
• Straight hair on the affected side vs curly hair on the other side
• Autosomal dominant hereditary form exists (often with congenital iris depigmentation)
• Adams & Victor's Principles of Neurology 12e; Localization in Clinical Neurology 8e

11. Imaging Protocol (NANOS Recommendation)

• New-onset Horner = urgent workup to exclude life-threatening causes
• MRI brain + neck (full sympathetic axis imaging)
• MRA or CTA of head and neck if carotid dissection suspected (especially with ipsilateral neck or face pain)
• CT/MRI chest to evaluate lung apex (Pancoast tumor)
• Ultrasonography is NOT reliable for diagnosing carotid dissection in isolated Horner
• Old photographs are useful - to determine if Horner is truly new or longstanding (chronic Horner is more likely benign)
• Lymph node biopsy if lymphadenopathy is present
• MIBG scan if neuroendocrine tumour suspected
• Wills Eye Manual, pp. 640-641; Medscape

12. Carotid Dissection - The Urgency Trigger

• Internal carotid artery dissection is life-threatening (risk of disabling stroke)
• Presents with: painful Horner + ipsilateral face/neck pain + pulsatile tinnitus + dysgeusia
• Requires: MRI/MRA of brain and neck
• Treatment: antiplatelet therapy (aspirin) to prevent carotid occlusion and hemispheric stroke; rarely anticoagulation; surgical intervention if ischemic symptoms persist
• Wills Eye Manual; Medscape

13. IOP Change

• Transient decrease in IOP (ocular hypotony) is seen in the acute phase due to reduced episcleral vascular tone
• Not permanent
• Localization in Clinical Neurology 8e; Wills Eye Manual

14. Pontine Lesions and Bilateral Miosis

• Pontine lesions cause extreme bilateral miosis (not Horner per se) - due to interruption of descending pupillodilator fibers bilaterally
• Clinically important differential for small bilateral pupils (along with narcotic ingestion)
• Adams & Victor's Principles of Neurology 12e