Optic Neuropathy

General clinical features

• Reduced visual acuity
• RAPD
• Reduced light sensitivity
• Reduced colour vision
• VF defects eg. negative scotoma
• Optic disc abnormalities
• Retrobulbar pain

Optic neuritis

General subtypes

• Papillitis
• Retrobulbar neuritis
• Neuroretinitis

Either idiopathic or associated with systemic disease

• MS
• NMO
• Syphilis
• Sarcoidosis
• Lyme disease
• Wegener’s, SLE (and other collagen vascular diseases)

Acute demyelinating optic neuritis

• Demyelination is the most common cause of optic neuritis

• Is the presenting feature of MS in 20% of cases

• 3:1 female to male preponderance

• Typically unilateral

• Time course:

  • Rapid decrease in VA (rarely to NPL thought)
  • Recovery begins within 2 weeks and may continue for months

• Associated features: reduced colour vision, field loss, retrobulbar pain (typically precedes reduced VA), photopsia, RAPD, disc swelling (only in 1/3rd)

  • Reduced contrast sensitivity is the most sensitive test for optic neuritis
  • Retrobulbar pain was present in 92% of patients in the ONTT (therefore absence of pain should call the diagnosis into question)
  • Field loss typically a central scotoma

Corticosteroids

• Did not affect final VA in Optic Neuritis Study Group (ONTT) study
• No conclusive evidence for benefit
• May be considered if poor VA in fellow eye or severe pain
• Oral prednisolone was associated with higher risk of recurrent episodes

Prognosis

• >90% improve to 6/9

• However abnormalities in contrast sensitivity, colour vision, stereopsis, VF may remain

• 1/3rd have second episode within 5 years

• The 10 year recurrence risk was 35% in the ONTT

• Poorer visual prognosis:

  • Greater length of optic nerve involved on MRI (with FLAIR)
  • Intracanalicular involvement
  • Poor VA at presentation

Risk factors for MS (in patients with isolated optic neuritis)

• Overall risk in clinically isolated optic neuritis is 38%

• Female

• Multiple white matter lesions on MRI

  • 25% risk (in 15 years) of MS if MRI is normal
  • 75% risk (in 15 years) if >1 white matter lesion seen
  • Cumulative risk of 50% at 15 years after onset of optic neuritis

• CSF oligoclonal bands

• Lower risk:

  • Male
  • Painless
  • Poor vision (NPL)
  • Severe optic disc swelling eg. haemorrhagic, exudates

Paediatric optic neuritis

• More typically bilateral and with disc swelling

Atypical

• Cases which do not fulfil the above criteria should be investigated to exclude compressive lesions or other pathology

  • Gadolinium-enhanced MRI

    • If normal, sequential follow-up may be all that is needed
    • If showing demyelination, IVMP could be considered and referral to a neurologist
    • Imaging of the spinal cord is important in possible Devic’s

  • CXR

  • Bloods: FBC, U&Es, ESR/CRP, LFTs, glucose, ACE, ANA, ANCA, syphilis serology, NMO (anti-aquaporin 4) and anti-MOG

  • Genetic testing for LHON

  • LP for microscopy, protein, glucose, oligoclonal bands and cytology

• Differential diagnosis

  • Compressive lesion: disc pallor, pain, involvement of other structures
  • Sphenoid sinus disease: pyrexia, sinusitis, diabetic
  • Sarcoidosis: uveitis, steroid-responsive
  • Vasculitis: eg. SLE
  • Syphilis: disc swelling, uveitis, leucocytosis in CSF, HIV positive
  • AION: segmentally swollen disc, altitudinal field loss, older patients
  • Toxic/nutritional: slowly progressive, symmetrical
  • LHON: sequential VA loss, telangiectasia at the disc, young adults especially male with family history
  • Post-viral demyelination: often bilateral, post-vaccination
  • Optic perineuritis
    • Can be clinically indistinguishable from demyelinating optic neuritis
    • T1 MRI shows enhancement and thickening of the optic nerve sheath butnotof the nerve itself (features also seen with optic nerve sheath meningiomas)
    • Considered on the spectrum of orbital pseudotumour (idiopathic orbital inflammation)
    • Does not carry the same risk of future MS
    • Requires work up to exclude sarcoidosis, GCA, lymphoma, Wegener’s, TB and syphilis

Multiple sclerosis

• T cell mediated autoimmune neurodegenerative disorder

• Inflammation in CNS myelin followed by sclerosis

• Northern Europeans

• HLA DR2

• 3-7/100,000/year in the UK

• Ophthalmic clinical features

  • Optic neuritis
  • Internuclear ophthalmoplegia
  • VF defects
  • Uveitis, typically periphlebitis and intermediate uveitis
  • Nystagmus

• Diagnosis is based on clinical features supported by MRI (showing white matter lesions disseminated in time and space) and CSF analysis (showing oligoclonal bands)

• Subtypes

  • Relapsing-remitting (85%)
  • Secondary progressive (initially relapsing-remitting)
  • Primary progressive

• Treatment: acute episodes can be managed with glucocorticoids or plasmapheresis. Immunomodulatory therapies are used as prevention and to reduce disability

  • Interferon-beta (Avonex) has been shown to reduce the risk of progression to MS in patients with a demyelinating event and an MRI with 2 or more lesions in the CHAMPS trial

• Prognosis: highly variable. Life expectancy is normal/near-normal

• OCT in MS:

  • There is evidence that the peripapillary RNFL is significantly reduced in eyes with previous optic neuritis
  • The GCL-inner plexiform layer complex may be thinned during acute attacks
  • Fingolimod(an oral sphingosine-1-phosphate receptor modulator) is associated with macular oedema in 0.3-0.4% of cases. Macular oedema resolves within 6 months of stopping drug. Ocular screening is recommended with VA and OCT

Neuromyelitis optica (Devic’s disease) spectrum disorders (NMOSD)

• Primarily affects the optic nerves and spinal cord, ** sparing the brain**

• Combined inflammation and demyelination with autoimmune component

• F>M, mean age in the late 30s

• Suspect in atypical optic neuritis

  • Profound visual loss (ie. <6/60)
  • Bilateral or sequential recurrent optic neuritis with anormal contrast MRI brain
  • Transverse myelitis: often recurrent

• Three core clinical characteristics

  • Optic neuritis
  • Acute myelitis with longitudinally extensive transverse myelitis (LETM)
  • Postrema syndrome: lesions in the brain causing vomiting/hiccups

• Diagnostic criteria

  • Aquaporin-4 IgG positive with 1 of the above
  • Aquaporin-4 IgG negative and two of the above

• Tests

  • Aquaporin-4 IgG: AQP4 is a water channel

    • >75% have a positive test with >99% specificity
    • May become seropositive later if initially negative

  • Serum myelin oligodendrocyte glycoprotein (MOG) antibodies: may be positive in AQP4 negative cases

    • MOG is a protein on the oligodendrocyte surface

  • MRI head and spinal cord with contrast

    • Relative paucity of cerebral involvement
    • Involvement of 3 or more spinal cord segments
    • Optic nerve enhancement

  • CSF analysis: pleocytosis and/or glial fibrillary acidic protein (elevated in the acute phase)

    • No oligoclonal bands!

• Management

  • Acutely: high-dose IVMP followed by long oral taper
  • Long-term: steroid-sparing agents eg MMF, azathioprine, rituximab, eculizumab (a C5a complement inhibitor), mitoxantrone
  • NB: interferons used for MS make NMOSD worse!

• Prognosis

  • Monophasic: 20% have permanent visual loss and 30% have permanent paralysis
  • Relapsing:
    • 55% relapse within 1 year and 90% within 5 years
    • 50% have permanent visual loss or paralysis within 5 years
    • 70% 5 year survival

Ischaemic optic neuropathy

Anterior ION is significant cause of visual loss in the elderly

• 10/100,000/year in those over 50
• 90-95% non-arteritic
• 5-10% arteritic

Arteritic vs Non-arteritic
Arteritic	Non-arteritic
GCA Less commonly:- Churg-strauss - PAN - GPA - RA - SLE - Takayasu arteritis Pathology is of vasculitis in the short posterior ciliary artery leading to ischaemia of the optic nerve head	HTN Diabetes Disc-at-risk Smoking Hyperlipidaemia Acute hypotension OSA Anemia/haemodilution Disc drusen Cataract surgery in NAION eye: increases risk of NAION in fellow eye! Cardiac surgery Hypercoagulable states Drugs- Amiodarone - Sildenafil Radiation
Mean age 70, more common in males	Mean age 60
VA typically <6/60	VA typically >6/60 with altitudinal field loss (45% have inferior and 15% superior field)
Associated scalp tenderness, jaw claudication, PMR, weight loss, night sweats, warning amaurosis
Swollen, pallid disc with RAPD, peripapillary haemorrhages, CWS May be associated CRAO, BRAO, CN palsies	Sectorally swollen (typically superior disc), hyperaemic, telangiectasia, small/crowded disc, with RAPD Associated “disc-at-risk” in the fellow eye
Raised ESR, CRP and platelets Enhancement of the optic nerve is seen on MRI Patchy choroidal filling on FFAdue to vasculitic occlusion of posterior ciliary arteries
15% improve. With treatment there is a 10% risk to the fellow eye (95% if untreated) Other complications:- TIA/stroke - MI - Neuropathies - Mesenteric artery occlusion - Thoracic artery aneurysm: consider 2-yearly CXRs to monitor - Death	40% improve

Traditional GCA criteria

• Age over 50
• New onset localised headache
• Temporal artery tenderness and reduced pulse
• ESR >50
• Arterial biopsy showing necrotizing arteritis with predominance of mononuclear cell infiltrates or granulomas
• 3 or more of these criteria has a 93.5% sensitivity and 91.2% specificity for GCA

Temporal artery biopsy

• Recommended length of at least 2cm to avoid skip lesions
• Should be done within 1 week although can be positive up to 6 weeks after starting treatment
• Should be done on the side of visual loss
• If clinical picture and inflammatory markers suggest GCA but the biopsy is negative, the patient should still be managed for GCA
• Risks
  • Scarring
  • Haematoma
  • Infections
  • Scalp/skin necrosis
  • Facial nerve injury
  • Missing the artery
  • Cerebral infarction: rare

GCA Treatment

• IVMP (1g/day for 1-3 days) followed by oral pred taper
• Tocilizumab (an IL-6 receptor antagonist) has been shown to work in facilitating steroid remission at 1 year

Non-arteritic AION

• Thought to be due to perfusion insufficiency in the short posterior ciliary arteries

• Most common acute optic neuropathy in those over 50 years old

• Presents with sudden loss of vision which may be progressive, typically >6/60

  • Commonly occurs overnight therefore nocturnal hypotension may play a role
  • Classically cause sectoral oedema of superior disc leading to inferior altitudinal field defects

• GCA must be ruled out first

• Tests:

  • FBC, glucose, lipids, blood pressure
  • Consider a vasculitic screen if they are under 50

• Treatment: no proven treatment

  • Low-dose aspirin commonly given
  • Refer to physician for vascular risk factor assessment

• Prognosis

  • The Ischemic Optic Neuropathy Decompression Trial found 43% improved at 6 months with 3 or more Snellen lines; while 12% lost 3 lines or more
  • 14.7% risk of second eye involvement over 5 years
    • Poor initial VA and diabetes predict second eye involvement

Pseudo Foster Kennedy syndrome

• Sequential NAION
• Demonstrates one swollen nerve and one atrophic nerve (due to NAION event at least 6-8 weeks earlier)
• Both nerves show visual field defects consistent with NAION (altitudinal or arcuate defects)

Foster Kennedy syndrome

• Intracranial mass, classically a frontal meningioma
• The mass initially causes a unilateral compressive optic neuropathy, but grows to obstruct CSF flow leading to raised ICP
• The compressed nerve is atrophic so does not swell but the fellow nerve does
• The atrophic eye demonstrates variable field defects
• The swollen nerve demonstrates an enlarged blind spot

Posterior ischaemic optic neuropathy (PION)

• Rare

• Abrupt ischaemia of the posterior optic nerve, which is supplied by the pial plexus from the ophthalmic artery

• Aetiology

  • Blood loss/shock/hypotension/non-ocular surgery (eg. prolonged spinal surgery/prone position surgeries)
  • Anaemia
  • GCA

• Clinical features

  • Sudden visual loss with an RAPD (although it is commonly bilateral)
  • Normal appearance of the optic disc: pallor develops 6-8 weeks later

• Tests

  • Rule out GCA
  • FBC, glucose, blood pressure, lipids and a vasculitic screen if under 50
  • Consider an MRI to exclude a compressive/infiltrative lesion

Other optic neuropathies

Leber’s hereditary optic neuropathy (LHON)

• Rare, maternally inherited

• Point mutations in mitochondrial DNA

• May present at any age, but typically young male adult (M>F)

• 50% have family history

• Identified mutations at these nucleotide positions (which affect complex I of the respiratory chain)

  • 11778 (95%): worst prognosis
  • 3460
  • 14484

• LHON may be precipitated by a toxic insult

• Clinically

  • Sudden painless LOV typically 6/60 to HM
  • Second eye affected within 2 months
  • Dense centrocecal scotoma
  • Reduced colour vision
  • Peripapillary telangiectasia
  • Peripapillary RNFL swelling early with late pallor
  • Normal pupil reactions

• Tests

  • Mitochondrial DNA analysis
  • Screen for differential causes eg. toxins/nutritional deficiencies

• Treatment

  • No clear benefit with idebenone
  • Gene therapy in future

• Poor visual prognosis. Spontaneous recovery has been seen in the 14484 mutation

Nutritional/toxic neuropathies

• All behave similarly: thought to be due to reduced mitochondrial function through B vitamin deficiency and toxic effects of poisons (such as cyanide)

Tobacco-alcohol amblyopia

• Clinical features

  • The papillomacular bundle appears particularly susceptible hence:
  • Subacute painless bilateral loss of vision typically 6/9-6/60
  • Small centrocecal scotoma (relatively symmetrical)
  • Reduced colour vision
  • Early peripapillary swelling of the disc with latetemporal pallor
  • Peripheral neuropathies

• Tests

  • Detailed history
  • B vitamin levels
  • Folic acid levels
  • Heavy metal screening eg lead

-Management

• Replace deficiencies (B12 is given IM along with folate)

• Prophylactic supplementation in alcoholics

• Possible drug toxins:

  • Amiodarone
  • Ethambutol
  • Methanol
  • Carbon monoxide
  • Cyanide
  • Isoniazid
  • Lead
  • Triethyl tin

• Prognosis can be good with a slow recovery if patients comply with treatment

Dominant optic atrophy

• Aka Kjer syndrome
• Most common hereditary optic neuropathy
• Autosomal dominant
• Mutation in nuclear OPA1 gene on chromosome 3 which encodes a GTPase involved in mitochondrial energy production and integrity
• Bilateral symmetrical reduction in VA typically 6/9-6/36
• Develops in mid-late childhood
• Subtle, temporal or diffuse optic atrophy
• Typically progresses gradually over decades

Behr syndrome

• Comprises

  • Optic atrophy (diffuse)
  • +/- nystagmus
  • Ataxia
  • Spasticity
  • Reduced IQ

• Autosomal recessive

Wolfram syndrome (DIDMOAD)

• Diabetes insipidus, diabetes mellitus, optic atrophy and deafness
• Various mutations and modes of inheritance
• Typically presents between ages 5 and 20
• Diffuse, severe optic atrophy
• Poor visual prognosis
• Other variable systemic abnormalities