Thanks to Amran for presenting an interesting case of a 84yo M with RA on MTX & Prednisone, and an unspecified self-resolving total body rash 1 month prior to presentation, presenting with pain, redness, and vision in both eyes. Detailed fundoscopic exam was consistent with bilateral anterior granulomatous uveitis as well as retinitis, consistent with a panuveitis picture. Initial work up revealed RPR and EIA positivity, his HLA-B27 also returned positive but he has no other findings suggestive of spondylosing arthropathy. His vitreal centesis returned positive for VZV!

In Summary:

• Tertiary syphilis without CNS/ocular involvement
• Panuveitis secondary to VZV
• Incidental HLA-B27 without e/o ankylosing spondylitis

Let’s start off with a basic review of the eye anatomy:

The Uvea consists of the iris, ciliary body, and the choroid. Uveitis is inflammation of any of these structures.

The Standardization of Uveitis Nomenclature (SUN) Working group guidance on uveitis terminology categorizes uveitis anatomically as follows;

• Anterior uveitis; localized primarily to the anterior segment of the eye, involving iris and pars plicata.
• Intermediate uveitis; localized to the vitreous cavity and pars plana, presence of WBC in the vitreous.
• Posterior uveitis; localized to the choroid and retina.
• Panuveitis; inflammation involving anterior, intermediate and posterior uveal structure

Uveitis can be further classified into granulomatous (presence of macrophages, multinucleated giant cells) vs non-granulomatous. A granulomatous uveitis is typically more likely to be an infectious process (although can still be idiopathic or Sarcoidosis).

Etiology of Uveitis

• Infectious:
  • HSV:
    • Usually unilateral, might have other clues such as presence of vesicles.
  • Toxoplasmosis:
    • Ocular toxoplasmosis for some reasons occurs more frequently in immunocompetent hosts.
  • Lyme Disease
  • Syphilis:
    • Accounts for less than 1% of cases of uveitis but can affect any part of the eye.
  • TB (Yes ocular TB exists!)
    • Uncommon in North America, suspect in endemic regions and worsening sx with glucocorticoids.
  • CMV:
    • Almost exclusively in immunocompromised hosts i.e. AIDS patients.
    • CD4 < 50 typically.
  • Bartonella (ocular bartonellosis) aka Cat Scratch Disease:
    • Typically unilateral, has a characteristic “macular star” on fundoscopic exam.
  • West Nile virus
  • Ebola (case reports)
  • Zika virus
  • Varicella Zoster Virus: Can affect any part of the eye

• Non-infectious: Most common = HLA-B27 related arthropathies and reactive arthritis, tends to be unilateral and causes an anterior uveitis picture
  • Sarcoidosis
  • IBD
  • Ankylosing spondylitis
  • Relapsing polychrondritis:
  • Behcets
  • Juvenile idiopathic arthritis
  • Psoriatic arthritis
  • Reactive arthritis
  • TINU (tubulointerstitial nephritis and uveitis) syndrome
    • Uncommon, occurs in adolescent/young F, fever, myalgias, anemia, LFT elevation, chronic uveitis, interstitial nephritis.
  • MS: Optic neuritis
  • Vogt-Koyangi-Harada(VKH)Syndrome:
    • Japanese and Hispanics, bilateral panuveitis, neurological/auditory sx
  • Penetrating trauma
  • Drug-induced:
    • Rifbutin, fluoroquinolone, monoclonal ab

• Other conditions that might mimic uveitis
  • Retinal tears
  • Ischemia
  • Leukemia
  • Lymphoma
  • Ocular melanoma
  • Pigmentary dispersion syndrome
  • Retinitis pigmentosa
  • Retinoblastoma

Management

• Treat underlying cause
• If viral: Anti-virals (acyclovir, valacyclovir), add on topical corticosteroids.
• Non-infectious uveitis: Management typically with topical steroids. If posterior, some have suggested using difluprednate or periocular glucocorticoid injections. Systemic tx is reserve for pts with bilateral disease, inability to tolerate intraocular injections, or systemic conditions i.e. Behcets.
• If refractory to steroids in non-infectious causes, can consider MTX, azathioprine, mycophenolate, cyclosporine, or tacrolimus.
• TNF alpha inhibitors u.e. adalimumab has good evidence in the tx of non-infectious intermediate, posterior, and panuveitis. Can also be considered first line in management of Behcet.
• Sulfasalazine has been shown in a few small studies to prevent HLA-B27 associated uveitis.

Please refer to this previous blog post for more details on tertiary syphilis!

Thanks to Arathi for presenting the case of a middle-aged man with poorly controlled diabetes who presented with blurry vision and ear pain, found to have multiple cranial nerve palsies, diagnosed with skull base osteo, septic dural sinus thrombosis, and orbital cellulitis!

Clinical Pearls

• Septic thrombophlebitis is venous thrombosis with inflammation in the setting of bacteremia and can impact any vein.  Most common cause of this condition in the hospitalized patient is indwelling lines and catheters.
  • Septic thrombophlebitis of the jugular vein is called Lemierre’s syndrome and is frequently preceded by pharyngitis.
• Septic dural sinus thrombosis is extremely rare (only several hundred cases diagnosed in recent history).  The most common presenting symptom is headache.  There are three types:
  1. Cavernous sinus thrombosis
  2. Lateral (transverse) sinus thrombosis (rare)
  3. Superior sagittal sinus thrombosis (very rare)
• Cavernous sinus thrombosis can present with CN III, IV, V1, V2, VI palsies.  Of these, CN VI is the first one to get affected.  So for patients presenting with lateral gaze palsy and headache, think cavernous sinus thrombosis!
• The mainstay of treatment for septic dural sinus thrombosis is antibiotics.  Most common organism involved is staph aureus.
  • The role of anticoagulation is controversial.  The few retrospective studies done have shown a potential reduction in mortality/morbidity without a significant increase in risk of ICH.  Common practice currently is to start anticoagulation with heparin early on especially in patients with unilateral symptoms.

Septic dural sinus thrombosis

• Uncommon disease with only several hundred cases reported in the antibiotic era. So you might only see one in your whole career!
• Difficult to diagnose and often diagnosis and treatment are delayed.
• Encompasses three basic syndromes: manifestations of each are unique
  1. Cavernous sinus thrombosis
  2. Lateral sinus thrombosis
  3. Superior sagittal sinus thrombosis
• All three manifest as severe headaches which are often the presenting symptom.

Septic cavernous sinus thrombosis

• Most common. Lots of trabeculae to trap bacteria.
• Clinical manifestations
  • Headache and cranial nerve palsies should raise your suspicion!
  • Fever, periorbital edema. Pain is usually unilateral, retroorbital and frontal in nature with radiation to the occiput.
  • Diplopia
  • Altered mental status especially in older people
  • Less common: photophobia, tearing, and ptosis
• Exam:
  • Fever
  • B/l ptosis, proptosis, chemosis, and ocular muscle paralysis but can be subtle
  • Fundoscopic exam with papilledema
  • Ophthalmoplegia
    • Lateral gaze palsy (isolated CN VI) is the first manifestation because of the location of the nerve in the cavernous sinus.
  • Loss of visual acuity from papilledema
  • Compression of optic nerve by mycotic aneurysm of the intercavernous segment of the internal carotid/ophthalmic artery can lead to blindness.
• Labs:
  • CSF can show inflammatory cells in 75% of cases.
  • Micro
    • Staph aureus is the most common (70%) followed by strep and anaerobes.
  • Imaging:
    • CT venogram or MR venogram
  • Treatment
    • Antibiotics: IV and prolonged for at least 3 weeks b/c thrombus may prevent abx penetration
    • Anticoagulation: No prospective data. One retrospective study showed a significant reduction in mortality in patients with unilateral involvement who presented early and received heparin. A second showed no change in mortality but decreased morbidity.  No increased risk of ICH.  Based on these small studies, experts suggest heparin early on in patients with unilateral CST.  Duration of anticoagulation is at the discretion of the clinician (no data).
    • Surgery: Drainage of sinus infection if present, otherwise no benefit.
    • No role for steroids
• Outcomes
  • Mortality is 30%
  • Infection can spread to meninges and the pituitary and morbidity can reach 50%.
  • 30% suffer serious sequelae:
    • Persistent oculomotor weakness
    • Blindness
    • Hemiparesis
    • Pituitary insufficiency

Septic lateral sinus thrombosis

• Rare due to early treatment of otitis media. Generally results from untreated OM à mastoiditis à lateral sinus thrombosis.
• Earache is generally the first symptom for several weeks

Septic superior sagittal sinus thrombosis

• Extremely rare
• Usually due to bacterial meningitis
• Complete thrombosis is universally fatal.

Differential for cavernous sinus obstruction:

• Infectious
  • fungal
  • TB
  • septic thrombosis
  • intra-orbital abscess
• autoimmune/rheum
  • Tolosa-Hunt syndrome (granulomatous inflammation of the superior orbital vein and cavernous sinus)
  • Polyarteritis nodosa (Cogan syndrome)
  • sarcoid
  • IgG4 dz
  • GPA
• malignant
  • Lymphoma
  • Nasopharyngeal tumor
• Vascular
  • Thrombus

Skull base osteomyelitis:

• Frequently seen in elderly patients with poorly controlled diabetes or immunocompromise
• Most commonly a complication of malignant otitis externa.
• Results in multiple cranial nerve palsies VII through XII due to involvement of the stylomastoid, jugular, and hypoglossal foramens.
• Treatment requires antibiotics for at least 4-6 weeks.