Curr Treat Options Neurol (2019) 21:36

DOI 10.1007/s11940-019-0579-9

Neurologic Ophthalmology and Otology (R Shin and D Gold, Section Editors)

Treatment Strategies
for Neuroretinitis: Current
Options and Emerging
Therapies
Aaron M. Fairbanks, MD1
Matthew R. Starr, MD1
John J. Chen, MD, PhD1,2
M. Tariq Bhatti, MD1,2,*
Address
*,1
Department of Ophthalmology, Mayo Clinic, 200 First Street Southwest, Roch-
ester, MN, 55905, USA
Email: [email protected]
2
Department of Neurology, Mayo Clinic, Rochester, MN, USA

* Springer Science+Business Media, LLC, part of Springer Nature 2019

This article is part of the Topical Collection on Neurologic Ophthalmology and Otology

Keywords Neuroretinitis I Bartonella I Disc edema I Macular star I Cat scratch optic neuropathy

Abstract
Purpose of review To explore and critically appraise the published data on the
current and emerging treatment modalities for neuroretinitis.
Recent findings The optimum treatment strategy for neuroretinitis due to Bartonella henselae
in immunocompetent individuals is not clear and a matter of debate. The role of systemic
corticosteroids in infectious neuroretinitis and the optimum immunosuppressive regimen for
use in recurrent idiopathic neuroretinitis also remains ill defined.
Summary There is no class 1 evidence to support a specific treatment strategy for
neuroretinitis. For uncomplicated B. henselae–associated neuroretinitis in immunocompetent
patients, initiation of antibiotic and corticosteroid therapy remains controversial. In patients
with severe vision loss and/or moderate to severe systemic symptoms, a 4- to 6-week regimen
of doxycycline or azithromycin with rifampin may provide some benefit. The routine use of
systemic corticosteroids in infectious neuroretinitis is not recommended. Targeted antimi-
crobial agents should be instituted in cases of neuroretinitis due to specific infectious
etiologies (e.g., syphilis, Lyme disease, tuberculosis). Azathioprine may be beneficial in
cases of recurrent idiopathic neuroretinitis. There is a need for collaborative, multicenter
prospective studies to provide definitive guidelines regarding the use of antibiotics and
corticosteroids and to evaluate future therapies in infectious and recurrent idiopathic
neuroretinitis.
 36 Page 2 of 16 Curr Treat Options Neurol (2019) 21:36

Introduction
Neuroretinitis is clinically defined as the combina- [14], syphilis [7], varicella zoster [15], Epstein-
tion of optic disc edema with macular edema, Barr [16], herpes simplex [17], West Nile [18],
typically in a star-like configuration, but does not Zika [19], chikungunya [20], and histoplasmosis
connote a specific etiology [1••]. In 1916, Leber [21].
described a patient with unilateral vision loss with A heterogeneous group of inflammatory dis-
optic disc edema and radially oriented retinal exu- eases have also been associated with neuroretinitis
dates, which he termed stellate maculopathy [2]. such as sarcoidosis [22], polyarteritis nodosa [23],
However, in 1977, Gass coined the term Takayasu’s arteritis [24], systemic lupus erythema-
neuroretinitis, based on the fluorescein angiogra- tosus [25], Vogt-Koyanagi-Harada disease [26],
phy (FA) findings of the macular edema emanating and inflammatory bowel disease [27]. There have
from the optic disc, rather than the retina itself [3]. also been reports of neuroretinitis in patients with
More recently, from an anatomical perspective, it paraneoplastic syndrome [28] and anti-myelin ol-
has been shown that fluid flows directly from the igodendrocyte glycoprotein (MOG) antibodies
disc surface into the outer plexiform layer (OPL), [29•]. Cancer patients treated with immune check-
down through the external limiting membrane to point inhibitors have also been documented to
collect beneath the neurosensory retina; ultimately develop neuroretinitis [30•, 31]. As the name im-
departing a lipid-rich exudate in a star-like pattern plies, neuroretinitis is a prominent clinical feature
due to the radial configuration of the OPL (Fig. 1) of the rare entity, idiopathic retinal vasculitis, an-
[4]. eurysms, and neuroretinitis (IRVAN) syndrome
The exact pathophysiology behind the optic disc [32].
vascular permeability in neuroretinitis remains un- Up to a half of cases have no identifiable cause and
certain but is thought to be due to either direct are termed idiopathic neuroretinitis [2]. In addition to
invasion of infectious vectors or an autoimmune the above potential causes of neuroretinitis, it is impor-
phenomenon [5]. The direct invasion hypothesis tant to exclude mimickers of optic disc edema and mac-
has garnered increasing traction because the most ular exudates (Table 1).
common cause of neuroretinitis is infectious, spe- While most cases of idiopathic neuroretinitis are
cifically due to the fastidious Gram-negative bacil- monophasic with substantial visual recovery even
lus, Bartonella henselae, the causative agent of cat without treatment, there is a small subset of pa-
scratch disease (CSD) [1••, 6]. In cases of tients with recurrent idiopathic neuroretinitis char-
B. henselae–associated neuroretinitis, the mean age acterized by recurrent attacks and poor recovery
of presentation is 24.5 years with a female to male [27, 33–35]. In these patients, the average age at
ratio of 1.8:1 with nearly 75% of patients presentation is 28 years with no gender predilec-
experiencing systemic symptoms [1••, 6]. On exam, tion. Unlike infectious neuroretinitis, recurrent idi-
these patients often have decreased visual acuity opathic neuroretinitis is not typically accompanied
and optic disc edema with or without macular by systemic symptoms prior to the onset of visual
exudates. A relative afferent pupillary defect and symptoms [33, 35]. The majority of these patients
central or cecocentral visual field defect may be experience sequential bilateral involvement with an
present. The disease is typically self-limited with average of 3.6 attacks with a three-year interval
spontaneous resolution and return of good visual between episodes. Cecocentral, arcuate, and altitu-
function. dinal visual field defects commonly occur. In stark
The etiology of neuroretinitis can be divided difference to other forms of neuroretinitis, the vi-
into three broad categories: infectious, inflamma- sual deficit often persists after an attack and recur-
tory, and idiopathic [7]. In addition to B. henselae, rent attacks have a cumulative effect on vision,
a variety of bacterial, viral, and fungal causes of portending a poorer visual prognosis. In the largest
neuroretinitis have been identified including study evaluating this population, only 36% of pa-
Rocky Mountain spotted fever [8], tuberculosis tients had both 6/12 (20/40) vision or better and
[9], salmonellosis [10], Lyme disease [11], toxo- retained more than two-thirds of their visual field
plasmosis [12], leptospirosis [13], toxocariasis [35].
Curr Treat Options Neurol (2019) 21:36 Page 3 of 16 36

Diagnostic evaluation
Most patients with neuroretinitis present with painless unilateral vision loss but
occasionally can have bilateral simultaneous or sequential involvement. Detailed
medical history should include recent travel, animal exposure, skin changes,
lymph node enlargement, and systemic symptoms. Queries should be targeted

Fig. 1. Multimodality imaging of neuroretinitis: a14-year-old male with acute, painless, unilateral vision loss left eye. a Color
fundus photography reveals diffuse optic disc edema with Patton’s lines radiating around the optic disc with a stellate maculopathy
and denser central exudates at the fovea. b Fundus autofluorescence with very faint circular hyperautofluorescence within the fovea
corresponding to the denser foveal exudates. c Optical coherence tomography (Cirrus, Zeiss, Jena, Germany) of the optic nerve
revealing massive disc edema with surrounding subretinal fluid and retinal thickening. d Optical coherence tomography (Cirrus,
Zeiss, Jena, Germany) of the macula shows retinal thickening, blunted foveal contour, subretinal fluid extending from the optic
disc, intraretinal hyperreflective material within the outer retinal layers, and subfoveally vitelliform deposits. e Early (15 s)
fluorescein angiogram of the left eye demonstrates focal early hyperfluorescence of the superotemporal disc. f Late (5 min)
fluorescein angiogram of the left eye shows diffuse disc edema with prominent leakage superotemporally.
 36 Page 4 of 16 Curr Treat Options Neurol (2019) 21:36

Table 1. Differential diagnosis of optic disc with concomitant macular edema

Neuroretinitis
Arterial hypertension
Diabetic papillopathy
Papilledema
Anterior ischemic optic neuropathy
Posterior vitreous traction syndrome
Toxic (procarbazine and bischloroethylnitrosurea)
Juxtapapillary tumors/compressive lesions

toward identifying an underlying vascular disorder such as diabetes mellitus or

arterial hypertension and autoimmune conditions. Aside from a complete
neuroophthalmic examination, multimodality testing may be needed such as FA,
fundus autofluorescence (FAF), optical coherence tomography (OCT), and fun-
dus photography (Fig. 1). During the early phase, the classic macular star may
not be present making the diagnosis challenging on fundoscopy alone. The
macular fluid is often present for several weeks, before the visible radial exudates
(i.e., macular star) form in the OPL [1••]. OCT can infer the diagnosis during this
early stage of the disease process by identifying retinal thickening, flattening of
the foveal contour, intraretinal fluid within the OPL and/or subretinal fluid, and
early intraretinal hyperreflective exudates [36–38]. OCT is also useful in identi-
fying peripapillary neurosensory retinal detachments in cases that never develop
a macular star [36]. FA will reveal diffuse or segmental disc leakage, sometimes
associated with leaking from a specific optic disc vessel [4]. Finally, FAF may
reveal hyperautofluorescent macular exudates [39].
Neuroimaging is not routinely needed in the evaluation of neuroretinitis, but
if done, it is preferable to obtain a dedicated orbital magnetic resonance imaging
(MRI) study with fat suppression and contrast administration to rule out a
retrobulbar optic neuritis. Optic neuritis due to multiple sclerosis (MS) can
mimic neuroretinitis [40]; however, true neuroretinitis is not associated with MS
[41]. Williams et al. postulated an association between MS and neuroretinitis;
however, all of the patients with so-called neuroretinitis had an atypical fundus
appearance and had been treated with interferon beta, which may have led to
increased optic disc vascular permeability [40]. In some cases of neuroretinitis,
the MRI may show enhancement of the intraocular portion of the optic nerve
(i.e., optic disc) or extend slightly posteriorly behind the globe, but not to the
same extent as seen with retrobulbar optic neuritis [42, 43]. Some experts have
argued that this retrobulbar short segment enhancement is specific for
B. henselae–associated neuroretinitis [43], but in other studies, no discernible
differences could be made in differentiating the various etiological subtypes of
neuroretinitis [27].
Laboratory testing should be performed depending on the zoonotic exposure
history, systemic manifestations, and examination findings. As mentioned above,
because CSD is the most common cause of neuroretinitis, B. henselae titers should
be obtained in all cases, even if there is no patient recall of kitten exposure [1••,
Curr Treat Options Neurol (2019) 21:36 Page 5 of 16 36

44, 45•, 46, 47] and can be repeated after 4 to 6 weeks if the initial titers are
negative and the clinical suspicion remains high [48]. Purified protein derivative
or QuantiFERON-TB Gold testing should be obtained for patients with high risk
tuberculosis exposure. For those with tick exposure or residing in endemic areas,
testing for Lyme disease and Rocky Mountain spotted fever is recommended.
Patients suspected of having sarcoidosis should undergo serum angiotensin
converting enzyme levels as well as chest imaging (X-ray or computed tomogra-
phy). Those with an exposure history to sexually transmitted diseases require
testing for syphilis and the human immunodeficiency virus. Patients from en-
demic areas, particularly from the Ohio River Valley, should have histoplasmosis
serology [49].
Management
The treatment of neuroretinitis is contingent upon the underlying etiology. As
mentioned previously, a plethora of infectious and inflammatory conditions
can result in neuroretinitis. Therefore, a careful diagnostic evaluation must be
undertaken with the goal of initiating targeted therapy against the offending
agent or process.

Infectious neuroretinitis
The following section will provide treatment recommendations for infectious
neuroretinitis, with a special emphasis on CSD. It should be noted that all the
available treatment data to date is from case reports, case series, and retrospec-
tive reviews. The lack of randomized trials upon which to make clear and firm
clinical recommendations is an overarching theme that underscores the need
for continued research and a collaborative multicenter approach.

Antibiotic therapy
Given the relatively benign natural history, there is debate whether to treat an
episode of B. henselae–associated neuroretinitis. Several studies have examined
the effect of antibiotics, corticosteroids, or a combination of both with conflicting
results. In the only double-blind, randomized, placebo-controlled trial evaluating
the use of azithromycin in patients with CSD, but without neuroretinitis, there
was an 80% reduction in total lymph node volume in 50% of treated patients
compared to only 7% in the placebo group [50]. Notably, there was no difference
in any other clinical outcome measure. A retrospective review of 268 patients
with CSD without neuroretinitis determined that the mean duration of lymph-
adenopathy was reduced in patients with moderate to severe systemic disease
who were treated with effective antibiotics compared to those who were ineffec-
tively treated or untreated [51]. The effective antibiotics included rifampin,
ciprofloxacin, gentamicin, and trimethoprim-sulfamethoxazole, all of which
have an intracellular action of inhibiting bacterial DNA or protein synthesis.
B. henselae has a predilection for infecting endothelial cells and erythrocytes that
sequesters it from antibiotics that primarily act against the bacterial cell wall
(Appendix) [52].
Regarding antibiotic therapy in CSD with ocular involvement, two small case
series demonstrated decreased disease duration and hastened visual recovery after
treatment with doxycycline and rifampin (seven patients) [47] and marked
36 Page 6 of 16 Curr Treat Options Neurol (2019) 21:36

improvement in vision with ciprofloxacin with or without prednisone or doxy-

cycline alone (four patients) [53]. A retrospective case series of 37 eyes of 24
patients with intraocular manifestations of CSD (six patients with neuroretinitis)
demonstrated a vision of 20/200 or better in 86.5% of eyes who received a variety
of different antibiotic therapies [54]. This perceived benefit is difficult to interpret
because there was no control group for comparison. A more recent multicenter
retrospective cohort study of 86 patients found a worse visual outcome in
patients who received antibiotics alone compared to the combination of antibi-
otics and corticosteroids (see systemic corticosteroids and immunosuppressive
medications section) [45•].
Immunocompromised patients infected with Bartonella species, including
those with acquired immunodeficiency syndrome (AIDS), tend to experience
worse systemic and visual complications and should be treated with antibiotic
therapy [55, 56]. The use of a particular antimicrobial agent(s) depends on the
specific clinical manifestation (endocarditis, bacillary angiomatosis, peliosis
hepatis, bacteremia, etc.), but effective therapies include doxycycline, rifampin,
azithromycin, erythromycin, and gentamicin. The recommended regimen for
central nervous system involvement is a combination of doxycycline and rifam-
pin [57].
In comparison, CSD in immunocompetent patients has been shown to be a
self-limited disease process with excellent systemic and visual prognosis without
treatment [56, 58]. In a retrospective case series of 24 patients with ocular
Bartonella infection, final visual acuity was 20/25 or better in 74% of the patients
and there was no difference in visual outcome between those who received
antibiotic therapy (13 patients), with or without steroids, compared to those that
were untreated [59]. A large, multicenter, retrospective chart review of 53 patients
with CSD optic neuropathy found 68% of patients had a final visual acuity of 20/
40 or better. Patients who presented with good (20/40 or better) visual acuity and
those without systemic symptoms had better visual outcomes. However, there
was no association between improved final visual outcome and antibiotic ther-
apy [60]. The Centers for Disease Control and Prevention (CDC) acknowledges
that most cases of CSD resolve without treatment, and the routine use of
antibiotics in uncomplicated cases has not been established [61].
In addition to CSD, the treatments of other infectious causes of neuroretinitis
have been evaluated, including Lyme disease, syphilis, and Mycobacterium tuber-
culosis (MTB). A case of Lyme associated neuroretinitis had initial worsening of
vision after empiric initiation of oral prednisone (40 mg daily) followed by
significant improvement once on oral doxycycline [11]. In another case of Borrelia
associated neuroretinitis, the vision improved after a three-week course of ceftri-
axone alone [62]. Both of these case reports suggest that antimicrobial therapy is
needed prior to, or in concert with, the initiation of corticosteroid treatment in
the setting of Lyme disease. In the broader literature examining the treatment of
Lyme disease, there is a lack of consensus about the preferred treatment for
neuroretinitis and the CDC defers to the primary literature to provide recom-
mendations for the treatment of neuroborreliosis. Current guidelines recom-
mend a 10- to 28-day course of oral doxycycline for ambulatory patients with
early disseminated disease or acute neurologic Lyme disease. This includes pa-
tients with meningitis, cranial neuropathy (e.g., facial nerve palsy), and sensory or
motor radiculopathy. However, intravenous ceftriaxone for 14 to 28 days is
recommended for patients with more severe neuroborreliosis (e.g., encephalitis)
Curr Treat Options Neurol (2019) 21:36 Page 7 of 16 36

[63–65]. Where neuroretinitis falls on the spectrum of mild to severe

neuroborreliosis has not been well defined. Furthermore, a European study
demonstrated equivocal efficacy of a 14-day course of oral doxycycline compared
to intravenous ceftriaxone in patients with neuroborreliosis [66]. Accordingly, in
ambulatory patients with mild to moderate vision loss, but without evidence of
other severe neurologic impairment from Lyme disease, we recommend treatment
with oral doxycycline. In patients with evidence of more significant vision loss or
neurologic disease, and who are more likely to be hospitalized, we recommend
the use of intravenous ceftriaxone. Regarding syphilitic neuroretinitis, according to
the CDC, aqueous crystalline penicillin G is the recommended treatment regimen
for cases of ocular syphilis [67–70]. Limited evidence suggests ceftriaxone might be
an effective alternative in penicillin allergic patients [67]. Patients for whom MTB
is the suspected etiology of neuroretinitis should be treated in a similar manner to
pulmonary disease. The CDC, American Thoracic Society, and the Infectious
Diseases Society of America recommend the use of quadruple therapy (rifampin,
isoniazid, pyrazinamide, and ethambutol) for two months followed by a four to
seven-month continuation phase typically consisting of rifampin and isoniazid
[71–73].
In summary, for B. henselae–associated neuroretinitis, there is no class I
evidence to provide firm guidelines regarding the use of antibiotics. However,
based upon the available data, working in concert with an infectious disease
specialist, empiric treatment with doxycycline or azithromycin in addition to
rifampin is appropriate for patients that are immunocompromised and patients
that are immunocompetent with moderate to severe systemic symptoms or
significant vision loss (Table 2). For those patients endorsing an allergic reaction
to these medications, ciprofloxacin or trimethoprim-sulfamethoxazole may be
substituted. For immunocompetent patients with mild to moderate vision loss
without significant systemic symptoms, the decision to start antibiotic therapy
becomes a nuanced discussion between the clinician and patient. One consid-
eration is to treat empirically until an alternate infectious etiology has been
excluded thereby allowing for either discontinuation or change in therapy. In
terms of broad coverage, it is the opinion of the authors that doxycycline with
rifampin for four to six weeks is appropriate because it not only covers CSD,
Lyme disease, Rocky Mountain spotted fever, Weil’s disease (leptospirosis), and
with possible benefit against syphilis but also is generally well tolerated with
good penetration into the central nervous system [47, 64, 67, 74, 75]. If an
alternate infectious etiology is found, treatment should be tailored accordingly.

Pediatric consideration
For children less than eight years old, azithromycin and rifampin are the pre-
ferred choices. Traditionally, doxycycline has been avoided in children due to the
possibility of tooth discoloration and enamel hypoplasia. However, a recent
study supported by the CDC found no visible dental staining in children treated
with doxycycline at an average dose of 2.3 mg/kg, average duration of seven
days, and average of 1.8 courses per child for Rocky Mountain spotted fever [76].

Systemic corticosteroids and immunosuppressive medications

As with antibiotic therapy, there are no randomized, controlled clinical trials
that have examined the role of systemic corticosteroids in B. henselae–associated
Table 2. Recommended antibiotic regimens for Bartonella henselae–associated neuroretinitis, neuroborreliosis, neurosyphilis, and intraocular Mycobacterium tuberculosis
36

Medication Recommended dose Duration Side effects Comments

Adults Children
Bartonella Doxycycline 100 mg twice daily ≥ 45 kg = Adult dosing 4–6 weeks Photosensitivity Avoid in pregnancy. Avoid in
henselae– G 45 kg = 2.2 mg/kg Dental staining children G 8 years old**
associated twice daily Intracranial hypertension
Page 8 of 16

neuroretinitis
Hypersensitivity reaction
Esophagitis
Hepatotoxicity
Rifampin 300 mg twice daily 10 mg/kg twice daily 4–6 weeks Red/orange discoloration Avoid in patients with
of body fluids HIV/AIDS on
Agranulocytosis antiretroviral
therapy—drug-drug
DIC
interactions.
Hepatotoxicity
Hypersensitivity reaction
Azithromycin 500 mg × 1 day, then 9 45.5 kg = Adult dosing 4–6 weeks QT prolongation/Torsades Avoid in patients with a long
250 mg daily ≤ 45.5 kg = 10 mg/kg × 1 de Pointes QT interval and history of
day, then 5 mg/kg daily Transaminase elevation and significant hepatic
hepatotoxicity disease
Nausea/vomiting/diarrhea
Myasthenic crisis
Stevens-Johnson syndrome
Ciprofloxacin 500 mg twice daily 10–20 mg/kg/dose 4–6 weeks Arthropathy, tendon rupture Avoid in children and the
twice daily Diarrhea elderly
CNS effects
Peripheral neuropathy
Myasthenic crisis
QT prolongation
Trimethoprim- 160 mg (trimethoprim) 4 mg/kg (trimethoprim) 4–6 weeks Nausea/vomiting Avoid in patients with
sulfamethoxazole twice daily twice daily Rash/allergy (sulfonamides) sulfonamide allergy, HIV,
pregnancy, children
Inaccurate serum creatinine
Curr Treat Options Neurol

G 2 months old
testing
Folate deficiency
Megaloblastic anemia
Stevens-Johnson syndrome
Lyme disease Doxycycline 100 mg twice daily ≥ 45 kg = Adult dosing 10–28 days Photosensitivity May be used in early
G 45 kg = 2.2 mg/kg Dental staining neurologic Lyme disease
twice daily** in ambulatory patients.
Intracranial hypertension
(2019) 21:36

Used to treat neuroborreliosis

Hypersensitivity reaction
in Europe.
Esophagitis
Hepatotoxicity
Table 2. (Continued)
Medication Recommended dose Duration Side effects Comments
Adults Children
Ceftriaxone (IV) 2 g daily 75–100 mg/kg/day 14–28 days Diarrhea, Clostridium Preferred in cases of
difficile colitis moderate to severe
Biliary stasis neuroborreliosis
ceftriaxone-calcium salt
precipitate within the
Curr Treat Options Neurol

gallbladder (pseudolithiasis)
Syphilis Aqueous crystalline 3–4 million units every 200,000-300,000 10–14 days Hypersensitivity and Further treatment with
penicillin G (IV) 4h units/kg/day anaphylactic reactions benzathine penicillin (2.4
in divided doses Diarrhea million units IM once per
every 4–6 h week for 3 weeks) can be
Anemia, leukopenia,
considered after initial
thrombocytopenia
neurosyphilis treatment
Seizure to ensure eradication in
(2019) 21:36

adults
Intraocular Rifampin 10 mg/kg daily (typically 10–20 mg/kg daily 8 + 18 weeks Red/orange discoloration of Must be used with other
Mycobacterium 600 mg) (min) body fluids agents or resistance likely
tuberculosis Agranulocytosis to develop.
DIC Drug-drug interactions
prevalent.
Hepatotoxicity
Hypersensitivity reaction
Isoniazid 5 mg/kg daily (typically 5 mg/kg daily 8 + 18 weeks Hepatotoxicity Peripheral neuropathy from
300 mg) (estimated) (min) Peripheral neuropathy pyridoxine deficiency may
be prevented with
supplementation of
50 mg vitamin B6 daily
Pyrazinamide Weight based 35 mg/kg daily 8 weeks Hepatotoxicity May obtain serum uric acid in
40–55 kg = 1 g Gastrointestinal intolerance patients with history of
gout.
56–75 kg = 1.5 g Gout exacerbation, arthralgia
76–90 kg = 2 g
(daily)
Ethambutol Weight based (daily) 20 mg/kg daily 8 weeks Optic neuritis Ocular adverse effects are less
40–55 kg = 800 mg Optic atrophy common in patients
taking G 15 mg/kg and
56–75 kg = 1200 mg Optic disc edema
may be reversible after
76–90 kg = 1600 mg Central scotoma stopping the medication.
Red-green dyschromatopsia
Gastrointestinal intolerance

Adult doses are the maximum doses to be given and all doses assume normal renal function
Page 9 of 16

CNS central nervous system, DIC disseminated intravascular coagulation, HIV/AIDS human immunodeficiency virus/acquired immunodeficiency syndrome, IV intravenous, IM intramuscular, min minimum
**Doxycycline is typically avoided in children less than 8 years old for concern of irreversible dental staining, although this may not occur with a short course of treatment
36
36 Page 10 of 16 Curr Treat Options Neurol (2019) 21:36

neuroretinitis. The strongest evidence for adjunctive use of corticosteroids

comes from the multicenter retrospective cohort study of 86 patients with
ocular manifestations due to CSD, which demonstrated an improvement in
visual acuity of three lines or more in patients treated with the combination of
antibiotic and corticosteroid (14/16 patients [88%]) compared to antibiotic
alone (12/24 patients [50%]) [45•]. However, this was a retrospective study
with a potential selection bias influencing the choice of treatment. In addition,
the majority of the case reports in the literature, including the eight cases of
intravenous and/or oral prednisone in the retrospective review by Chi et al. [60],
showed no benefit in CSD optic neuropathy. Given the significant morbidity
associated with systemic corticosteroids (including infection, hypertension,
osteoporosis, diabetes mellitus, peptic ulcer disease, and avascular necrosis),
and the lack of convincing benefit, routine use of systemic corticosteroids is not
recommended in most cases of infectious neuroretinitis. However, the potent
anti-inflammatory effects of systemic corticosteroids could theoretically offer
some benefit in severe cases and therefore may be reserved for those patients
with profound vision loss, fulminant optic disc edema, or significant intraoc-
ular inflammation. For example, a four to six-week corticosteroid taper is often
used in addition to anti-mycobacterial therapy in patients with intraocular MTB
and may improve outcomes [73, 77].

Recurrent idiopathic neuroretinitis

Similar to infectious neuroretinitis, few case series and retrospective reviews
have been published examining the role of chronic immunosuppression for
recurrent idiopathic neuroretinitis. In a case series of seven patients with recur-
rent neuroretinitis who received prompt treatment with oral or intravenous
corticosteroids, there was no improvement in visual acuity or visual field [34].
Interestingly, one patient had no recurrence for three years while on azathio-
prine but then developed an acute attack upon discontinuation. In contrast,
Purvin et al. performed a retrospective review of seven patients with recurrent
idiopathic neuroretinitis treated with oral prednisone and/or azathioprine and
found a 72% reduction in recurrent attacks per year after starting immunosup-
pressive therapy [33]. Several years later, the same group published a follow-up
retrospective study that included four patients from the prior study and nine
new patients and found that long-term immunosuppression with azathioprine
(50 to 150 mg/day) and/or oral prednisone (10 mg every other day) resulted in
the same 72% reduction in recurrent attacks per year [35]. Of note, the use of
corticosteroids acutely following an attack did not appear to be of benefit in
these patients. Therefore, based on the available published data, we recom-
mend patients who have had at least two episodes of idiopathic neuroretinitis
be initiated on immunosuppressive therapy in an attempt to reduce the number
of attacks and preserve vision. Currently, azathioprine seems to be the first line
medication, but newer and more potent agents may be more efficacious but
have yet to be studied.

Emerging treatments
Although idiopathic neuroretinitis is typically a self-limited disease with most
patients experiencing excellent visual recovery without treatment, there are
Curr Treat Options Neurol (2019) 21:36 Page 11 of 16 36

some patients that have recurrent disease resulting in irreversible visual loss [5,
27, 78]. It is this latter group that stands to gain the greatest amount in the quest
for more effective treatment modalities.

Intravitreal approach
Angiogenesis is characteristic of Bartonella infection; therefore, anti-vascular en-
dothelial growth factor (VEGF) therapy has the potential to be an effective
treatment strategy [79]. A case report described the use of intravitreal triamcino-
lone plus anti-VEGF in a patient with idiopathic neuroretinitis with return of
normal visual acuity and resolution of both the macular and optic disc edema
[80].
Intraocular steroid injections and implants are another possible emerging
treatment for neuroretinitis. A short acting dexamethasone (Ozurdex®,
Allergan, Madison, NJ) implant or triamcinolone intravitreal injection could
theoretically help reduce intraocular inflammation and macular edema. A
longer acting agent like the recently US Food and Drug Administration (FDA)-
approved three-year fluocinonide acetate implant (Yutiq®, EyePoint Pharma-
ceuticals, Watertown, MA) could help prevent recurrences. Dexamethasone
implants have been used in cases of IRVAN and have showed some promise in
treating the macular edema [81–83].

Immunosuppressive agents
There have been no studies which have evaluated the role of immunosuppres-
sive medications such as rituximab, tumor necrosis factor (TNF) inhibitors, or
other monoclonal antibodies in recurrent idiopathic neuroretinitis. A case
report did demonstrate improvement in visual acuity and retinal exudation
after administration of infliximab in two cases of IRVAN that were refractory to
high-dose corticosteroids [84].

Chemotherapeutic agents
The immune check point inhibitor ipilimumab (an anti-cytotoxic T
lymphocyte antigen-4 monoclonal antibody) has been linked to one
case of bilateral neuroretinitis [31] and two cases of optic neuropathy
[30•]. This class of medications disinhibits the immune system in order
to help recognize self-antigens typically expressed in higher quantities on
neoplastic cells, but with the collateral adverse activity of creating a state
of autoimmunity. In the case of ipilimumab induced neuroretinitis, the
medication was discontinued and a combination of topical and oral
corticosteroid therapy was given with resolution of the ocular inflam-
mation and improved vision over two months [31]. Accordingly, the
mainstay of treatment for neuroretinitis secondary to the use of biologic
agents, including checkpoint inhibitors and other chemotherapeutic reg-
imens such as procarbazine and carmustine, involves discontinuation of
the offending agent(s) and administration of topical and/or systemic
corticosteroids over a period of weeks to months [85]. The duration and
taper of the steroid therapy will depend on the clinical course of the
patient and the expected elimination half-life of the causative medica-
tion, which for ipilimumab is 14.7 days [85].
 36 Page 12 of 16 Curr Treat Options Neurol (2019) 21:36

Conclusion
Infectious neuroretinitis has many causes, and therefore, a targeted diagnostic
evaluation must be undertaken to elucidate a specific cause in order to initiate a
clearly defined treatment strategy. In cases of Bartonella henselae–associated
neuroretinitis, immunocompetent patients with mild to moderate visual loss
may be observed as the expected visual outcome is favorable. Empiric treatment
may be considered in patients with a history suggestive of CSD while diagnostic
tests are pending. Treatment is recommended for those with moderate to severe
systemic symptoms, immunosuppressed patients, and those with severe vision
loss. The preferred regimen is a four to six-week course of oral doxycycline and
rifampin. Azithromycin may be used as an alternative to doxycycline, and in
patients with documented allergy, ciprofloxacin or trimethoprim-
sulfamethoxazole may be considered. There is no conclusive evidence that cor-
ticosteroid therapy is beneficial in infectious neuroretinitis, and because of the
potential for significant adverse events, it should not be given routinely. However,
corticosteroids can be used as an adjunct to antimicrobial therapy for cases with
severe vision loss, significant optic disc edema, and a high degree of intraocular
inflammation. Patients with an identified cause of infectious neuroretinitis
(Lyme disease, syphilis, etc.) should receive the appropriate targeted therapy.
For patients with recurrent idiopathic neuroretinitis, high-dose intravenous
and/or oral corticosteroid therapy with transition to an immunosuppressive
agent are recommended to prevent recurrence and further loss of vision. To date,
only azathioprine has been reported in the literature, but for patients with
thiopurine methyltransferase (TMPT) deficiency, or for those with recurrences
despite azathioprine use, newer immunosuppressive agents like rituximab and
possibly other monoclonal antibodies may be beneficial.
Finally, intravitreal anti-VEGF therapy and implantable or injectable ocular
corticosteroid therapies have theoretical, but not proven, efficacy and could result
in severe complications, including endophthalmitis, and are therefore not cur-
rently recommended in the treatment of neuroretinitis. Further research involving
the use of these agents may provide additional treatment options and greater
insight into the pathophysiology of neuroretinitis.

Compliance with Ethical Standards

Conflict of Interest
The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

Dr. Bhatti participated in the following two studies that involved human subjects: Schmalfuss IM, Dean CW,
Sistrom C, Bhatti MT. Optic neuropathy secondary to cat scratch disease: distinguishing MR imaging features from
other types of optic neuropathies. AJNR Am J Neuroradiol. 2005;26 (6):1310–6; Chi SL, Stinnett S, Eggenberger E,
Foroozan R, Golnik K, Lee MS, et al. Clinical characteristics in 53 patients with cat scratch optic neuropathy.
Ophthalmology. 2012;119 (1):183–7.
Curr Treat Options Neurol (2019) 21:36 Page 13 of 16 36

Appendix
Note: Specific antibiotic dosing is provided in Table 2.

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