Acute cortical blindness caused by neuropsychiatric systemic lupus erythematosus

Abstract

A man in his 30s, who presented with fevers and a diffuse purpuric rash, developed sudden-onset visual loss on day 2. He was unable to perceive light in either eye. Examination by a neurologist confirmed cortical blindness, and the MRI showed subtle juxtacortical infarcts and leptomeningeal enhancement in the occipital region. Further history taken in the patient’s native language revealed a history of untreated systemic lupus erythematosus. A diagnosis of central nervous system lupus was made and he was treated promptly with pulse methylprednisolone and cyclophosphamide. His vision gradually improved to 80% on day 10 and eventually returned to baseline. He continued with high-dose prednisolone and monthly cyclophosphamide for 6 months and remained on hydroxychloroquine and mycophenolate mofetil with no relapses. This case shows the importance of approaching the uncommon but potentially dangerous issue of acute visual loss with a broad differential.

Background

Neuropsychiatric systemic lupus erythematosus (NPSLE) is difficult to diagnose and distinguish from non-rheumatological causes. It is estimated to affect at least 20% of patients with SLE.¹ Nineteen syndromes have been defined, with 12 affecting the central nervous system and 7 affecting the peripheral nervous system.² Neuro-ophthalmological complications of SLE are rare, with an estimated prevalence of 1%–4%.³ There are multiple causative mechanisms, including infective, vascular, thrombotic, inflammatory and psychogenic. Treatment is cause-dependent, and in severe cases, may involve the use of induction methylprednisolone followed by monthly cyclophosphamide, based on a small controlled trial.⁴

Case presentation

A man in his early 30s presented with a diffuse, non-blanching rash affecting his limbs 5 hours following the commencement of esomeprazole, amoxicillin and clarithromycin for treatment of Helicobacter pylori (figure 1). He had been investigated by the gastroenterologists for intermittent abdominal pain with a previous CT abdomen showing enteritis from the distal duodenum to the proximal jejunum, suspicious for inflammatory bowel disease. On admission, he was febrile at 39.2° and hypotensive at 85/45 mm Hg. Blood cultures were taken and intravenous cephazolin was commenced for sepsis from presumed cellulitis. Esomeprazole, amoxicillin and clarithromycin were also ceased due to the potential drug eruption given the short time frame between medication ingestion and rash.

Figure 1.

Diffuse erythematous and purpuric rash on presentation (patient de-identified).

On day 2 at 7:00 hours, the patient reported sudden-onset visual loss in both eyes, and was unable to perceive any light despite having had normal vision the day before. He was reviewed by a neurologist, who established the diagnosis of cortical blindness based on normal pupillary reflexes, absent optokinetic nystagmus and normal funduscopy. His MRI brain, performed 8 hours following symptom onset only revealed mild leptomeningeal enhancement in the occipital region, along with two minor juxtacortical infarcts in the temporal and parieto-occipital regions (figure 2). There was no pathology in the optic nerves, optic chiasm, large vessels or features suggestive of posterior reversible encephalopathy syndrome (PRES).

Figure 2.

Day 2, tiny juxtacortical white matter acute infarcts in the right temporal (A, B) and left parieto-occipital regions (C, D) with restricted diffusion on diffusion-weighted imaging (DWI) and low signal on apparent diffusion coefficient (ADC).

Later in the day, he developed headaches, neck stiffness and vomiting. A lumbar puncture was performed and this revealed markedly elevated protein (1.48 g/L), normal glucose, and mildly elevated polymorphs (6×106 /L) and lymphocytes (7×106 /L). He was commenced on empirical treatment for meningoencephalitis (benzylpenicillin, acyclovir, ceftriaxone, vancomycin and intravenous dexamethasone 4 mg). Skin biopsies showed leucocytoclastic vasculitis. His case was discussed with the rheumatologist, neuro-ophthalmologist and the infectious diseases physician, and the decision was made to hold off on high-dose corticosteroids given the possibility of infection. On further questioning in the patient’s native language, his wife reported a history of cutaneous lupus from the previous year, but the patient had stopped treatment due to worsening joint pains, thought to be medication related.

Differential diagnosis

This was a bizarre presentation and a broad range of differential diagnoses were considered. Workup and treatment for meningoencephalitis were prioritised initially given the acute presentation with fevers, hypotension, headaches and the presence of markedly elevated protein in the cerebrospinal fluid. Multiple sets of blood cultures were taken and empirical antibiotics were given promptly after the onset of headaches. Meanwhile, retinal and optic nerve-related causes of visual loss were thought to be less likely due to normal pupillary reflexes, lack of rapid afferent pupillary defects and normal ophthalmoscopy examination. Also, pathology anterior to the optic chiasm typically affects one eye at a time. The MRI of his optic nerves was also normal. Psychogenic causes were ruled out from intact proprioception and absence of menace reflexes and optokinetic nystagmus. PRES could also cause acute visual loss, but the patient did not have any risk factors such as hypertension or immunosuppressive medications, nor were there supportive MRI findings. Antiphospholipid syndrome is associated with lupus, but no large infarcts were visualised on MRI. After the diagnosis of untreated cutaneous lupus was elicited from the patient’s partner, cortical blindness caused by NPSLE became the main differential diagnosis. This may have been precipitated by H. pylori treatment, hence it was ceased. However, high-dose immunosuppression was withheld until infection was thought to be less likely, supported by negative blood cultures and gram stain on cerebrospinal fluid by day 3.

Treatment

On day 3, his blood cultures remained negative. His antinuclear antibodies were positive with a speckled pattern and a titre of 1 in 640, and his antiphoslipid antibodies were negative. Following consultation with the rheumatologist, a 3-day course of methylprednisolone 1 g was commenced with pantoprazole for ulcer prophylaxis. His vision improved gradually, and he was able to see a moving hand on day 4 and read an analogue wall clock on day 6. Blood tests showed positive anti-Smith and anti-SSA antibodies and low complements, confirming the diagnosis of SLE (table 1). This was also the likely cause of his enteritis, previously thought to be inflammatory bowel disease. Eventually, a letter was obtained from his previous rheumatologist from interstate mentioning his previous treatment with hydroxychloroquine for SLE. On day 6, he was weaned onto prednisolone 50 mg and later had a single dose of intravenous cyclophosphamide 1260 mg after counselling him regarding side effects. He was restarted on hydroxychloroquine and educated regarding the importance of compliance to prevent complications. On day 10 when he was discharged, he reported his vision had recovered to approximately 80%, testing 20/30 in both eyes with glasses.

Table 1.

Summary of results

Blood results with reference ranges in brackets
Haematology and biochemistry		Autoimmune screen
Haemoglobin	141 g/L (130–170)	C3	0.40 g/L (0.90–1.80)
White cell count	4.8×109 /L (4.0–10.0)	C4	0.07 g/L (0.10–0.40)
Platelets	158×109 /L (150-410)	Antinuclear antibodies	1/640 (speckled)
Lymphocytes	0.64×109 /L (1–3 X 109 /L)	Extractable nuclear antigen	Positive
Creatinine	61 micromols/L (60–110)	Anti-Smith	Positive
eGFR	>90 mL/min/1.73 m2	Anti-Ro (SSA)	Positive
C reactive protein	3.0 mg/L (<5.0)	Anti-RNP	Weakly positive
Cerebrospinal fluid		Anti-Jo 1, topoisomerase, La (SSB)	Negative
Glucose	2.9 mmol/L (2.8–4.4)	Anti-dsDNA, ANCA, cryoglobulins	Negative
Protein	1.48 g/L (0.15–0.45)	Serum protein electrophoresis	Normal levels of polyclonal globulins
Cell counts	6 polymorphs (<1×106 /L) 7 lymphocytes (< 6×106 /L) 5 erythrocytes (<1×106 /L)	Antiphospholipid screen
		Lupus anticoagulant, anticardiolipin antibodies	Negative
Herpes simplex, varicella zoster, cryptococcal antigen, mycobacterial culture	Negative

ANCA, antineutrophil cytoplasmic antibodies; eGFR, estimated glomerular filtration rate; RNP, ribonucleoprotein; SSA, Sjögren's-syndrome-related antigen A; SSB, Sjögren's-syndrome-related antigen B.

Outcome and follow-up

After discharge, he was scheduled to have monthly cyclophosphamide, and his prednisolone was eventually weaned to 15 mg daily. Two months following the first presentation, his follow-up MRI showed bilateral occipital lobe infarcts on diffusion-weighted imaging not present on prior imaging, as well as areas of less recent infarction (figure 3). He was asymptomatic and tested 20/30 in his right eye and 20/25 in his left. He was treated with a 3-day course of intravenous methylprednisolone 1 g and then weaned onto 50 mg of prednisolone. His transoesophageal echocardiogram ruled out Liebman Sachs endocarditis or cardiac thrombi. He was discharged on aspirin 100 mg daily, and his hydroxychloroquine was increased to 400 mg daily. He completed a 6-month course of intravenous cyclophosphamide and was changed to mycophenolate mofetil at 1 g two times per day. His prednisolone was cautiously weaned to 5 mg daily over 12 months with regular outpatient monitoring and ongoing pantoprazole for ulcer prophylaxis. Two years on from his initial presentation, his vision remains normal and he continues to work full-time without any relapses.

Figure 3.

Two months following presentation. Areas of restricted diffusion (A) with low ADC signal (B) in the occipital region. Further areas of normal signal on DWI (C) with increased signal on FLAIR (D), suggestive of subacute infarcts likely from the initial presentation. ADC, apparent diffusion coefficient; DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery.

Discussion

Acute visual loss in SLE is a rare but serious occurrence, with less than 70 published articles to date. The summary of some of the case reports are summarised in table 2. There are a broad range of causes with important implications for treatment. While the temptation may be to commence high-dose immunosuppression immediately, this may not always be the solution, and may even lead to harm. This occurred in a patient who progressed from having monocular to binocular visual loss following heavy immunosuppression. She was ultimately diagnosed with disseminated varicella zoster virus.⁵

Table 2.

Summary of case reports of blindness in patients with SLE

Authors, year	Age, sex	Symptoms, signs, initial visual acuity (VA): right eye, left eye	Cause of blindness and neuroimaging	Treatment	Outcome with VA if available: right eye, left eye
Tizazu et al5 2019	53 years old, female	Two weeks of bilateral leg weakness, multiple cranial neuropathies, 1 week of painless visual loss in left eye Necrotising retinitis, progressive outer retinal necrosis on ophthalmic exam VA: not reported	Initially thought to be neuromyelitis optica, then later revised as disseminated varicella zoster with retinitis, encephalitis and myelitis MRI: Multiple enhancing parenchymal and leptomeningeal lesions, transverse myelitis	Initial: pulse methylprednisolone for 5 days then 80 mg daily, plasmaphresis, rituximab	Following initial treatment, blindness progressed to right eye. Treatment changed to intravenous aciclovir. Two-month follow-up: ‘stable bilateral vision loss’
Lee and Kim22 2020	59 years old, female	Sudden visual loss in right eye Relative afferent pupillary defect, optic disc swelling with haemorrhage, macular oedema, Bull’s eye maculopathy on autofluorescent imaging VA: counting fingers, 20/25	Neuroretinitis and hydroxychloroquine-induced toxic retinopathy	Intravenous methylprednisolone 1 g daily for 3 days then oral prednisolone for 11 days, hydroxychloroquine ceased	Final VA: hand motion, 20/25
Siatkowski et al23 2001	32 years old, female	Monocular visual loss over 7 days, periocular pain Swollen and pale optic discs VA: light perception, 20/15	Optic neuropathy and chiasmopathy MRI: Gadolinium enhancement of both optic nerves and chiasm	Intravenous methylprednisolone, monthly cyclophosphamide	Final VA: 5/200, 20/200
Khan et al24 2017	16 years old, female	Acute, painless, bilateral visual impairment Normal pupillary reflexes, cranial nerve examination and slit-lamp exam VA: Hand movements, light perception	Cortical blindness MRI: Normal including diffusion imaging	Intravenous methylprednisolone 1 g for 3 days then high dose oral prednisolone and mycophenolate mofetil	Complete resolution of visual symptoms after 3 days
Leroux et al25 2008	40 years old, female	Sudden-onset hypertension, headaches, blindness, thrombocytopaenia, haemolytic anaemia, deranged liver function tests, acute renal failure VA: not reported	Posterior reversible encephalopathy syndrome MRI: Bilateral occipito-parieto-frontal hyperintensities on FLAIR and T2-weighted sequences	Intravenous methylprednisolone 500 mg for 3 days then prednisone 40 mg daily, intravenous immunoglobulin 30 g daily for 4 days, plasma exchange for thrombocytopaenia, low molecular weight heparin and nicardipine	Recovery of VA in 3 days
Altaie et al26 2009	36 years old, female,	Severe eye pains and visual loss over 3 days following topical use of plant material on cornea Bilateral eyelid swelling, conjunctival injection, severe corneal melting VA: light perception, light perception	Bilateral severe corneal melting and perforation from topical use of plant material	Bilateral emergency penetrating keratoplasty, corneal transplant	Final VA: 20/25, 20/30

FLAIR, fluid-attenuated inversion recovery; SLE, systemic lupus erythematosus; VA, visual acuity.

A focused history should be taken with attention to baseline visual history, current immunosuppression regimen, compliance with therapy and features of antiphospholipid syndrome. Hydroxychloroquine can cause retinopathy but is typically detected on routine screening and not usually associated with acute visual loss. A thorough eye examination conducted by a neurologist or ophthalmologist if available may reveal signs which can localise the site of pathology (table 2). Psychogenic or non-organic visual loss should be ruled out with simple bedside tests mentioned earlier to avoid unnecessary and potentially harmful tests and treatment.⁶

Apart from routine blood tests, patients should have blood cultures, SLE antibodies and antiphospholipid antibodies. An urgent MRI could help diagnose optic neuritis, optic chiasmitis, PRES, ischaemic strokes and other less common differentials.⁷ A lumbar puncture should be undertaken to rule out meningitis or encephalitis as uncommon causes of blindness, especially in those who are immunosuppressed.^{8 9}

The role of drug-induced vasculitis was studied given the short timing between medication ingestion and rash onset. Amoxicillin, clarithromycin and esomeprazole have uncommonly caused vasculitis, mostly with cutaneous manifestations.^10–12 They can be associated with antineutrophil cytoplasmic antibodies and antiphospholipid antibodies.^{13 14} The onset of symptoms is variable, but is usually in the order of days to weeks.¹³ Fortunately, amoxicillin and pantoprazole have since been used in our patient without causing further flares. From an SLE perspective, the patient had evidence of active, untreated disease during symptom onset, supported by positive anti-Smith antibodies and the history of undifferentiated enteritis. Anti-Smith antibodies have also been shown to correlate with disease activity and with NPSLE.^15–17 In the end, the authors thought that the underlying pathology is likely to be NPSLE, potentially precipitated by esomeprazole or clarithromycin. These two medications have been listed as allergies and the patient was informed not to take them under any circumstances.

Treatment is guided by the underlying pathology, and there are very few randomised controlled trials due to the rarity of NPSLE cases.⁴ Immunosuppressive treatment typically involves the use of induction corticosteroids, with 3 days of pulse intravenous methylprednisolone 1000 mg daily before weaning onto high dose oral steroids or monthly intravenous cyclophosphamide. If antiphospholipid syndrome is diagnosed and haemorrhage has been ruled out, lifelong anticoagulation with warfarin is required.¹ Patients should also be on hydroxychloroquine, as evidence suggests benefits in delaying onset of NPSLE symptoms.¹⁸ Prognosis is variable and cause-dependent but would likely be more favourable in those where prompt diagnosis and treatment are achieved.

One of the challenges highlighted in this case was to provide equitable care to patients from culturally diverse backgrounds. Despite the use of an interpreter on admission, the history of lupus was not ascertained until a collateral history was obtained from his wife, and only after specifically stating the word lupus using a translation app. Fortunately, the delayed diagnosis and treatment did not affect the patient’s long-term outcome. Studies have shown that patients with SLE from culturally diverse backgrounds often fare worse than their Caucasian counterparts.¹⁹ While ineffective communication may be the main cause, other factors may be at play, including low health literacy, variable treatment adherence, prior negative experiences in Western healthcare, socioeconomic factors and reluctance to escalate concerns.²⁰ Doctors should take a history in a non-judgemental manner, specifically when enquiring about treatment compliance and the use of alternative medicines. From a systems perspective, implementation of cultural competence and communication skills training sessions may help healthcare professionals appreciate and overcome barriers to provide holistic and patient-centred care.²¹

Patient’s perspective.

I was terrified at first when I was unable to see, but I felt reassured by the doctors, and was motivated to get better. I am really thankful for the care received. It was of great help to be able to see again.

Learning points.

• Clinicians should consider a broad range of differentials for symptoms resembling neuropsychiatric systemic lupus erythematosus, including infections, thrombosis, medications and psychogenic causes.

• In acute visual loss, bedside examination with involvement of neurologists and ophthalmologists, if available, can quickly localise the likely site of lesion and rule out psychogenic causes.

• High-dose immunosuppression should be considered only after ruling out other pathology, especially infections.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).