Intracranial hypertension and papilloedema as a complication to low antiretroviral therapy adherence in a man living with chronic HIV

Abstract

We describe a 61-year-old man living with HIV on antiretroviral therapy (ART), who presented with headache, dizziness and blurred vision. Latest CD4⁺ cell count 3 months prior to admission was 570×10⁶ cells/mL and HIV viral load <20 copies/mL. The patient was diagnosed with cerebrospinal fluid (CSF) lymphocytic pleocytosis, raised intracranial pressure and papilloedema. Neuroimaging showed normal ventricular volume and no mass lesions, suggesting (1) neuroinfection (2) idiopathic intracranial hypertension or (3) retroviral rebound syndrome (RRS) as possible causes. Neuroinfection was ruled out and idiopathic intracranial hypertension seemed unlikely. Elevated plasma HIV RNA level was detected consistent with reduced ART adherence prior to admission. RRS is a virological rebound after ART interruption, which can mimic the acute retroviral syndrome of acute primary infection. To the best of our knowledge, we describe the second case of RRS presenting as CSF lymphocytic pleocytosis and elevated intracranial pressure after low ART adherence.

Background

Retroviral rebound syndrome (RRS) is a virological rebound after antiretroviral therapy (ART) interruption leading to symptoms that resemble the primary HIV infection.¹ The acute illness is typically developed 1–6 weeks after discontinuation of ART with a dramatic increase in plasma HIV RNA levels and decrease in CD4 cell count commonly accompanied by fever, fatigue, pharyngitis, lymphadenopathy, rash and weight loss.^{2 3} Other more rare manifestations of RRS have also been reported including meningoencephalitis with detectable HIV viral load (VL) in cerebrospinal fluid (CSF) after cessation of ART.⁴

Elevated intracranial pressure (ICP) can occur at different stages of HIV infection and has mostly been described in advanced stages related to opportunistic infections such as a complication to AIDS-associated cryptococcus meningitis,^{5 6} tuberculosis or malignant mass lesions.⁷ Elevated ICP is a rather uncommon phenomenon in the absence of parenchymal lesions and in aseptic lymphocytic meningoencephalitis.^{1 8 9}

Here, we report a patient living with HIV, presenting with several symptoms correlating with elevated ICP and accompanied by CSF lymphocytic pleocytosis due to low ART adherence.

Case presentation

A 61-year-old man living with HIV was hospitalised in September 2019 due to symptoms of increased ICP, progressing over a couple of months. Symptoms included headache, dizziness, blurred vision, nausea, vomiting along with fever, night sweats and an unintended weight loss of 4–5 kg.

In 2015, the patient was diagnosed with an HIV infection, sexually transmitted. AIDS defining events included Pneumocystis jiroveci pneumonia and cytomegalovirus (CMV) colitis. Nadir CD4⁺ cell count was <0.01 × 10⁶cells/mL and HIV VL 199 448 copies/mL. ART containing efavirenz, lamivudine and tenofovir disoproxil was promptly initiated. Genotypic HIV drug resistance test revealed no drug resistance conferring mutations.

Since 2015, the patient was seen every 3–6 months in the outpatient clinic at Department of Infectious Diseases. Consecutive VLs had been below the limit of detection (20 copies/mL) and the CD cell count had normalised. Latest CD4⁺ cell count 3 months prior to admission was 570×10⁶ cells/mL and VL <20 copies/mL. The patient’s medical history included syphilis (2017) and gastroenteritis due to a Campylobacter jejuni infection 3 months prior to admission. Travel history included annual work-related assignments in Greenland. Besides ART, he was not treated with any additional medication prior to admission.

Investigations

During admission, the physical examination revealed no pathological findings, including no skin rash or lymphadenopathy. A complete blood sample including a white cell differential count displayed leucocytosis of 9.7×10⁹/L (3.5–8.8 × 10⁹/L). Liver function test (alanine aminotransferase, 17 U/L), serum creatinine (75 µmol/L) and C reactive protein (10 mg/L) were within normal range. Eye examination disclosed bilateral visual loss to 0.4, and computerised visual field measurements showed bilateral enlarged blind spots and partial arcuate visual field defects. Funduscopy revealed bilateral severe papilloedema with pronounced peripapillary haemorrhages, cotton wool spots and macular oedema (figure 1). Pupillary reflexes were normal, slit lamp examination without signs of uveitis and intraocular pressure was 9/10 mm Hg (11–21 mm Hg). Raised ICP due to intracranial pathology was suspected. An enhanced CT with venography of the brain, and a subsequent MRI of the brain and orbit were normal apart from fluid retention and meningeal distension around the optic nerves as a sign of intracranial hypertension (ICH) (figure 2). No space occupying lesion, venous sinus thrombosis, optic nerve inflammation or meningeal enhancement was found. CSF pressure was 36 cm H₂O (9–18 cm H₂O), determined by spinal tap. CSF analysis revealed lymphocytic pleocytosis of 29 cells × 10⁶/L (<5 cells × 10⁶/L), glucose within normal range, lactate within normal range and a slightly elevated protein level of 0.78 g/L (0.15–0.50 g/L). Blood glucose level was within normal range and blood pressure was normal. Negative microbial test of CSF included bacterial and fungal culture, cryptococcal antigen, and PCR testing of enterovirus, herpes simplex virus 1–2, varicella zoster, Epstein-Barr virus, CMV, BK polyomavirus, JC polyomavirus and Toxoplasmosis. Tick-borne encephalitis antibodies in serum and intrathecal test for syphilis and Borrelia burgdorferi sensu lato complex were negative. Microscopy, culture and PCR for Mycobacterium tuberculosis were also negative. CSF was further screened for immune-mediated conditions such as multiple sclerosis and neurosarcoidosis, including immunoglobulin IgG complex and oligoclonal bands which came out negative.

Figure 1.

Funduscopy: bilateral severe papilloedema with pronounced peripapillary haemorrhages, cotton wool spots and macular oedema.

Figure 2.

MRI brain: coronal T2 fat sat sequence through the orbits (A) showing distension of the perioptic subarachnoidal spaces bilaterally. Axial T2 fat sat sequence at the level of orbits (B) showing mild tortuosity of the optic nerves with distension of the perioptic subarachnoid spaces and subtle flattning of posterior sclera at the level of optic discs bilaterally.

A flour-deoxyglucose positron-emission tomography (¹⁸-FDG PET-CT) ruled out underlying malignancy. Further investigations focused on rheumatological and immune-mediated diseases. Elevated interleukin 2 receptor level to 1360 kU/L (158–523 kU/L) raised suspicion of neurosarcoidosis. However, the normal ¹⁸-FDG PET-CT and a negative peptidyl peptidase A (ACE) argued against this. Vasculitis, Sjögren syndrome and systemic lupus erythematosus were investigated by measuring plasma levels of antinuclear antibodies, antineutrophil cytoplasmic antibodies, anti-Sjögren’s-syndrome-related antigen A/B, antidouble-stranded DNA antibodies, antimyelin oligodendrocyte glycoprotein and antiaquaporin-4 IgG4 which all came out within normal range.

Plasma HIV RNA on day 4 of admission was 1590 copies/mL consistent with that the patient had been non-adherent to ART a few weeks prior to admission. Concomitant, HIV-RNA in CSF measured twice (on day 1 and day 4 of admission) was undetectable. The ART regimen was changed to efavirenz, emtricitabine and tenofovir disoproxil to simplify ART regimen (1-tablet regimen). However, HIV genotypic drug resistance test confirmed susceptibility to all ARTs.

Treatment

The ICH was treated with repeated lumbar punctures for CSF drainage and peroral acetazolamide 1 g three times a day. Normal ICP was documented by spinal tap 11 weeks later and the overall clinical status of the patient gradually improved during the following 3 months. Visual acuity improved to 0.9 and 0.6 as papilloedema and the macular oedema resolved while visual fields remained unchanged. Plasma HIV RNA was undetectable during follow-up.

Discussion

The patient presented with symptoms and signs related to elevated ICP following non-adherence of ART and was detected with CSF lymphocytic pleocytosis. Neurological conditions, rheumatic disease and underlying malignancy were all excluded with appropriate laboratory and neuroimaging investigations. ART was resumed and the patient recovered over the following weeks on symptomatic treatment. Possible underlying causes of the patient’s condition included (1) neuroinfection (2) idiopathic intracranial hypertension (IIH) or (3) RRS.

The comprehensive microbiological investigations and the course of the disease with improvement on symptomatic treatment argues against an undiagnosed CNS infection, such as cryptococcal infection or other common opportunistic infections. Further, the severity of the symptoms with elevated ICP and papilloedema argues against an undiagnosed mild infection.

IIH is a disorder that involves symptoms and signs of elevated ICP together with normal CSF and normal neuroimaging. The lumbar puncture opening pressure is typically well above 20 cm H₂O in IIH. More than 90% of IIH cases occur in young females with obesity and IIH is primarily a diagnosis of exclusion.^{10 11} A coincidental IIH in a 61-year-old man with HIV, who prior to hospitalisation had been non-adherent to ART, is unlikely. Further, our patient had abnormal CSF analyses with lymphocytosis and elevated protein levels which contrasts with the definition criteria of IIH.¹² However, there have been reports of clinical phenotypes similar to IIH in HIV-infected patients with the absence of opportunistic infections or malignant mass lesions.^{13 14} Recently, elevated ICP was observed as the sole finding in a patient who was eventually diagnosed with primary HIV infection.¹⁵ Further, amphotericin B,¹³ cotrimoxazole,¹⁶ and ART initiation¹⁴ have also been associated with elevated ICP in case reports. Our patient did not receive any medication that has been associated with elevated ICP.

RRS is an acute illness that mimic the primary HIV infection developed after discontinuation of ART in patients with chronic HIV infection.^{1 17–20} There have been reports of RRS with involvement of CNS presenting as meningoencephalitis with detectable HIV RNA in CSF⁴ and ICH.¹ Our patient demonstrated all elements associated with RRS including the clinical presentation with onset after treatment interruption, the absence of other identified causes, the observed increase in HIV RNA levels in plasma, and the clinical and viral response after resumption of ART. The neurological manifestations with lymphocytic pleocytosis and elevated protein in CSF suggested CNS involvement; however, HIV RNA was not detected in CSF. The time span from ART initiation to viral clearance of HIV RNA in CSF has been reported to vary from 5 days to around 3 months,²¹ and thus, it is possible that the absence of HIV RNA in CSF in this patient was due to the non-adherence episode being weeks prior to CSF sampling. The relatively low plasma HIV RNA levels detected during admission, where the patient had already resumed ART, is also in line with this assumption.

It has been suggested that CNS may be a reservoir for HIV and viral re-emergence may occur in CNS following ART interruption.²² However, a recent study found that only one-third of HIV patients had detectable HIV RNA in CSF during and after ART interruption and during plasma viral rebound.²³ Another study reported that median HIV RNA levels were significantly lower in CSF compared with plasma among patients with HIV with neurological symptoms.²⁴ Thus, a non-correlation between plasma and CSF VL is not uncommon, even in patients with signs of CNS involvement.

Although, ART discontinuation may be relatively frequent due to non-adherence, toxicity or structured treatment interruption strategies,²⁵ RRS is not a common phenomenon as most reports are based on a single or few cases.4 17 18 20 26–28 The diagnosis could be overlooked due to often mild and transient symptoms or the symptoms may be attributed to other more common infections. On the other hand, lack of or vague symptoms may be related to an incapable immune response in patients with low CD4 cell count who cannot mount a rapid and potent T-lymphocyte response. Accordingly, RRS has been related to more severe manifestations with fatal outcome²⁸ and this syndrome should be considered in HIV-infected patients who present with any symptoms. Our patient presented with several symptoms related to severe elevated ICP, which threatened the patient’s vision. Further, at time of diagnosis, our patient had very low nadir CD4 cell count, which has been associated with poorer outcome.²⁹ Thus, a very low nadir CD4 cell count could condition a greater severity of RRS in case of poor ART adherence.

This case illustrates an example of the potential serious consequence of treatment discontinuation in an HIV-infected patient. Although the diagnosis of ICH was determined quickly after hospitalisation, the diagnosis of RRS as the underlying cause was delayed mainly due to ART reinstitution by the patient prior to admission leading to extensive diagnostic procedures.

To the best of our knowledge, we describe the second case of RRS presenting as ICH and CSF lymphocytic pleocytosis due to low ART adherence.

Learning points.

• This case shows the importance of the medical interview including questions regarding adherence to prescription medication.

• The importance of communication between medical specialists, in this case between neurologists, ophthalmologists and specialists in infectious diseases.

• For the clinician to consider various causes of ICH, especially to consider retroviral rebound syndrome in patients with HIV with ICH and antiretroviral therapy non-adherence as an alternative diagnosis.