Posterior reversible encephalopathy syndrome in disseminated histoplasmosis and advanced HIV infection

Introduction

Histoplasmosis is rare in the UK. This case describes a patient with hypercalcaemia secondary to disseminated histoplasmosis who developed posterior reversible encephalopathy syndrome (PRES) which presented as seizures.

Case reports for PRES in patients with human immunodeficiency virus (HIV) infection are few, being associated with hypertension, end-stage kidney disease, combination antiretroviral therapy (cART) and opportunistic infection (tuberculosis, Mycobacterium avium intracellularae [MAI], blastomycosis and varicella zoster virus infection).^1–6 Hypercalcaemia has been associated with PRES in patients with HIV: an adult with MAI ⁵ and a child with advanced HIV. ²

Case description

A 26-year-old Nigerian woman with no medical or medication history presented with vomiting, abdominal pain and cough for three weeks.

On examination, she had a palpable smooth liver and left-sided neck nodes. Her initial serum investigations are seen in Table 1.

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Table 1.

Laboratory results (note seizures on day 36 and day 61).

Test	Day 1	Day 36	Day 61	Normal range
Haemoglobin (g/dL)	8.0	5.7	8.2	13.0–16.5
MCV (fL)	74.9	94.4	83.7	77.0–95.0
Platelets (×109/L)	115	419	174	150–450
White cell count (×109/L)	1.55	2.33	3.10	4.0–11.1
Neutrophils (×109/L)	1.21	1.68	2.26	2.2–6.3
Lymphocytes (×109/L)	0.26	0.36	0.49	1.3–4.0
Creatinine (µmol/L)	54	109	59	45–120
eGFR	>90	53	>90	–
AST (IU/L)	238	63	21	10–50
ALP (IU/L)	272	767	480	30–130
INR	1.42	1.04	1.40	0.9–1.2
Corrected calcium (mmol/L)	2.48	3.36	2.98	2.15–2.6
C-reactive protein	151	40.7	24.6	<5.0
Intact PTH (ng/L)	–	81	–	10–70
Systolic blood pressure  (avg./24 h)	106	198	128	95–135

An HIV test was positive for antibodies to HIV-1, with a CD4 count of 2 cells/μl (1%) and an HIV-1 RNA of 5.5 log copies/ml. A computed tomography (CT) scan of the abdomen, pelvis and thorax showed hepatosplenomegaly. A diagnosis of Histoplasma capsulatum was confirmed on Grocott staining of a cervical lymph node and bone marrow trephine. She was started with liposomal amphotericin B 3 mg/kg OD. No other opportunistic infections were identified on bronchoalveolar lavage, cerebrospinal fluid (CSF), blood or bone marrow cultures. CSF analysis was normal. She was transferred to critical care with worsening renal and liver functions. She became anuric on day 11 and commenced on haemofiltration (creatinine 204 µmol/L, eGFR 26).

The patient subsequently suffered two generalised seizures on day 36. A magnetic resonance imaging (MRI) of the brain showed features suggestive of PRES (see Figure 1) with bilateral parieto-occipital oedema affecting predominantly the white matter. Hypercalcaemia was thought to be secondary to histoplasmosis infection and treated with prednisolone 40 mg daily.^7,8 Hypertension was treated with amlodipine and metoprolol. Tenofovir, emtricitabine and raltegravir were commenced. OPEN IN VIEWER

Corrected calcium was 2.56 g/ml after seven days of corticosteroids, which were stopped on day 50. Corrected calcium levels increased to 2.98 g/ml after steroid cessation and she became confused. She had a further single generalised seizure on day 61. Corticosteroids were restarted and tapered over four weeks with close monitoring of serum calcium. CT brain at the time of the second seizure episode showed bilateral parieto-occipital low density change consistent with PRES. An MRI of the brain scan two weeks later, when calcium was normal, showed resolution of the radiological features of PRES (see Figure 1).

Discussion

PRES is characterised by headache, confusion, seizures and visual loss. It is thought to occur due to vasogenic oedema due to disruption of the bloodflow to the blood-brain barrier leading to white-matter changes and has a number of aetiologies. ⁶ PRES is diagnosed on the basis of clinical as well as neuroradiological findings. In patients with PRES and normal blood pressure, including hypercalcaemia,^1,9 the mechanism is thought to be cytotoxicity. Immune system (T-cell) activation leads to endothelial cell activation, resulting in vascular instability. This results in vasoconstriction and downstream hypoperfusion with subsequent blood-brain barrier dysfunction and vasogenic cerebral oedema. ⁶

Disseminated histoplasmosis rarely causes hypercalcaemia, ¹⁰ the cause of which is believed to be similar to other granulomatous diseases where hypercalcaemia is caused by an extrarenal overproduction of calcitriol. ⁷ Hypercalcaemia in these cases is treated with steroids. ⁸ This patient had a raised parathyroid hormone as a result of renal failure^11,12; unfortunately, vitamin D levels were not performed. However, the rapid response of the calcium level to steroids on two occasions suggests the aetiology is unlikely to be primary hyperparathyroidism. ¹³ Subsequent calcium levels post-discharge have been normal.

Disseminated histoplasmosis is a rare diagnosis in HIV-infected individuals in Europe. Hypercalcaemia is a rare complication. PRES is a clinicoradiological diagnosis of a reversible cause of white matter change with multiple aetiologies.

In this patient, a single cause for the first episode of PRES is difficult to determine as the patient was hypertensive with hypercalcaemia and renal failure. However, at the time of the second seizure episode, the patient was normotensive with normal renal function making hypercalcaemia more likely.

The cause of PRES is often multifactorial. ⁶ Although uncommon in patients with HIV infection, it should be considered as a differential in immunosuppressed patients who develop neurological signs.

The patient remains well after one year of follow-up.