SUDANESE JOURNAL OF PAEDIATRICS

2020; Vol 20, Issue No. 2

CASE REPORT

An unusual neurological presentation: systemic lupus erythematosus mimicking central nervous system infection

Barnali Das (1), Rekha Khaund Borkotoky (1), Amrit Lal Saha (1), Geetanjali Sahariah Khound (1), Puja Banerjee Barua (1), Siba Prosad Paul (2)

(1) General Paediatrics, Apollo Hospitals, (Unit: International Hospital), Guwahati, India

(2) General Paediatrics, Torbay Hospital, Torquay, UK

Correspondence to:

Siba Prosad Paul

Consultant Paediatrician, Vowden Hall, Torbay Hospital, Torquay, Devon, UK

Email: siba [at] doctors.org.uk

Received: 13 August 2019 | Accepted: 01 July 2020

How to cite this article:

Das B, Khaund Borkotoky R, Saha AL, Sahariah Khound G, Banerjee Barua P, Paul SP. An unusual neurological presentation: systemic lupus erythematosus mimicking central nervous system infection. Sudan J Paediatr. 2020;20(2):170–175.

https://doi.org/10.24911/SJP.106-1565526532

ABSTRACT

Systemic lupus erythematosus (SLE) is an autoimmune multisystem disease. Childhood-onset SLE is extremely rare and comprises only 10% to 20% of all cases. In this case report, we present a 9-year-old boy from northeastern India who presented with fever, cough, vague abdominal pain, lethargy and swelling of face and legs. Initial impression was one of sepsis with central nervous system (CNS) involvement and was treated accordingly. Detailed clinical examination with subsequent laboratory and imaging studies clinched the diagnosis of SLE. The patient showed rapid resolution of symptoms with immunoglobulins, cyclophosphamide and steroid therapy. A brief discussion on childhood neuropsychiatric lupus syndrome and SLE with CNS infections is included here.

---

KEYWORDS

Systemic lupus erythematosus; Children; Neurological manifestations; Neuropsychiatric systemic lupus erythematosus; Sepsis; Resource-limited settings.

---

INTRODUCTION

Systemic lupus erythematosus (SLE) is a chronic autoimmune condition affecting all age groups and is characterised by multisystem inflammation and the presence of circulating autoantibodies directed against self-antigens [1]. It is estimated that the incidence of SLE in childhood varies between 0.3 and 2.2 per 100,000 children-years [1]. There is definite sex predilection in females (≈90%), with the reported prevalence of 5:1 in pre-pubertal girls increasing to 9:1 during reproductive years [1]. The most common manifestations include rash, arthritis and fatigue. At the most severe end of the spectrum, SLE can present with nephritis, neurological problems, anaemia and thrombocytopaenia [1,2].

The Systemic Lupus International Collaborating Clinics (SLICC) criteria for SLE classification [1] require:

1. Fulfilment of at least four criteria, with at least one clinical criterion ‘and’ one immunological criterion
2. ‘Or’ lupus nephritis as the sole clinical criterion in the presence of antinuclear antibodies or anti-dsDNA antibodies.

We present the case of a 9-year-old boy presenting with SLE whose initial features were suggestive of central nervous system (CNS) infection with multi-organ dysfunction.

---

CASE REPORT

A 9-year-old boy, from the northeastern part of India, attended the emergency department in a specialist centre with chief complaints of ‘on and off fever’ for the preceding 2 months. Fever was associated with cough, non-specific abdominal pain for 2 months, swelling of face which progressed to the limbs in the preceding one-and-a-half months and lethargy. He was not responding well to verbal commands for the last 24 hours. He was previously admitted twice with a similar presentation in a local hospital. On both occasions he was diagnosed as a case of pancytopenia with acute kidney injury, possibly secondary to sepsis, and treated with ceftriaxone, meropenem, tigecycline, methyl prednisolone, and packed red cell transfusion.

On examination, the patient was minimally responding to commands with a vacant look, and had icterus and peripheral oedema. There was sub-conjunctival haemorrhage in the right eye and black macular rash over his face with interspersed hyper-hypo pigmented areas (Figure 1). His blood pressure was 160/100 mm Hg, pulse rate was 64/minute, respiratory rate was 24/minute, with normal central capillary refill time (<2 seconds) but febrile with a temperature of 38.2°C. His weight was 20 kg (between 3rd and 10th centiles according to Indian Academy of Paediatrics growth chart) at the time of admission. Abdominal examination revealed hepatomegaly with a three finger breadth below the right sub-costal margin with normal bowel sounds auscultated.

On neurological examination, the Glasgow Coma Scale (GCS) was 8/15; deep tendon reflexes were intact, pupils were equal, normal in size and normally reacting to light. Left plantar reflex was extensor. Cardiovascular examination revealed normal first and second heart sounds with a short systolic murmur. Jugular venous pressure was normal and peripheral pulses were all palpable. On respiratory examination, bilateral air entry with crepitations were auscultated. In view of his worsening clinical status and repeated episodes of seizures with a low GCS (8/15), he was intubated and put on mechanical ventilation on the day of admission.

Figure 1. Facial rash at presentation.

Blood results which became available later that day showed:

• Total leucocyte count - 5,820/μl (4,000-11,000/μl) with a marked left shift and low eosinophil counts
• Erythrocyte sedimentation rate - 108 mm/hour (0-15 mm/hour)
• C-reactive protein - 3 mg/l (0-5 mg/l)
• Haemoglobin - 9.3 g/dl (13-18 g/dl)
• Platelet count - 1,08,000/µl (150,000-400,000/µl)
• Normal peripheral blood smear, malarial parasite not detected
• Normal coagulation profile
• Blood urea - 92 mg/dl (7-20 mg/dl)
• Serum creatinine - 0.76 mg/dl (0.6-1.2 mg/dl)
• Liver function tests
  • Total serum bilirubin - 4.27 mg/dl (<1.2 mg/dl)
  • Serum glutamic-oxaloacetic transaminase - 246 U/l(15.0-37.0 U/l)
  • Serum glutamic-pyruvic transaminase - 69 U/l (16-63 U/l)
  • Alkaline phosphatase - 246 IU/l (44-147 IU/l)
• Total protein - 5.8 g/dl (6-8 g/dl)
• Albumin - 1.9 g/dl (3.5-5.0 g/dl)
• Globulin - 3.9 g/dl (2.3-3.5 g/dl)
• Pro-calcitonin - 29.38 ng/ml (<0.15 ng/ml)
• Cholesterol - 172 mg/dl (<200 mg/dl)
• Urine analysis showed a trace of albumin, and 24 hour urine protein excretion was 3.2 g/24-hours (nephrotic range proteinuria >3.5 g/24-hours).

Chest X-ray (AP view) showed bilateral opacities and apparent cardiomegaly. Electrocardiogram was suggestive of sinus arrhythmia with left ventricular hypertrophy. Ultrasound of chest and abdomen showed bilateral renal parenchymal disease with mild hepatomegaly, mild ascites and left pleural effusion with normal renal Doppler study. A two-dimensional echocardiography conducted on day 2 of admission showed dilated left atrium and left ventricle, pericardial fluid was present, with good biventricular function. His electroencephalogram (EEG) showed an abnormal record with slowing in background activity.

A provisional diagnosis of severe sepsis with multi-organ dysfunction was made. The patient was started on meropenem and piperacillin/tazobactam. To regulate his blood pressure, multiple anti-hypertensive drugs were started, following discussion with the cardiologist. Fosphenytoin was added to control the seizures symptomatically.

Bone marrow aspiration and cultures were carried out, which showed trilineage haematopoiesis of normal morphology. Repeat peripheral blood smear showed abundance of schistocytes. Blood, urine, cerebrospinal fluid (CSF) and bone marrow cultures were reported as showing no growth.

After 7 days of admission, his platelet count decreased to 78,000/µl, total leucocyte count was <4,000/µl and his haemoglobin level was very low at 5.5 g/dl. His ferritin levels were 2,000 ng/ml (high) and fibrin degradation products were also strongly positive (>20 µg/ml) in his serum.

As the boy was not showing much improvement, with standard therapies and other supportive measures, possibility of an autoimmune disorder was considered and antinuclear antibody reflex panel profile was conducted, which showed positive antinuclear antibodies with an endpoint titre of 1:2,560, positive anti-dsDNA with an endpoint titre of 1:320, nucleosome antibodies strongly positive and AMA-M2 antibodies borderline positive. Perinuclear anti-neutrophil cytoplasmic antibodies were strongly positive and complement (C3, C4) levels were reported as low.

A diagnosis of SLE was made as the case fulfilled the following SLICC clinical criteria [1,3]:

1. Macular rash
2. Pleural effusion and pericardial effusion
3. Neurological symptoms (as seizures were present)
4. Renal involvement (as 24 hour urine protein was 3.2 g)
5. Leucopenia <4,000/µl without any sign of infection or being drug induced
6. Low platelet count <100,000/µl without portal hypertension or evidence of thrombotic thrombocytopaenic purpura;

‘And’ the following immunological criteria were also met:

1. Positive antinuclear antibody
2. Positive anti-dsDNA
3. Low complement levels

After discussion with the rheumatologist, intravenous immunoglobulin 2 g/kg (total of 40 g/dose) and IV cyclophosphamide 200 mg once monthly (for 6 months) was started. Oral prednisolone 10 mg once daily was also started. The decision to use immunoglobulin was based on the child’s condition, initial concerns of infection, deranged liver enzymes, low platelets, possible steroid sparing benefit, male sex, presence of lupus nephritis at initial presentation and other benefits described in the literature.

Since the boy remained on mechanical ventilation for 9 days, he underwent tracheostomy, as requirement for prolonged ventilation was anticipated. He was extubated after 2 days, following tracheostomy. Tracheostomy wound was closed after 7 days of initiation of treatment for SLE. Magnetic resonance imaging (MRI) scan of brain was conducted after 2 days of extubation, which showed parenchymal bleed of varying ages with oedema and mass effect, ventricular bleed and compressions.

With the ongoing treatment, his general condition gradually improved along with his haematological test results. His blood pressure started stabilising and his anti-hypertensive drugs were weaned off as advised by the cardiologist.

Initially, he was on nasogastric tube (NGT) feeds and intravenous fluids. Post-extubation his total daily requirements of nutrients were managed only on NGT feeds till the discharge. He started responding to commands and was able to recognise his family members within a week of starting cyclophosphamide. The patient was discharged after 1 month of admission, with follow-up advice and monthly doses of cyclophosphamide injection, for the next 5 months. At the time of discharge, his weight was 15 kg. After a month during follow-up, the patient weighed 18 kg. He was able to talk and responded well to commands.

---

DISCUSSION

Childhood SLE is a lifelong remitting and relapsing condition with multiple systemic involvement. Diagnosis at times can be difficult due to heterogeneity of the clinical symptoms with varying prevalence amongst affected individuals [1,4,5]. The child in this case study, a male, which is uncommon, initially presented with signs and symptoms mimicking sepsis with multi-organ dysfunction syndrome. In retrospect, the boy very likely presented with signs of SLE with CNS involvement mimicking sepsis.

SLE can involve both central and peripheral nervous systems, described as neuropsychiatric syndromes and additional unclassified neuropsychiatric manifestations (NPSLE) [1,5]. According to the American College of Rheumatology classification criteria, CNS syndromes are reported in 25% of the cases at diagnosis of SLE in children, whereas peripheral nervous system syndromes are seen in only 1% of cases [5]. In NPSLE, the common complaints are headache, mood disorders, cognitive dysfunction, psychosis and seizures [1]. Seizures in NPSLE are rarely an isolated event and are usually generalised in nature. Any patient presenting with new neurological symptoms requires a full diagnostic work-up that should include lumbar puncture, MRI brain scan and EEG [1].

Review of the literature estimates that 18% to 67% of patients with SLE have CNS involvement. It is important to note that up to 81% of NPSLE patients may not have any other systemic SLE activity [6]. In SLE, infections account for 20%-55% of morbidity and mortality, although CNS infections are relatively uncommon (3%) [7,8]. The most commonly identified pathogenic organisms in patients with SLE are Mycobacterium tuberculosis, followed by Cryptococcus neoformans [6,9]. The incidence of meningitis in SLE is rare. A Mexican study with 1,411 patients with SLE revealed an incidence of meningitis at <2% [10]. The main microorganisms isolated in the CSF were: Mycobacterium tuberculosis (33%), Listeria monocytogenes (33%) and Cryptococcus neoformans (20%) [10]. However, the same study also reported that in 40% of cases, microorganisms were not isolated from the CSF cultures [10].

In SLE with severe manifestation, the drug of choice remains a high dose of methyl prednisolone with cyclophosphamide; however, benefits of immunoglobulin therapy are gradually becoming evident from the literature. A systematic review and meta-analysis, including 13 studies published over a 25-year period (1989-2013), highlighted a significant reduction in the SLE disease activity scores and improvement in complement levels with intravenous immunoglobulin therapy (p = 0.002) [11]. The same article highlighted that the cyclophosphamide arm needed a higher steroid dose (4,719 mg) in comparison to the immunoglobulin arm (3,334 mg); however, this difference did not reach statistical significance [11]. The role of immunoglobulin as a steroid-sparing agent needs further comparison studies. In a retrospective case records review study from the USA with 116 paediatric SLE cases treated over a 15-year period (1997-2011), 86 cases matched the inclusion/exclusion criteria and 6 of them had hypogammaglobulinaemia (IgG < 500 mg/dl) [12]. The study reported a significant association of hypogammaglobulinaemia with male sex (p = 0.009), lupus nephritis (present in all cases) at diagnosis of SLE (p = 0.004) and white ethnicity (p = 0.029) [12].

---

CONCLUSION

Early suspicion and a focused approach with involvement of relevant specialists are necessary to diagnose SLE. Clinical diagnosis and approaching the condition by keeping an overview of all the symptoms together, and conducting a thorough general physical examination is very important. Focused laboratory tests and inclusion of specific and pathogenic autoantibodies are important, keeping in mind the financial constraints in resource-limited settings. It is worth mentioning that children with SLE have to deal with this unpredictable, relapsing-remitting disease during puberty, an important and challenging phase of their life. Paediatricians have a vital responsibility to counsel the family sensibly about the condition and ensure that the child remains under regular follow-up.

---

ACKNOWLEDGEMENT

The authors thank the parents for providing consent to publish this case and the photographs of their child.

The authors would also like to thank Dr Madhumita Priyadarshini Das, Consultant Rheumatologist who helped us in managing the case.

---

FUNDING

None.

---

CONFLICT OF INTEREST

The authors declare that there are no conflicts of interest.

---

ETHICAL APPROVAL

Signed informed consent for participation and publication of medical details and photography was obtained from the parents of the child. Ethical clearance and approval to publish this case report was obtained from the Ethics Committee and Additional Director of Medical Education, Apollo Hospitals Guwahati, India.

---

REFERENCES

1. Levy DM. Childhood-onset systemic lupus erythematosus (SLE): clinical manifestations and diagnosis. UpToDate 2019. [cited 2019 Aug]. Available from: https://www.uptodate.com/contents/childhood-onset-systemic-lupus-erythematosus-sle-clinical-manifestations-and-diagnosis
2. Manson JJ, Rahman A. Systemic lupus erythematosus. Orphanet J Rare Dis. 2006;1:6. https://doi.org/10.1186/1750-1172-1-6
3. Petri M, Orbai AM, Alarcón GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and validation of the systemic Lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64:2677–86. https://doi.org/10.1002/art.34473
4. Levy DM, Kamphuis S. Systemic lupus erythematosus in children and adolescents. Pediatr Clin North Am. 2012;59:345–64. https://doi.org/10.1016/j.pcl.2012.03.007
5. Silva CA. Childhood-onset systemic Lupus erythematosus: early disease manifestations that the paediatrician must know. Expert Rev Clin Immunol. 2016;12:907–10. https://doi.org/10.1080/1744666X.2016.1195685
6. Ribeiro FM, Signorelli F. The role of infections in neuropsychiatric lupus. Lupus. 2017;26:490–6. https://doi.org/10.1177/0961203317691375
7. Zhong Y, Li M, Liu J, Zhang W, Peng F. Cryptococcal meningitis in Chinese patients with systemic lupus erythematosus. Clin Neurol Neurosurg. 2015;131:59–63. https://doi.org/10.1016/j.clineuro.2015.01.023
8. Sivalingam SK, Saligram P, Natanasabapathy S, Paez AS. Covert cryptococcal meningitis in a patient with systemic lupus erythematous. J Emerg Med. 2012;42:e101–4. https://doi.org/10.1016/j.jemermed.2009.03.022
9. Yang CD, Wang XD, Ye S, Gu YY, Bao CD, Wang Y, et al. Clinical features, prognostic and risk factors of central nervous system infections in patients with systemic lupus erythematosus. Clin Rheumatol. 2007;26:895–901. https://doi.org/10.1007/s10067-006-0424-x
10. Baizabal-Carvallo JF, Delgadillo-Ma’rquez G, Estan˜ol B, Garcı’aRamos G. Clinical characteristics and outcomes of the meningitides in systemic lupus erythematosus. Eur Neurol. 2009;61:143–8. https://doi.org/10.1159/000186504
11. Lim E, Tao Y, White AJ, French AR, Cooper MA. Hypogammaglobulinemia in pediatric systemic lupus erythematosus. Lupus. 2013;22:1382–7. https://doi.org/10.1177/0961203313507990
12. Sakthiswary R, D’Cruz D. Intravenous immunoglobulin in the therapeutic armamentarium of systemic lupus erythematosus: a systematic review and meta-analysis. Medicine (Baltimore). 2014;93:e86. https://doi.org/10.1097/MD.0000000000000086