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Multisystem Inflammatory Syndrome in Children Presenting With Pseudotumor Cerebri and a Review of the Literature

Bilen, Nimet Melis MD; Sahbudak Bal, Zumrut MD; Yildirim Arslan, Sema MD; Kanmaz, Seda MD; Kurugol, Zafer MD; Ozkinay, Ferda MD

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The Pediatric Infectious Disease Journal: December 2021 - Volume 40 - Issue 12 - p e497-e500
doi: 10.1097/INF.0000000000003327
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Abstract

The first cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were reported in China at the end of 2019. Subsequently, SARS-CoV-2 spread worldwide, and the World Health Organization (WHO) declared a pandemic on March 11, 20201 SARS-CoV-2 infection is generally asymptomatic or mildly symptomatic in children, and mortality rates are lower than in adults.2 At the end of April 2020, the Pediatric Intensive Care Society (PICS) reported cases with hyperinflammatory findings and severe multisystemic inflammation similar to Kawasaki disease and toxic shock syndrome.3 This new syndrome is named multisystem inflammatory syndrome in children (MIS-C). It is a rare but life-threatening inflammatory immune response associated with SARS-CoV-2 infection.4 Centers for Disease Control and Prevention (CDC), WHO and Royal College of Pediatrics and Child Health defined diagnostic criteria for MIS-C.1,5,6 The main aspects of diagnosis are persistent fever, symptoms of two or more organ dysfunction, laboratory evidence of inflammation, lack of alternative diagnosis and evidence of recent or current SARS-CoV-2 infection or exposure.1,5,6 The majority of patients have been presented with hypotension, shock, gastrointestinal, cardiovascular and mucocutaneous symptoms. The incidence of neurologic symptoms in MIS-C was 13%–21% of patients, and they are not well described.7–9 Headache, altered mental status, seizures, brain edema, encephalopathy, aseptic meningitis and intracranial hypertension are some of the reported neurologic findings.4,9,10 Therefore, we report a case of MIS-C presented with neurologic symptoms due to pseudotumor cerebri (PTC).

CASE PRESENTATION

A previously healthy 8-year-old boy was admitted to the emergency room with a high fever and fatigue history for 7 days of the duration. He was initially managed as an upper respiratory tract infection but readmitted to the emergency room after 3 days because of persistent fever, headache, vomiting, abdominal pain, redness and swelling in both eyes. His father had a history of SARS-CoV-2 infection 1 month ago, but the patient was not tested for SARS-CoV-2. On admission, his physical examination revealed a fever (38.1oC) and tachycardia (heart rate, 130/min). He had bilateral nonpurulent conjunctivitis. On neurologic examination, his mental status and cranial nerve examination were normal, bilateral papilledema was detected by fundus examination. Detailed ophthalmologic examination showed stage 3 papilledema, and visual functions were as follows: visual acuity as a counting finger from 4 meters, and minimal enlargement of the blind spot. Initial laboratory results were as follows: total leukocyte count: 15.3 × 103/μL (neutrophil 64.8%, monocyte 4.9 % and lymphocyte 22.9%), hemoglobin 9.7 g/dL, platelet count: 506 × 103/μL, C-reactive protein (CRP): 12 mg/L, procalcitonin: 0.19 μg/L, fibrinogen: 237 mg/dL, D-dimer: 4313 μg/L FEU, erythrocyte sedimentation rate: 26 mm/h, albumin: 2,7 mg/L, Pro-BNP: 1087 ng/L and troponin: 13 ng/L. A SARS-CoV-2 polymerase chain reaction (PCR) test from the nasopharyngeal swab was negative. SARS-CoV-2 serology was positive for IgM and IgG antibodies. His contrast-enhanced brain magnetic resonance imaging (MRI) showed signs of intracranial hypertension characterized by flattening of the posterior sclera, enlargement of the perioptic nerve subarachnoid cerebrospinal fluid space, vertical tortuosity of the optic nerve (Fig. 1) and MR venography was normal. Lumbar puncture (LP) demonstrated a normal opening pressure (12 cm H2O) without pleocytosis and normal cerebrospinal fluid (CSF) glucose and protein levels, which indicated probable PTC. No viral or bacterial pathogens were detected in CSF PCR testing. According to the MIS-C definition provided by the CDC/WHO (1,5), our patient was considered MIS-C. The patient was treated with intravenous immunoglobulin (IVIG) 2 gr/kg for MIS-C and acetazolamide. Low molecular weight heparin treatment was initiated due to elevated D-dimer levels. Corticosteroids were not initiated because the patient did not show signs of shock, and his fever resolved after IVIG. On the second day of treatment, his headache and visual functions improved remarkably. On day 45, papilledema was completely regressed, and acetazolamide treatment was gradually tapered off.

FIGURE 1.
FIGURE 1.:
Brain magnetic resonance imaging scan showed signs of intracranial hypertension: (a) flattening of the posterior sclera, (b) distention of the perioptic nerve subarachnoid cerebrospinal fluid space, vertical tortuosity of the optic nerve.

DISCUSSION

We present an MIS-C case with symptoms of increased intracranial pressure. Several studies reported that most MIS-C patients present with gastrointestinal, cardiovascular and mucocutaneous symptoms.7–9,11–13 Neurologic symptoms in MIS-C are rare manifestations when compared with other organ system involvements. Dufort et al9 reported headache, altered mental status and confusion as neurologic symptoms were present in 13% of the patients 0–5 years of age and 38% of patients 13–20 years of age. Feldstein et al11 also demonstrated that 21% of 186 MIS-C cases had neurologic symptoms.

The etiology of neurologic symptoms in SARS-CoV-2 infection and MIS-C have not been well described. Laboratory studies have shown that angiotensin-converting enzyme 2 (ACE2) is expressed in the brain.14,15 Therefore, it is a potential target for the virus. Besides, the virus causes coagulation disorder, which increases the risk of thrombosis.16 Schupper et al17 presented two cases of MIS-C with neurologic manifestations due to a stroke caused by thrombosis. Therefore, we performed an MRI and MR venography to rule out a stroke and other neurologic disorders caused by thrombosis. Abdel-Mannan et al18 presented four cases of severe MIS-C with encephalopathy. Their MRI findings were consistent with lesions in the splenium of the corpus callosum, which may also be observed in ischemia. Our patient had a headache and papilledema and elevated D-dimer levels at the presentation. His MRI showed signs of intracranial hypertension without thrombosis.

Papilledema is the swelling of optic nerves due to increased intracranial pressure, and if untreated, it may cause optic nerve damage and lead to loss of vision.19 It is usually the hallmark of pseudotumor cerebri syndrome. Diagnostic criteria for definite pseudotumor cerebri syndrome are papilledema, regular neurologic examination except for abducens palsy, normal MRI findings and elevated opening pressure in LP. In some cases, like our case, LP opening pressure can be within expected ranges. In these cases, the diagnosis is considered probable pseudotumor cerebri.20 Inflammatory disorders such as systemic lupus erythematosus and Kawasaki disease may present with increased intracranial pressure.21–23 Becker et al4 presented 4 cases of MIS-C with clinical, LP, and neuroimaging findings of increased intracranial pressure, and one of them had papilledema. Baccarella et al23 also reported two MIS-C cases with symptoms of increased intracranial pressure and papilledema, all of their patients had neurologic symptoms including headache, altered mental status and nuchal rigidity at presentation, as our patient, suggesting that increased intracranial pressure may be an etiologic reason for neurologic symptoms of MIS-C. A review of the MIS-C cases with increased intracranial pressure in the literature is presented in Table 1.

Table 1. - Review of the MIS-C Cases With Increased Intracranial Pressure in Literature
Clinical Progression
Case report Age, sex Systemic symptoms Neurologic symptoms Fundus examination LP Neuroimaging Treatment Outcome
Verkuil et al24 14 y/o Female Fever Headache Bilateral Papilledema OP: 36 cm H2O MRI: eversion of the right optic disc and flattening of the posterior right globe MR venography: normal IVIG Discharged after 14 days resolution of papilledema and abducens palsy
Rash Abducens palsy IVMP
Diarrhea WBC: 2 Antibiotics
Dyspnea RBC: 0 Hydrocortisone
Glucose: N Acetazolamide
Protein: N
Baccarella et al23 9 y/o Male Fever Headache No papilledema OP: 34 cm H2O MRI: IVIG Discharged with clinical symptoms and papilledema resolved
Abdominal pain Diplopia WBC: 0 Normal IVMP
RBC: 0 MR Venography: normal Antibiotics
Glucose: N Hydrocortisone
Protein: N Acetazolamide
Aspirin
LMWH
6 y/o Male Fever Diplopia Bilateral papilledema OP: 14 cm H2O MRI: kinking and distention of both optic nerve sheaths with protrusion of the optic discs into the globes IVIG Discharged with clinical symptoms resolved
Hypotension, shock Abducens palsy WBC: 0 IVMP
RBC: 0 Antibiotics Papilledema resolved 5 months later
Glucose: N Hydrocortisone
Protein: N Acetazolamide
Aspirin
LMWH
Becker et al4 14 y/o Female Fever Headache Bilateral papilledema OP: >36 cm H2O CT: normal IVIG Discharged with clinical symptoms resolved
Dyspnea Blurry vision WBC:4 MRI: restricted diffusion of optic nerve sheaths, flattening of the posterior sclera, and eversion of the optic discs IVMP
Emesis Abducens palsy RBC:0 Antibiotics Papilledema resolved 2 months later
Diarrhea Glucose: 57 MR venography: flattening of the left transverse and sigmoid sinuses Acetazolamide
Diffuse erythematous rash Protein: 37 Hydrocortisone
Aspirin
LMWH
6 y/o Female Fever Irritability - OP:31 cm H2O CT: cerebral edema IVIG Discharged with clinical symptoms resolved
Rash Nuchal rigidity WBC:34 (34% neutrophils) IVMP
Conjunctivitis Antibiotics Papilledema resolved 5 months later
RBC:0 Aspirin
Cracked lips LMWH
Anakinra
Emesis Glucose: 98
Diarrhea Protein: 28
13 y/o Female Fever Encephalopathy - OP:>38 cm H2O CT: normal IVIG Discharged with clinical symptoms resolved
WBC:218 (90% neutrophils) MRI: normal IVMP
Abdominal pain Nuchal rigidity Hydrocortisone
Emesis Headache RBC:6 Antibiotics
Glucose: 58
Protein: 130 Aspirin
LMWH
Tocilizumab
12 y/o Male Fever Encephalopathy - OP:34 cm H2O CT: normal IVIG Discharged with clinical symptoms resolved
Emesis Nuchal rigidity WBC:3 IVMP
Diarrhea RBC:2 Antibiotics
Glucose:137 Aspirin
Protein: 19 LMWH
Current case 8 y/o Male Fever Headache Bilateral papilledema OP: 12 cm H2O MRI: Flattening of the postrior sclera, distention of the perioptic nerve subarachnoid cerebrospinal fluid space, vertical tortuosity of the optic nerve. IVIG Discharged with clinical symptoms resolved
Abdominal pain Blurry vision WBC: 0 Antibiotics
Vomiting RBC:0 Acetazolamide Papilledema resolved 1.5 months later
Aspirin
LMWH
Conjunctivitis Glucose: 55 MR venography: normal
Protein: 31
CT indicates computed tomography; IVIG, intravenous immunoglobulin; IVMP, intravenous methylprednisolone; LMWH, low molecular weight heparin; MRI, magnetic resonance imaging; OP, opening pressure; RBC, red blood cell; WBC, white blood cell.

In contrast to previous cases, our patient was well and hemodynamically stable.4,18,22 It made it easier to perform an LP which did not reveal any significant results. The patient’s headache resolved, and his vision improved after LP, but papilledema was not entirely resolved. We treated the patient with acetazolamide for his papilledema. The hyperinflammatory process was resolved with IVIG in our patient, and visual functions improved on the second day. His papilledema completely regressed on follow-up. Steroids may be reserved for patients without a rapid improvement in visual functions. Fundus examination should be performed in MIS-C patients, mainly showing symptoms compatible with pseudotumor cerebri syndrome. Papilledema is a rare manifestation of MIS-C that can lead to vision loss and may be resolved with standard anti-inflammatory treatment for MIS-C and acetazolamide.

In conclusion, PTC should be kept in mind in MIS-C patients with neurologic symptoms, and treatment should be started immediately to prevent vision loss even in mild cases of MIS-C.

REFERENCES

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Keywords:

MIS-C; papilledema; SARS-CoV-2; pseudotumor cerebri

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