Aseptic Meningitis after BNT-162b2 COVID-19 Vaccination: Case Report and Literature Review
Article ID: 2022-0034-CR
Details
Article ID: 2022-0034-CR
We encountered a-27-year-old female patient who developed refractory severe headache and photophobia after the first dose of COVID-19 vaccine. Despite her prior history of migraine, we diagnosed COVID-19 vaccine-induced aseptic meningitis. Symptoms were significantly resolved after methylprednisolone therapy. On reviewing the literature, we could find only nine similar cases, with over half of them affecting women aged 20–40 years. Although uncommon, aseptic meningitis should be suspected in patients with persistent or delayed onset of headache following COVID-19 vaccination.
Vaccination has been an essential part of the measures used to control the COVID-19 pandemic. Although the safety of vaccines is monitored during clinical trials,1 some rare side effects might not be identified until they are used for vaccination of the general population. Adverse reactions have been increasingly reported because of an increase in vaccination.
Aseptic meningitis is characterized by inflammation of the meninges and a lack of bacterial involvement as confirmed by negative results of routine bacterial cultures. Aseptic meningitis is commonly caused by viral infections, but in rare cases may also be caused by drugs, including vaccines. Reports of aseptic meningitis following COVID-19 vaccination are still scarce because mRNA vaccines are a relatively new class of vaccine. Headache is a common complication after vaccination, especially in patients with a history of headache2 and these symptoms are usually ignored or managed with conservative therapy. Clinical suspicion and careful investigation infer rare adverse events such as aseptic meningitis and lead to prompt and appropriate treatment. Here, we report the case of a 27-year-old female patient who developed aseptic meningitis after COVID-19 vaccination. The discussion of this case includes a review of similar rare cases that have been reported in the literature.
A 27-year-old woman had a history of episodic migraine without aura [International Classification of Headache Disorders 3rd Ed. (ICHD-3), code 1.1] twice per week.3 The headaches were resolved by taking oral loxoprofen sodium. She had no history of allergy to food or cosmetics. Eight days after receiving the first dose of the BNT 262b2 mRNA vaccine (30 µg), she developed a persistent bifrontal-throbbing headache that was more severe than her usual migraine attacks. Although she took oral loxoprofen sodium, the headache did not resolve. After 2 days, she visited a nearby medical institution, where brain computed tomography was unremarkable. With worsening headache and nausea, brain magnetic resonance imaging was performed the next day, which showed no abnormalities. After five consecutive days without food or drink because of nausea, the patient was administered fluid replacement. Finally, she was transferred to our hospital because of refractory headache on day 17 after onset.
On arrival, the patient had no fever without antipyretics. Neck stiffness, Kernig sign, and other neurological signs were negative but jolt accentuation was positive with headache and nausea. The patient declined to remove an eye mask because of photophobia. Laboratory findings revealed white blood cell counts of 3450 /μL (neutrophils 44.9%, lymphocytes 47.0%, monocytes 7.2%, basophils 0.6%), C-reactive protein level of 0.08 mg/dL, and d-dimer level of 0.97 µg/mL. Meningitis was suspected, and a lumber puncture was performed. A cerebrospinal fluid (CSF) analysis revealed pleocytosis (56 /mm3; mononuclear cells 100%), slightly elevated protein level (54 mg/dL), normal glucose level, normal immunoglobulin G (IgG) index (0.50), and normal interleukin 6 (2.2 pg/mL) with high opening pressure (30 cmH2O). On admission, magnetic resonance imaging and angiography revealed no abnormal findings and contrast-enhanced computed tomographic venography did not reveal cerebral venous sinus thrombosis. Acyclovir was administrated for 8 days until multiplex polymerase chain reaction assay for the detection of herpesvirus DNA (QIAsymphony DSP Virus/Pathogen Mini Kit, Qiagen) was confirmed negative. Autoimmune serological analyses for rheumatoid factor, proteinase 3 anti-neutrophil cytoplasmic antibody, myeloperoxidase anti-neutrophil cytoplasmic antibody, anti-double stranded DNA, and Sjogren’s antibodies (SS-A, SS-B) were negative, whereas the antinuclear antibody titer (>1:80) was positive. The patient’s headache showed no improvement. We suspected COVID-19 vaccine-induced aseptic meningitis and began 6 days of intravenous methylprednisolone (500 mg/day) 5 days after admission. After 3 days of administration, her headache, nausea, and photophobia were significantly improved. The patient was discharged from hospital on day 12 and remained well without severe headache at 1-month follow-up.
Evaluating the serum titers of IgG antibody (Chemiluminescent Enzyme Immunoassay, Fujirebio), we observed a positive test for IgG antibody against SARS-CoV-2 spike protein (23.2 AU/mL) and a negative test for IgG antibody against SARS-CoV-2 nucleocapsid protein (<1.0 AU/mL). These results suggested vaccination rather than infection. The CSF titers for these antibodies were negative. Informed consent was obtained from the patient for publication of the details of the case.
It took some time to make the diagnosis of aseptic meningitis in the present case because the patient had a history of migraine and did not present with fever or neck stiffness. In addition, although photophobia is highly prevalent in aseptic meningitis and is adopted in the diagnostic criteria of headache attributed to aseptic meningitis (ICHD-3, code 7.3.2), it is not a point of differentiation from migraine.3,4 Migraine-like headaches associated with aseptic meningitis have been reported,5,6 in which treatment response to triptans was reported.7,8 Even in patients meeting the diagnostic criteria for migraine headache, when the headache worsens, aggressive differentiation from secondary headache is necessary, and lumbar puncture is particularly important.
The diagnosis of aseptic meningitis induced by vaccine is not straightforward. Theoretically, the chances of meningitis following vaccination are considerably low and other direct causes are more likely.9 However, other possible explanations were ruled out in the present case and the clinical course after vaccination was largely consistent with previous reports.10,11,12,13,14 There is a possibility that molecular mimicry activated by vaccination and/or the mediators involved in the immune response to the vaccine can cause autoimmune meningitis. Based on the genetic background and the memory of the immune system, this neuroinflammation has been observed across a spectrum from mild (aseptic meningitis) to severe (transverse myelitis).13 Further investigation on this mechanism is needed.
Table 1 displays previously reported cases of aseptic meningitis after COVID-19 vaccine.10,11,12,13,14,15,16,17 Seventy percent of those patients were young women and they all received mRNA vaccine (BNT162b2) except one (AZD 1222; a viral vector vaccine).13 This may simply reflect the fact that BNT162b2 currently is the most commonly administered COVID-19 vaccine in many regions worldwide. In the described cases, meningitis was noted following the first or second vaccine dose in equal numbers. Clinical meningitis symptoms in three patients were already present on the first day after vaccine administration, as opposed to a period of 1–2 weeks in other patients. Only two authors reported a considerable fraction of granular cells in CSF pleocytosis,10,17 whereas the remaining patients presented with almost mononuclear cell pleocytosis. Although it is difficult to explain the pathophysiology of a positive test for COVID-19 antibodies in CSF, it is considered to be of some help in diagnosing aseptic meningitis.14 The authors in six out of ten previous cases speculated on an immune-reactive etiology and treated with steroids, which led to a rapid decrease in inflammation markers and clinical symptoms.10,11,12,13,14 However, the remaining patients did not receive steroid therapy.15,16,17Therefore, the aseptic meningitis appeared to be self-limiting in those cases. Clinical outcomes were good in all cases.
| Author | Age (years)/sex | Vaccine | Vaccine dose | Onset of symptoms | CSF pleocytosis (/µL) | CSF protein (mg/dL) | COVID-19 IgG in CSF | Treatment | Prognosis |
|---|---|---|---|---|---|---|---|---|---|
| Saito | 42/F | BNT 162b2 | First | 7 days | 176 (M64.1%, G34.8%) | 35.7 | Positive | mPSL | Good |
| Dupon | 34/F | BNT 162b2 | Second | 6–8 h | 188 (lymphocytic pattern) | NA | NA | mPSL | Good |
| Chan | 43/F | BNT 162b2 | Second | 4 days | 265 (M91%, N4%) | 96 | Positive | NSAIDs | Good |
| 38/F | BNT 162b2 | First | 10 days | 340 (M95%, N0%) | 74 | Positive | NSAIDs | Good | |
| Lee | 18/M | BNT 162b2 | Second | 3 weeks | 115 (M99.1%) | 67.2 | NA | Antibiotics | Good |
| Reis Carneiro | 62/F | BNT 162b2 | First | 1 day | 101 (M100%) | 154 | NA | DMX | Good |
| Zavari | 26/F | AZD 1222 | First | Several hours | 5 (M100%) | 54 | NA | PSL | Good |
| Kang | 32/M | BNT 162b2 | Second | 2 weeks | 480 (M90%, N1%) | 118 | Positive | mPSL | Good |
| Bogs | 15/M | BNT 162b2 | Second | 13 days | 242 (M55%, N45%) | 69.4 | NA | Antibiotics | Good |
| Current case | 27/F | BNT 162b2 | First | 8 days | 56 (M100%) | 54 | Negative | mPSL | Good |
M, monocyte; G, granulocyte; N, neutrophil; CSF, cerebrospinal fluid; NA, not available; mPSL, methylprednisolone; NSAIDs, non-steroidal anti-inflammatory drugs; DMX, dexamethasone; PSL, prednisolone.
Here, we report the case of a young woman who had prior history of migraine and developed aseptic meningitis after COVID-19 vaccination. Whether such patients should be revaccinated is not clear and remains an issue for future investigation. Aseptic meningitis should be considered during the differential diagnosis of patients with persistent or delayed onset of headache and fever following COVID-19 vaccination.
The authors declare no conflict of interest.
