Abstract
We present a case of a 42-year-old woman with paraneoplastic anti-N-Methyl-D-Aspartat (NMDA)-receptor encephalitis and concurrent neuroborreliosis that was initially misdiagnosed as post-COVID-19 syndrome. Clinically, the patient presented with a range of chronic and subacute neuropsychiatric symptoms and recalled a tick bite weeks prior to admission. The patient had undergone psychiatric and complementary medical treatments for 1 year before admission and was initially diagnosed with post-COVID-19 syndrome. Admission was performed because of acute worsening with fever, confusion, and unsteady gait. Cerebrospinal fluid (CSF) analysis revealed pleocytosis with elevated borrelia Immunoglobulin M (IgM) and Immunoglobulin M (IgG) CSF/blood antibody indices, indicating acute neuroborreliosis. Anti-NMDA receptor antibodies were identified in the CSF via a cell-based assay and were confirmed by an external laboratory. Other paraneoplastic antibodies were ruled out during in-house examination. Cranial Magnetic resonance imaging (MRI) revealed basal meningitis, rhomb- and limbic encephalitis. A subsequent pelvic Computer tomography (CT) scan identified an ovarian teratoma. The patient’s clinical condition improved dramatically with antibiotic treatment and plasmapheresis, the teratoma was surgically removed and she was started on rituximab. Our case highlights that amidst the prevailing focus on COVID-19-related health concerns, other well-established, but rare neurological conditions should not be neglected. Furthermore, our case illustrates that patients may suffer from multiple, concurrent, yet pathophysiologically unrelated neuroinflammatory conditions.
Introduction
In the wake of the COVID-19 pandemic, a considerable number of patients are dealing with a range of intricate neurological and neuropsychiatric symptoms. 1 However, the spotlight on post-acute COVID-19 syndrome may also obscure the diagnostic focus on other well-established yet rare neurological conditions, such as autoimmune encephalitis. Among these, anti-NMDA-receptor (anti-NMDAR)-encephalitis is the most prevalent form of autoimmune encephalitis, usually presenting with progressive neuropsychiatric symptoms, seizures, abnormal movements, or coma. 2 Distinguishing the disease from a primary psychiatric disorder is often challenging. Certain tumor entities, such as ovarian teratoma, as well as infectious conditions, such as herpes simplex encephalitis are well-established triggers of anti-NMDAR-encephalitis2,3; however, it is unclear whether other pathogens can also cause anti-NMDAR-encephalitis. Here, we are the first to describe a case of paraneoplastic anti-NMDA receptor encephalitis and concurrent neuroborreliosis, which was initially misdiagnosed as post-COVID syndrome.
Case report
A 42-year-old female patient was referred from a primary care hospital where she presented with acute disorientation, dysphasia, and unresponsiveness for some minutes. Importantly, the patient had a history of persistent neuropsychiatric symptoms, including depression, memory loss, and irritability, following a COVID-19-infection 12 month prior to this admission. Thereafter, she had struggled to resume work and had undergone a temporary hospitalization for depression and anxiety [Figure 1(a)]. However, her condition failed to improve, despite treatment involving antidepressants and psychotherapy. As a consequence, she additionally underwent several expensive complementary and alternative medicine-procedures including bioelectrical impedance analysis and homeopathic therapy. Importantly, the patient was diagnosed with post-COVID-19 syndrome, and no further diagnostic workup, such as cranial MRI, was carried out.
(a) Disease course illustration: a visual representation outlining the progression of our patient’s medical journey. (b) Indirect immunofluorescence staining: a representative image showcasing the immunofluorescence staining of our patient’s CSF on rat cerebellar sections. The white box designates the region of focus magnified in (c). (d) MRI image – rhombencephalitis and mesiotemporal hyperintensities: axial FLAIR image exhibiting the presence of rhombencephalitis and mesiotemporal hyperintensities, indicated with arrows. (e) MRI image – basal meningeal enhancement: coronal FLAIR post gadolinium contrast enhancement image illustrating basal meningeal enhancement, depicted by the white arrow. (f) Doppler-duplex sonography: an image derived from Doppler-duplex sonography conducted on the basal brain arteries, demonstrating accelerated blood flow (300 cm/s). (g) Pelvic CT scan – ovarian mass lesion: pelvic CT scan revealing a partially calcified mass lesion within the right ovary, highlighted by the white arrow.
Approximately 3 weeks before her presentation, she recalled experiencing a tick bite, but was unaware of any subsequent rash or exanthema [Figure 1(a)]. After admission to the primary care hospital, a first cerebrospinal fluid (CSF) examination revealed lymphocytic pleocytosis (40 leukocytes/µL), elevated lactate-, and decreased glucose levels relative to serum, suggestive of acute meningitis. Consequently, the patient received an initial guideline-conform anti-infective regimen comprising aciclovir, ampicillin, ceftriaxone, and dexamethasone, which was later adjusted. On referral to our university medical center the patient presented with an array of neuropsychiatric symptoms (confusion, anxiety, intermittent speech arrest), as well as signs of acute meningitis, including fever and meningism. However, beyond this acute worsening of her condition, she and her relatives reported a rather gradual emergence of behavioral changes over the last weeks.
The initial cranial CT-scan and CT-angiogram findings were devoid of ischemia, hemorrhage and generalized, or focal swelling. Following initial stabilization, neurological examination revealed a disoriented, agitated, and anxious demeanor, as well as word-finding difficulties. Additionally, the patient exhibited unsteady gait with a propensity to fall. There was no evidence of hallucinations or other psychotic symptoms. Repeated lumbar puncture yielded a pleocytosis (143 lympho-monocytic cells/µL) alongside elevated lactate levels (5.1 mmol/L). Furthermore, there was evidence of blood–brain barrier disruption (QAlb: 44.92) and intrathecal synthesis of IgG, IgM, and IgA including the presence of oligoclonal bands (Table 1). The cytological examination of the CSF additionally revealed the presence of plasma cells. In light of these findings, the diagnosis of meningoencephalitis was confirmed. Subsequent investigative efforts encompassed viral, bacterial, mycobacterial, and immunological studies. Western blot analysis of both blood and CSF samples disclosed the presence of borrelia IgM and IgG antibodies. Notably, the CSF/blood antibody index was elevated, exceeding 2.83 and 5.28, respectively (Table 1). This led to an adjustment in the anti-infective regimen, with a transition to exclusive ceftriaxone therapy. An extensive serological autoimmune work-up, which encompassed tests for antinuclear antibodies, anti-DNA antibodies, c-Antineutrophil cytoplasmic antibodies (ANCA) and p-ANCA antibodies, as well as thyreoglobulin and thyreoperoxidase antibodies, yielded unremarkable results. Additional comprehensive analysis of the CSF, which was prompted by a 1 year history of neuropsychiatric symptoms, unveiled the presence of anti-NMDAR autoantibodies through cell-based assays (titer: 1:10). Importantly, these autoantibodies were absent in serum samples. Furthermore, immunohistochemistry studies demonstrated a distinct fluorescence pattern on rat cerebellar sections, specifically highlighting staining within the granular and molecular cell layers [Figure 1(b) and (c)]. Other paraneoplastic and neuronal surface antibodies were ruled out during in-house examination.
CSF and serum diagnostics.
Lymphomonocytic pleocytosis: activated lymphocytes and plasma cells. Some neutrophil granulocytes.
Anti-NMDAR, anti-NMDA receptor; CSF, cerebrospinal fluid; OCB, oligoclonal bands (type 3 pattern); QAlb, albumin quotient; QIgA, immunoglobin A quotient; QIgG, immunoglobin G quotient; QIgM, immunoglobin M quotient.
Electroencephalogram findings indicated diffuse theta/delta slowing without seizure activity. Cranial MRI results revealed signs of basal meningitis and rhombencephalitis, accompanied by mesio-temporal hyperintensities [Figure 1(d) and (e)]. Duplex sonography performed on the brain arteries displayed evidence of blood flow acceleration within the vertebral and medial cerebral arteries, consistent with intracranial vasospasms [Figure 1(f)]. Following the detection of anti-NMDAR autoantibodies, a diligent search for an underlying tumor was initiated. Subsequent pelvic CT-scan investigations unveiled the presence of a partially calcified mass lesion located within the right ovary [Figure 1(g)]. The nature of this lesion raised suspicions of an ovarian teratoma. Thus, in light of these findings, the diagnosis of acute neuroborreliosis and concomitant anti-NMDAR-encephalitis was established.
In addition to the anti-infective regimen, the patient was started on five cycles of plasma exchange therapy as well as intravenous glucocorticoids. Subsequently, the patient began to improve substantially and was prescribed a B-cell depleting therapy with rituximab, and the ovarian teratoma was surgically removed. Subsequent pathological examinations conclusively verified the existence of an ovarian teratoma, comprising epidermal, alongside mesenchymal tissues, such as hair and lipomatous structures.
Discussion
Anti-NMDAR-encephalitis is the most common form of autoimmune encephalitis, which is associated with antibodies against the GluN1 subunit of anti-NMDAR. 3 It typically affects young adults, and women more often than men. Furthermore, despite being the most prevalent form of autoimmune encephalitis, its diagnosis can often present a challenging task. 4 Clinically, anti-NMDAR-encephalitis presents with subacute onset of progressive neuropsychiatric symptoms and behavioral impairments. Overall, anti-NMDAR-encephalitis has been associated with certain tumor entities, such as ovarian teratoma. 3 Furthermore, it is well-established that herpes simplex and varicella-zoster virus infections can cause postinfectious anti-NMDAR-encephalitis. 5 Molecular mimicry and/or bystander activation has been proposed as a possible pathophysiological mechanism linking infections and cancer to autoimmune encephalitis.5,6 In line with this, it remains unclear whether other pathogens, such as borrelia burgdorferi can also cause anti-NMDAR-encephalitis. However, it is worth noting that within the context of neuroborreliosis, the documentation of anti-NMDAR autoantibodies is limited to a few sporadic case reports.7,8 In the case of our patient, however, considering the emergence of neuropsychiatric symptoms and the presence of an ovarian teratoma, neuroborreliosis appears to be more of a concurrent condition rather than a causative one. Overall, it is not unlikely that borrelia immunoglobulins may have caused a cross-reaction with the anti-NMDAR-antigen in our cell-based assays. 9 Yet, this seems improbable, as neuropsychiatric symptoms arose several months before the tick bite, and the presence of an ovarian teratoma, as well as the immediate improvement upon plasmapheresis, suggests a paraneoplastic etiology. Moreover, the cranial MRI of our patient unveiled a composite presentation featuring basal meningitis, rhombencephalitis, and distinct mesiotemporal hyperintensities. Consequently, it can be inferred that the interplay of subacute/chronic neuropsychiatric symptoms and acute meningitis arose from the combined impact of both acute neuroborreliosis and already established anti-NMDAR-encephalitis. Especially, the presence of fever and meningeal irritation is suggestive of acute borrelia meningitis. Therefore, it is unlikely borrelia IgM and IgGs merely represent residual antibodies of a prior, asymptomatic infection. Hence, our observations are most appropriately accounted for by a diagnosis of NMDAR-encephalitis and concurrent, albeit pathophysiologically unrelated, acute neuroborreliosis.
Anti-NMDAR-antibodies have also been detected in patients with COVID-19-infections, thus one could also speculate that the COVID-19-infection of our patient may have triggered anti-NMDAR immunoreactivity. 6 However, in light of an ovarian teratoma this seems rather unlikely.
Another intriguing aspect of our case is that our patient had previously received an obvious misdiagnosis of post-acute COVID-19 syndrome, without subsequent efforts for differential diagnosis. In the wake of the COVID-19 pandemic, a considerable number of patients are dealing with a range of intricate neurological and neuropsychiatric symptoms (e.g. depression, anxiety, fatigue, pain). Together with pulmonary or cardiovascular complaints, these manifestations have been summarized as post-acute COVID-19 syndrome. 1 Given the substantial volume of affected individuals, conducting a thorough diagnostic evaluation and differential diagnosis presents a considerable challenge. Consequently, there is a substantial risk for misdiagnosis, with COVID-19-related complications potentially overshadowing the consideration of other conditions, such as autoimmune encephalitis.
In this context, our presented case serves as an illustration for the need to conduct an extensive and thorough differential diagnostic assessment in patients who present with a subacute onset of neuropsychiatric symptoms. Thus, amid the prevailing focus on COVID-19-related health concerns, other well-established but rare neurological conditions, such as autoimmune encephalitis should not be overlooked. Furthermore, this case illustrates that patients may experience more than one concurrent, but ultimately unrelated inflammatory condition simultaneously. These conditions can synergistically interact, contributing to symptom generation. Therefore, the diagnosis of a single inflammatory condition should not preclude a comprehensive diagnostic investigation for other coexisting disorders, especially when the medical history is ambiguous.
