Encephalitis associated with a monoclonal protein band present in blood, urine and cerebrospinal fluid

Abstract

Introduction

Monoclonal protein bands are present mainly in blood and secondary in urine representing specific antibody produced in excess by abnormal lymphocytes or plasma cells.We describe a case of a patient with acute encephalitis associated with an unexpected finding of a monoclonal protein band present in blood, urine and in cerebrospinal fluid (CSF).

Case presentation

This 50-year-old woman with no significant past medical history, with the exception of unintentional weight loss exceeding 5 kg over the last 3 months, presented to the emergency department with seizures and altered mental status, after 3 days of vomiting and headaches. Magnetic Resonance Imaging showed lesions suspicious for infectious encephalitis/meningitis and for ischemia possibly related to central nervous system (CNS) autoimmune vasculopathy/vasculitis. The patient died the following day after losing brainstem reflexes. Testing for the previously mentioned etiologies returned negative with the exception of high protein concentration and increased immunoglobulin gamma (IgG) concentration in the CSF. Protein electrophoresis, ordered in error, showed a well-defined IgG with lambda light chain monoclonal protein band running in similar positions in serum, urine and in CSF. Due to SARS-CoV-2 PCR positivity no autopsy was performed.

Conclusion

The presence of this monoclonal protein band produced in the CNS suggests the diagnosis of CNS myeloma. The accelerated course in this case could be the result of the CNS myeloma or lymphoma responding to SARS-CoV-2 infection. Testing for monoclonal protein bands in CSF, in patients with pertinent clinical presentation would boost the awareness of this these diseases improving patient care.

1. Introduction

Meningitis/encephalitis symptoms are generally caused by hemorrhage, infectious or autoimmune etiologies [1]. The big majority of reference laboratories will recommend different testing algorithms focused mainly on infectious agents or autoimmune causes [2,3]. In very rare cases a monoclonal protein producing diseases like plasma cell neoplasms or lymphomas will present with encephalopathy.

Infiltration of CNS by plasma cell myeloma is observed in less than 1% of patients and it carries a very poor prognosis [4,5]. Non-Hodgkin lymphomas (NHL) will secondarily affect the CNS in rare instances, involving up to 10.1% of Non-Hodgkin lymphoma cases [6]. Clinical presentation depends on the locations of spread. Leptomeningeal spread is most common, occurring in up to 8% of NHL cases [6]. These cases typically present with mental status changes, neck pain, headache, back pain, weakness, and seizures [7]. Similarly, CNS myeloma can present with weakness, mental status change and cranial nerve palsies [8]. We are presenting a patient with clinical signs of meningoencephalitis, but no identifiable autoimmune or infectious etiology with the exception of a newly recognized monoclonal protein band present in blood, urine and in CSF. Other than the unintentional weight loss, there were no other clinical signs suggesting a preexisting condition.

2. Case presentation

This was a 50-year-old woman with no significant past medical history presenting at the emergency department with altered mental status, and seizures after 3 days of loss of appetite with vomiting and one day of headaches. Brain MRI showed findings suspicious for encephalitis/meningitis with acute infarcts possibly related to CNS autoimmune vasculopathy/vasculitis. Restriction of the pons and other areas of brain consistent with ischemia correlated with the loss of brainstem reflexes triggering her demise on the second day of hospitalization. Patient was found to be positive for Sars-CoV-2 (variant BA.2.12.1 – omicron). She was fully vaccinated one year prior, but not boosted. Assessment for identification of the possible infectious and/or autoimmune etiology was performed and returned negative. A protein electrophoresis in blood and urine ordered in error was performed after the patient's demise as part of the clinical laboratory's training program and a well-defined IgG lambda monoclonal band running in similar positions in both serum and in urine was observed. A corresponding band was later on identified in her CSF (Fig. 1). Increased total protein concentration associated with an increased IgG production in the central nervous system (CNS) was detected in the CSF. No other significant abnormal findings were identified. Fig. 1 shows the protein immunofixation performed on these 3 specimens using Sebia, Hydrasis 2.

Fig. 1.

Protein immunofixation serum, urine, CSF.

The patient underwent extensive testing both in-house as well as at Quest Diagnostics Reference Laboratory as follows:

Serologic or pathogen detection for the following infectious agents was negative:

Herpes simplex virus (HSV) type 1 and 2, Hepatitis virus A, B and C, Human Immunodeficiency Virus (HIV), West Nile Virus (WNV), Respiratory Syncytial Virus, Influenza A/B, Parainfluenza, Treponema pallidum, Borrelia burgdorferi, Rickettsia typhi, Rocky Mountain spotted fever, and Cryptococcus. Blood and CSF bacterial and fungal cultures showed no growth.

Immunology and general laboratory testing with results within normal range are as follows:

chemistry assays in blood (glucose, urea, creatinine, glomerular filtration rate, sodium, potassium, chloride, calcium, phosphorus, magnesium, total protein, bilirubin total, alkaline phosphatase, alanine amino transferase, high sensitivity troponin, creatine kinase, creatine kinase MB, acetaminophen), inflammation markers (erythrocyte sedimentation rate, antinuclear antibody screen, anti-double stranded DNA antibody, antineutrophil cytoplasmic antibody screen with reflex to autoantibodies to myeloperoxidase and to autoantibodies to proteinase 3, cryoglobulins, immunoglobulins quantitative serum, C4 and C3 complement, Dilute Russels's Venom Viper Time, Hexagonal Phase Phospholipid Neutralization, cardiolipin gamma immunoglobulin antibody), coagulation (Prothrombin Time, activated Partial Thromboplastin Time), red blood cell count and parameters, urinalysis, and urine drug screen.

Abnormal results have been obtained for the following tests (reference ranges in parenthesis): SARS-CoV-2 PCR positive (negative), Interleukin-6 84 (<7 pg/ml), C reactive protein 2.83 (<0.5 mg/dl) became elevated on the last day of hospitalization, total white blood count 16.48 (4.5–11 10³/μl), absolute neutrophil count 13.51 (2–7 10³/μl), absolute monocyte count 2.47 (0.2–0.8 10³/μl), absolute immature granulocyte count 0.16 (0.01–0.03 10³/μl), absolute lymphocyte count 0.33 (1.5–4 10³/μl), Burr cells 1+, platelet count 114 (150–400 10³/μl), measured osmolality 308 (275–295 mOsm/kg); aspartate aminotransferase (AST) 46 (10–35 IU/L), arterial blood gases – variable and abnormal with disease progression.

Protein electrophoresis in serum: albumin 4.41 g/dl (3.4–5.2 g/dl), alpha 1 fraction 0.2 g/dl (0.1–0.3 g/dl), alpha 2 fraction 0.6 g/dl (0.5–1.0 g/dl), beta fraction 0.8 g/dl (0.6–1.2 g/dl), gamma fraction 1.2 g/dl (0.7–1.4 g/dl) and a monoclonal spike of 0.6 g/dl representing 9.4% of the total protein concentration. Fig. 1 shows the immunofixation of the serum, urine and in CSF.

CSF test results (performed by Quest Diagnostics) show clear (normal is clear) colorless fluid (normal is colorless), 0 nucleated cells (normal 0 to 5 cells/mm³), 3.3 red blood cells/mm³, (normal 0 to 10 cells/mm³) glucose 76 mg/dl (50–75 mg/dl), protein 218 mg/dl (20–40 mg/dl). Lyme disease antibody in CSF: no bands detected (reference range: no bands detected), West Nile virus IgG and IgM negative (reference range: negative), myelin basic protein: negative (reference range: negative) Immunoglobulin IgG synthesis/rate index, CSF (QIGG-SR test code 7558 Quest Diagnostics) shows evidence of increased IgG synthesis in the central nervous system.

Autopsy or other additional postmortem studies were not performed.

3. Conclusion/discussions

Most cases of meningo-encephalitis have infectious or autoimmune origin. The most common infectious agents are Enteroviruses, HSV (90% type-1), followed by Varicella Zoster Virus, West Nile Virus and Epstein Barr Virus. Less common are bacterial agents such as Mycobacterium tuberculosis, pyogenic bacteria and Bartonella species. Even less common are fungal, parasitic and prion agents [9,10]. In this patient common infectious as well as autoimmune etiologies were excluded.

The etiologic agent of encephalitis often cannot be identified. The Encephalitis Surveillance through the Emerging Infections Program, 1997–2010, which represents a large cohort of over 5000 patients, did not identify an underlying cause of encephalitis in approximately half of all cases, despite the rigorous diagnostic testing algorithm [10]. The infectious etiologies like viral, bacterial, parasitic, prion and fungal agents, depend on the season, exposures, clinical features and geography. The California Encephalitis Project identified a definite or probable etiologic agent for only 16% of 1570 immunocompetent patients enrolled from 1998 to 2005 (69% viral 20% bacterial, 7% prion, 3% parasitic, 1% fungal). In an additional 13% of patients a possible cause was identified with a lower level of certainty. The etiology of encephalitis, despite excessive autoimmune and infectious work ups, remains unknown in most cases [9].

The presence of the monoclonal protein band in this patient suggests CNS myeloma or CNS lymphoma.

Lymphomas can present with monoclonal protein bands and show CNS manifestations. IgG is the most common paraprotein identified for both aggressive lymphomas and CNS myeloma [4,11]. In CNS myeloma there is a mild lambda light chain predominance over kappa, unlike non-CNS medullary and extramedullary lymphoma [8]. CNS involvement can occur in all stages of myeloma while it tends to occur more commonly in late stage disease in secondary non-Hodgkin lymphomas [8,12]. Secondary CNS lymphomas, however, tend to present after a protracted course of disease or after solid organ and/or bone marrow involvement [12]. Primary CNS lymphomas involve the CNS at presentation. They are much more common in immunocompromised patients, especially HIV/AIDS. These lymphomas involve the brain parenchyma or spinal cord more often than the leptomeninges and, therefore, more commonly present with focal, neurological deficits (70% of patients). Approximately 7% of cases initially diagnosed as primary CNS lymphoma are found to have systemic disease and later turn ou to be secondary [13].

The presence of this IgG lambda monoclonal protein band in the CSF associated with the increased production of IgG in the CNS raises the possibility of a very rare diagnosis of plasma cell myeloma infiltrating the CNS. The reported median age of onset of CNS myeloma is often younger (50–60 years) than the usual median age for multiple myeloma diagnosis (70 years). Up to 20–25% of CNS myeloma cases are discovered at the initial myeloma diagnosis [8]. IgG lambda monoclonal protein is more predominant in CNS myelomas while the IgG kappa is the most frequent manifestation of myelomas overall [8]. The median overall survival with CNS myeloma is low at 2 months from diagnosis [8]. Younger age (50 years old), initial diagnosis presentation and type of monoclonal (IgG lambda) were present in our patient, all very consistent with the diagnosis of CNS myeloma. However, because of the rapid course of this patient's disease and focus on severe CNS symptoms, it is unknown if this patient would satisfy the criteria required for a diagnosis of multiple myeloma [14]. Her laboratory tests showed normal calcium and normal creatinine and normal calculated glomerular filtration rate. Unfortunately, we did not have the opportunity to check for bone marrow involvement or for lytic lesions.

It is recognized that SARS-CoV-2 can be associated with CNS manifestations [15]. To our knowledge none of the reported cases were associated with definite protein monoclonal bands present in blood, urine and CSF. The fulminant clinical course in this patient could be the result of the weakened immune system due to plasma cell myeloma combined with the SARS-CoV-2 infection.

This case demonstrates an increased need for awareness of CNS myeloma and CNS lymphomas, even in the absence of lymphadenopathy or other symptoms suggestive of myeloma or lymphoma, as a possible etiology for symptoms of meningo-encephalitis. In patients with pertinent clinical presentations, screening for monoclonal protein could improve the recognition of CNS myeloma and CNS lymphomas.

The addition of protein electrophoresis of serum, urine and CSF as a readily available, fast and relatively inexpensive test to a meningoencephalitis work-up might increase the detection of CNS-myeloma and CNS lymphomas and improve patient care [16,17], especially given the potential for rapid progression of these diseases.

Declaration of competing interest

None of the authors have any conflict of interest. Please see orginal submission.

Data availability

No data was used for the research described in the article.