Open Journal Systems

CLINICAL CASES

Received: August 14^th 2014

Accepted: August 7^th 2015

Bacterial meningitis as first manifestation of a patient with multiple myeloma. A case report

Sergio Gálvez-Acosta,^a César Enrique Garnica-Camacho^a

^aServicio de Medicina Interna, Hospital General de Tijuana, Secretaría de Salud del Estado de Baja California, Tijuana, Baja California, México

Communication with: Sergio Gálvez-Acosta

Telephone: (664) 230 8133

Email: sgalveza@hotmail.com

Background: Multiple myeloma (MM) is a plasma cell neoplasm characterized by clonal proliferation of plasma cells in the bone marrow and monoclonal protein in serum and/or urine in association to target organ damage. Infections are a frequent finding and they are multifactorial and presented mainly in the first months of diagnosis.

Clinical case: We reported the case of a 62 years old woman, with impaired alertness, drowsiness, fever, incoherent speech and meningeal signs, cerebrospinal fluid showed polymorphonuclear pleocytosis, hypoglycorrhachia, hyperproteinorrhachia, and Gram positive cocci, she received antibiotic treatment and improved until resolution of symptoms, however when conscious she referred paraplegia and back pain, anemia, lymphopenia, elevation of serum globulins, calcium and CRP. The bone marrow aspiration showed infiltration by plasma cells and the serum protein electrophoresis and immunofixation showed the presence of monoclonal gamma IgA lambda spike. Smears of cerebrospinal fluid was absent of plasma cells. The diagnosis of multiple myeloma stage III-A is established.

Conclusions: Association between (MM) and infection is high and although rare as first manifestation of MM, should take focus and high suspicion in patients with suggestive manifestations not explained by the infection itself.

Keywords: Multiple myeloma; Meningitis; Bacterial infections; Plasma cells

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Multiple myeloma (MM) is a neoplastic disease of the post-germinal B-cells characterized by clonal proliferation of plasma cells in the bone marrow and the presence of monoclonal protein in serum and urine in association with target organ damage.¹

It is the second most common hematologic malignancy, corresponding to 10% of hematologic malignancies^2,3 and 1% of all malignancies.

The presence of infection is a common finding, and it is attributed to a defect in humoral immunity, although other mechanisms have been described.⁴

The most common causative organisms are encapsulated and Gram-negative.⁵

Although infections are highly frequent in the context of MM, especially in the first months, MM debuting with an infectious episode has only been reported in isolated cases.⁶

The case of a woman with infectious meningitis as the first manifestation of MM is presented here.

Clinical case

Female patient 62 years old, Mexican, presented at the emergency department with alterations in alertness, disorientation, drowsiness, on admission had a fever up to 40 °C, BP 90/mm/Hg, HR 120x', RR 20x', visual hallucinations and incoherent speech, stiff neck and positive Brudzinski’s and Kernig’s signs, with symmetrical decreased strength in all four limbs 3/5, without targeting, papilledema not identified upon examining the fundus. Her medical history includes prior history of hysterectomy for uterine fibroids with major elements, she reported back pain for the past 2 weeks, without functional limitation and without having received treatment, not taking medication, drugs or herbal supplements and with no other relevant medical facts. Leukocytosis was identified by neutrophilia, cerebrospinal fluid (CSF) was obtained and identified as murky, with hypoglycorrhachia of 13 mg/dl (range 40-70), protein levels of 3200 mg/dl (range 20-45), predominantly polymorphonuclear pleocytosis 85%, and the presence of Gram-positive cocci. The diagnosis of bacterial meningitis was made and treatment was initiated with ceftriaxone, vancomycin, and ampicillin, without bacterial growth developing in culture. The patient had resolution of meningeal signs, however, upon regaining consciousness she experienced intense back pain, pain in the pelvic limbs, and paraplegia. Plain radiography and tomography (Figures 1 to 3) identified the presence of compression fracture at T12 and L3 and lytic lesions in dorsal and lumbar vertebral bodies, skull, humerus, sacrum, and pelvis; she was assessed by neurosurgery and considered not a candidate for surgical decompression.

Other laboratory tests during her stay identified normocytic anemia, with Hb 8.5 g/dl, leukocytosis 18,600/mm³, neutrophilia 16,900/mm³, lymphopenia 600/mm³, elevated protein albumin 1.8 mg/dl, globulins 5.0 g/dl, LDH 290 IU (range 60-165), hypercalcemia 11.1 mg/dl, creatinine 0.6 mg/dl, C-reactive protein (CRP) 12.6 mg/l (range 0-5), erythrocyte sedimentation rate (ESR) 145 mm/h (range 0-30), serum electrolytes, liver function tests, and urinalysis without relevant findings, Na 144 mEq/L, K 3.5 mEq/L, AST 65, ALT 30, bilirubin 1.1, BD 0.5, LDH 224 U/L, general urinalysis with albuminuria 15 mg/dl. The blood smear revealed anisocytosis and presence of Rouleaux phenomenon, and in bone marrow 16% plasma cells with dysplastic morphology, some binucleate and 1% plasmablasts. Electrophoresis of proteins in serum showed peak in the gamma fraction of 3.43 g/dl, alpha1 0.37 g/dl, alpha2 0.62 g/dl, beta 0.56 g/dl, and proteinuria of 67 mg/dl with monoclonal band in urine 45.9 mg/dl, serum protein immunofixation revealed peak lambda IgA, with IgA 4.4 g/dl (range 70-400) and decreased IgG 464 g/l, IgM 28 g/l, and IgD 9.2 mg/l. CSF smears in all its determinations showed absence of plasma cells. The diagnosis of multiple myeloma stage III-A was made and treatment began with thalidomide, melphalan, prednisone, and zoledronic acid.

Discussion

MM is a malignancy characterized by the proliferation of plasma cell clones that produce monoclonal protein.⁶ It is the second most common hematologic malignancy and accounts for about 1% of all malignancies.⁷

The association of MM with infection is highly prevalent and occurs mostly in the first months of diagnosis or during treatment; it is 7-15 times more frequent than in patients hospitalized for other reasons,⁵ matched by age.⁶ It occurs in 0.8-2.2 patients per year.

Three quarters of the episodes of infection occur in the first 3-8 months of diagnosis, most of them in the context of treatment,⁶ especially in higher intensity treatments,⁸ although it may well happen before initiation. The greatest risk of infection is during the first 2 months of initiation of anti-myeloma treatment and in patients with refractory disease or relapse; newly diagnosed patients and those with good response to chemotherapy are generally considered at low risk.⁵

Up to 15% of patients with multiple myeloma have been associated with infections at diagnosis,⁵ however, these episodes are defined as the occurrence of infection before hospitalization or prior to initiation of treatment, and not necessarily as the initial symptom. Infectious episodes as the main or only previous finding in the diagnosis of myeloma have been described only in case reports,⁶ with anemia, bone pain, hypercalcemia, and renal failure being the most common findings at diagnosis.⁹

Recently there has been a change in the known CRAB criteria (hyperCalcemia, Renal damage, Anemia, lytic Bone lesions), which define target organ damage with CRAB-O, including Other criteria (hyperviscosity, amyloidosis, and recurrent infections), so that patients with asymptomatic myeloma infection can be classified as carriers of active myeloma even in the absence of other lesions.¹

Infectious complications remain the leading cause of morbidity and mortality in patients with MM.^5,10 They represent an emergency and must be treated promptly and aggressively.⁷ End-stage infections are often cause of death.⁵

Most infections are of bacterial origin, mainly encapsulated, and the most severe are bacteremia, meningitis, and pneumonia.¹⁰ Streptococcus pneumoniae is by far the germ most frequently associated with infections in patients with MM; other common pathogens are Staphylococcus aureus and Haemophilus influenzae in case of respiratory tract infections, and Gram-negative (E. coli, Pseudomonas sp, Proteus sp, Enterobacter, and Klebsiella) in cases of urinary tract infections.^4,5,6,10 Less common pathogens have also been reported such as Strongyloides stercoralis,¹¹ sinusitis, and fungal meningitis, followed by neuroaspergilosis¹² in chemotherapy and post-transplant.

The main cause of susceptibility to infection is poor functional immunoglobulin production by plasma cells and B cells, although the etiology is multifactorial.^4,5,10,13 Other causes include CD4/CD8 ratio imbalances, opsonization defects, neutrophil adhesiveness and migration, post-treatment myelosuppression, and steroid use, particularly at high doses of dexamethasone, renal failure,⁵ quantitative and qualitative defects of lymphocytes, natural killer and dendritic cells, or complementary system abnormalities⁴ and bacterial meningitis with thalidomide use.¹⁰

Severe neutropenia at diagnosis is rare. It occurs mildly in around 10% and is most common after treatment; these patients have a high risk of multiple organ failure and death.¹³ Although neutropenia aggravates infections in MM, unlike in other malignancies there can be severe bacteremia even with normal neutrophil levels.⁵

Empirical treatment in a patient with MM and suspected infection should include coverage for encapsulated and Gram-negative agents, guided by the local flora of the hospital and their resistance, susceptibility results, and clinical response.^5,7

Anti-infective prophylaxis in MM is controversial, but can be beneficial, especially in the first few months after initiation of therapy and particularly in high-risk patients. Acyclovir is recommended in the context of bortezomib therapy for herpes zoster prophylaxis, as is the use of fluoroquinolones or trimethoprim/sulfamethoxazole in patients at high risk of developing bacterial infections. Use of fluconazole is reserved for patients on high doses of steroids and pneumocystosis prophylaxis in patients with transplant protocols.⁷

Vaccination against pneumococcus, Haemophilus influenza, and viral influenza A and B is recommended in all patients.⁷

The immunosuppression intrinsic to MM and related to treatment increases the risk of infections, but it is little known whether the infection influences the biology and progression of the myeloma. Some microorganisms produce proinflammatory cytokines and can activate toll-like receptors of the myeloma cells that can contribute to disease growth, survival, and progression. Different authors have identified increased risk of MM in patients who have suffered previous infections.^14,15 The hypothesis is currently proposed that prophylactic treatment with levofloxacin or macrolides in patients at high risk of infection could change the course of MM by decreasing disease progression and helping to achieve remission, but there are still no prospective studies evaluating this theory.⁴

In monoclonal gammopathy of undetermined significance and asymptomatic myeloma, infections are less frequent than in MM, and prophylactic treatment is not recommended for infections.²

Analysis

In the case presented, the patient presents with neurological changes typical of acute meningitis, with physical and cerebrospinal fluid findings compatible with it, so accurate diagnosis of bacterial meningitis was established prior to suspicion of MM, and is therefore considered a symptom of the disease debut. It was the alterations in the albumin/globulin ratio, the presence of normocytic anemia, hypercalcemia, and the presence of vertebral compression fractures that led to thorough study with confirmatory tests, such as bone marrow aspirate that identified plasma cell infiltration, and protein electrophoresis and serum immunofixation that identified the lambda IgA monoclonal peak, making it possible to conclude the diagnosis of multiple myeloma with target organ damage.

In addition to altering the humoral immunity related to the clonal production of ineffective immunoglobulins by myeloma cells, the IgG reduction being the most prominent and noticeable, this patient presented with lymphopenia that could contribute to the development of infection, without other risk factors for this being identified.

In this case Gram-positive cocci were identified in the analysis of CSF, and pneumococcus was the suspected agent, however culture showed no growth in two independent determinations 5 days apart, although both samples were taken after the start of antibiotics, which may reduce bacterial growth in culture media and result in false negatives.

The use of antibiotics was established empirically prior to the diagnosis of MM, according to the hospital's general recommendations and guidelines of their attending physicians; the response was favorable, achieving full remission of clinical and laboratory findings that led to the diagnosis of acute meningitis, suggesting that conventional treatment is useful in patients with MM and infection, provided it includes coverage against encapsulated Gram-positive and Gram-negative germs, which are the most frequently involved, and also starting it immediately after suspected diagnosis, to minimize the risk of serious complications.

Other infectious complications were not presented after the start of treatment.

Although it is a rare complication, myelomatoid meningitis should be considered in the differential diagnosis of patients with bacterial meningitis and multiple myeloma for its significance in treatment failure and mortality, as described by Chamberlain and Glantz.¹⁶ CSF tests determined the absence of plasma cells by staining in all samples tested.

Conclusion

While the incidence of MM in patients with pneumococcal infections is low, this case reinforces the need to suspect multiple myeloma in a patient with bacterial meningitis (or other infectious processes) in the presence of additional clinical and paraclinical findings unexplained by the infection and compatible with target organ damage by MM, such as leukopenia, anemia, renal failure, hypercalcemia, or paraproteinemia.

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