Case Presentation

An Iranian woman, aged 72, underwent a sudden alteration in mental status and was admitted to the emergency department on March 2, 2025. Her relatives reported that in the hours leading up to her presentation, she exhibited increasing confusion, disorientation, and fatigue. They reported a temperature exceeding 38°C the previous day and episodes of vomiting.

She was awake and responsive but disoriented to time and place. Vital signs revealed mild tachycardia and mildly decreased oxygen saturation. Neurological examination revealed no focal deficits. Pupillary reactions and extraocular movements were normal, without nystagmus or gaze deviation. There were no fasciculations, muscle atrophy, or involuntary movements; tongue movements were normal, and the gag reflex was intact. There was no nuchal rigidity, and Kernig's and Brudzinski's signs were negative. Speech was notable for dysarthria without aphasia. Cardiovascular and abdominal examinations were unremarkable. Laboratory tests showed high levels of inflammatory markers, leukocytosis, thrombocytosis, and coagulopathy (Table 1). Supplementary specialized immunologic, microbiologic, and imaging investigations were performed and are summarized in Table 2.

Category | Findings
Hematology | WBC 12,800–13,700/μL (neutrophils 90%–95%); band forms 9%; metamyelocytes 2%; Hb 8.6–10.1 g/dL; MCV 74–77 fL; MCH 22–24 pg.; MCHC 30–31 g/dL; anisocytosis (+); platelets 510–687 × 103/μL
Coagulation | PT 13–31 s; PTT 14–78 s; INR 4.5 (day 1) → < 1.5 afterward; D‐dimer 1760 ng/mL (day 2)
Metabolic panel | Na 135–144 mEq/L; K 3.2–4.5 mEq/L; BUN/Cr 16/0.8 → 24/0.9; glucose 98–168 mg/dL
Inflammatory markers | ESR 120–130 mm/h; CRP 35 mg/L
Liver function tests | AST 41–106 U/L; ALT 15–26 U/L; ALP 195–320 U/L; bilirubin 0.6–0.7 mg/dL; albumin 2.3–3.7 g/dL
LDH | 1001–1504 U/L
Urinalysis | Initial UA normal → repeat (day 6): pyuria (20–22 WBC/hpf), hematuria (25–30 RBC/hpf), yeast present

Category | Findings
Microbiology | Urine culture: Yeast positive (day 6); other urine cultures negative; blood cultures negative on days 1, 6, and catheter culture negative (day 11)
Infectious serologies | HBsAg –, HBsAb –, HCV Ab –, HIV Ab –; influenza PCR –, COVID‐19 PCR —
Autoimmune panel | ANA 0.2 IU/mL; anti‐dsDNA 15 IU/mL; RF 8.6 IU/mL; C3 121 mg/dL; C4 31 mg/dL; CH50 120 U/mL
Antiphospholipid profile | Anticardiolipin IgM < 3.0 MPL; IgG 8 GPL; β2‐glycoprotein I IgM 1.5 U/mL; IgG 8 U/mL; lupus anticoagulant 55 s
Other immunologic tests | Anti‐SSA (Ro) 5.7 U/mL (borderline); anti‐SSB (La) < 3 U/mL
Coombs/brucella tests | Direct Coombs –, indirect Coombs –; 2‐mercaptoethanol –; Wright agglutination —
CSF analysis (Day 9) | Glucose 61 mg/dL; protein 9.48 mg/dL; LDH 27 U/L; WBC 5/μL; RBC 0–1/μL; CSF culture negative
Protein electrophoresis (Serum) | Total protein 6 g/dL; albumin 1.8; α1 0.6; α2 1.0; β1 0.4; β2 0.7; γ 1.5 g/dL; no monoclonal spike
Protein electrophoresis (Urine) | Albumin 71.4%; transferrin 2%; RBP 9.3 mg/L; free light chains 26.9 mg/L; α1‐microglobulin 11.1 mg/L; IgG 5.9%; lysozyme 12%; IgA 1.8%; haptoglobulins 9.8%
Blood gas analysis | pH 7.45 (respiratory alkalosis) → pH 7.06, PCO2 49 (acute respiratory acidosis)
Echocardiography | EF ≈50%; mild global hypokinesia; mild MR/TR; calcified AV without stenosis; no vegetations

The patient was admitted to the intensive care unit with a provisional diagnosis of encephalitis or sepsis of unknown origin. Despite receiving initial assistance, her fever and AMS persisted, necessitating further testing.

Patient History

The patient had a history of Type 2 diabetes mellitus, hypertension, hyperlipidemia, and atrial fibrillation, managed with metformin, rivaroxaban, bisoprolol, valsartan/amlodipine, and atorvastatin. Ten weeks before admission, she developed right groin cellulitis accompanied by transient AMS; neurologic evaluation, including EEG and brain CT, was unremarkable, and symptoms improved with antibiotics. Family history was noncontributory.

Hospital Course and Multisystem Evaluation

Given concern for bacterial meningitis or viral encephalitis, empirical meropenem, vancomycin, and acyclovir were initiated. Cardiovascular, abdominal, and initial neurologic examinations were otherwise unremarkable. On the first hospital day, Doppler ultrasonography of the upper limbs detected thrombosis of both cephalic veins, while evaluation of the lower extremities showed no evidence of deep venous thrombosis. Home rivaroxaban had already been discontinued on admission because of an elevated INR (4.5); once the INR normalized to 1.5 after three days, prophylactic subcutaneous heparin (5000 IU twice daily) was initiated and subsequently transitioned, on cardiology recommendation, to therapeutic enoxaparin (60 mg subcutaneously twice daily).

Further cardiac workup did not support infective endocarditis. Electrocardiography demonstrated sinus tachycardia, and transthoracic echocardiography showed preserved left ventricular systolic function (EF approximately 50%), mild valvular insufficiency, and absence of vegetations. A contrast‐enhanced abdominopelvic CT scan obtained on the second day of admission identified enlarged lymph nodes in the pelvic, external iliac, and bilateral inguinal regions (Figure 1). Subsequent physical examination confirmed palpable, firm, painless axillary and inguinal lymphadenopathy, raising suspicion for disseminated nodal disease. Breast ultrasonography revealed bilateral axillary lymphadenopathy with loss of preserved fatty hila, the largest node measuring 21 mm, without detectable breast parenchymal lesions; the examination was categorized as BI‐RADS 0 (Figure 2). Additional microbiologic, immunologic, and diagnostic investigations are summarized in Table 2. Neurologic evaluation revealed AMS with impaired speech but no focal deficits. Therapeutic enoxaparin was held prior to lumbar puncture, performed on Day 9, which showed unremarkable cerebrospinal fluid findings (Table 2). Brain MRI demonstrated mild cortical atrophy and periventricular white‐matter changes without acute intracranial pathology or leptomeningeal enhancement. Because of fluctuating mental status, levetiracetam was initiated empirically for possible subclinical seizure activity. By hospital Day 11, fever and acute confusion improved, allowing transfer to the general ward, although mild temporal disorientation and short‐term memory impairment persisted. On Day 12, an excisional biopsy of a left inguinal lymph node was performed to investigate the generalized lymphadenopathy. On Day 13, given the prolonged interruption of oral anticoagulation, cardiology consultation recommended resuming oral anticoagulation with apixaban (5 mg twice daily); however, the patient experienced sudden cardiopulmonary arrest on Day 13 and could not be revived despite advanced life‐support measures. The specific cause of death was not determined, and the family refused an autopsy.

FIGURE 1: Axial and coronal contrast‐enhanced abdominopelvic CT demonstrating enlarged external iliac lymph nodes (arrows) with surrounding fat stranding, consistent with lymphadenopathy and possible inflammatory or infiltrative involvement.

FIGURE 2: Ultrasound of the axillary region showing multiple enlarged lymph nodes with loss of the normal echogenic fatty hilum. Nodes demonstrated oval morphology, abnormal internal echotexture, and short‐axis diameters of 10 mm (right) and 21 mm (left), findings consistent with pathological lymphadenopathy suggestive of a lymphoproliferative/neoplastic process.

Histopathology and Immunohistochemistry

A diffuse sheet of large atypical lymphoid cells completely effaced normal lymph node architecture without residual follicles in Figure 3 H&E sections from the left inguinal lymph node biopsy. Vesicular nuclei, prominent nucleoli, and frequent mitotic and apoptotic figures indicated a high‐grade lymphoid neoplasm. Immunohistochemistry revealed strong diffuse CD20 positivity in almost 70%–80% of tumor cells, while CD3 stained only background T cells and was negative in tumor cells [15]. CD30 and CD15 were negative. PAX5 showed unexpectedly weak, focal positivity in < 20% of cells. Ki‐67 was not available. The findings are consistent with aggressive B‐cell lymphoma. However, low PAX5 expression, lack of Ki‐67, and lack of MYC/BCL2/BCL6 FISH studies add some diagnostic uncertainty.

FIGURE 3: Histopathology and immunohistochemistry of the left inguinal lymph node biopsy.