Meningitis mirage

This narrative, clinical problem-solving exercise was developed collaboratively with an expert who was unaware of the diagnosis. A 73-year-old man presented with recurrent episodes of fever and headache, accompanied by cerebrospinal fluid pleocytosis, yet negative microbiology. He later developed generalized edema, effusions, and elevated creatinine. Comprehensive diagnostic evaluations, including contrastenhanced computed tomography, contrast-enhanced magnetic resonance imaging of the head, upper and lower gastrointestinal endoscopy, skin biopsies, and fluorodeoxyglucose positron emission tomography, were performed to investigate potential autoimmune, autoinflammatory, and neoplastic causes, all of which were inconclusive. Through a process of meticulous clinical reasoning and additional diagnostic testing, a diagnosis was made. A 73-year-old man was admitted for evaluation of 5 months of recurrent headache, fatigue, fever, limb swelling, and elevated polymorphonuclear (PMN) leukocyte counts in the cerebrospinal fluid (CSF). He had undergone four courses of antibiotics for a diagnosis of meningitis, with only temporary resolution of symptoms. Prior CSF cultures were all negative. His headache was mild, bilateral, and associated with neck stiffness, but not associated with vision or neurologic changes. This patient presented with recurrent meningitis and persistent systemic inflammation, yet without neurological deficits. The patient's condition is likely associated with a systemic disease or uncommon infection, as isolated bacterial meningitis would typically resolve with appropriate therapy. Malignancies, infections, autoimmune disorders, and medication side effects could cause recurrent meningitis and a persistent inflammatory response. Considering the temporal association, limb edema and meningitis are likely caused by the same factor. Asking about his symptoms at onset 5 months ago may reveal a clue that narrows the differential diagnosis. Five months prior, he presented to an outside hospital with fever and headache. He exhibited neck stiffness, and Kernig's sign was positive. His CSF showed elevated PMN leukocyte count of 170/μL, a mildly increased protein level of 60 mg/dL, and a glucose level of 65 mg/dL. He was treated empirically for presumed infectious meningitis with ceftriaxone and acyclovir. His symptoms improved, but he returned 2 weeks later with fever, malaise, and elevated CSF PMN cell counts (86/μL), prompting a second course of ceftriaxone and acyclovir. A month later, he was readmitted with lower leg edema and increased serum C-reactive protein (CRP) but no fever or headache. His edema was attributed to possible heart failure with preserved ejection fraction and improved with a prescription for azosemide. After a month, the fever, headache, and CSF PMN elevation recurred (250/μL), prompting a third course of ceftriaxone and acyclovir. A contrast-enhanced computed tomography (CT) of the chest and abdomen showed no significant findings. He was transferred to a neurology service at a referral hospital for further investigation. He was treated with meropenem and vancomycin, leading to improved symptoms and discharge. Weeks later, however, he was readmitted with fever, headaches, fatigue, and limb edema. Ceftriaxone and vancomycin were started for suspected bacterial meningitis, and the general medicine service was consulted on the 4th day of hospitalization. Common infectious etiologies are less likely given negative CSF cultures and low leukocyte counts. Viruses, Bartonella, Brucella, Coxiella, Lyme disease, syphilis, mycobacterium, fungi, and parasites remain in the differential. CSF testing should be extended to search for the above microorganisms. More history is needed including exposure to infectious etiologies of meningitis (such as cats, rodents, dogs, pigs, bats, goats, and pigeons), possible immunodeficiency, and trauma causing anatomical obstruction or communication with CSF. Anatomical causes such as sinusitis or skull base fistula could be considered, but they do not account for systemic edema and inflammation. Aseptic meningitis from medications (e.g., NSAIDs, antibiotics) is another possibility, requiring a thorough medication review. Immune-mediated mechanisms should also be considered, including autoimmune or lymphoproliferative conditions and immunosuppression-related opportunistic infections. Given the potential link between his fluctuating meningitis and limb edema, vascular pathology emerges as a plausible unifying explanation. Primary or secondary vasculitis—including giant cell arteritis, lymphoma, and sarcoidosis—should be carefully evaluated. A detailed history, including jaw and gait claudication, cutaneous pain or numbness, hemoptysis, hematuria, and physical examination (searching for tenderness of superficial arteries, palpable purpura), and imaging tests such as ultrasound or CT for evaluating medium-to-large vessel vasculitis, including temporal artery, are necessary. He had a history of well-controlled hypertension, GERD, inguinal hernia surgery, cholecystectomy, and colon polypectomy. His medications included azosemide, famotidine, rebamipide (gastroprotective hippuric acid), and magnesium oxide. He had an allergy to iodinated contrast media. He did not drink or smoke, and he was not sexually active. He worked as a consultant, traveling within Japan, but no recent overseas travel. He had several cats but reported no scratches. Five months before, he slipped on snow and suffered a minor head injury for which he did not seek care. Review of systems was negative for rash, arthritis, jaw or leg claudication, hemoptysis, or hematuria. His family history was unremarkable. He does not take medications known to cause recurrent meningitis or systemic inflammation. The clinical presentation is suggestive of systemic inflammation, evidenced by fatigue, fever, limb swelling, and elevated inflammatory marker (CRP). Routine business travel within Japan does not involve unique risks, and his sexual history reduces the likelihood of newly acquired human immunodeficiency virus (HIV) or syphilis. Exposure to cats is notable, and if no other causes are identified, investigating related pathogens would be reasonable. The head trauma 5 months ago raises the slight possibility of communication between the intracranial and extracranial spaces (e.g., a fistula between the skull base and nasal cavity), which might explain recurrent meningitis but not systemic inflammation. Head CT, with bone window to assess for fistula is warranted. On examination, he appeared tired. His temperature was 38.1°C, blood pressure 109/58 mmHg, heart rate 77 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 96% while breathing ambient air. There was no nuchal rigidity or temporal artery tenderness. Pulmonary, cardiovascular, and abdominal examinations were normal, with no rash or joint swelling. Pitting edema was noted on the forearms, hands, and lower legs. The white-cell count was 30,800/μL with 92% neutrophils, 4% lymphocytes, 3% monocytes, and 1% eosinophils; the hemoglobin level was 9.3 g/dL, MCV 76 fl, and platelet count 233,000/μL. Ferritin was 302 ng/mL, erythrocyte sedimentation rate (ESR) 89 mm/h, and CRP 13.3 mg/dL. Liver enzymes and bilirubin were normal. Total protein was 5.3 g/dL, albumin 1.7 g/dL. Urea nitrogen was 37.2 mg/dL, creatinine 3.0 mg/dL (1.2 on admission), sodium 132 mmol/L, potassium 3.9 mmol/L, and chloride 100 mmol/L. BNP was 476 pg/mL. Urinalysis was negative for red cells and bacteria but showed 1+ leukocytes and protein. Head CT showed no abnormalities. Noncontrast CT of the chest and abdomen was performed due to impaired renal function and his history of allergies, which precluded the use of contrast agents. The imaging revealed no evidence of nodules, masses, or lymphadenopathy, but mild pericardial and pleural effusions were identified (Figure 1). The absence of neck stiffness and temporal artery tenderness argue against infectious meningitis or GCA, though these conditions cannot be entirely ruled out by physical exam. Notable findings include fever, limb edema, neutrophil-predominant leukocytosis, and elevated inflammatory markers. Renal function abnormalities are likely prerenal, given his recent use of diuretics and the lack of glomerular damage on urine tests or hydronephrosis on CT. Testing urine electrolytes, giving fluids, and monitoring creatinine is warranted. The decrease in albumin is nonspecific. The CT without significant lymph nodes, nodules, or masses makes metastatic cancer less likely. Evaluating arterial wall inflammation using non-contrast CT presents substantial challenges. The differential diagnosis still includes GCA, medium-to-large vessel vasculitis, and malignancies without lymphadenopathy (e.g., intravascular lymphoma). Infectious causes include Bartonella, Brucella, Coxiella, syphilis, tuberculosis, and Lyme disease, which must also be considered because these infectious conditions can cause secondary vasculitis. The pitting edema may be attributable to hypoalbuminemia, but increased vascular permeability associated with systemic vasculitis, could also explain this finding. CSF nucleic acid testing for Escherichiacoli K1, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae, Streptococcuspneumoniae,Cytomegalovirus, Enterovirus, Herpes simplex virus 1 and 2, Human herpesvirus 6, Human parechovirus, Varicella zoster virus, and Cryptococcus neoformans/gattii were all negative. Bacterial cultures of blood and CSF, and mycobacterial cultures of CSF were negative. Cytological examination of the CSF, including previoussamples, revealed no malignancy. Tests for antinuclear, anti-Ro,anti-dsDNA, anti-cycliccitrullinated peptide antibodies, rheumatoid factor, PR3-ANCA, and MPO-ANCA were negative. A contrast-enhanced brain magnetic resonance image (MRI) showed no masslesion or dural thickening. Radioisotope cisternography revealed no evidence of CSF leakage. Echocardiography showed normal valves, an ejection fraction of 67%, and left ventricular apical hypertrophy. A random skin biopsy revealed no evidence of intravascularlymphoma or vasculitis. Vancomycin was discontinued to avoid drug-induced nephropathy. He gradually became afebrile and his creatinine improved to 2.2 mg/dL. His edema decreased with an increased dose of azosemide. Ceftriaxone was discontinued after 7 days, and he was discharged. A temporal artery biopsy should be considered if imaging is negative for GCA. Due to sampling error concerns, this diagnosis should not be dismissed after one negative biopsy if suspicion remains high. Fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT), being less invasive, could support the diagnosis of a malignancy or vasculitis. FDG-PET/CT showed no abnormal findings. One month later, he was admitted with fever and malaise but no headaches. His temperature was 38.5°C, blood pressure 118/74 mmHg, heart rate 81 beats per minute, respiratory rate 20 breaths per minute, and oxygen saturation 96% on ambient air. No nuchal rigidity was observed. Mild edema was noted in the lower legs, but no other significant abnormalities were found during physical examination. His white-cell count was 29,400/μL with 91% neutrophils. Hemoglobin was 9.5 g/dL, platelet count 169,000/μL, and CRP 18.9 mg/dL. Total protein was 7.2 g/dL, albumin 2.3 g/dL. Urea nitrogen was 26.9 mg/dL, and creatinine was 1.6 mg/dL. Urinalysis was negative for leukocytes, red cells, and bacteria but showed 1+ protein. CT scans of the chest and abdomen showed reduced pleural and pericardial effusions with no other abnormal findings. Blood and urine cultures were negative. A temporal artery biopsy was performed, but no significant findings were noted. His symptoms and inflammatory markers improved without antibiotics, leading to his discharge after 1 week. Subsequently, he experienced daily fevers, managed with as-needed acetaminophen, allowing him to continue with his daily activities. The FDG-PET/CT results did not show abnormal findings suggesting vasculitis or intravascular lymphomas. Despite the negative temporal artery biopsy, a repeat biopsy remains an option, given the strong clinical suspicion for GCA. Four strategies can be considered at this moment: first, if urgent intervention is not necessary, manage symptoms and repeat temporal artery biopsy later; second, repeat temporal artery biopsy immediately; third, consult other hospitalist colleagues or use an artificial intelligence clinical decision support system to surface very rare diagnoses; fourth, to “repeat simple things,” revisit the patient's history and physical examination in deeper detail, including hidden history of jaw claudication, tenderness of superficial arteries, all of which may suggest vasculitis. Although the initial temporal artery biopsy was negative, a second biopsy was performed based on a strong clinical suspicion of GCA and through shared decision-making with the patient. A repeat temporal artery biopsy revealed disruption or partial defect and multilayering of the internal elastic lamina, along with intimal thickening and nearly circumferential luminal stenosis (Figure 2). These findings were consistent with the healed phase of giant cell arteritis (GCA). Contrast-enhanced MRI of the thoracic aorta, performed to evaluate the presence of large-vessel inflammation, revealed enhancement of the vascular walls extending from the bilateral common carotid arteries to the internal carotid arteries (Figure 3). These findings led to the diagnosis of GCA, prompting treatment with prednisolone 40 mg daily and tocilizumab 162 mg weekly. In long-term follow-up, his fevers resolved, his creatinine improved to 1.0 mg/dL, and his inflammatory markers normalized. GCA is a chronic autoimmune vasculitis affecting mid- and large-sized arteries in patients over the age of 50. GCA can present with a wide range of cranial and extracranial symptoms caused by granulomatous inflammation in the arterial wall, leading to luminal narrowing and occlusion.1 The average patient age is 74–76 years.2 Women are more affected than men (2–3:1), and the condition is more prevalent in the northern hemisphere.2, 3 Its pathogenesis remains poorly understood, with clues suggesting age, genetics, and unidentified triggers stimulating inflammatory cascades. Headache is one of the most common symptoms of GCA, with 40–70% of patients reporting scalp or temporal artery tenderness.2 Jaw claudication, a manifestation of ischemia in the masticatory muscles, is present in 30%–70%.2 Constitutional symptoms, such as fever, fatigue, and weight loss, are reported in only 20%–50% of cases.2, 4 Some patients present with muscle pain and stiffness consistent with the distribution patterns of polymyalgia rheumatica, an associated disease that occurs in approximately half of patients with GCA.2 Neck stiffness is extremely rare in patients with GCA but may occur as a reflection of inflammation involving intracranial or meningeal vessels.5, 6 Extracranial large vessel vasculitis is found in 25% of patients.2 However, many are asymptomatic, and findings such as asymmetrical blood pressure readings or limb claudication are relatively uncommon.2 When evaluating multisystem disease in the setting of systemic inflammation, vasculitis should be included in the differential diagnosis. When the affected organs are not limited to those typically associated with small- to medium-vessel disease—such as pulmonary lesions, glomerulonephritis, or mononeuritis multiplex—and when there are no findings suggestive of malignancy, such as lymphadenopathy, large-vessel vasculitis should be considered more strongly, especially in patients over 50 years. CRP and ESR are usually obtained first, and although both markers are typically elevated in untreated patients, their specificity is low; thus, normal results do not exclude the disease.1-3 When GCA is suspected based on history, physical, and laboratory findings, diagnostic evaluation with ultrasound of the temporal and axillary arteries or temporal artery biopsy is recommended.1, 7, 8 The recommendations of the European Alliance of Associations for Rheumatology (EULAR), the British Society for Rheumatology (BSR), and the American College of Rheumatology (ACR) differ regarding which test should be performed first, due to the dependence of ultrasound diagnostic accuracy on the examiner's expertise. While temporal artery ultrasound was previously recommended primarily for the cranial phenotype of GCA, current guidelines support its use in all patients suspected of GCA, reflecting the recognition of GCA as a single disease spectrum encompassing both cranial and extracranial phenotypes.7 To improve diagnostic accuracy, evaluation of the axillary artery in addition to the temporal artery is also recommended.7, 8 The pooled sensitivity and specificity of temporal and axillary artery ultrasound in diagnosing GCA are reported to be 88% and 96%,7 respectively, though examiner expertise remains a critical factor. Ultrasound allows for a broader assessment than temporal artery biopsy, and when performed by experienced examiners, it has a higher sensitivity than biopsy.8 In patients with a strong clinical suspicion of GCA and a positive ultrasound, a diagnosis may be made without the need for biopsy,7 thereby reducing the number of patients requiring invasive procedures.8 Conversely, in patients with a low clinical probability of GCA and a negative ultrasound, the likelihood of GCA is further diminished.7 In other situations, additional evaluation with temporal artery biopsy or alternative imaging modalities may be necessary to establish a diagnosis.1, 7 If an experienced examiner is not available, biopsy should be sought first. Given the frequent presence of skip lesions, obtaining a temporal artery biopsy specimen of at least 1 cm is recommended.1, 2, 8 Bilateral biopsies can increase diagnostic yield by approximately 13%.9, 10 If biopsy results are negative but other findings support a diagnosis of GCA, bilateral biopsies should be artery biopsy should be but treatment should not be when there is a of vision If has a biopsy should be performed within 2 2 MRI of the temporal arteries and large and FDG-PET/CT for the diagnosis of GCA may be considered in are not or when patients to temporal artery MRI of the temporal artery a sensitivity of and a specificity of Contrast-enhanced of large is for vascular stenosis or FDG-PET/CT is primarily to and assess disease in suspected of large vessel vasculitis, with pooled sensitivity and specificity of and Although diagnostic guidelines do not of the and 8 it has a sensitivity of and specificity of for large vessel When is to evaluate fever of it may GCA or including and is not performed during the diagnostic process for however, mild CSF protein elevation and reported in of intracranial vasculitis in GCA 6, In this although no abnormalities were in the intracranial on MRI or in the CSF the possibility of intracranial or meningeal vasculitis. The treatment for newly GCA patients is recommended to with by a the dose to a dose of within months and after 1 to However, for patients with or loss, at mg to 1 daily for to 3 is recommended 8 In patients at of or those with or disease, the addition of tocilizumab or should be This was due to its presentation recurrent meningitis and negative results from both the initial temporal artery biopsy and imaging The patient experienced inflammation for over 5 months a diagnosis was the of evaluating this the of man in his presented with recurrent meningitis and systemic inflammation with limb and vascular pathology as a unifying were to the diagnosis. in situations, a common vascular based on an appropriate can diagnostic testing, the of the disease the GCA is an autoimmune vasculitis affecting the mid- and large-sized arteries in patients 50 or with a wide range of cranial (e.g., headache, vision symptoms, and jaw and extracranial symptoms (e.g., fever, fatigue, and limb meningitis may be in patients with GCA, likely reflecting inflammation of intracranial or meningeal the diagnosis of GCA, the need for a has when available, ultrasound of the temporal and axillary arteries is recommended first. In the setting a is not available, temporal artery biopsy should be however, given that temporal arteritis in GCA presents with skip lesions, bilateral or biopsies may be warranted. and of the of Rheumatology and and of the of for their to the patient's The no of