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Abstract
A man in his 60s presented to the clinic due to night sweats and weight loss following pneumonia. He was found to have hyponatraemia due to a syndrome of inappropriate antidiuretic hormone (SIADH). CT of the thorax was concerning for pulmonary nodules. He was ultimately diagnosed with pulmonary coccidioidomycosis (CM) and started on fluconazole 400 mg daily with improvement in symptoms. Due to the report of headaches, head MRI was conducted which suggested central nervous system (CNS) involvement. Cerebrospinal fluid analysis was consistent with CNS CM and head magnetic resonance angiography confirmed the presence of CNS vasculitis. Fluconazole dose was increased to 800 mg daily which the patient continued to tolerate and showed improvement. This report depicts a case of SIADH associated with CNS CM with vasculitis and demonstrates the importance of high clinical suspicion for SIADH secondary to CNS CM in the setting of hyponatraemia and headache.
- Infectious diseases
- Infection (neurology)
- Neuroimaging
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Background
Syndrome of inappropriate antidiuretic hormone (SIADH) release is a condition defined by the unsuppressed release of antidiuretic hormone from the pituitary gland or non-pituitary sources or its continued action on vasopressin receptors leading to hypotonic hyponatraemia. This syndrome has commonly been associated with central nervous system (CNS) abnormalities including stroke, haemorrhage, infection, trauma, mental illness and psychosis as well as malignancy and medications as well as other causes.1–3 Coccidioidomycosis (CM) is caused by the dimorphic fungus Coccidioides immitis or Coccidioides posadasii, which is endemic to the arid regions of the western hemisphere and can present with a wide variety of clinical manifestations, from asymptomatic infection to fatal disease.1–3 Infections of the CNS are relatively rare but can present with focal or systemic symptoms and require lifelong treatment to manage complications of the disease.
Case presentation
A retired physician in his 60s from the Southwest US presented to the family medicine clinic with a 2-week history of night sweats and an 8 kg weight loss for 3 months. He has a history of asthma, basal cell carcinoma, small cell lung cancer in remission, hyperlipidaemia and prostate cancer status post resection 10 years ago with local recurrence treated with radiotherapy 7 years ago. Current cancer screening was up-to-date and negative. He had a reading greater than 100.0 F on one occasion, but otherwise was afebrile. He reported not sleeping well with increased fatigue. He denied sick contacts or others with similar symptoms. He denied cough or any difficulty with breathing or shortness of breath but had an episode of community-acquired pneumonia 3 months ago. Chest radiography did not show signs of active disease. CT thorax with contrast revealed scattered granulomas and nodules in the right apex and left upper lobes (figure 1). CT abdomen and pelvis with contrast did not reveal a suspicious large adrenal mass. Complete blood counts with differential had no derangements, and a comprehensive metabolic panel disclosed low sodium with no other abnormalities. He was referred to nephrology for further evaluation.
(A) Chest radiography without signs of active disease. (B) CT thorax revealed scattered granulomas and nodules in the right apex and left upper lobes with the largest nodule measuring 1.28 cm×1.55 cm.
On presentation to the nephrology clinic, he appeared euvolaemic on examination and laboratories demonstrated sodium of 131 mmol/L (previously 128, 127 and 130), despite adherence with water restriction, increased salt intake and increased protein. Longitudinal values for serum sodium are reported in table 1.
Serum sodium values over time
Additional laboratory values at that time were urine sodium 76 mmol/L (Normal Limit (NL)<20 mmol/L), urine osmolality 747 mOsm/kg (NL: 100–900 mOsm/kg), serum osmolality 270 mOsm/kg (NL 280–301 mOsm/kg), glomerular filtration rate of 62 mL/min (NL>60 mL/min) and creatinine of 1.19 mg/dL (NL 0.6–1.5 mg/dL) and no white blood cells, red blood cells or protein in urine. Findings were suggestive of hypotonic hyponatraemia. Nephrology workup at that time was negative for polydipsia, hypothyroidism, adrenal insufficiency and reset osmostat. He was ultimately diagnosed with SIADH.
Differential diagnosis
He was referred to a pulmonology clinic for evaluation of lung nodules seen on CT thorax. Non-invasive workup was performed which included a negative QuantiFERON-TB, severe acute respiratory syndrome coronavirus 2 (SARS-CoV)-PCR and Legionella pneumophilia IgG and IgM. Coccidioides enzyme immunoassay (EIA) IgM for tube precipitin (TP) and immunodiffusion IgM (TP) were negative. Coccidioides EIA IgG for compliment fixation (CF) and immunodiffusion IgG (CF) were positive. CF titres were elevated to 1:64. At this time the patient was started on fluconazole 400 mg daily orally (PO) and referred to infectious diseases for further evaluation.
On evaluation in the infectious disease clinic, he reported improvement in symptoms since initiating fluconazole about one and a half months prior with a return to at least 80% of baseline. Due to the report of headaches during the initial months of his illness and SIADH, a lumbar puncture and an MRI of the brain with and without contrast were obtained to evaluate for CNS involvement (figures 2 and 3). Cerebral spinal fluid (CSF) analysis showed elevated white blood cells 70/mm3 with 83% lymphocytes, 8% neutrophils, 9% monocytes (no eosinophils reported), red blood cell count of 3 cells/mm3, hypoglycorrhachia of 34 mg/dL (no serum glucose obtained at the same time) and elevated protein of 158 mg/dL. CSF Coccidioides antibody IgG was positive and CSF Coccidioides compliment fixation titre was 1:8. CSF Coccidioides antigen quantitative EIA was positive. Patient laboratories are summarised in table 2.
Summary of laboratory testing results
Axial post-contrast T1 MPRAGE sequence. (A) Extensive nodular enhancement in basilar cisterns and right greater than left bilateral Sylvian fissures. (B) Questionable thickening of pituitary stalk and nodular leptomeningeal enhancement of cerebellar vermis. (C) Nodular leptomeningeal enhancement in bilateral insular regions. (D) Nodular leptomeningeal enhancement in left frontal convexity.
Precontrast sagittal T1 spin echo image demonstrates unremarkable pituitary gland and pituitary stalk. There is non-visualisation of the posterior pituitary bright spot, which is a non-specific finding and may be within normal limits. (B) Post-contrast sagittal T1 MPRAGE image demonstrates thickening of the pituitary stalk and asymmetrically increased enhancement of the posterior pituitary.
MRI brain showed findings concerning for extensive enhancement of the basal cisterns with multiple scattered supra and infratentorial areas of leptomeningeal thickening and enhancement, mild third ventricle enlargement without frank hydrocephalus and probable mural enhancement of supraclinoid internal carotid arteries (figure 2) as well as pituitary stalk thickening (figure 3). Follow-up MR angiogram brain showed findings suggestive of vasculitis of the right carotid terminus and bilateral middle, anterior and posterior cerebral arteries (figure 4). Taken together, the patient’s imaging and CSF findings are consistent with CNS CM with vasculitis.
Axial post-contrast black blood sequence demonstrating abnormal thickening and enhancement of the basilar cisterns. Nodular leptomeningeal enhancement is also seen in right greater than left Sylvian fissures. Abnormal nodular enhancement of right carotid terminus consistent with probable infectious vasculitis. Temporal horns of the lateral ventricles are mildly dilated, which is a concerning finding for developing hydrocephalus.
Treatment
Due to the extent of CNS involvement, fluconazole dose was increased to 800 mg daily. Sodium improved with free water restriction, high protein diet and after initiation of fluconazole at CNS dosing levels. At diagnosis, Coccidioides CF titre was 1:64; and remained at 1:64 3 months into treatment (1 month after a higher dose fluconazole) before declining to 1:32 about 9 months into treatment (7 months after a higher dose fluconazole) (table 3).
Coccidioidomycosis serum compliment fixation titre trend post-treatment
Outcome and follow-up
He developed diplopia and esotropia of the left eye which is thought to be a sequela of his CNS CM and is being treated with prism glasses and is followed by ophthalmology. Otherwise, he reports doing well with essentially returned to his baseline energy level and regular activities.
Discussion
CM is an endemic fungal infection of the western hemisphere predominantly found in dry low-rainfall climates in which the fungus is found in the soil and dirt.2 3 Endemic areas in the USA include Arizona, parts of California (Kern, San Louis Obispo and Tulare counties), New Mexico along Rio Grande, Texas, and endemic areas internationally include Mexico, Guatemala, Honduras, Venezuela, Brazil, Argentina and Paraguay determined by soil testing, skin testing and clinical cases reported in the literature.2 3 Human and animal infections result from inhalation of arthroconidia, the fungal spore of C. immitis and C. posadasii. Most often, this is an asymptomatic event. When illness occurs, it is primarily a pneumonic presentation. A small minority of infections lead to disseminated disease where patients predominantly present with meningitis, osteoarticular or integumentary disease.1
Diagnosis of CM is commonly made by serological testing via EIA or via immunodiffusion techniques to IgM and IgG but is also done by growth of Coccidioides in cultures or by visualisation of characteristic spherules on pathology.2 Of note, experts have reported that CSF cultures are often negative in CM and minimally reactive test results should not be dismissed as insignificant.1 A negative serologic test result does not exclude the presence of CM as these may be negative in early disease. Therefore, it is recommended that testing should be repeated over the course of at least 2 months.2 Complement-fixing antibodies can be detected in other body fluids, and their detection in CSF is an especially important aid in the diagnosis of CNS CM.2 4 5 Previous reports of the CT and MR imaging findings in cerebral CM have described dense leptomeningeal enhancement on post-gadolinium images that are characteristically localised to the basal cisterns or can be diffuse.6 This enhancement may also extend inferiorly along the spinal cord. Accompanying this enhancement may be evidence of vasculitis and subarachnoid haemorrhage around the basal cisterns or infarction involving deep perforating artery territories in structures of the brain such as those located in the thalamus, basal ganglia cerebellum and brainstem.6 Focal leptomeningeal enhancement may be appreciated.6 The case reported herein reports evidence of extensive leptomeningeal enhancement involving the basilar and perisylvian cisterns as well as some of the convexity sulci consistent with the patient’s known fungal meningitis and suggestive of a vasculitis secondary to cerebral CM.
Fluconazole is the drug of choice for CNS CM due to its superior CNS penetration, dose of 400–1200 mg intravenous/PO; following clinical improvement, fluconazole is continued at 400 mg PO lifelong, as the relapse rate is high when therapy is stopped. Amphotericin B is used in life-threatening infections (in intensive care unit, rapidly progressive) and transition to fluconazole once the patient has stabilised.1–3 7
At the time of publishing this case report, there exists only one other report to our knowledge describing SIADH secondary to CNS CM.8 There exist limited reports of other CNS vasculitides presenting as SIADH notably in a patient with Kawasaki disease9 and giant cell arteritis.10 Additionally, there are reports of other CNS infections, such as tuberculous meningitis11 or tick-borne encephalitis and meningitis,12 that presented with SIADH. The diagnosis of SIADH is based on the classic Schwartz and Bartter criteria which was first described in 1967 by William Schwartz and Frederic Bartter who first detected this syndrome in two patients with lung cancer and electrolyte abnormalities.13 The Schwartz and Bartter Clinical Criterion for SIADH include serum sodium less than 135 mmol/L, serum osmolality less than 275 mOsm/kg, urine sodium greater than 40 mEq/L and urine osmolality greater than 100 mOsm/kg. These findings must be present in a patient with the absence of clinical evidence of hypovolaemia, the absence of other causes of hyponatraemia including adrenal insufficiency, hypothyroidism, cardiac failure, pituitary insufficiency, renal disease with salt wastage, hepatic disease and drugs that impair renal water excretion.13 SIADH treatment involves correction and maintenance of corrected sodium levels and treatment of inciting disease processes such as hypothyroidism or pulmonary or CNS infections.
Our case adds to the literature that one must consider CNS infections such as CM in the appropriate setting for the evaluation of SIADH in Coccidioides endemic regions.
Patient’s perspective
‘During my initial workup, the healthcare world was so focused on COVID-19, as well as the cold/influenza season. As I got sicker, with a £40 weight loss, no appetite, headaches, sleeping over 20 hours per day, it was clear that I was not doing well and needed a diagnosis. I was truly amazing how quickly I felt better when started on high dose fluconazole. My recovery did take over 1 year, but now I have my strength and balance back, eating and sleeping well, and feeling like myself again.’
Learning points
Among patients with pulmonary coccidioidomycosis, symptoms of headaches and decreased mentation warrant an MRI brain and lumbar puncture to rule out central nervous system (CNS) coccidioidomycosis.
CNS coccidioidomycosis can have myriad presentations including meningitis, brain abscess, arachnoiditis, hydrocephalus and cerebral vasculitis.
Though rare, hyponatraemia due to syndrome of inappropriate antidiuretic hormone in the setting of CNS coccidioidomycosis is possible as illustrated by our case.
Ethics statements
Patient consent for publication
Footnotes
Twitter @goyo_bran
JL and TR contributed equally.
Contributors The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms and critical revision for important intellectual content: GLB, HTO, JL and TR. The following authors gave final approval of the manuscript: TR.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.