Episode 164: More Than Just A Headache

Dr. Song presents a case of a subacute headache that required an extensive workup and multiple visits to the hospital and clinic to get a diagnosis. Dr. Arreaza added comments about common causes of subacute headaches.    

Written by Zheng (David) Song, MD. Editing and comments by Hector Arreaza, MD.  

You are listening to Rio Bravo qWeek Podcast, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California, a UCLA-affiliated program sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home. This podcast was created for educational purposes only. Visit your primary care provider for additional medical advice.

Introduction to the episode: We are happy to announce the class of 2027 of the Rio Bravo / Clinica Sierra Vista Family Medicine Residency Program. Our new group will be (in alphabetical order): Ahamed El Azzih Mohamad, Basiru Omisore, Kenechukwu Nweke, Mariano Rubio, Nariman Almnini, Patrick De Luna, Sheila Toro, and Syed Hasan. We welcome all of you. We hope you can enjoy 3 enriching and fulfilling years. During this episode, you will hear a conversation between Dr. Arreaza and Dr. Song. Some elements of the case have been modified or omitted to protect the patient’s confidentiality. 

1. Introduction to the case: Headache. 

A 40-year-old male with no significant PMH presents to the ED in a local hospital due to over a month history of headaches. Per the patient, headaches usually start from the bilateral temporal side as a tingling sensation, and it goes to the frontal part of the head and then moves up to the top of the head. 8 out of 10 severities were the worst. Pt reports sometimes hypersensitivity to outdoor sunlight but not indoor light. OTC ibuprofen was helpful for the headache, but the headache always came back after a few hours. 

The patient states that if he gets up too quickly, he feels slightly dizzy sometimes, but it is only for a short period of time. There was only one episode of double vision lasting a few seconds about 2 weeks ago but otherwise, the patient denies any other neurological symptom. 

He does not know the cause of the headache and denies any similar history of headaches in the past. The patient denies any vomiting, chest pain, shortness of breath, cough, abdominal pain, or joint pain. The patient further denies any recent traveling or sick contact. He does not take any chronic medication. The patient denies any previous surgical history. He does not smoke, drink, or use illicit drugs. 

What are your differential diagnoses at this moment? 

Primary care: Tension headache, migraines, chronic sinusitis, and more.

2. Continuation of the case: Fever and immigrant.

Upon further inquiries, the patient endorses frequent “low-grade fever” but he did not check his temperature. He denies any significant fatigue, night sweats, or weight loss. He migrated from Bolivia to the U.S. 12 years ago and has been working as a farm worker in California for the past 10 years. He is married. His wife and daughter are at home in Bolivia. He is currently living with friends. He is not sexually active at this moment and denies having any sexual partners. 

Differential diagnoses at this moment?  Tension headache, migraine, infections, autoimmune disease, neurocysticercosis. 

3. Continuation of the case: Antibiotics and eosinophilia. 

As we kept asking for more information, the patient remembered he visited a clinic about four months ago for a dry cough and was told he had bronchitis and was given antibiotics and the cough got better after that. He went to another local hospital ED one month after that because the cough came back, now with occasional phlegm and at that time he also noticed two “bumps” on his face but nothing significant. After a CXR at the ED, the patient was diagnosed with community-acquired pneumonia and sent home with cough medication and another course of antibiotics. His cough improved after the second round of antibiotics. We later found on the medical record that the CXR showed “mild coarse perihilar interstitial infiltrates of unknown acuity”. 

His blood works at the ED showed WBC 15.2, with lymphocyte 21.2%, monocyte 10.1%, neutrophil 61.7%, eosinophil 5.9% (normally 1-4%), normal kidney, liver functions, and electrolytes, and prescribed with benzonatate 100mg TID and doxycycline 100mg bid for 10 days. 

He went to the same ED one month before he saw us for headache and fever (we reviewed his EMR, and temp was 99.8F at the ED). After normal CBC, CMP and chest x-ray. The patient was diagnosed with a viral illness and discharged home with ibuprofen 400mg q8h.

Due to the ongoing symptoms of headache and fever, the patient went back to the same clinic he went to four months ago for a dry cough and requested a complete physical and blood work. The patient was told he had a viral condition and was sent home with oseltamivir (Tamiflu®) for five days. However, the provider did order some blood work for him. 

Differential diagnoses at this moment?  Patients with subacute meningitis typically have an unrelenting headache, stiff neck, low-grade fever, and lethargy for days to several weeks before they present for evaluation. Cranial nerve abnormalities and night sweats may be present. Common causative organisms include M. tuberculosis, C. neoformans, H. capsulatum, C. immitis, and T. pallidum. 

At his physical exam visit, the patient actually asked the provider specifically to check him for coccidiomycosis because of his job as a farm worker and he heard from his friends that the infection rate is pretty high in the Central Valley of California. 

His serum cocci serology panel showed positive IGG and IGM with CF titer of 1:128. His HIV, syphilis, HCV, HBV are all negative. 

The patient was told by that clinic to come to ED due to his history of headache, fever, and very high serum coccidiomycosis titer.  

The senior and resident intern were on the night shift that night and we were contacted by the ED provider at around 9:30 pm for this patient. When reviewing his ED record, his vitals were totally normal at the ED, the preliminary ED non-contrast head CT showed no acute intracranial abnormality. 

A lumbar puncture was performed by the ED provider, which showed WBCs (505 - 71%N, 20%L, 7%M), RBC (1), glucose (19), and protein (200). CSF: High Leukocytes, low glucose, and high protein.

On the physical exam, the patient was pleasant and cooperative, he was A&O x 4, he had a normal examination except for two brown healing small nodules on his forehead and left cheek and slight neck stiffness. 

At that point, we knew the patient most likely had fungal meningitis by cocci except for the predominant WBC in his CSF fluid was neutrophil not the more typical picture of lymphocyte dominant. And because of his very benign presentation and subacute history, we were not 100% sure if we had a strong reason to admit this patient. We thought this patient could be managed as an outpatient with oral fluconazole and referred to infectious disease and neurology. 

4. Continuation of case: Admission to the hospital.

Looking back, one thing that was overlooked while checking this patient in the ED was the LP opening pressure. Later, the open pressure was reported as 340mm H2O (very high). The good thing was, after speaking to the ED attending and our attending, the patient was admitted to the hospital and started on oral fluconazole.  

Three hours after the admission, a rapid response was called on him. While the floor nurses were doing their check-in physical examination, the patient had a 5-minute episode of seizure-like activity which included bilateral tonic arm/hand movements, eye deviation to the left, LOC unresponsive to sternal rub, and the patient desaturated to 77%. He eventually regained consciousness after the seizure and pulse oximetry increased to 100% on room air. 

The patient was started on Keppra and seen by a neurologist the following day. His 12-hour EEG was normal, but his head MRI showed “diffuse thickening and nodularity of the basal meninges are seen demonstrating enhancement, suggesting chronic meningitis, possibly related to cocci. Other etiologies including sarcoidosis and TB meningitis and/or infiltration by metastatic process/lymphoma are not excluded. The ventricles are slightly prominent in size”. 

MRI of the cervical, thoracic, and lumbar spines also showed extensive diffuse leptomeningeal thickening, extensive meningitis, and nodular dural thickening. 

Also, his chest x-ray showed “some heterogeneity and remodeling of the distal half of the left clavicle. Metabolic bone disease, infectious etiology and/old trauma considered”. 

This could also be due to disseminated cocci infection. 

The infectious disease doctor saw this patient and recommended continuing with fluconazole, serial LPs until opening pressure is less than 250 mmH2O and neurosurgery consultation for possible VP shunt placement. The neurologist recommended the patient continue with Keppra indefinitely in the context of structural brain damage secondary to cocci meningitis.

Take home points: Suspect cocci meningitis in patients with subacute headache associated with respiratory symptoms, new skin lesions, photophobia, neck stiffness, nausea, vomiting, eosinophilia, erythema nodosum (painful nodules on the anterior aspect of legs). Other symptoms to look for include arthralgias, particularly of the ankles, knees, and wrists.

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Brief summary of coccidiomycosis. 

Etiology 

Coccidioidomycosis, commonly known as Valley fever, is caused by dimorphic soil-dwelling fungi of the genus Coccidioides (C. immitis and C. posadasii). They are indistinguishable in clinical presentation and routine laboratory test results.1, 2, 3, 5

Epidemiology 

In the United States, endemic areas include the southern portion of the San Joaquin Valley of California and the south-central region of Arizona. However, infection may be acquired in other areas of the southwestern United States, including the southern coastal counties in California, southern Nevada, southwestern Utah, southern New Mexico, and western Texas (including the Rio Grande Valley). There are also cases in eastern Washington state and in northeastern Utah. Outside the United States, coccidioidomycosis is endemic to northern Mexico as well as to localized regions of Central and South America.1, 2

Overall, the incidence within the United States increased substantially over the 1998-2019, most of that increase occurred in south-central Arizona and in the southern San Joaquin Valley of California. From 1998 to2019, reported cases in California increased from 719 to 9004.1, 6

The risk of infection is increased by direct exposure to soil harboring Coccidioides. Past outbreaks have occurred in military trainees, archaeologists, construction or agricultural workers, people exposed to earthquakes or dust storms. However, in endemic areas, many cases of Coccidioides infection occur without obvious soil or dust exposure and are not associated with outbreaks. Change in population, climate change, urbanization and construction activities, and increased awareness and reporting, are possible contributing factors.1, 2, 5 

Pathology 

In the soil, Coccidioides organisms exist as filamentous molds. Small structures called arthroconidia from the hyphae may become airborne for extended periods. Arthroconidia are usually 3-5 μm—small enough to evade bronchial tree mucosal mechanical defenses and reach deep into the lungs.1, 3

Once inhaled by a susceptible host into the lung, the arthroconidia develop into spherules (theparasitic existence in a host), which are unique to Coccidioides. Endospores from ruptured spherules can themselves develop into spherules, thus propagating infection locally.1, 3, 5

Although rare cases of solid organ donor-derived or fomite transmitted infections have been reported, coccidioidomycosis does not occur in person-to-person or zoonotic contagion, and transplacental infection in humans has never been documented.2, 5

Cellular immunity plays a crucial role in the host’s control of coccidioidomycosis. Among individuals with decreased cellular immunity, Coccidioides may spread locally or hematogenously after an initial symptomatic or asymptomatic pulmonary infection to extrathoracic organs.1, 3, 7

Clinical manifestation

The majority of infected individuals (about 60%) are completely asymptomatic. Symptomatic persons (40% of cases) have symptoms that are related principally to pulmonary infection, including cough, dyspnea, and pleuritic chest pain. Some patients may also experience fever, headache (common finding in early-stage infection and does not represent meningitis), fatigue, night sweats, rash, myalgia.1, 2, 3, 5

In most patients, primary pulmonary coccidioidomycosis usually resolves in weeks without sequelae and lifelong immunity to reinfection. However, some patients may develop chronic pulmonary complications, such as nodules or pulmonary cavities, or chronic fibrocavitary pneumonia. Some individuals with intense environmental exposure or profoundly suppressed cellular immunity (e.g., in patients with AIDS) may develop a primary pneumonia with diffuse reticulonodular pulmonary process in association with dyspnea and fever.1, 3, 5

Fewer than 1% of infected individuals develop extrathoracic disseminated coccidioidal infection. Common sites for dissemination include joints and bones, skin and soft tissues, and meninges. One site or multiple anatomic foci may be affected. 1, 2, 3, 7

It is estimated that coccidioidal meningitis, the most lethal complication of coccidioidomycosis, affects only 0.1% of all exposed individuals. Patients with coccidioidal meningitis usually present with a persistent headache (rather than a self-limited headache in some patients with primary pulmonary infection), with nausea and vomiting, and sometimes vision change. Some may also develop altered mental status and confusion. Meningismus such as nuchal rigidity, if present, is not severe.

Hydrocephalus and cerebral infarction may develop in some cases. Papilledema is more commonly observed in pediatric patients.1, 3, 4, 5, 7

When meningitis develops, most patients may not have any respiratory symptoms nor radiographic manifestation of pulmonary infection. However, a large number of these individuals also present with other extrathoracic lesions.7

Diagnosis

Although early diagnosis carries obvious benefits for patients and the health care systems as a whole (e.g., decreases patient anxiety, reduces the cost of expensive and invasive tests, removes the temptation for empirical antibacterial or antiviral treatments, and allows for early detection of complications), considerable diagnostic delays up to several weeks to months are common in both endemic areas and non-endemic areas.3, 7 

Most symptomatic persons with coccidioidal infection present with primarily pulmonary symptoms and are often misdiagnosed as community-acquired bacterial pneumonia and treated with antibiotics. In endemic areas like south-central Arizona, previous studies found up to 29% of community-acquired pneumonia is caused by coccidioidomycosis. Healthcare providers thus should maintain a high clinical suspicion for coccidioidomycosis when evaluating persons with pneumonia who live in or have traveled to endemic areas recently. Elevated peripheral-blood eosinophilia of over 5%, hilar or mediastinal adenopathy on chest radiography, marked fatigue, and failure to improve with antibiotic therapy should prompt suspicion and testing for infection with coccidioidomycosis in endemic areas.1, 3, 5

Serological testing plays an important role in establishing a diagnosis of coccidioidomycosis. Enzyme immunoassay (EIA) to detect IgM and IgG antibodies is highly sensitive and therefore commonly used as the screening tool. Immunodiffusion is more specific but less sensitive than enzyme immunoassay. It is used to confirm the diagnosis of positive EIA test results. Complement fixing (CF) test, which indirectly detects the presence of coccidioidal antibodies by testing the consumption of serum complement, are expressed as titers. Serial measurements of titers are of not only diagnostic but also prognostic value.1, 2, 3, 5

Other methods, including culture, microscopic, or polymerase chain reaction (PCR) exam on tissue or respiratory specimens, are limited by their availability, sample obtaining and handling, or lack of sufficient evaluation.1, 2, 3, 5

Cerebrospinal fluid (CSF) examination in coccidioidal meningitis usually demonstrates lymphocyte dominated elevation of leukocytes, although polymorphonuclear leukocyte dominance can also be seen in the early stage of the infection. Profound hypoglycorrhachia and elevated protein levels in CSF examination are also very common in coccidioidal meningitis.1, 7

Although isolating Coccidioides from CSF or other CNS specimens are diagnostic for coccidioidal meningitis, in practice, diagnoses are often made based on the combination of clinical presentation, CSF examination that suggesting fungal infection, and positive Coccidioides antibodies found in CSF.7

Imaging, especially enhanced magnetic resonance imaging (MRI), can help in diagnosing coccidioidal meningitis. Basilar leptomeningeal enhancement is a more common finding even though hydrocephalus, cerebral infarction, and vertebral artery aneurysm can also be seen.7

Treatment

Most patients with focal primary pulmonary coccidioidomycosis do not require antifungal therapy. According to 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline, antifungal therapy should be considered in patients with concurrent immunosuppression that adversely affect cellular immunity (e.g., organ transplant patients, AIDS in HIV-infected patients, and patients receiving anti–tumor necrosis factor therapy) and those with significantly debilitating illness, extensive pulmonary involvement, with concurrent diabetes, pregnant women, or who are otherwise frail because of age or comorbidities. Some experts would also include African or Filipino ancestry as indications for treatment. Conversely, humoral immunity comprise splenectomy, hypocomplementemia, or neutrophil dysfunction syndromes are not major risk factors for this disease.1, 2, 3, 4, 5

Triazole antifungals (fluconazole or itraconazole) are currently considered as the first-line medications used to treat most cases of coccidioidomycosis. Amphotericin B is reserved for only the most severe cases of dissemination and patients with coccidioidal meningitis in whom triazole antifungal therapy has failed. It is also the choice of therapy for coccidioidomycosis in pregnant women during the first trimester because of the possible teratogenic effect of high-dose triazole therapy during this period of time.1, 3, 4, 5

Treating coccidioidal meningitis (CM) poses a special challenge because untreated meningitis is nearly always fatal. Lifelong therapy is recommended for CM because the majority 80% patients with CM experience relapse when therapy is stopped despite initial response to antifungal treatment. Shunting of CSF is required in cases of meningitis complicated by hydrocephalus.1, 3, 4, 5, 7

Prevention 

Avoidance of direct contact with contaminated soil in endemic areas (e.g., respirator use by construction workers) may reduce disease risk, although clear evidence of its benefit is lacking.1, 5

Some special population groups may benefit from prophylactic use of antifungals, such as those about to undergo allogeneic solid-organ transplantation or patients with a history of active coccidioidomycosis or a positive coccidioidal serology in whom therapy with tumor necrosis factor α antagonists is being initiated. The administration of prophylactic antifungals is not recommended for HIV-1-infected patients even if they live in an endemic region.1, 5

Conclusion: Now we conclude episode number 164, “More than just a headache.” Dr. Song explained that a headache with an indolent course, accompanied by subacute respiratory symptoms, nausea, vomiting, photophobia, neck stiffness, and skin lesions can be secondary to Valley Fever. The Central Valley of California, as well as other areas with dry climate, are endemic and we need to keep this disease in our differential diagnosis.

This week we thank Hector Arreaza and Zheng (David) Song. Audio editing by Adrianne Silva.

Even without trying, every night you go to bed a little wiser. Thanks for listening to Rio Bravo qWeek Podcast. We want to hear from you, send us an email at [email protected], or visit our website riobravofmrp.org/qweek. See you next week! 

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References:

1. Roos KL, Tyler KL. Acute Meningitis. McGraw Hill Medical. Published 2023. Accessed August 18, 2023. https://accessmedicine.mhmedical.com/content.aspx?bookid=2129§ionid=192020493
2. Information for Healthcare Professionals. Published 2023. Accessed August 18, 2023. https://www.cdc.gov/fungal/diseases/coccidioidomycosis/health-professionals.html#print
3. Valley Fever (Coccidioidomycosis) a Training Manual for Primary Care Professionals. Accessed August 18, 2023. https://vfce.arizona.edu/sites/default/files/valleyfever_training_manual_2019_mar_final-references_different_colors.pdf
4. Ampel NM. Coccidioidomycosis. Idsociety.org. Published July 27, 2016. Accessed August 18, 2023. https://www.idsociety.org/practice-guideline/coccidioidomycosis/
5. Herrick KR, Trondle ME, Febles TT. Coccidioidomycosis (Valley Fever) in Primary Care. American Family Physician. 2020;101(4):221-228. Accessed August 18, 2023. https://www.aafp.org/pubs/afp/issues/2020/0215/p221.html
6. Valley Fever Statistics. Published 2023. Accessed August 18, 2023. https://www.cdc.gov/fungal/diseases/coccidioidomycosis/statistics.html
7. UpToDate. Uptodate.com. Published 2023. Accessed August 18, 2023. https://www.uptodate.com/contents/coccidioidal-meningitis?search=7%20Coccidioidal%20meningitis&source=search_result&selectedTitle=1~10&usage_type=default&display_rank=1
8. Royalty-free music used for this episode: Tropicality by Gushito, downloaded on July 20, 2023, from  https://www.videvo.net/