Scott Plummer, DVM, DACVIM (neurology)
As veterinarians practicing in Arizona, it is common to make a diagnosis of Coccidioidomycosis. Respiratory infections are the most characteristic form of the disease and can be self-limiting or present with bronchopneumonia and tracheobronchial lymphadenopathy. Typical signs, but not necessarily pathognomonic, include fever, lethargy, anorexia, weight loss, and coughing or dyspnea.
Unfortunately, some patients develop disseminated Coccidioidomycosis following a respiratory infection, which might have even been subclinical.
A common site for Coccidioidomycosis dissemination is to the central nervous system. It can spread either directly to the CNS and cause neurological signs, or secondarily through osseous involvement of the vertebral column or skull. With direct CNS dissemination, the most common areas affected are the cerebral hemispheres, followed by the cerebellum and, rarely, the brainstem or spinal cord.
Clinical signs are related to the area involved, but typically forebrain signs are most characteristic and can include seizures, altered mentation, circling and hemiparesis. If the cerebellum is involved, then truncal ataxia, tremors or head tilt might be noticed.
With osseous involvement of the vertebral column, pain is the most common clinical sign followed by paresis (mono-, para- or tetra-).
Serologic testing can be helpful for diagnosing osseous dissemination, but it is important to realize titers are frequently lower with direct CNS infections than with other forms of disseminated Coccidioidomycosis and can occasionally be negative. It can also be difficult to determine whether low positive titers are from an active infection of the CNS or from exposure alone.
We have found MR imaging vastly superior to CT imaging for diagnosing CNS Cocci, as it has the highest diagnostic yield and can usually differentiate Cocci granulomas of the brain from other abnormalities such as brain tumors, which is frequently not the case with CT imaging. Furthermore, MR imaging can reveal how extensive perilesional edema is, which can assist with planning therapeutic intervention. Many times we have seen small granulomas measuring only a few millimeters in diameter with extensive brain edema. Detailed imaging can help determine whether ancillary treatment with hypertonic (7.2%) saline, mannitol and/or corticosteroids is indicated.
CSF analysis and measuring of titers in CSF has been relatively unrewarding.
The treatment of choice for CNS Cocci is fluconazole. Typically we use a higher dose of 10 mg/kg PO bid up to a maximum of 400 mg. If an anticonvulsant is required, we strongly recommend avoiding medications that require hepatic metabolism such as phenobarbital or zonisamide and prefer to use levetiracetam or potassium bromide. We have seen many dogs develop toxic levels of phenobarbital when used concomitantly with fluconazole. There also appears to be a greatly increased risk of developing a hepatopathy with this combination.
Furthermore, since the treatment period for CNS frequently exceeds a year or more in length, we advise starting patients immediately on hepatoprotectants such as Denamarin. We frequently recommend running baseline bloodwork every three to four months during the first year of treatment to ensure the patient is not developing any adverse reactions to medication. Since treatment for Valley Fever will continue for a year or longer, it is not necessary to repeat titers within the first 12 months.
If the patient does not tolerate fluconazole at higher doses, usually because of the development of a hepatopathy, or if the improvement is inadequate, then we will consider the use of lipid complexed Amphotericin B (Abelcet®). The lipid complexed formulation is less toxic than conventional Amphotericin B and also penetrates the CNS in greater quantities.
When it comes to determining if the infection has been eradicated, there is no clear-cut answer. If possible, MR imaging is repeated after a year of treatment. If reimaging is not possible, then we repeat titers and treat until there is a negative titer. It has been our experience that stopping therapy before the titer is negative, even if it is only 1:2 or <1:2, runs a high risk of recrudescence of the infection. We have been able to successfully treat most patients using these recommendations.