BVNS Neurotransmitter 2.0 Technically Speaking March 2017

The Fungus Among Us

How would an animal get infected with a fungus?
Fungi are ubiquitous organisms that live in the soil and in the environment. They often perform important ecological roles such as helping to break down organic debris (rotting food, stool or plant material). Most infections can be acquired by ingestion, inhalation, or even through the skin (transdermally). Fungal infections may reach the brain and spinal cord by direct spread from an adjacent infection occurring in the nasal cavity, sinuses, outer ear, Eustachian tube, and middle/inner ear. Infection may also be transmitted via a migrating foreign body. Fungal infections of the central nervous system (CNS) in dogs and cats are uncommon; however, when they do occur, they can be devastating and particularly aggressive. Fungal infection is more likely in young to middle-aged dogs and cats (1-7 years). Several types of fungi can invade the CNS including Cryptococcus, Coccidioides, Blastomyces, Histoplasma, and Aspergillus species. Opportunistic fungi, such as Aspergillus and Cryptococcus, usually require a debilitated or immunosuppressed host to establish infection; however, all strains are capable of producing a primary infection despite this compromised state. Cryptococcus neoformans is the most common fungal organism associated with infection of the CNS in dogs and cats.

Clinical Signs

Clinical signs are dependent on the lesion location (whether in the brain, spinal cord or both) and severity of the infection. These signs are often multifocal or diffuse in nature making diagnosis somewhat difficult. Neurological signs may reflect brain involvement (ie. seizures, depression, disorientation, circling, anisocoria, pupillary dilation, and central blindness), spinal cord involvement, (ataxia, pelvic limb paresis, paraplegia, and spinal hyperesthesia) or a combination of these signs. Deficits of one or several cranial nerves are often present. Patients can show evidence of concurrent systemic disease with signs such as skin lesions, nasal/frontal sinus swelling or drainage, fever, weight loss, inflammation of the iris of the eye, blindness, lameness, enlarged lymph nodes, coughing, and wheezing. While neurologic dysfunction may be acute in onset and rapidly progressive, fungal infection of the CNS is often characterized by a slow progression over weeks to months with a period of non-specific illness (lethargy or anorexia) beforehand. Thus, fungal disease can be all too easily missed until it has spread into vital areas of the body and become overwhelming and potentially fatal.

Diagnosis of a fungal infection within the CNS is ultimately based on direct visualization of the organism. Routine laboratory tests are often normal, although there may be evidence of chronic disease such as anemia. Fungal elements are occasionally identified on urinalysis. Thoracic radiographs may show evidence of a fungal disease process by either a diffuse or nodular interstitial lung pattern with those pathogens which can infect the respiratory system. Magnetic resonance imaging (MRI) can be used and is likely to show lesions that strongly contrast enhance. Both focal lesions, such as a fungal granuloma, and more diffuse disease processes, such as meningitis, can be visualized on MRI. These findings are useful for therapeutic decisions and grading severity of the infection. Fungal serology can also be used whenever direct visualization is not possible or to support a diagnosis and is easily done in routine clinical practice. With serology, a blood sample is collected and serum sent to specialized laboratory in order to assess for antibodies against specific fungal antigens. For Cryptococcus, serum is directly tested for detection of the antigen itself.

Definitive diagnosis is made via cytology, biopsy, or culture of an affected organ or cerebrospinal fluid (CSF). Cytology is performed either by impression smears or fine needle aspirate and fungal hyphae or spores may be visualized under the microscope. If surgery is pursued, a portion of the specimen can be obtained by surgical biopsy and submitted for histopathology. This allows for a larger sample to be collected compared to cytological collection techniques. Cultures are frequently used in suspected fungal cases but have the drawback of delayed results while waiting for the pathogen to grow in the laboratory. In these cases, treatment is usually begun before confirming the diagnosis so that more life threatening symptoms do not develop. Cerebrospinal fluid is collected from the cerebellomedullary cistern at the back of the head or the subarachnoid space in the lumbar region and should only be performed by highly trained veterinary professionals. Typical abnormalities seen that support infection include an increased protein content, increased numbers of white cells as well as the presence of eosinophils. On CSF cytology, fungal organisms may be visible. Practitioners should combine a variety of the available tests to confirm the presence of a pathogen and decide on the best course of treatment.

Fungal infections within the CNS of animals can be difficult to treat for a host of reasons. While antifungal therapy is considered the primary treatment for fungal infections, most antifungal agents do not adequately cross the blood-brain-barrier (BBB). One of the few antifungal drugs that will cross the BBB is fluconazole. It constitutes the first line course of treatment because high drug concentrations can be achieved in the CNS. Fluconazole has the added benefit of being available in a variety of formulations; however, higher doses are usually needed for CNS disease. Voriconazole is especially effective against several fungal species, but reserved for when other -azole fungal agents fail. It is very expensive and can lead to client frustration and non-compliance. Amphotericin B is especially toxic to the kidneys and should only be used in severe cases as some renal damage is possible following treatment. Itraconazole has the fewest side effects of all the -azole agents, but does not reach minimum inhibitory concentrations in the cerebrospinal fluid.

Unfortunately, in some cases, antifungal medications by themselves are not enough to completely treat infection. Surgical removal/debulking of intracranial granulomas may be indicated depending on the size, location, and the presence of any potential fatal complications (ie. increased intracranial pressure, edema). Surgical intervention comes with significant cost to the client, risk to the patient, and significant recovery time which should be discussed at length before pursuing this treatment route. While corticosteroids are frequently utilized to reduce secondary inflammation and cerebral edema, their use is controversial and usually contraindicated in fungal infections due to immunosuppression. If corticosteroids are used, they should be used judiciously and short term. Lastly, it is not uncommon for fungal organisms to lie dormant in the CNS and return after withdrawal of antifungal therapy. As a result, clients need to be prepared emotionally and financially for long-term treatment, sometimes greater than the period of a year, even after clinical signs of the disease appear to be gone. The decision regarding when to discontinue antifungal therapy should be based on presence of clinical signs, repeat CSF results, and CSF/serum titers for the organism.

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