Treatment of thoracolumbar spinal cord compression associated with Histoplasma capsulatum infection in a cat

Arathi Vinayak Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4474.

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Sharon C. Kerwin Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4474.

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Roy R. Pool Department of Veterinary Pathobiology, College of Veterinary Medicine, Texas A&M University, College Station, TX 77843-4474.

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Abstract

Case Description—A 7-year-old domestic shorthair cat with a 2-month history of decreased appetite and weight loss was examined because of paraparesis of 1 week's duration that had progressed to paraplegia 3 days earlier.

Clinical Findings—Neurologic examination revealed normo- to hyperreflexia and absence of deep pain sensation in the hind limbs and thoracolumbar spinal hyperesthesia. Neuro-anatomically, the lesion was located within the T3 through L3 spinal cord segments. Biochemical analysis and cytologic examination of CSF revealed no abnormalities. Radiography revealed narrowing of the T11-12 intervertebral disk space and intervertebral foramen suggestive of intervertebral disk disease. Myelography revealed an extradural mass centered at the T12-13 intervertebral disk space with extension over the dorsal surfaces of T11-13 and L1 vertebral bodies.

Treatment and Outcome—A right-sided hemilaminectomy was performed over the T11-12, T12-13, and T13-L1 intervertebral disk spaces, and a space-occupying mass was revealed. Aerobic bacterial culture of samples of the mass yielded growth of a yeast organism after a 10-day incubation period; histologically, Histoplasma capsulatum was identified. Treatment with itraconazole was initiated. Nineteen days after surgery, superficial pain sensation and voluntary motor function were evident in both hind limbs. After approximately 3.5 months, the cat was ambulatory with sling assistance and had regained some ability to urinate voluntarily.

Clinical Relevance—In cats with myelopathies that have no overt evidence of fungal dissemination, differential diagnoses should include CNS histoplasmosis. Although prognosis associated with fungal infections of the CNS is generally guarded, treatment is warranted and may have a positive outcome.

Abstract

Case Description—A 7-year-old domestic shorthair cat with a 2-month history of decreased appetite and weight loss was examined because of paraparesis of 1 week's duration that had progressed to paraplegia 3 days earlier.

Clinical Findings—Neurologic examination revealed normo- to hyperreflexia and absence of deep pain sensation in the hind limbs and thoracolumbar spinal hyperesthesia. Neuro-anatomically, the lesion was located within the T3 through L3 spinal cord segments. Biochemical analysis and cytologic examination of CSF revealed no abnormalities. Radiography revealed narrowing of the T11-12 intervertebral disk space and intervertebral foramen suggestive of intervertebral disk disease. Myelography revealed an extradural mass centered at the T12-13 intervertebral disk space with extension over the dorsal surfaces of T11-13 and L1 vertebral bodies.

Treatment and Outcome—A right-sided hemilaminectomy was performed over the T11-12, T12-13, and T13-L1 intervertebral disk spaces, and a space-occupying mass was revealed. Aerobic bacterial culture of samples of the mass yielded growth of a yeast organism after a 10-day incubation period; histologically, Histoplasma capsulatum was identified. Treatment with itraconazole was initiated. Nineteen days after surgery, superficial pain sensation and voluntary motor function were evident in both hind limbs. After approximately 3.5 months, the cat was ambulatory with sling assistance and had regained some ability to urinate voluntarily.

Clinical Relevance—In cats with myelopathies that have no overt evidence of fungal dissemination, differential diagnoses should include CNS histoplasmosis. Although prognosis associated with fungal infections of the CNS is generally guarded, treatment is warranted and may have a positive outcome.

A 7-year-old 4-kg (8.9-lb) castrated male domestic shorthair cat was referred to the Texas A&M University Veterinary Teaching Hospital for evaluation because of a 2-month history of decreased appetite and weight loss and paraparesis of 1 week's duration that had progressed to paraplegia 3 days prior to this initial assessment. The cat was housed indoors with outdoor access, and there was no known history of trauma. Vaccinations against feline leukemia, feline viral rhinotracheitis-calicivirus-panleukopenia, and rabies were current, and the result of a combined test for FeLV and FIV infections was negative. A neurologic examination performed by the referring veterinarian 3 days prior to referral revealed an absence of voluntary motor function and deep pain sensation in both hind limbs.

The cat had been examined at our institution 4 years previously because of a severe intrathoracic esophageal stricture of unknown etiology; the cat received palliative treatment that included 12 balloon dilatation procedures. Despite those ballooning procedures, the cat had continued to have occasional bouts of vomiting or regurgitation. Biannual CBCs and serum biochemical analyses that were performed as part of routine monitoring during the period prior to onset of paraparesis revealed hyperglobulinemia (4.3 to 4.7 mg/dL; reference range, 2.3 to 3.8 mg/dL), which was presumed to be secondary to chronic antigenic stimulation from the existing esophageal disease.

At the time of initial evaluation (day 1), the cat was alert but seemingly apprehensive; rectal temperature was 38.4°C (101.2°F), heart rate was 195 beats/min, and respiratory rate was 36 breaths/min. Moderate muscle atrophy was evident in both hind limbs and paraspinal musculature of the thoracolumbar region. Grade I/IV medial patellar luxation was detected in both stifle joints during orthopedic examination. On neurologic examination, reflexes and responses of cranial nerves and mentation were considered normal. The cat was paraplegic. Postural reactions (including conscious proprioception and hopping) were apparently normal in the forelimbs. Patellar, cranial tibial, and gastrocnemius reflexes were hyperresponsive to clonic, and withdrawal reflexes in the hind limbs were seemingly normal. All spinal reflexes were considered normal in the forelimbs. The perineal reflex was also considered normal, but the panniculus reflex was absent caudal to the thoracolumbar vertebral junction. Severe hyperesthesia was detected in the region of the thoracolumbar junction on palpation of the vertebral column. In both hind limbs, superficial pain sensation (assessed as response to pinching of the skin between the third and fourth digits with a hemostat) and deep pain sensation (assessed as response to clamping the middle phalanx of the third and fourth digits with a hemostat) were absent. On the basis of neurologic findings, the lesion was localized within the T3 through L3 spinal cord segments.

A CBC revealed normocytic, normochromic, nonregenerative anemia (Hct, 21.4%; reference range, 24% to 45%). Mild hyperglobulinemia (4.0 g/dL; reference range, 2.3 to 3.8 g/dL) was the only abnormality detected via serum biochemical analyses. Results of analysis performed on a urine sample collected via cystocentesis were unremarkable. Three orthogonal radiographic views of the thorax were obtained to assess the cat for disseminated pulmonary fungal disease and metastatic neoplasia, and no important abnormalities were detected.

To perform additional diagnostic assessments, the cat was anesthetized. The cat was premedicated with butorphanol (0.2 mg/kg [0.09 mg/lb], SC) and glycopyrrolate (0.011 mg/kg [0.005 mg/lb], SC). Induction of anesthesia was performed with propofol (4 mg/kg [1.8 mg/lb], IV), and the anesthetic plane was maintained via inhalation of sevoflurane and oxygen. A continuous rate infusion of fentanyl (0.02 mg/kg/h [0.009 mg/lb/h], IV) was also administered during surgery. Cefazolin (22 mg/kg [10 mg/lb], IV) was administered before surgery (just after induction of anesthesia) and repeated 90 minutes later during the surgical procedure. Before radiography was performed, a cisternal sample of CSF was collected, and subsequent analysis and cytologic examination of the fluid revealed no abnormalities.

Survey radiography of the vertebral column performed prior to myelography revealed narrowing of the T11-12 intervertebral disk space and intervertebral foramen, suggesting disk degeneration (Figure 1). In addition, agenesis of the 13th rib on the left side was evident. Myelography was performed with iohexola injected by use of a 1.5-inch, 22-gauge spinal needle positioned in the L4-5 ventral subarachnoid space. In the region of T11 through L1, the dorsal and ventral contrast columns were narrowed with ventral deviation of the dorsal contrast column; this was most marked over the T12-13 disk space (Figure 2). These findings were consistent with a dorsal extradural compressive lesion located primarily over the T12-13 intervertebral disk space with some extension over the T11-12 and T13-L1 intervertebral disk spaces. A lateral right dorsal–left ventral oblique radiographic view revealed this lesion to be slightly more prominent on the right side, compared with findings in the lateral left dorsal–right ventral oblique view.

Figure 1—
Figure 1—

Left lateral thoracolumbar radiographic view of a 7-year-old cat that was evaluated because of paraplegia. Notice the narrow appearance of the intervertebral disk space and intervertebral foramen (black arrows) at the level of T11-12, which is consistent with probable disk degeneration. T13 = 13th rib.

Citation: Journal of the American Veterinary Medical Association 230, 7; 10.2460/javma.230.7.1018

Figure 2—
Figure 2—

Lateral right dorsal–left ventral oblique radiographic view of the cat in Figure 1 after myelography. Notice the absence of the 13th rib on the left side. Thin dorsal and ventral contrast columns and ventral deviation of the dorsal contrast column consistent with an extradural compression (black arrows) can be seen primarily over the T12-13 intervertebral disk space with extension over the T11 and T13 vertebral bodies. See Figure 1 for remainder of key.

Citation: Journal of the American Veterinary Medical Association 230, 7; 10.2460/javma.230.7.1018

On the basis of myelographic findings, primary differentials included intervertebral disk extrusion, extradural hematoma, neoplasia, abscess, and granuloma. An exploratory right-sided hemilaminectomy (centered over the T11 through L1 intervertebral spaces) was performed (day 1) to further characterize the lesion and decompress the spinal cord. A routine surgical approach was used to perform the hemilaminectomy. A moderate amount of dense tan material was present extradurally on the right dorsal aspect of the T12-13 intervertebral disk space and was causing spinal cord compression. Smaller amounts of the tan material were overlying the T11-12 and T13-L1 intervertebral disk spaces. The material was removed, and a sample was submitted for histologic examination. A sample was also collected for aerobic and anaerobic microbial cultures and antimicrobial susceptibility testing. A durotomy revealed no gross abnormalities of the spinal cord parenchyma. At the time of surgical closure, the spinal cord appeared decompressed and there was no evidence of disk degeneration. Recovery from anesthesia was uneventful. Pain management included administration of a continuous rate infusion of fentanyl (0.04 mg/ kg/h [0.018 mg/lb/h], IV) for the first 36 hours followed by buprenorphine (0.015 mg/kg [0.007 mg/lb], PO, q 4 to 6 h) for 10 days. Postoperative rehabilitation consisted of bladder expressions performed every 6 to 8 hours and passive ROM exercises to support joint health (starting day 3 and performed 3 times/d). Electrical stimulation was started on a biweekly basis on day 14 and was continued during the entire hospitalization period.

Histologic examination of the specimens of the mass that had covered the dorsal spinal dura at the thoracolumbar junction revealed a diffuse pyogranulomatous inflammatory cell infiltrate that was composed of large macrophages, which often contained single to multiple, round to oval, pale basophilic-staining fungal organisms. Organisms in the cytoplasm of the macrophages were 2 to 4 Mm in diameter and surrounded by a narrow clear halo, which was most evident in sections treated with a fungal stain (Figure 3). Small numbers of lymphocytes and plasma cells were frequently located around small-caliber blood vessels at the borders of the mass. These findings were consistent with a histopathologic diagnosis of spinal cord histoplasmosis. Anaerobic microbial cultures of the excised material yielded no growth after 72 hours of incubation (ie, day 3). A yeast organism was isolated via aerobic culture after an extended 10-day incubation period, which supported the diagnosis of infection with Histoplasma capsulatum. Further identification of the organism was not performed because of concerns for safety of laboratory personnel.

Figure 3—
Figure 3—

Photomicrograph of a section of a mass that was removed from the dorsal surface of the thoracolumbar dura mater of the cat in Figure 1. Notice the clusters of egg-shaped fungal organisms located in the cytoplasm of unstained macrophages. Gomori methenamine silver stain; bar = 10 Mm.

Citation: Journal of the American Veterinary Medical Association 230, 7; 10.2460/javma.230.7.1018

On the basis of the histopathologic findings, treatment with itraconazole (10 mg/kg [4.5 mg/lb], PO, q 24 h) was started on day 4. In addition, phenoxybenzamine (2.5 mg/kg [1.14 mg/lb], PO, q 12 h), an A-adrenergic receptor blocking agent, was used to decrease the tone of the internal urethral sphincter to facilitate urinary bladder expression. On day 5, the cat had hematochezia and defecated a small volume of formed mucoid feces. Zinc and sugar floatation assessments were performed on the feces, and no trophozoites, eggs, or giardial cysts were detected. Histoplasma organisms were not observed on cytologic examination of a rectal scrape specimen or feces. Abdominal ultrasonography was performed to evaluate the intestinal tract and other organs for evidence of disseminated histoplasmosis, and no abnormalities were evident. The cat was fed a low-fat, high-fiber diet, and the hematochezia resolved by day 7. The hematochezia was attributed to stress colitis.

Weekly monitoring for the first 5 weeks consisted of a CBC and serum biochemical analyses. Compared with findings before surgery, the cat's anemia remained relatively unchanged and was nonregenerative until day 25 (Table 1). With bone marrow regeneration (indicated by an increase in the percentage of reticulocytes) evident on days 25 and 35, the anemia resolved by day 35, and Hct values improved steadily during the following 20 days. Mild hyperglobulinemia, similar to that detected before surgery, was the only abnormality identified via serum biochemical analyses during the 5-week monitoring period (range, 4.0 to 5.2 g/dL; mean, 4.24 g/dL).

Table 1—

Hematologic variables assessed at intervals from the time of initial evaluation (day 1) in a cat with histoplasmosis involving the CNS.

VariableDays since initial evaluationReference range
7121825354653
Hct (%)21.422.92321.725.830.535.124.0–45.0
RBC (× 106 cells/μL)4.694.944.854.315.376.737.705.00–10.00
MCV (fL)45.646.347.550.448.145.345.539.0–55.0
MCHC (%)34.234.333.132.633.333.332.231.0–35.0
Reticulocyte* (%)10.40.63.82.2**0.2–1.6
Plasma total protein (g/dL)77.37.87.17.78.88.06.0–8.0

Reticulocyte counts are not routinely performed in the laboratory used in this report when Hct is > 25%.

MCV = Mean corpuscular volume. MCHC = Mean corpuscular hemoglobin concentration.

Because urinary tract infections are common in animals that are not able to urinate voluntarily, microbial cultures of urine were performed periodically throughout the treatment period. Results of culture of a urine sample collected at the initial evaluation (day 1) were negative. Another sample of urine was submitted for microbial culture on day 18 because a foul odor was evident and the cat had signs of abdominal discomfort during bladder expressions. This culture yielded Escherichia coli that was susceptible to amoxicillin trihydrateclavulanate potassium, and the cat was treated with the antimicrobial for 21 days (13.75 mg/kg [6.25 mg/lb], PO). During treatment (day 28) and 1 week after discontinuation of antimicrobial administration (day 46), a urine sample was collected for microbial culture; results of both cultures were negative. All urine samples were obtained via cystocentesis, and all culture results were reported after 5 days of incubation.

Ten days after starting treatment with itraconazole (day 14), the cat's appetite was decreased, and this progressed to complete anorexia by day 17. An examination of the oral cavity and abdominal radiography revealed no abnormalities. The anorexia was thought to be a drug-related reaction to itraconazole. On day 17, the cat was administered butorphanol (0.2 mg/kg, SC) and anesthesia was induced with propofol (4 mg/kg, IV). Anesthesia was maintained via inhalation of sevoflurane and oxygen, and a PEG tube was placed. A PEG tube was chosen rather than an esophageal feeding tube because of the cat's preexisting esophageal disease and history of regurgitation and vomiting. Recovery from anesthesia and the procedure was uneventful. The cat was offered canned food on a free-choice basis; oral intake was supplemented with a pureed high-calorie diet administered every 6 hours via the feeding tube starting the day after PEG tube placement. Itraconazole, amoxicillin-clavulanic acid, and phenoxybenzamine were administered through the feeding tube as well. Tube feedings were discontinued on day 49 when caloric intake from oral feedings was in excess of the calculated resting energy requirement; however, the medications were still administered via the PEG tube.

A complete neurologic examination of the cat was performed every day during the period of hospitalization. No changes in the neurologic status were evident until day 14, at which time deep pain sensation returned in the right hind limb. Superficial pain was present in the right hind limb by day 17. Delayed conscious proprioception and some voluntary motor signs were also detectable in the right hind limb. By day 19, superficial and deep pain sensations were present in the left hind limb. However, there was no evidence of voluntary urination until day 49 when the cat started to void small amounts (approx a third of the urinary bladder volume) of urine in its litter box. Manual urinary bladder expressions were still performed every 8 hours because the cat was not voiding the entire contents of its bladder. Voluntary motor signs and strength in the hind limbs gradually increased with continued rehabilitation; after day 19, active, assisted ROM exercises consisting of sling walks with assisted limb movement and joint ROM exercises were performed 2 to 3 times daily. By day 64, postural reactions (including conscious proprioception and hopping) were apparently normal in the right hind limb and delayed in the left hind limb. At day 110, the cat was still hospitalized for rehabilitation. At this time, the cat was ambulatory with sling assistance but still required expression of the urinary bladder to facilitate complete emptying. Resolution of anemia, return of normal appetite, and weight gain (from 4.0 to 4.3 kg [8.9 to 9.5 lb]) were considered to be indications of adequate control of histoplasmosis. At that time, the treatment plan included continued administration of itraconazole for an additional 3 months (treatment duration, 6 months) and the cat's progress was to be monitored via neurologic examinations, serum biochemical analyses, and CBCs performed monthly.

After 7.5 months of itraconazole treatment, during which the cat remained hospitalized for rehabilitation, no further neurologic improvement was detected during daily neurologic examinations. At this time, treatment with itraconazole was discontinued because of financial constraints. The continuing rehabilitation plan included electrical stimulation and active assisted joint ROM exercises. Supportive care included manual bladder expressions performed every 8 hours.

Discussion

Histoplasma capsulatum is a dimorphic saprophytic fungus that grows well in nitrogen-rich soils, such as those containing bird or bat feces.1 The organism's distribution is worldwide, and H capsulatum has been reported in 31 states in the United States, especially in the Ohio, Missouri, and Mississippi river valleys and Texas.1,2 In soil (at 25°C [77°F]), the organism exists in an environmentally resistant mycelial form, from which fruiting bodies are formed. The smaller of the 2 types of fruiting bodies, the microconidia (2 to 5 Mm), is the source of infections in mammals. Inhalation of microconidia allows the organism to transform into a yeast phase in the lungs (at 37°C [98.6°F]); subsequently, phagocytosis of the yeastlike organisms by macrophages occurs.3 Most animals infected with H capsulatum have subclinical disease despite the presence of the organism in lungs and pulmonary lymph nodes; however, massive intracellular budding in reticuloendothelial cells in some animals can lead to dissemination via hematogenous and lymphatic routes early in the course of the disease.1,3 Affected cats are usually young (≤ 4 years),4 and sex predilection has not been reported. Insidious onset and nonspecific clinical signs including signs of depression, weight loss, fever, anorexia, and pale mucous membranes can make diagnosis challenging. Gastrointestinal tract signs including inappetence, tenesmus, hematochezia, and mucoid feces are uncommon in cats, compared with dogs. In cats, involvement of the respiratory system is typical and can result in dyspnea, tachypnea, or harsh lung sounds.2,5,6 Ocular, dermatologic, orthopedic, and oral lesions are uncommon and CNS involvement is rare in dogs and cats.7

Although not pathognomonic for histoplasmosis, normocytic, normochromic, nonregenerative anemia (similar to that detected in the cat of this report) is the most common hematologic abnormality.3,7,8 Chronic inflammatory disease, bone marrow infection with H capsulatum, and blood loss from the gastrointestinal tract are often implicated as probable causes of nonregenerative anemia in animals with histoplasmosis. Pancytopenia in cats with severe histoplasmosis has also been reported.3,8,9 In the cat of this report, the nonregenerative anemia became regenerative within 21 days (day 25) of treatment with an appropriate antifungal agent, and the cat was no longer anemic after 31 days (day 35) of treatment. In companion animals with histoplasmosis, results of serum biochemical analyses are usually unremarkable; however, hyperproteinemia and hyperglobulinemia from chronic antigenic stimulation, hypoalbuminemia and mildly high alanine aminotransferase activity as a result of liver dysfunction, and hypercalcemia secondary to granulomatous disease have been reported.3,8 When the cat had signs of neurologic disease, hyperglobulinemia was detected. This may have been a result of antigenic stimulation by Histoplasma antigens, but the cat had high serum globulin concentration during the 4 years prior to the diagnosis of histoplasmosis.

Dormancy of H capsulatum can develop in immunocompetent hosts; reactivation of infection occurs following an immunosuppressive event (eg, development of other diseases, stress, or inoculation with a large number of fungal organisms).7,10,11 In the cat of this report, the high serum globulin concentrations detected during the previous 4 years may have been associated with a dormant Histoplasma infection. In a study4 in which records of 571 cats with deep mycoses were reviewed, cats with histoplasmosis had the highest incidence of concurrent FeLV infection, suggesting that immunosuppression was a contributing factor in disease development. However, other investigators have not found evidence to support an association of histoplasmosis with immunosuppression.2,3,5,8 For the cat of this report, the results of a combined FeLV-FIV ELISA (performed with a whole blood sample) were negative. Although abnormalities in urine among dogs and cats with histoplasmosis have not been reported, microbial cultures of urine samples from the cat were performed to monitor for urinary tract infection, which may develop in paraplegic animals.

Nervous system involvement in dogs, cats, and humans with histoplasmosis is rare. An autopsy series12 revealed that 25% of humans with disseminated histoplasmosis had lesions in the CNS; however, only 25% of those patients had neurologic clinical signs at initial evaluation. This suggests that the true prevalence of histoplasmosis in the CNS may be higher than that detected clinically. The most common CNS abnormalities in humans are intracranial mass lesions and acute or chronic meningitis.13 Similarly, meningitis and granulomas in the brain or brain stem have been reported as the primary lesions in 3 dogs and 1 cat with histoplasmosis.8,11,14,15 None of those 4 animals had signs of spinal cord involvement. Two of the 3 dogs11,14 were administered an anti-fungal agent but were euthanized shortly after initiation of treatment because of worsening of the clinical signs.

In the veterinary medical literature, histoplasmosis-associated CSF abnormalities reported have included mixed-cell pleocytosis in 1 dog11 and a mononuclear pleocytosis in another14 that had high CSF protein concentration. Histoplasma organisms were identified within the cytoplasm of macrophages in the CSF of the dog with mixed-cell pleocytosis. Similar CSF abnormalities in humans with histoplasmosis have been reported.16 However, findings of CSF analysis that are within reference limits do not rule out histoplasmosis in humans. Analysis and cytologic examination of a sample of CSF obtained from the cat of this report revealed no abnormalities in the WBC count and protein concentration, and no organisms were detected within macrophages.

To the authors' knowledge, only 1 cat with histoplasmosis involving the CNS has been described.8 At its initial evaluation, that cat initially had nonspecific clinical signs of histoplasmosis and no neurologic abnormalities. A granuloma in the brain was discovered as an incidental finding during necropsy, and the primary lesions were present in the lungs, liver, and spleen. In 7 of 12 other cats with disseminated histoplasmosis in that same study,8 treatment was attempted; however, necropsy findings were not correlated to the cats that received treatment. Thus, it is unclear whether the cat with histoplasmosis involving the CNS received treatment with an antifungal agent. We believe that this report is the first in which a companion animal with extradural spinal histoplasmosis and neurologic clinical signs compatible with the spinal lesion has been described. Like disseminated mycoses involving other organs, definitive diagnosis of histoplasmosis involving the CNS requires identification of the organism via evaluation of tissue biopsy specimens, aspirates, or impression smears.1,2 Routine fungal isolation is not recommended because the organism is slow growing and capable of transforming from the yeast phase into the infective mycelial phase during prolonged incubation periods.7 The prognosis for cats or dogs with CNS mycotic involvement is probably guarded to fair and complicated by the difficulty in obtaining specimens of neural tissue for histologic and cytologic analyses, the findings of which may affect selection of appropriate treatment. For the cat of this report, the owners were committed to surgery and long-term medical treatment and rehabilitation, despite the guarded to poor prognosis.

Antifungal treatment for histoplasmosis in both humans and companion animals consists of amphotericin B (a lipophilic polyene) and azole derivatives (itraconazole and fluconazole). Amphotericin B is the primary choice for life-threatening meningitis in humans,17 but the parenteral route (IV or SC) of administration and expense often prohibit its use in animals. In humans, treatment with azoles is instituted for maintenance once the condition is no longer life-threatening or as the initial choice for moderate to severe Histoplasma-associated meningitis. Itraconazole or fluconazole is often the primary drug choice for animals with histoplasmosis. Of those 2 azoles, itraconazole is the drug of choice in humans and animals with extraneural histoplasmosis. Controversy exists as to whether fluconazole should be used in dogs and cats with CNS disease because of its ability to cross the blood-brain barrier and achieve higher concentrations in the CSF than itraconazole.18 However, in people with histoplasmosis involving the CNS, fluconazole administration has been associated with treatment failures and disease relapses.19–22 Moreover, fluconazole is less effective than itraconazole against Histoplasma in vitro.23 The efficacy of itraconazole in CNS infections, despite negligible CSF concentrations, may be attributable to concentrations in nervous tissues that exceed the plasma concentration; the drug has been used to successfully treat CNS histoplasmosis in humans.7,24 Because histoplasmosis involving the CNS is uncommon in people and animals, well-defined guidelines do not exist regarding antifungal agent choice or duration of treatment. For the cat of this report, itraconazole was selected because subclinical dissemination to other organs was probable and treatment failures and relapses are more commonly reported with administration of fluconazole.22

Relapses of the infection have also been associated with short durations of treatment.14 A minimum of 4 to 6 months of treatment with itraconazole is recommended for pulmonary and osseous histoplasmosis.7,25,26 Thus, a decision was made to treat the cat of this report for at least 6 months; monthly clinicopathologic analyses were to be performed to monitor the cat for increases in liver enzyme activities and changes in cell lines. It has been suggested that, on completion of all treatments, magnetic resonance imaging of the thoracolumbar region of the cat's vertebral column may be useful to determine whether gross disease is present; however, scar tissue in the T11 through L1 region as a result of surgery may make this determination difficult.

The authors believe that an important factor contributing to the positive outcome of treatment for the cat of this report was the physical rehabilitation, which commenced as passive ROM exercises on day 3 after surgery. Passive ROM was performed 3 times daily to help maintain joint health.27 Active, assisted ROM consisting of sling walks with assisted limb movement and joint ROM was performed 2 to 3 times daily once the voluntary motor function was detected in both hind limbs on day 19. This type of physical therapy has been useful in neuromuscular reeducation and improving proprioception and gait in animals with upper motor neuron deficits.28 In human medicine, electrical stimulation has been shown to improve ROM,29 increase muscle strength,30 and enhance limb function.31 Electrical stimulation to promote muscle contraction via stimulation of a motor nerve was started biweekly on day 14, consistent with current recommendations.32 Although the condition of the cat of this report improved following surgical decompression of the spinal cord and medical treatment with an antifungal agent, it is presently unknown whether the cat will have complete recovery of neurologic functions or have a relapse of the infection in the future.

ABBREVIATIONS

ROM

Range of motion

PEG

Percutaneous endoscopic gastrostomy

a.

Omnipaque (Iohexol), Amersham Health, Princeton, NJ.

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    Bamberger DM. Successful treatment of multiple cerebral histoplasmomas with itraconazole. Clin Infect Dis 1999;28:915916.

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  • 23

    Perfect JR, Savani DV, Durack DT. Comparison of itraconazole and fluconazole in the treatment of cryptococcal meningitis and Candida pyelonephritis in rabbits. Antimicrob Agents Chemother 1986;29:579583.

    • Search Google Scholar
    • Export Citation
  • 24

    Grooters AM, Taboada J. Update on antifungal therapy. Vet Clin North Am Small Anim Pract 2003;33:749758.

  • 25

    Wolf AM. Diagnosing and treating the four most common pulmonary mycoses in cats. Vet Med 1990;85:9941001.

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    Wolf AM. Successful treatment of disseminated histoplasmosis with osseous involvement in two cats. J Am Anim Hosp Assoc 1988;24:511516.

    • Search Google Scholar
    • Export Citation
  • 27

    Brody LT. Mobility impairment. In:Hall CM, Brody LT, ed.Therapeutic exercise: moving toward function. Philadelphia: The Williams & Wilkins Co, 1999;87111.

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    Millis DL, Lewelling A, Hamilton S. Range-of-motion and stretching exercises. In:Millis DA, Levine D, Taylor RA, ed.Canine rehabilitation and physical therapy. Philadelphia: WB Saunders Co, 2004;228243.

    • Search Google Scholar
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  • 29

    de Kroon JR, Ijzerman MJ, Lankhorst GJ, et al. Electrical stimulation of the upper limb in stroke: stimulation of the extensors of the hand vs. alternate stimulation of flexors and extensors. Am J Phys Med Rehabil 2004;83:592600.

    • Search Google Scholar
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  • 30

    Fitzgerald GK, Piva SR, Irrgang JJ. A modified neuromuscular electrical stimulation protocol for quadriceps strength training following anterior cruciate ligament reconstruction. J Orthop Sports Phys Ther 2003;33:492501.

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  • 31

    Popovic MB, Popovic DB, Sinkjaer T, et al. Clinical evaluation of functional electrical therapy in acute hemiplegic subjects. J Rehabil Res Dev 2003;40:443453.

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  • 32

    Steiss JE, Levine D. Physical agent modalities. Vet Clin North Am Small Anim Pract 2005;35:13171333.

  • Figure 1—

    Left lateral thoracolumbar radiographic view of a 7-year-old cat that was evaluated because of paraplegia. Notice the narrow appearance of the intervertebral disk space and intervertebral foramen (black arrows) at the level of T11-12, which is consistent with probable disk degeneration. T13 = 13th rib.

  • Figure 2—

    Lateral right dorsal–left ventral oblique radiographic view of the cat in Figure 1 after myelography. Notice the absence of the 13th rib on the left side. Thin dorsal and ventral contrast columns and ventral deviation of the dorsal contrast column consistent with an extradural compression (black arrows) can be seen primarily over the T12-13 intervertebral disk space with extension over the T11 and T13 vertebral bodies. See Figure 1 for remainder of key.

  • Figure 3—

    Photomicrograph of a section of a mass that was removed from the dorsal surface of the thoracolumbar dura mater of the cat in Figure 1. Notice the clusters of egg-shaped fungal organisms located in the cytoplasm of unstained macrophages. Gomori methenamine silver stain; bar = 10 Mm.

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    Bamberger DM. Successful treatment of multiple cerebral histoplasmomas with itraconazole. Clin Infect Dis 1999;28:915916.

  • 22

    Wheat JL, MaWhinney S, Hafner R, et al. Treatment of histoplasmosis with fluconazole in patients with acquired immunodeficiency syndrome. Am J Med 1997;103:223232.

    • Search Google Scholar
    • Export Citation
  • 23

    Perfect JR, Savani DV, Durack DT. Comparison of itraconazole and fluconazole in the treatment of cryptococcal meningitis and Candida pyelonephritis in rabbits. Antimicrob Agents Chemother 1986;29:579583.

    • Search Google Scholar
    • Export Citation
  • 24

    Grooters AM, Taboada J. Update on antifungal therapy. Vet Clin North Am Small Anim Pract 2003;33:749758.

  • 25

    Wolf AM. Diagnosing and treating the four most common pulmonary mycoses in cats. Vet Med 1990;85:9941001.

  • 26

    Wolf AM. Successful treatment of disseminated histoplasmosis with osseous involvement in two cats. J Am Anim Hosp Assoc 1988;24:511516.

    • Search Google Scholar
    • Export Citation
  • 27

    Brody LT. Mobility impairment. In:Hall CM, Brody LT, ed.Therapeutic exercise: moving toward function. Philadelphia: The Williams & Wilkins Co, 1999;87111.

    • Search Google Scholar
    • Export Citation
  • 28

    Millis DL, Lewelling A, Hamilton S. Range-of-motion and stretching exercises. In:Millis DA, Levine D, Taylor RA, ed.Canine rehabilitation and physical therapy. Philadelphia: WB Saunders Co, 2004;228243.

    • Search Google Scholar
    • Export Citation
  • 29

    de Kroon JR, Ijzerman MJ, Lankhorst GJ, et al. Electrical stimulation of the upper limb in stroke: stimulation of the extensors of the hand vs. alternate stimulation of flexors and extensors. Am J Phys Med Rehabil 2004;83:592600.

    • Search Google Scholar
    • Export Citation
  • 30

    Fitzgerald GK, Piva SR, Irrgang JJ. A modified neuromuscular electrical stimulation protocol for quadriceps strength training following anterior cruciate ligament reconstruction. J Orthop Sports Phys Ther 2003;33:492501.

    • Search Google Scholar
    • Export Citation
  • 31

    Popovic MB, Popovic DB, Sinkjaer T, et al. Clinical evaluation of functional electrical therapy in acute hemiplegic subjects. J Rehabil Res Dev 2003;40:443453.

    • Search Google Scholar
    • Export Citation
  • 32

    Steiss JE, Levine D. Physical agent modalities. Vet Clin North Am Small Anim Pract 2005;35:13171333.

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