Diagnosis and Treatment

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1 Diagnosis and Treatment of Pituitary Pars Intermedia Dysfunction (PPID) Prepared by the PPID Working Group: Nicholas Frank, DVM, PhD, DACVIM (Group Coordinator) Frank Andrews, DVM, MS, DACVIM Ben Buchanan, DVM, DACVIM, DACVECC Andy Durham, BSc, BVSc, CertEP, DECEIM, MRCVS Janice Kritchevsky, VMD, MS, DACVIM Dianne McFarlane, DVM, PhD Hal Schott, DVM, PhD, DACVIM September 2011

2 Table 1 Clinical presentation of PPID Early Advanced Decreased athletic performance Change in attitude/lethargy Delayed hair coat shedding Regional hypertrichosis Change in body conformation Regional adiposity Laminitis Lethargy Generalized hypertrichosis Loss of seasonal hair coat shedding Skeletal muscle atrophy Rounded abdomen Abnormal sweating (increased or decreased) Polyuria/polydipsia Recurrent infections (eg, sole abscesses) Regional adiposity Absent reproductive cycle/infertility Laminitis Hyperglycemia Neurologic deficit/blindness

3 Table 2 Resting adrenocorticotropin hormone (ACTH) concentration test Procedure Plastic tubes containing ethylenediaminetetraacetic acid (EDTA; purple top) recommended Collect at any time of the day Some clinicians collect 2 samples 15 min apart and submit both or pool equal amounts of plasma Keep samples cool (ice packs or refrigerator) at all times Centrifuge within 8 h Ship via overnight mail with ice packs Preservatives (eg, aprotinin) or freezing are not required Samples can be frozen Assays used Chemiluminescent assay Reference intervals provided below are for this assay Radioimmunoassay Lower values are often obtained with these assays Use reference intervals provided by the testing laboratory Interpretation of results* Use reference intervals provided by the laboratory November to July 29 pg/ml Negative 35 pg/ml Above reference interval August to October 47 pg/ml Above reference interval Negative * Note that resting ACTH concentrations are variable, so another sample should be submitted or an evocative test performed if the result falls close to the upper limit of reference interval (ie, equivocal). Liphook Equine Hospital ( Cornell University Animal Health Diagnostic Laboratory (

4 Table 3 Overnight DST Procedure A single cortisol measurement is adequate Veterinarian administers 0.04 mg/kg dexamethasone (20 mg for 500-kg horse) via intramuscular injection at approximately 5 PM Blood is collected into a tube without anticoagulant at noon (19 h) the next day Some clinicians prefer to measure cortisol concentrations at 0 h (pre-injection) and 19 h, although a single cortisol measurement at 19 h is adequate in most cases Allow blood to clot and then keep samples cool (ice packs or refrigerator) Centrifuge any time during work day Ship via overnight mail with ice packs Samples can be frozen Assays used Multiple assays available Most diagnostic laboratories currently use the cortisol radioimmunoassay Interpretation of results November to July <10 ng/ml (1.0 µg/dl; 27 nmol/l) Negative >10 ng/ml August to October <10 ng/ml Negative >10 ng/ml or false positive (cannot be interpreted)

5 Table 4 Thyrotropin-releasing hormone (TRH) stimulation test Procedure Veterinarian administers 1.0 mg (total dose) TRH intravenously Blood samples are collected in tubes containing EDTA at 0 min and 30 min relative to TRH administration Submit plasma for measurement of ACTH Assays used Chemiluminescent assay Reference intervals listed below were established with this assay Interpretation of results November to July <35 pg/ml* Negative >35 pg/ml at 0 min or 30 min August to October Reference values not available at this time * Cornell University Animal Health Diagnostic Laboratory (

6 Table 5 Diagnostic Testing for PPID Supportive Findings Relative neutrophilia and lymphopenia Hyperglycemia Hyperinsulinemia* Hypertriglyceridemia Tier 1 Resting ACTH concentration(s) Overnight DST Tier 2 TRH stimulation test with ACTH measured Other available tests with lower recommendation Oral domperidone challenge test Combined dexamethasone suppression/trh stimulation test with cortisol measured Magnetic resonance imaging (MRI) specific for pars intermedia enlargement Other potential tests that are not commercially available a-melanocyte-stimulating hormone concentrations Bioactive ACTH concentrations Pro-opiomelanocortin (POMC) concentrations b-endorphin concentrations Corticotropin-like intermediate peptide (CLIP) concentrations Not indicated for PPID diagnosis ACTH stimulation test Not useful Resting cortisol concentration Diurnal cortisol rhythm TRH stimulation test with cortisol measured (without DST) Urinary cortisol concentration Salivary cortisol concentration * Collect blood under short-term (6 8 h) fasting conditions. Measure insulin in the baseline (time = 0) blood sample when performing a DST because insulin concentrations may increase after dexamethasone administration.

7 Table 6 Treatment of PPID and monitoring Initial treatment plan Pergolide is administered at an initial dosage of 2 µg/kg (0.5 mg for a 250-kg pony; 1.0 mg for a 500-kg horse) every 24 h orally. Recheck after 30 days Initial response (first 30 days) Improved attitude Increased activity Improvement in polyuria/polydipsia Control of hyperglycemia Long-term response (1 12 months) Improvement in hair coat abnormalities Increased skeletal muscle mass Less pronounced rounding of the abdomen Fewer/milder episodes of laminitis Infections are less likely to develop Timeline Recheck plasma ACTH concentrations (2 samples collected 15 min apart preferred) and/or the overnight DST after 30 days* A period of 2 months is required before conclusions should be drawn about changes in clinical signs Treatment strategies Adequate laboratory response If test results are negative at the 30-day recheck, the dosage is held constant and the patient is placed on an every 6-month recheck schedule, with 1 appointment occurring in the August October season. This allows assessment of the patient during the seasonal increase in ACTH concentrations and ensures that treatment is adequate during this period. Inadequate laboratory response with good clinical response If test results remain positive at 30 days, yet the patient is responding well clinically, the dosage can be held at the same level or increased, according to the veterinarian s preference Inadequate laboratory response with poor clinical response If test results remain positive at 30 days and the patient is not responding well clinically, increase the dosage by 1 2 µg/kg/day ( mg/day for a 500-kg horse) and recheck after 30 days Maximum dosages The maximum dosage for pergolide is 10 µg/kg (5 mg for a 500-kg horse) daily. Cyproheptadine can be administered in combination (0.25 mg/kg orally every 12 h or 0.5 mg/kg every 24 h) with pergolide once the maximum dosage has been attained * Plasma ACTH concentrations can be rechecked as early as 7 days after initiating treatment.

8 Figure 1 Diagnosis and treatment reference chart Horse with history and clinical signs consistent with PPID Tier 1: Resting ACTH* Single sample or 2 samples taken 15 min apart and combined Tier 1: Overnight DST* 2 samples (0 h and 19 h) or 1 sample at 19 h Use seasonally adjusted reference intervals Negative Negative >10ng/mL (1.0 µg/dl) at 19 h Initiate treatment Horse is not affected by PPID Diagnostic testing complete November to July Initiate treatment August to October Cannot be interpreted Option 1: Perform another Tier 1 test Resting ACTH concentration Overnight DST Option 2: Perform Tier 2 test TRH stimulation test with ACTH measured* Negative Initiate treatment * See Tables 1 4 inside. If clinical signs persist or progress, retest 6 to 12 months later or perform a Tier 2 test. PPID Working Group sponsored by: 2011 Boehringer Ingelheim Vetmedica, Inc. BI

11/27/2017. Re-thinking PPID Advances in Diagnostics and Disease Recognition. Overview. Disclosures. Employed by Boehringer Ingelheim Animal Health

11/27/2017. Re-thinking PPID Advances in Diagnostics and Disease Recognition. Overview. Disclosures. Employed by Boehringer Ingelheim Animal Health Re-thinking PPID Advances in Diagnostics and Disease Recognition Craig F. Shoemaker DVM, MS Professional Service Boehringer-Ingelheim Vetmedica Inc. 2 Disclosures Overview Overview of PPID Clinical signs