11/27/2017

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Re-thinking PPID

Advances in Diagnostics and

Disease Recognition

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Craig F. Shoemaker DVM, MS

Professional Service

Boehringer-Ingelheim Vetmedica Inc.

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Disclosures

Employed by Boehringer Ingelheim Animal Health

Overview

• Overview of PPID

• Clinical signs

• Diagnostic

– EEG Updates

• I.D. PPID

• Treatment/Management

• Additional considerations

• Take homes

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Terminology

• PPID is the most common endocrine disorder in horses

• Equine Cushing's Disease should now be identified as:

• Pituitary Pars Intermedia Dysfunction (PPID)

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Cushing’s Disease in Dogs/Man

• PU/PD

• Polyphagia

• Abdominal enlargement

• Lethargy

• Alopecia, pruritis

• Thin skin, pyoderma

• Panting

• Infertility

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Anatomy of the Equine Pituitary Gland

Three regions:

Pars distalis

Pars intermedia

Pars nervosa

Dopamine

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Pathophysiology of PPID

• Dopamine interacts with D2 receptors in PI melanotrophs and inhibits activity

• Dopaminergic neurons undergo oxidative damage with aging

• Accelerated process in some horses

• As dopaminergic neurons are lost, melanotrophs are less inhibited

• Hyperplasia develops and melanotrophs secrete more hormones

• Permissive environment for neoplasia; functional pituitary adenomas develop

(McFarlane et al., J Neuroendocrinol 2005)

(Courtesy of Dianne McFarlane)

Pathophysiology

of PPID

(McFarlane D, et al. Nitration and increased alpha-synuclein expression associated with dopaminergic

neurodegeneration in equine pituitary pars intermedia dysfunction. J Neuroendocrinol 17:73-80, 2005.)

• In part, a consequence of oxidative damage

• Accumulation of misfolded α-synuclein in dopaminergic nerve terminals, similar to patients with Parkinson’s disease

• Both diseases are slowly progressive

• But why don’t PPID horses shake?

PPID and Parkinson's:

Loss of Dopaminergic Neurons

Risk Factors: Who Gets PPID?

• Risk Factors: Age, Breed

– Ponies are more susceptible

• Morgan horses

• Paso Fino

• Arabian

• Quarter horses

• Saddlebreds

• Warmbloods

• TWH

• 15-30% horses/ponies > 15 years of age

Rohrbach, Andrews F. Sommerdahl C. et al. J Vet Intern Med 2012

Frank N, Geor R. Bailey S. Durham A. and Johnson P, J Vet Intern Med 2006

What about horses younger than 15yr?

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Risk Factors

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Equine Metabolic Syndrome (EMS)

• Genetic predisposition to obesity

• Accompanied by insulin dysregulation (ID)

• Increased laminitis risk

– Accelerated degeneration of dopaminergic neurons

– Transitional period between diseases

– PPID developing in younger horses

– PPID exacerbates ID

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PPID Clinical Signs: Early vs.Late

Early

• Decreased athletic performance

• Change in attitude/lethargy

• Regional hypertrichosis

• Delayed haircoat shedding

• Skeletal muscle atrophy

• Typically beginning along the topline

• Regional Adiposity

• Laminitis

Advanced • Lethargy

• Generalized hypertrichosis

• Loss of seasonal haircoat shedding

• Skeletal muscle atrophy

• Rounded abdomen

• Abnormal sweating (increased or decreased)

• Polyuria/polydipsia

• Recurrent infections

• Regional adiposity

• Absent reproductive cycle / infertility

• Laminitis

• Seizure like activity/blindness

• Parasitism

• Tendon laxity/desmitis

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Clinical Signs:

Change in Body Conformation/Condition

• Too FAT in some places

• Cresty neck

• Fat pads at tail head

• Bulging supraorbital fat

“Regional Adiposity”

• Too THIN in others

• Loss of topline muscle mass

• Swayed back

• Ribs visible

• Advanced: Rounded abdomen (pot-bellied)

"He's just getting old" 14

Early Signs

• Change in attitude:

• Little more lethargic

• Is he really that old?

• Delayed shedding of winter hairs

• Compare to other horses in the barn

• Discolored hairs

• Slow gradual loss of muscle mass

• Over the topline

• Unexplained Laminitis

(unconfirmed cause)

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Abnormal Shedding

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Abnormal Shedding

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Abnormal Shedding

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Laminitis

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Chronic laminitis:

• ~60-65% of PPID horses suffer from laminitis

• Insidious episodes that escape owner detection.

• Radiographic prevalence (43%) > clinical

evidence (12%) (Schott, 2011)

• Insulin status

• Main cause of euthanasia

Clinical Signs: Laminitis and PPID

Polyuria/Polydipsia

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• May go unrecognized

• Freq. filling of water buckets

• Stall wetter than before/smells bad

• Hovering over water source

• Measure intake; provide additional

water sources

Increased Susceptibility to Infection

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• Decreased WBC function – Immunosuppression

• Solar abscesses; systemic (liver, tongue)

• White line disease

• Dental disease – Sinusitis/tooth root abscesses

• Respiratory

• Skin

• Parasitism – Higher FEC’s

• Other infectious diseases?

Other symptoms

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• Infertility/inappropriate lactation

• Abnormal sweating or inability to sweat

• Delayed wound healing

• Osteoporosis

• Recurrent tendon/ligament injury

Clinical Signs Associated with

PPID In The Equine Athlete

Kirchherr KF, Baus MR, Kremburg JR, Grubbs ST, Neal DL, and

Keefe TR

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Many of the same clinical signs identified in early or advanced PPID may be

recognized in the sport horse

Including tendon or suspensory ligament degeneration

Suspensory ligament injuries

Considered a common cause of lameness in the equine athlete

A recent histopathological study concluded that an association exists between

PPID and suspensory ligament (SL) degeneration

Introduction PPID – Diagnostic challenges in the sport horse

Study Objective

The objective of this study was to identify the most common

clinical signs associated with PPID in the sport horse

Material and Methods (Study Design)

Sport horses >10 years of age, any breed, and sex were eligible for study

enrollment

Must be exhibiting one or more of the early or advanced clinical signs of PPID

Including suspensory ligament desmitis

Forty-nine horses were enrolled

Demographic data, signalment, and a physical examination was conducted

Each horse was tested for PPID using the TRH stimulation test

Measuring ACTH at 0 (T0ACTH) and 10 (T10ACTH) minutes

Insulin and glucose levels were also determined

Normal horses were excluded from the study

Blood samples were shipped overnight to:

The Animal Health Diagnostic Center, Cornell University, Ithaca, NY for analysis

39% Positive

Percent PPID+ Horses

Results

*32% PPID+ were HI+ 7% PPID- were HI+ *(p = 0.022)

Percent HI+ Stratified By PPID Status

Results Results The most common clinical signs observed in the PPID+ horses were:

Delayed regional shedding

Loss of epaxial muscle mass

Regional adiposity

Skeletal muscle atrophy

Suspensory desmitis

PPID+ was significantly (P= 0.023) associated with lameness

(suspensory desmitis, tendon laxity, superficial digital flexor tendonitis)

Of the horses that were lame, 70% were PPID+

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Diagnostics

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• Nicholas Frank, DVM, PhD, DACVIM

• 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, DACVIM

• Hal Schott, DVM, PhD, DACVIM

http://sites.tufts.edu/equineendogroup/

TRH Stimulation

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TRH Stimulation

Interpretation of Results

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Thyrotropin Releasing Hormone (TRH)

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Sources:

• Reagent grade from Sigma; expensive

• Protirelin- Compounded from Wedgewood

– Validated by EEG

– 1mg/ml

– 1ml vial $45.00

– 5ml vial $60.00

– Can be frozen

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Resting ACTH

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Seasonal Rise in ACTH (Copas, Durham, 2012)

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Sensitivity and Specificity Resting ACTH

Sensitivity: 70–80%

Specificity: 80%

39 Beech et al. 2007; 2011;

Durham et. al. PPID diagnosis. Equine vet. Educ. (2014) 26 (4) 216-223

McGowan et al. 2013

Advanced Cases

(November through June)

Early Cases

(November through June)

Sensitivity: at best shown to be 50%

Specificity: unsure, less than 80%

During Fall Time-period

(August through October)

Sensitivity 100%

Specificity 95%

ACTH Stability Post Collection

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ACTH Stability

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• Whole blood and plasma evaluated at 4°, 20° -21° and -

80°C for 30 days.

• Time affected ACTH levels with storage beyond 48hrs.

@ 4° and 21°

• Freezing good for 30 days

• Allows practitioners to reasonably store samples without

centrifugation for up to 24hrs.

Insulin Assessment

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Must know insulin status to manage

PPID appropriately

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Fasting Insulin

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Insulin Assessment

Oral Sugar Test

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ID PPID

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Purpose: To gather clinical information that includes signalment, clinical signs, resting ACTH, fasting insulin, and fasting glucose results obtained at diagnosis from horses within the US that have at least one clinical sign associated with PPID.

ACTH TESTING OVERALL RESULTS

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526

217

0

100

200

300

400

500

600

# o

f H

ors

es

Samples Submitted

PPID Positive

41% Positive

PPID Master_537 n= 537

Percent PPID+ Horses

Age Groups of Horses Enrolled n=526

48

33

103

158

137

69

26

0

20

40

60

80

100

120

140

160

180

Under 10 10--15 15--20 20--25 25--30 30 and older

# o

f H

ors

es

*2 horses with unknown age

PPID by age table n= 526

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PPID+ Horses

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4

21

52

70

51

19

33

103

158

137

69

26

0

20

40

60

80

100

120

140

160

180

under 10 10--15 15-20 20-25 25-30 30 andolder

# o

f H

ors

es

PPID positive

Total

12%

20%

33%

51%

74%

73%

PPID by age table n= 526

PPID+ Horses By Age

Clinical Signs Present At Initial Diagnosis

50

294

267

181 181 170 161 161

51 50 44 42 38

0

50

100

150

200

250

300

350

Delayedshedding

Cresty neck Decreasedathletic

behavior

Laminitis Loss ofmuscle mass

Weight loss Potbelly/weight

gain

Excessiveurination

Excessivethirst

Abnormalsweating

Recurrentinfections

Other

# o

f H

ors

es

*Categories are NOT Mutually Exclusive

and are Independent of ACTH test results

Clinical Signs Table n= 537 11 horses had missing ACTH value

Results

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Five-hundred fifteen horses in final data

66 breeds/cross-breeds represented

222 (43%) were PPID+

203 (39.4%) were HI+*

Further stratified into1 of 4 groups

(PPID+/HI-)

(PPID+/HI+)

(PPID-/HI+)

(PPID-/HI-)

*IR = Insulin resistant

Results

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Of the 515 horses:

115 (22.3%) were PPID+/HI-

97 (18.8%) were PPID+/HI+

106 (20.6%) were PPID-/HI+

197 (38.3%) were (PPID-/HI-)

318 (61.7%) horses diagnosed with endocrine disease

Treatment

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• Prascend® gold standard of care

• Only FDA licensed product

– Dopamine agonist

– Safety and efficacy studies

– Product support

– 1mg 60 and 160 tablet blister packs

– Easily administered

– Demonstrated STABILITY!

– Improves quality of life

Pergolide Cloud/Veil

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• Horses occasionally appear depressed when treatment

initiated; may show inappetance

• Practical approach:

– Stop treatment for 2 days

– Start treatment at .5mg/day

– Gradually return to full treatment dose

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Treatment and monitoring

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• Perform baseline diagnostics (ACTH or TRH stim.)

• (Initiate Prascend® tx. (.5mg 250 kg pony/1.0mg 500kg)

• Retest with same test in 30 days

– May take 2 months to assess clinical signs

• Initial response (first 30 days)

– Incr. activity, improved attitude, PU/PD, hyperglycemia

• Long term response (1-12 months)

– Imprv. hair coat, incr. skeletal mm. mass, fewer infections

and episodes of laminitis

Uncle Sam- 6 mo. treatment

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Brown- 6 mo. treatment

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Phantom- 6 mo. treatment

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Other Considerations

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• Switching from compounded pergolide

– Current status of horse

– If well controlled consider lower Prascend® dose (50% reduction)

– Retest after 30 days

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Other Considerations

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• Removing horses from pergolide

– Missing doses due to exhibition/competition

• ACTH may begin to rise in 48 hours

– 3/6 50% rise by day 2

– 6/6 by day 10

• Risk of worsening clinical signs is low

• USEF considering exemption rule

Other Considerations

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• Diet and Exercise

– Feed selection based on body score and oral sugar

test

– Normal insulin; normal diet and pasture

– Obese (>7/9) lower energy diet/exercise

– Insulin dysregulation; lower NSC and limit pasture

– Dietary supplements?

Other Considerations

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• Wellness care

– Should include dentistry and parasite control

– Foot care

– Inadequate control predisposes to infections

– Attention to body condition

– Diet; insulin dysregulation

Summary

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• Treatment of PPID is truly individualized

medicine

• Test any time of year using resting ACTH • Dynamic test with seasonal reference ranges

• TRH stimulation mid Nov. to mid July • Early cases or where lab work does not “fit”

• No seasonally adjusted reference ranges

• Insulin/glucose status must be known

Manage the “whole horse” not just endocrine test results

Questions?

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