168 ScientificReports JAVMA,Vol235,No.2,July15,2009

SM

ALL

AN

IMA

LS

A 2.5-year-old castrated male Scottish Terrier for which a presumptive diagnosis of so-called Scottie cramp

had been made when the dog was a puppy was admitted to the Veterinary Medical Center at Colorado State Uni-versity for evaluation. Clinical history included episodes of kyphosis and pelvic limb spasticity that were elicited by exercise or excitement; these episodes had occurred since the clients had acquired the dog as a puppy. Exer-cise-induced episodes occurred on walks of > 10 minutes’ duration, but sometimes after walks as short as 2 minutes’ duration. The clients had resorted to use of a pet stroller to take the dog on long walks. Typically, the dog remained in the stroller during most walks. No treatment for the dog had been recommended previously.

On physical examination, the dog’s mentation was considered normal. It weighed 12.4 kg (27.3 lb) and had a body condition score of 6 (on a scale of 1 through 9).1 There were no obvious physical abnormalities. Results of orthopedic and neurologic examinations were within reference limits. Clinicopathologic variables assessed within the last 6 months were also within reference limits. The dog’s response to exercise was evaluated. Within 15 seconds of commencement of trotting and running, stiffening of the pelvic limbs became evident and the dog began to bunny-hop. During continued ex-ercise, the dog’s posture became kyphotic and spastic-

Use of a selective serotonin reuptake inhibitor for treatment of episodes of hypertonia

and kyphosis in a young adult Scottish Terrier

Kelly M. Geiger, dvm, ma, and Lisa S. Klopp, dvm, ms, dacvim

Case Description—A2.5-year-old12.4-kg(27.3-lb)castratedmaleScottishTerrierwaseval-uatedbecauseofepisodesofhypertoniaandkyphosisforwhichapresumptivediagnosisofso-calledScottiecramphadbeenmadewhenthedogwasapuppy.Clinical Findings—Findingsofgeneralphysical,orthopedic,andneurologicexaminationswerewithinreferencelimits.Pelviclimbhypertonicityandkyphosiswithoutsignsofpainwereinducedwithminimalexercise;ambulationreturnedtonormalafteraperiodofrest.Treatment and Outcome—Fluoxetine,aselectiveserotoninreuptakeinhibitor,wasadmin-isteredorallyatadosageof1.2mg/kg(0.55mg/lb)oncedailyfor1month.Afterthisperiodoftreatment,clinicalsignsofthediseaseweregreatlyreduced;thedosageoffluoxetinewaschangedto0.8mg/kg(0.36mg/lb)twicedaily,andresponsetotreatmentcontinued.Clinical Relevance—Administrationofbenzodiazepines,vitaminE,orphenothiazineshasbeenrecommendedfortreatmentofepisodesofhypertonicity,butoftendoesnotresultincontrolofclinicalsigns.IthasbeensuggestedthatthepathogenesisofthisdiseaseisrelatedtodeficienciesinconcentrationorfunctionofserotoninintheCNS;thus,alogicalchoicefortreatmentisadministrationofaserotoninreuptakeinhibitor.Inthedogofthisreport,fluoxetineresultedingoodcontrolofclinicalsigns.Theuseofaneffectivemedica-tion(otherthanacontrolledsubstance)thatisadministeredonceortwicedaily,hasmini-maladverseeffectsonthepatient’smentalstatus,andisinexpensivemayleadtobetterownercomplianceandanimprovedqualityoflifeforaffecteddogs.(J Am Vet Med Assoc2009;235:168–171)

ity in the pelvic limbs became more marked; stiffness developed in the thoracic limbs as well. The dog had no signs of pain and was aware of its surroundings. Fol-lowing a 5-minute period of rest, the dog was able to walk more normally again. The clinical features of the dog’s condition were considered classic for Scottie cramp. Oth-er potential causes included myasthenia gravis, primary metabolic or inflammatory myopathy or neuropathy, and seizure-like disorders. Further diagnostic testing such as electromyography and nerve conduction assessments, his-tologic examination of muscle biopsy specimens, evalua-tion of anti-acetylcholinesterase receptor antibody titers, and CSF analysis were declined by the clients.

On the basis of previous research,2,3 Scottie cramp has been associated with a deficiency in serotonin con-centration in the spinal cord. Therefore, treatment with fluoxetine,a which is a selective serotonin reuptake inhibi-tor, was initiated to determine whether the drug had any effect on the frequency, duration, or severity of episodes in this dog. A standard dosage is 1 mg/kg (0.45 mg/lb) administered orally once to twice daily, up to 3 mg/kg/d (1.36 mg/lb/d).4 For this dog, a dosage of 1.2 mg/kg (0.55 mg/lb) administered orally once daily was cho-sen. The clients were asked to keep a log of activity and occurrence of episodes and to return the dog after 1 month for reassessment.

From the Veterinary Medical Center, Colorado State University, Fort Collins, CO 80523. Dr. Klopp’s present address is The Sams Clinic, 489 Miller Ave, Mill Valley, CA 94941.

Address correspondence to Dr. Klopp.

Abbreviation

5-HIAA 5-hydroxyindoleacetic acid

JAVMA,Vol235,No.2,July15,2009 ScientificReports 169

SM

ALL A

NIM

ALS

One month later, the dog was returned for prog-ress evaluation. The owners reported that the dog could now walk for almost an hour with few, if any, exercise-induced episodes. However, during the latter part of the month, the owners had observed 3 episodes each of < 10 seconds’ duration. Scottie cramp episodes no lon-ger occurred during periods of excitement. As part of the reevaluation, the dog was exercised by running in the hallway of the hospital. No evidence of cramping occurred during 5 minutes of exercise and excitement. The dosage of fluoxetine was adjusted to 0.8 mg/kg (0.36 mg/lb) administered orally twice daily, and the owners were instructed to return the dog for a follow-up examination after 1 month. At the 2-month recheck visit, it was evident that the dog continued to respond well to treatment with fluoxetine. A follow-up tele-phone conversation with the owners at 1 year revealed that the dog’s episodes continued to be well controlled.

Discussion

The term Scottie cramp refers to nonpainful disease that affects the posture and locomotion of Scottish Terri-ers and was first described in 1942.5 The classic feature of the disease involves a progression of signs with increas-ing levels of exercise or excitement. Initially, the thoracic limbs may become abducted or there may be arching or kyphosis of the lumbar portion of the vertebral column, followed by overflexion of the pelvic limbs. The neck may become extended with the nose pointing to the ground. With increasing activity, tonicity of the muscles increases; as the pelvic limbs become increasingly affect-ed, the dog develops a goose-stepping or stringhalt gait. Increasing resistance to movement may cause walking in place, somersaulting, or falling. In a severely affected dog, forward progression of movement may become lim-ited and respiratory and facial muscles may be affected; the patient may curl into a ball. After 10 minutes or less of rest, the hypertonicity usually resolves and the dog is able to ambulate more normally. This disease is not associated with a loss or change in mentation or with behavioral abnormalities.6–8 Scottie cramp does not alter life span, nor is it associated with neonatal deaths.6–9

Clinical signs associated with Scottie cramp can be de-tected as early as 6 weeks of age and as late as 18 months. Severity of clinical signs can vary considerably among affected dogs, ranging from barely noticeable effects to severe incapacitating changes. It is thought that the dif-ferences in clinical signs are related to behavioral factors, environment, nutrition, and temperament of the affected dogs. The severity of the clinical signs in subsequent epi-sodes rarely worsens. However, changes in the dog’s health and environment are believed to cause stressors that may result in onset of signs when they were not previously ap-parent.6–9 Some dogs can learn to self-modify their activ-ity, which can lead observers to believe that remission of the disease has occurred. Results of pedigree analyses and inbreeding and outcross matings have suggested that this is an inherited autosomal recessive disorder.6,9 To explain the variability in clinical signs among dogs, it has been proposed that other genes may be associated with the de-fective gene and that those other genes modify or influ-ence the clinical expression of the disease.6

Diagnosis is made primarily on the basis of signal-ment and clinical signs. Tests performed in 10 affected Scottish Terriers in the late 1960s and the early 1970s did not reveal any biochemical, hematologic, or radio-graphic abnormalities.6 In other affected dogs, gross and histologic examinations of skeletal muscles, pe-ripheral nerves, and connective tissues did not reveal lesions, and no cardiovascular, endocrine, respiratory, digestive, or CNS abnormalities were detected.2 In ad-dition, blood lactate and pyruvate concentrations in affected dogs were comparable to values in control dogs without the disease (Scottish Terriers and other breeds). Electromyographic investigations of dogs with Scottie cramp have revealed increased interference pat-terns during episodes but no abnormal spontaneous discharges at rest.8

A considerable amount of experimental work2,3,7–10 has been performed in an attempt to understand the un-derlying pathogenesis of Scottie cramp. In those studies, Scottie cramp was compared with previously reported diseases of muscle. McArdle disease11,12,b (a glycogen stor-age disease that is caused by a deficiency of the enzyme glycogen phosphorylase) was ruled out by evidence of apparently normal muscle glycogen stores and normal function of myophosphorylase in affected dogs.8 Core myopathy13 was ruled out because core structures were not detected during histologic examination of skeletal muscle specimens.8 Myotonic myopathy is character-ized by prolonged muscle contraction upon voluntary contraction or can be initiated by mechanical (percus-sion), pharmacologic, or electrical stimulation.14–17 Re-sults of electromyographic investigations have indicat-ed that abnormal relaxation is responsible for myotonic myopathy; because myotonia is maintained even after neuromuscular block with procurare18 and spinal anes-thesia,16 the abnormality appears to be at the level of the myomembrane. In attempt to determine whether the defect in Scottie cramp was at the level of the muscle, neuromuscular junction, or peripheral nerve, Meyers et al8 performed a series of tests to inhibit function of these structures in affected dogs. Affected Scottish Ter-riers were anesthetized and administered tubocurarine as a neuromuscular blocking agent, and the quadriceps femoris, biceps femoris, gastrocnemius, biceps brachii, supraspinatus, deltoideus, and pectoralis muscles were both mechanically and electrically stimulated. Poststim-ulation discharge of the muscle could not be elicited. The function of the muscles was also evaluated follow-ing epidural administration of procurare; this treatment also blocked electrical activity. From these experiments, the authors proposed that the Scottie cramp defect is not in the peripheral nervous or muscular system, but within the CNS; they postulated that the abnormality was related to abnormal physiologic functioning of a neurotransmitter.

On the basis of results of pharmacologic experi-ments, it was suggested that the disease was related to mechanisms of serotonin within the CNS. When am-phetamine or parachlorophenyalanine (a noncompeti-tive inhibitor of tryptophan hydroxylase involved in serotonin synthesis19,20) was administered to affected dogs, the severity of clinical signs increased.8 Further-more, administration of tryptophan typically amelio-

170 ScientificReports JAVMA,Vol235,No.2,July15,2009

SM

ALL

AN

IMA

LS

rated the effects of parachlorophenylalanine. Adminis-tration of nialamide, a selective monoamine oxidase in-hibitor that prevents catabolism of serotonin, prevented the onset of signs or substantially reduced the severity of an episode.8 In addition, administration of methysergide, a selective serotonin receptor blocker, increases clinical signs in a dose-dependent manner and has been used as a provocative test for purposes of diagnosis.6 Following ad-ministration of methysergide at a dose of 0.1 to 0.3 mg/kg (0.045 to 0.14 mg/lb), clinical signs can be provoked and maintained for as long as 2 hours.

Another study2 was undertaken to further define the nature of the serotonin abnormality within the CNS and other body systems. In that study, the concentra-tion of the serotonin metabolite 5-HIAA was measured in urine collected over 24-hour periods for 3 days and in a minimum of 3 CSF samples that were collected at least 1 week apart from Welsh Terriers and affected and unaffected Scottish Terriers. No significant differ-ences in 5-HIAA concentrations in urine and CSF were identified among groups. Concentrations of serotonin were also measured in whole blood samples and mul-tiple areas of the brain and the lumbar portion of the spinal cord from affected and unaffected Scottish Ter-riers, and there were no significant differences between those groups. Probenecid blocks the amino acid trans-port mechanism that removes 5-HIAA from the brain and allows 5-HIAA accumulation in the cisternal pool of CSF21 and in brain tissues.22 When pobenecid was administered to the Welsh terriers and the affected and unaffected Scottish Terriers, the overall turnover rate was not significantly different among groups.2 From these findings, it was proposed that the biochemical defect was unlikely directly related to serotonin con-centrations. Later, studies3,6 revealed that the turnover of serotonin in the CNS of affected dogs is decreased following an episode of Scottie cramp, which suggests that neuronal function is normal at rest but there may be a functional deficiency during periods when clinical signs are apparent.

Recommended treatment options for Scottie cramp have included drugs that act on the CNS to facilitate muscle relaxation. Chlorpromazine was evaluated ini-tially because of its ability to antagonize the effects of amphetamine,23–25 which was shown to promote episodes of Scottie cramp.2,7 Following IM injection of chlorpromazine, clinical signs of Scottie cramp resolved within 15 minutes in 5 affected dogs.7 Acepromazine maleate (0.1 to 0.75 mg/kg [0.045 to 0.34 mg/lb], IM) has been used to treat dogs in clinical settings. Treat-ment with IM injection of diazepam during an acute episode of Scottie cramp results in reduction of clini-cal signs. Chronic usage of oral diazepam has been used to reduce the severity and number of episodes.6 Both of these treatments present a challenge to practi-cal management of affected dogs by clients. For a dog that has an episode of Scottie cramp once daily or more frequently, treatment via injection would likely not be tolerated for long by the patient, assuming that the cli-ent was able and willing to perform the injections. Also, acepromazine can cause profound sedation, an unde-sired effect. Although diazepam can also cause mild sedation, its status as a controlled substance also com-

plicates its use, especially when required on a lifelong basis. Diazepam has a short duration of action, which necessitates administration 3 times daily, and recommend-ed dosages of diazepam are fairly high (0.5 to 1.5 mg/kg [0.23 to 0.68 mg/lb], PO, q 8 h). These facts, coupled with the cost, potentially decrease the likelihood of compli-ance by owners to medicate their pets. It has also been suggested that vitamin E administered orally at doses > 125 U/kg/d (56.8 U/lb/d) may be effective in reducing the likelihood of episode occurrence but not the sever-ity of an episode. 6

An ideal treatment for Scottie cramp would be an effective medication (other than a controlled sub-stance) that is administered orally no more than twice daily, that has minimal adverse effects, and that is in-expensive. The selective serotonin reuptake inhibitor fluoxetine is generally used for behavior modification in animals. It has a wide safety margin and minimal adverse effects. Because fluoxetine is now available as various generic products, it can also be obtained inex-pensively from pharmacies. Once ingested, fluoxetine is detectable in the CNS within 1 hour.1 The half-life of the drug is approximately 2 to 3 days, allowing for a once- or twice-daily adminsitration.4 Selective sero-tonin reuptake inhibitors prevent uptake of serotonin by presynaptic neurons; thus, the extracellular concen-tration of serotonin increases for use by postsynaptic neurons. Given that the pathogenesis of this disease ap-pears to be related to deficiencies in concentration or function of serotonin in the CNS and that clinical im-provement is associated with experimentally induced increases in serotonin concentration, it seems likely that maintenance of higher serotonin concentrations would decrease the severity and frequency of the epi-sodes of Scottie cramp, thereby allowing affected dogs to have more normal lives.

In the dog of this report, the dosage of fluoxetine administered was within the recommended range. The dog’s clinical signs were greatly reduced, and it was able to lead a more normal life, including accompanying its owners on walks for longer than a few minutes. Treat-ment with fluoxetine is inexpensive and appears to be effective and associated with few adverse effects when administered once or twice daily, compared with sever-al other treatment options. On the basis of the apparent success of fluoxetine treatment in the dog of this report, the use of and response to this medication in dogs with Scottie cramp warrant further investigation.

a. Fluoxetine, PAR Pharmaceutical Co Inc, Spring Valley, NY.b. Mommaerts WF, Allingworth HM, Pearson CM, et al. A func-

tional disorder of muscle associated with the absence of phos-phorylase (abstr). Proc Natl Acad Sci U S A 1959;45:791.

References1. Purina. Understanding Your Dog’s Body Condition. www.purina.

com/dogs/health/bodycondition.aspx. Accessed Mar 23, 2008.2. Meyers KM, Schaub RG. The relationship of serotonin to a motor

disorder of Scottish terrier dogs. Life Sci 1974;14:1895–1906.3. Peters RI Jr, Meyers KM. Precursor regulation of serotonergic neuro-

nal function in Scottish Terrier dogs. J Neurochem 1977;29:753–755.4. Plumb DC. Fluoxetine. In: Veterinary drug handbook. 6th ed.

Ames, Iowa: Blackwell Publishing, 2008;404–405.5. Klavenbeck AS. Een aavalsgewijs optrendende stoornes in de

JAVMA,Vol235,No.2,July15,2009 ScientificReports 171

SM

ALL A

NIM

ALS

regulatie van de spiertonus: Waargenomen bij Schotsche terri-ers. Tijdschr Diergeneeskd 1942;69:14–21.

6. Clemmons RM, Peters RI, Meyers KM. Scotty cramp: a review of cause, characteristics, diagnosis, and treatment. Compend Con-tin Educ Pract Vet 1980;2:385–388.

7. Meyers KM, Lund JE, Padgett G, et al. Hyperkinetic episodes in Scottish Terrier dogs. J Am Vet Med Assoc 1969;155:129–133.

8. Meyers KM, Dickson WM, Lund JE, et al. Muscular hypertonicity. Episodes in Scottish terrier dogs. Arch Neurol 1971;25:61–68.

9. Meyers KM, Padgett GA, Dickson WM. The genetic basis of a ki-netic disorder of Scottish terrier dogs. J Hered 1970;61:189–192.

10. Peters RI, Meyers KM. Serotonergic-catecholaminergic antago-nism and locomotor control. Exp Neurol 1980;69:22–29.

11. McArdle B. Myopathy due to a defect in muscle glycogen break-down. Clin Sci 1951;10:13–33.

12. Schmid R, Mahler R. Chronic progressive myopathy with myo-globinuria: demonstration of a glycogenolytic defect in the mus-cle. J Clin Invest 1959;38:2044–2058.

13. Bethlem J, van Gool J, Hülsmann WC, et al. Familial non-progres-sive myopathy with muscle cramps after exercise. A new disease as-sociated with cores in the muscle fibres. Brain 1966;89:569–588.

14. Brown GL, Harvey AM. Congenital myotonia in the goat. Brain 1941;62:1–18.

15. Denny-Brown D, Nevin S. The phenomenon of myotonia. Brain 1941;64:1–18.

16. Kennedy F, Wolfe A. Experiments with quinine and prostigmine

in the treatment of myotonia and myasthenia. Arch Neurol Psy-chiatry 1937;37:68–74.

17. Landau WM. The essential mechanism in myotonia; an electro-myographic study. Neurology 1952;2:369–388.

18. Buchthal F, Clemmesen S. Electromyographical observations in congenital myotonia. Acad Psychiatry 1941;16:389–403.

19. Koe BK, Weissman A. p-Chlorophenylalanine: a specific depletor of brain serotonin. J Pharmacol Exp Ther 1966;154:499–516.

20. Jéquier E, Lovenberg W, Sjoerdsma A. Tryptophan hydroxylase inhibition: the mechanism by which p-chlorophenylalanine de-pletes rat brain serotonin. Mol Pharmacol 1967;3:274–278.

21. Guldberg HC, Ashcroft GW, Crawford TB. Concentrations of 5-hydroxyindolylacetic acid and homovanillic acid in the ce-rebrospinal fluid of the dog before and during treatment with probenecid. Life Sci 1966;5:1571–1575.

22. Neff NH, Spano PF, Groppetti A, et al. A simple procedure for calculating the synthesis rate of norepinephrine, dopamine and serotonin in rat brain. J Pharmacol Exp Ther 1971;176:701–710.

23. Henatsch HD, Ingvar DH. Chlorpromazine and spasticity; an ex-perimental electrophysiological study [in German]. Arch Psychiatr Nervenkr Z Gesamte Neurol Psychiatr (Bucur) 1956;195:77–93.

24. Hudson RD, Domino EF. Comparative effects of three substituted phenothiazines on the patellar reflex and mean arterial blood pres-sure of the rabbit. Arch Int Pharmacodyn Ther 1964;147:36–42.

25. Lasagna L, McCann WP. Effect of tranquilizing drugs on amphet-amine toxicity in aggregated mice. Science 1957;125:1241–1242.

Selected abstract for JAVMA readers from the American Journal of Veterinary Research

Comparison of tepoxalin, carprofen, and meloxicam for reducing intraocular inflammation in dogsMargi A. Gilmour and Terry W. Lehenbauer

Objective—To compare effects of orally administered tepoxalin, carprofen, and meloxicam for con-trolling aqueocentesis-induced anterior uveitis in dogs, as determined by measurement of aqueous prostaglandin E

2 (PGE

2) concentrations.

Animals—38 mixed-breed dogs.Procedures—Dogs were allotted to a control group and 3 treatment groups. Dogs in the control group received no medication. Dogs in each of the treatment groups received an NSAID (tepoxalin, 10 mg/kg, PO, q 24 h; carprofen, 2.2 mg/kg, PO, q 12 h; or meloxicam, 0.2 mg/kg, PO, q 24 h) on days 0 and 1. On day 1, dogs were anesthetized and an initial aqueocentesis was performed on both eyes; 1 hour later, a second aqueocentesis was performed. Aqueous samples were frozen at –80oC until assayed for PGE

2 concentrations via an enzyme immunoassay kit.

Results—Significant differences between aqueous PGE2 concentrations in the first and second

samples from the control group indicated that aqueocentesis induced uveitis. Median change in PGE2 concentrations for the tepoxalin group (10 dogs [16 eyes]) was significantly lower than the me-dian change for the control group (8 dogs [16 eyes]), carprofen group (9 dogs [16 eyes]), or meloxicam group (9 dogs [16 eyes]). Median changes in PGE

2 concentrations for dogs treated with meloxicam or

carprofen were lower but not significantly different from changes for control dogs.Conclusions and Clinical Relevance—Tepoxalin was more effective than carprofen or meloxicam for controlling the production of PGE

2 in dogs with experimentally induced uveitis. Tepoxalin may be an

appropriate choice when treating dogs with anterior uveitis. (Am J Vet Res 2009;70:902–907).

See the midmonth issues

of JAVMA

for the expanded

table of contents

for the AJVR

or log on to

avmajournals.avma.org

for access

to all the abstracts.

July 2009