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An excellent website to learn more about Cavaliers with episodic falling syndrome is
Cavalier Episodic Falling

YouTube videos of EFS

Episodic falling in the Cavalier King Charles spaniel. Herrtage ME, Palmer AC. Veterinary Record 1983;112:458-459. Quote: Sudden collapse has been known to occur in this breed for at least 20 years. This report is based on 9 clinical cases and reports from several breeders and veterinary surgeons. Relief obtained by administering the neuroleptic diazepam was only temporary. The clinical signs were similar to those of "Scottie cramp". There was not yet any definite evidence of a genetic trait.

Muscle hypertonicity in the cavalier King Charles spaniel - myopathic features. Wright JA, Brownlie SE, Smyth JBA et al. Veterinary Record 1986;118:511-512.

A myopathy associated with muscle hypertonicity in the Cavalier King Charles Spaniel. Wright JA, Smyth JBA, Brownlie S, Robins M. J Com Path 1987;97:559-565. Quote: "Clinical signs of electrically silent muscle hypertonicity are described in five Cavalier King Charles dogs. Biopsies of the biceps femoris and triceps muscles, when examined with the electron miscroscope, revealed evidence of sarcotubular and mitochondrial abnormalities. These included enlargement of the sarcoplasmic reticulum, hydropic degeneration of mitochondria, tubular proliferations in the vicinity of the triads and vacuolar invagination of mitochondria. The exact nature of these findings is not clear and it is suggested that utilization of tracer techniques would help to explain them."

Low cerebrospianl fluid concentration of free gamma-aminobutyric acid in startle disease. Dubowitz LM, Bouza H, Hird MF, Jackson J. Lancet 1992;340:80-81.

Mutations in the alpha 1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia. Shiang R, Ryan S, Ya-Zhen Z et al. Nature Genetics 1993;5:351-358.

Update on Mitral Valve Disease.  Jens Häggström and Clarence Kvart.  Proc. 15th ACVIM Forum; 1997. Quote: "An interesting observation that may be of comparative interest is that Cavalier King Charles Spaniels have been shown to have a high prevalence (30%) of thrombocytopenia and macrothrombocytosis. Humans with MVP [mitral valve prolapse] tend to have shortened platelet survival times and thromboembolic episodes primarily in the retinal and cerebral circulation.  Thromboembolic events in the retinal ore cerebral circulation may be involved in the disturbances described in the breed as 'episodic falling' and 'fly catching'."

Control of Canine Genetic Diseases. Padgett, G.A., Howell Book House1998, pp. 198-199, 234.

Hypertonicity in Cavalier King Charles Spaniels. Shelton GD, Comparative Neuromuscular Lab, June 2001. Quote: "A syndrome of exercise-induced muscle hypertonicity was described several years ago in young Cavalier King Charles Spaniels (CKCS) from the UK. The history of exercise and excitement-induced 'collapse' was preceded by a 'deer-stalking' action with the head held close to the ground and the bottom high in the air. An increasingly stilted gait was observed until there was finally collapse to one side. An increase in extensor tone of the muscles of all four limbs was evident during the period of collapse. The time period required for recovery of limb function was usually about ten minutes. Mentation was not abnormal throughout the episodes. Electromyographic evaluation showed the muscles were electrically silent. While muscle biopsy specimens were not abnormal at the light microscopic level, rather non-specific ultrastructural abnormalities were observed. A similar syndrome has recently been identified in five CKCS dogs from the USA (three males, two females). Two of the dogs were from Ohio and one each were from Louisiana, Florida, and Illinois (See video clip). Age at clinical presentation ranged from two-seven months. These dogs showed very similar clinical presentations to the dogs originally described from the UK. Where evaluated, neither electrophyiological or histological abnormalities were identified. ... Clonazepam has been used in two affected CKCS dogs with reports of approximately 70-80% improvement suggesting a problem with GABA neurotransmission. Investigators at the Comparative Neuromuscular Laboratory at the University of California, San Diego are interested in being notified of any other possibly affected dogs."

Muscular dystrophies and other inherited myopathies. Shelton GD, Engvall E,Vet Clin North Am Small Anim Pract 2002; 32:103-124.

Hypertonicity in Cavalier King Charles Spaniels. Garosi LS, Platt SR, Shelton GD.  J Vet Intern Med 2002; 16:330.  Quote: "A syndrome of exercise-induced muscle hypertonicity was described several years ago in young Cavalier King Charles Spaniels (CKCS) of common ancestry from the United Kingdom. Recently, 3 CKCS with very similar clinical presentations were evaluated in the UK and 4 dogs were identified in the USA. Age at presentation ranged from 4 to 7 months and both males and females were affected. A typical history included exercise and excitement-induced 'collapse' which was preceded by a 'deer-stalking' action with the head held close to the ground and the bottom high in the air. An increase in extensor tone of the muscles of all four limbs was evident prior to falling over and during the period of collapse. Mentation was not abnormal throughout the episodes. Hereditary hyperekplexia (also called startle disease), a syndrome described in humans, has a similar clinical presentation in which hypertonia may be elicited by unexpected auditory, visual, or sensory stimuli. Similar to the falling over that occurs in the CKCS, these attacks in humans may result in unchecked falling despite complete retention of consciousness. Hyperekplexia in humans responds dramatically although not completely to the benzodiazepine drug clonazepam, which enhances gamma-aminobutyric acid (GABA) neurotransmission. Low levels of CSF GABA have been reported in human patients. Following extensive neurological and neuromuscular evaluations that resulted in no specific abnormalities, a treatment trial with oral clonazepam (0.5 mg/kg TID) was performed in 2 affected CKCS dogs in the UK and 2 dogs in the USA. All 4 dogs responded dramatically to clonazepam therapy. Episodes of hypertonicity decreased from 25–30 per week to 1 every 2–3 months. after 2 years of therapy with clonazepam, the 2 dogs from the USA were described as clinically normal with only infrequent episodes. Although the inciting stimuli differ, the response to clonazepam therapy suggests a similar underlying disorder of GABA neurotransmission in the CKCS dogs and human hyperekplexia patients."

Clinical Neurology in Small Animals - Localization, Diagnosis and Treatment. K.G. Braund, International Veterinary Information Service, Ithaca, New York, USA; Paroxysmal Disorders (6-Feb-2003). Quote: "Episodic falling or hypertonicity is a well-recognized paroxysmal disorder in Cavalier King Charles Spaniels in the UK, and has been seen in the United States and Australia." www.ivis.org/special_books/Braund/braund29/ivis.pdf

A rare syndrome in cavaliers. G. Diane Shelton. AKC Gazette. Apr. 2003:24. Quote: "Dr. G. Diane Shelton, of the University of California at San Diego, reported on the treatment of several Cavalier King Charles Spaniels diagnosed with exercise- induced muscle hypertonicity. This syndrome was described several years ago in dogs from the United Kingdom, but seven cases that were identified recently included four dogs in the United States. Male and female Cavalier pups with a history of exercise- or excitement-induced collapse had been presented. They were between 4 and 7 months of age at the time. Exactly when the symptoms began is unclear. A typical event of this syndrome begins with activity that looks like stalking: The dog holds its head to the ground with its hindquarters up in the air. As the event progresses, the legs straighten and become tense, which ultimately causes collapse. Mentally, the dog remains normal. It knows what is happening and apparently sees clearly, but seems to lose control of its body. After extensive tests that yielded no specific abnormalities, two of the U.S. dogs and two of the U.K. dogs were treated with clonazepam, the drug commonly used to treat people with a similar syndrome called hereditary hyperekplexia (or startle disease) . With treatment, episodes decreased in frequency from between 25 and 30 each week down to one every two to three months. After two years of clonazepam, the two U.S. dogs were described as clinically normal. Episodes were infrequent."

Breed Predispositions to Disease in Dogs & Cats. Alex Gough, Alison Thomas. 2004; Blackwell Publ. 44-45.

Neurological diseases of the Cavalier King Charles spaniel. Rusbridge, C. J Small Animal Practice, 30 June 2005, 46(6): 265-272.

Efficient mapping of mendelian traits in dogs through genome-wide association. Elinor K Karlsson, Izabella Baranowska, Claire M Wade1, Nicolette H C Salmon Hillbertz, Michael C Zody, Nathan Anderson, Tara M Biagi, Nick Patterson, Gerli Rosengren Pielberg, Edward J Kulbokas III, Kenine E Comstock, Evan T Keller, Jill P Mesirov, Henrik von Euler, Olle Kämpe, Åke Hedhammar, Eric S Lander, Göran Andersson, Leif Andersson, Kerstin Lindblad-Toh. Nature Genetics. Sept. 2007;39:1321 - 1328. Quote: "With several hundred genetic diseases and an advantageous genome structure, dogs are ideal for mapping genes that cause disease. Here we report the development of a genotyping array with ~27,000 SNPs and show that genome-wide association mapping of mendelian traits in dog breeds can be achieved with only ~20 dogs. Specifically, we map two traits with mendelian inheritance: the major white spotting (S) locus and the hair ridge in Rhodesian ridgebacks. For both traits, we map the loci to discrete regions of <1 Mb. Fine-mapping of the S locus in two breeds refines the localization to a region of ~100 kb contained within the pigmentation-related gene MITF. Complete sequencing of the white and solid haplotypes identifies candidate regulatory mutations in the melanocyte-specific promoter of MITF. Our results show that genome-wide association mapping within dog breeds, followed by fine-mapping across multiple breeds, will be highly efficient and generally applicable to trait mapping, providing insights into canine and human health."

A Practical Guide to Canine and Feline Neurology. Curtis W. Dewey. John Wiley & Sons; 2008; 4-6, 482-483. Quotes: "Breed-associated neurologic abnormalities of dogs and cats. ... Cavalier King Charles Spaniels ... Episodic muscle hypertonicity ("falling cavaliers" -- probable dyskinesia" pg. 4-6. ""An age range ... has been reported of ... 14 weeks to 4 years for Cavalier King Charles Spaniels. ... Crossing of the thoracic limbs over the top of the head has been described in collapsing Cavalier King Charles Spaniels. ... Cavalier King Charles Spaniels tend to be less responsive to diaaepam than other breeds with the condition, but they can markedly improve with clonazepam treatment. Tolerance to clonzepam may develop in the long term. Other therapies reported to decrease frequency and severity of episodes include vitamin E and tryptophan. This is a nonprogressive disorder that tends to improve with therapy. Life spans of affected dogs do not appear to be shortened by the disease." pp. 482-483.

A canine DNM1 mutation is highly associated with the syndrome of exercise-induced collapse. Patterson EE, Minor KM, Tchernatynskaia AV, Taylor SM, Shelton GD, Ekenstedt KJ, Mickelson JR.  Nat Genet 2008; 40:1235-1239.

Muscular dystrophy in Cavalier King Charles spaniels. Piercy, Richard. J. and Walmsley, Gemma. Vet Rec. 2009 165 (2), p. 62. Quote: "We have recently identified the genetic cause of a form of muscular dystrophy in CKCS. The causative mutation is in the dystrophin gene and the X-linked disease is associated with weakness, muscle atrophy and exercise intolerance, detectable from a few months of age. Prominent signs in affected dogs are dysphagia [the symptom of difficulty in swallowing] and macroglossia (enlarged tongue)[tongue enlargement that leads to functional and cosmetic problems]. Serum creatine kinase is usually markedly elevated. Male dogs with the mutation [are] clinically affected and female dogs with the mutation are silent carriers. We are also keen to hear from veterinary surgeons who believe they may have seen an affected dog in their practice, in order to estimate the prevalence of this disease and limit its spread by genetic testing."  Contact Dr. Piercy at the Royal Veterinary College's Comparative Neuromuscular Diseases Laboratory at rpiercy@rvc.ac.uk

Breed Predispositions to Disease in Dogs & Cats (2d Ed.). Alex Gough, Alison Thomas. 2010; Wiley-Blackwell Publ. 52.

Update: Mutation Identified in Episodic Falling Syndrome in Cavalier King Charles Spaniel Dogs. Dr. Diane Shelton. Comparative Neuromuscular Lab, March 2011. Quote: "Almost 30 years ago a syndrome of exercise-induced muscle hypertonicity and falling (Episodic Falling, EFS) was described in young Cavalier King Charles Spaniels (1-3, and June 2001 Case of the Month). Clinical signs included exercise and excitement-induced “collapse” that was preceded by a “deer-stalking” action with the head held close to the ground and the bottom high in the air. An increasingly stilted gait was observed until there was finally collapse to one side. An increase in extensor tone in the muscles of both the thoracic and pelvic limbs was present during the period of collapse. The time period required for recovery of limb function was usually about 10 minutes. Mentation was normal throughout the episodes. Electromyographic evaluation showed the muscles were electrically silent. Dogs were neurologically normal between episodes. A microdeletion in the central nervous system gene BCAN1 has been shown to be highly associated with EFS in CKCS dogs and a scientific paper recently published (4). The carrier rate was approximately 13% suggesting that the EFS microdeletion is present at a high frequency in the general CKCS population. Molecular genetic testing for the EFS microdeletion is now available through Laboklin. Information regarding testing can be found here." 

Genetic Connection: A Guide to Health Problems in Purebred Dogs, Second Edition. Lowell Ackerman. July 2011; AAHA Press; pg 120. Quote: "Episodic falling is an autosomal recessive disorder of muscle innervation reported in the Cavalier King Charles spaniel. It is often detected in affected animals in their first year of life, when they are unable to relax, their muscles become rigid and they fall over. Typical triggers are exercise, excitementt, or frustration. Fortunately, DNA testing is available to detect clear, carrier, and affected animals."

New DNA tests for Cavalier King Charles spaniels. Vet Rec 2011 168(14):370. "NEW DNA tests to detect the mutations causing congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (dry eye and curly coat syndrome) and episodic falling in Cavalier King Charles spaniels will be available from the Animal Health Trust (AHT) later this month. Episodic falling is a neurological condition induced by exercise, excitement or frustration. The dog's muscle tone increases and the animal is unable to relax its muscles, becomes rigid and falls over. Dry eye and curly coat syndrome results in an affected dog producing no tears, so its eyes become sore. The skin becomes flaky and dry, particularly around the feet, which can make standing and walking difficult and painful. The syndrome appears to be unique to Cavalier King Charles spaniels and most dogs diagnosed  with it are euthanased. Researchers at the Kennel Club Genetics Centre at the AHT have now identified the mutations responsible  for the two conditions. This has allowed the development of the new DNA tests, which will be available from the AHT from April 18. Cathryn Mellersh, head of canine genetics at the AHT, said: To date there has been no long-term effective treatment  for either dry eye and curly coat syndrome or episodic falling so the development of the DNA tests is an important breakthrough for breeders and owners of Cavalier King Charles spaniels. As with all inherited disease, it's important that breeders  are armed with the facts and that they still continue to use carrier dogs in their breeding programmes. Breeding a carrier with a non-carrier will not produce affected puppies; however, breeding just clear dogs with other clear dogs could reduce  the gene pool within the breed and this could lead to other health problems in the future."

A canine BCAN microdeletion associated with Episodic Falling Syndrome. Jennifer L. Gill, Kate L. Tsai, Christa Krey, Rooksana E. Noorai, Jean-François Vanbellinghen, Laurent S. Garosi, G. Diane Shelton, Leigh Anne Clark, and Robert J. Harvey. Neurobiology of Disease. Jan 2012;45(1):130-136. Quote: "Episodic falling syndrome (EFS) is a canine paroxysmal hypertonicity disorder found in Cavalier King Charles spaniels. Episodes are triggered by exercise, stress or excitement and characterized by progressive hypertonicity throughout the thoracic and pelvic limbs, resulting in a characteristic 'deer-stalking' position and/or collapse. We used a genome-wide association strategy to map the EFS locus to a 3.48 Mb critical interval on canine chromosome 7. By prioritizing candidate genes on the basis of biological plausibility, we found that a 15.7 kb deletion in BCAN, encoding the brain-specific extracellular matrix proteoglycan brevican, is associated with EFS. This represents a compelling causal mutation for EFS, since brevican has an essential role in the formation of perineuronal nets governing synapse stability and nerve conduction velocity. ... Consistent with the unique clinical signs observed in affected dogs, we discovered that a homozygous microdeletion affecting BCAN is associated with EFS in CKCS dogs, confirming that this disorder is inherited in an autosomal recessive manner. This mutation was not detected in control DNA samples from 54 other dog breeds, confirming the unique nature of this genomic rearrangement. ... Certainly, since EFS appears to result from a central nervous system rather than a muscle defect, the associated sarcoplasmic reticulum pathology is likely to be a secondary manifestation of muscle overstimulation. ... Mapping of the deletion breakpoint enabled the development of Multiplex PCR and Multiplex Ligation-dependent Probe Amplification (MLPA) genotyping tests that can accurately distinguish normal, carrier and affected animals. Wider testing of a larger population of CKCS dogs without a history of EFS from the USA revealed that carriers are extremely common (12.9%). The development of molecular genetic tests for the EFS microdeletion will allow the implementation of directed breeding programs aimed at minimizing the number of animals with EFS and enable confirmatory diagnosis and pharmacotherapy of affected dogs."

Parallel Mapping and Simultaneous Sequencing Reveals Deletions in BCAN and FAM83H Associated with Discrete Inherited Disorders in a Domestic Dog Breed. Oliver P. Forman, Jacques Penderis, Claudia Hartley, Louisa J. Hayward, Sally L. Ricketts, and Cathryn S. Mellersh. PLoS Genet. 2012 January; 8(1): e1002462. Quote: "The domestic dog (Canis familiaris) segregates more naturally-occurring diseases and phenotypic variation than any other species and has become established as an unparalled model with which to study the genetics of inherited traits. We used a genome-wide association study (GWAS) and targeted resequencing of DNA from just five dogs to simultaneously map and identify mutations for two distinct inherited disorders that both affect a single breed, the Cavalier King Charles Spaniel. We investigated episodic falling (EF), a paroxysmal exertion-induced dyskinesia, alongside the phenotypically distinct condition congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (CKCSID), commonly known as dry eye curly coat syndrome. EF is characterised by episodes of exercise-induced muscular hypertonicity and abnormal posturing, usually occurring after exercise or periods of excitement. CKCSID is a congenital disorder that manifests as a rough coat present at birth, with keratoconjunctivitis sicca apparent on eyelid opening at 10–14 days, followed by hyperkeratinisation of footpads and distortion of nails that develops over the next few months. We undertook a GWAS with 31 EF cases, 23 CKCSID cases, and a common set of 38 controls and identified statistically associated signals for EF and CKCSID on chromosome 7 (Praw 1.9×10-14; Pgenome=1.0×10-5) and chromosome 13 (Praw 1.2×10-17; Pgenome=1.0×10-5), respectively. We resequenced both the EF and CKCSID disease-associated regions in just five dogs and identified a 15,724 bp deletion spanning three exons of BCAN associated with EF and a single base-pair exonic deletion in FAM83H associated with CKCSID. Neither BCAN or FAM83H have been associated with equivalent disease phenotypes in any other species, thus demonstrating the ability to use the domestic dog to study the genetic basis of more than one disease simultaneously in a single breed and to identify multiple novel candidate genes in parallel."

Frequency of two disease-associated mutations in Cavalier King Charles Spaniels, June 2012. Animal Health Trust. Quote: "In 2012 scientists at the Kennel Club Genetics Centre at the Animal Health Trust undertook a study to measure the frequency of the mutations responsible for congential keratoconjunctivitis sicca and ichthyosiform dermatosis (dry eye and curly coat syndromd) and episodic falling in Cavalier King Charles Spaniels in the UK. This report describes the study, its conclusions and recommendations for breeders."

Investigation of two disorders in the Cavalier King Charles Spaniel. Chapter 3 of "Advances in genetic mapping and sequencing techniques: a demonstration using the domestic dog model." Oliver Forman PhD thesis pp.63-102, University of Glasgow. 2013.

Phenotypic characterisation of canine epileptoid cramping syndrome in the border terrier. V. Black, L. Garosi, M. Lowrie, R. J. Harvey, J. Gale. J Small Anim Pract. January 2014;55(1):102–107. Quote: Objectives: To characterise the phenotype of Border terriers suspected to be affected by canine epileptoid cramping syndrome and to identify possible contributing factors. Methods: Owners of Border terriers with suspected canine epileptoid cramping syndrome were invited to complete an online questionnaire. The results of these responses were collated and analysed. Results: Twenty-nine Border terriers were included. Most affected dogs had their first episode before 3 years of age (range: 0·2 to 7·0 years). The majority of episodes lasted between 2 and 30 minutes (range: 0·5 to 150 minutes). The most frequent observations during the episodes were difficulty in walking (27 of 29), mild tremor (21 of 29) and dystonia (22 of 29). Episodes most frequently affected all four limbs (25 of 29) and the head and neck (21 of 29). Borborygmi were reported during episodes in 11 of 29 dogs. Episodes of vomiting and diarrhoea occurred in 14 of 29, with 50% of these being immediately before or after episodes of canine epileptoid cramping syndrome (7 of 14). Most owners (26 of 29) had changed their dog's diet, with approximately 50% (14 of 26) reporting a subsequent reduction in the frequency of episodes. Clinical Significance: This study demonstrates similarities in the phenotype of canine epileptoid cramping syndrome to paroxysmal dystonic choreoathetosis, a paroxysmal dyskinesia reported in humans. This disorder appears to be associated with gastrointestinal signs in some dogs and appears at least partially responsive to dietary adjustments.

Canine Paroxysmal Movement Disorders. Ganokon Urkasemsin, Natasha J. Olby. Vet. Clinics of No. Amer.: Small Animal Pract. Nov. 2014;44(6):1091-1102. Quote: "Paroxysmal dyskinesias are episodic movement disorders characterized by muscle hypertonicity that can produce involuntary movements. Signs emanate from the central nervous system; consciousness is not impaired, ictal electroencephalography is normal, and there are no autonomic signs, distinguishing them from seizure disorders. In humans they are classified into 3 groups, each responding to different therapies. A mutation in the gene for brevican (BCAN) has been identified as the cause of Episodic Falling in Cavalier King Charles spaniels. Further elucidation of the genetic causes will enhance our ability to identify and treat these canine diseases."

Dystonia and Paroxysmal Dyskinesias: Under-Recognized Movement Disorders in Domestic Animals? A Comparison with Human Dystonia/Paroxysmal Dyskinesias. Angelika Richter, Melanie Hamann, Jörg Wissel, Holger A. Volk. Frontiers in Vet. Sci. November 2015. Quote: "Generalized Movement Disorders Which Possibly Include Dystonic Features -- Paroxysmal Dyskinesias in Dogs -- Episodic falling in Cavalier King Charles Spaniels (CKCS), an autosomal-recessive inherited disorder, shares similarities with human paroxysmal dyskinesia. In affected dogs, exercise and excitement can precipitate episodes of abnormal gait and fallings which last up to several minutes. There are no signs of an impairment of consciousness or autonomic dysfunction during or after these attacks. Affected animals develop an increased extensor muscle tone of all four limbs, resulting in an immobilized, “deer-stalking” or “praying” position, sometimes falling with legs held in extensor rigidity. Other clinical signs are facial muscle stiffness, stumbling, a 'bunny-hopping' gait, and arching of the back. It is unclear if cocontractions of flexors are involved. Initial clinical signs of the disease typically appear between 3 and 7 months of age. Interestingly, in some cases, there is spontaneous remission, as sometimes observed in human paroxysmal dyskinesia. There is no evidence for metabolic alterations as a cause, and light microscopic examinations have not revealed any lesions in the CNS or peripheral nerves. Clonazepam may be effective in suppressing the episodes in some cases. Recently, a 15.7 kb deletion in BCAN, encoding the brain-specific extracellular matrix-proteoglycan brevican, was found to be associated with episodic falling in CKCS. This protein plays an important role in cell adhesion, migration, axon guidance, and neuronal plasticity. How this mutation leads to the manifestation of this hyperkinetic movement disorder in dogs has yet to be unraveled."

The Clinical and Serological Effect of a Gluten-Free Diet in Border Terriers with Epileptoid Cramping Syndrome. M. Lowrie, O.A. Garden, M. Hadjivassiliou, R.J. Harvey, D.S. Sanders, R. Powell, L. Garosi. J. Vete. Intern. Med. November 2015;29(6):1564-1568. Quote: Background: Canine epileptoid cramping syndrome (CECS) is a paroxysmal movement disorder of Border Terriers (BTs). These dogs might respond to a gluten‐free diet. Objectives: The objective of this study was to examine the clinical and serological effect of a gluten-free diet in BTs with CECS. Animals: Six client-owned BTs with clinically confirmed CECS. Methods: Dogs were prospectively recruited that had at least a 6-month history of CECS based on the observed phenomenology (using video) and had exhibited at least 2 separate episodes on different days. Dogs were tested for anti-transglutaminase 2 (TG2 IgA) and anti-gliadin (AGA IgG) antibodies in the serum at presentation, and 3, 6, and 9 months after the introduction of a gluten-free diet. Duodenal biopsies were performed in 1 dog.

Long-term treatment of canine paroxysmal dyskinesias with fluoxetine: 6 cases. T. Bouzouraa, C. Escriou. ESVN Abstract J. Vet. Int. Med. December 2015. Quote: "It is only recently that both clinical features and genetic basis of canine paroxysmal dyskinesias (CPDs) have been documented. Their management remains challenging though phenothiazine, benzodiazepines even anticonvulsants yielded unsatisfactory results. Fluoxetine, a selective serotonin reuptake inhibitor, seems promising. Three Scottish terriers (STs), 2 Cavalier King Charles Spaniels (CKCSs) suffering from Scottie Cramp (SC) and Episodic Falling, respectively, then an English Setter with a dyskinesia of unknown origin, displayed many daily episodes, triggered by exercise and/or excitement that definitely preventing them from living normally. All dogs received fluoxetine as a single treatment (2–4 mg/kg q24 h). Four dogs displayed early and complete remissions that persisted over long periods (1 year for 1 CKCS then 2, 6 and 7 years for the 3 STs). The remaining 2 cases showed a significant improvement with a decline to approximately one single episode every 2 months for both dogs. Transient relapses occurred when treatment was interrupted or tapered in 3 dogs. No treatment resistance or side effect was observed. Fluoxetine may be a good and safe option for the long-term management of CPDs, allowing dogs for resuming to normal activity and lifestyle. It can directly correct serotoninergic transmission imbalance suspected in SC. Its activity remains unclear in other CPDs; direct serotoninergic action is likely but indirect effect through a reduction of behavioral reactivity to triggering factors like stress, excitation or environmental stimulations is also plausible."

Natural history of canine paroxysmal movement disorders in Labrador retrievers and Jack Russell terriers. Mark Lowrie, Laurent Garosi. Vet. J. July 2016;213:33-37. Quote: In dogs, the first genetically mapped PD [paroxysmal dyskinesia] was that associated with EFS [episodic falling syndrome] in Cavalier King Charles Spaniels (Forman et al., 2012; Gill et al., 2012). The mutation was characterised as a deletion affecting the brevican gene (BCAN) which encodes a brain-specific component of the extracellular matrix proteoglycan complex. It is thought to be involved in homeostasis and mutations of this protein result in a disruption of axonal conduction and synaptic stability. An interesting observation in EFS is that the condition is self-limiting in some cases (Forman et al., 2012). It is suggested that compensatory pathways involving up regulation of other proteoglycans may occur and account for this rectification. Dogs in our study also seemed to show this improvement with age so a similar compensatory mechanism may be considered.

Frequency estimation of disease-causing mutations in the Belgian population of some dog breeds - Part 2: retrievers and other breed types. E. Beckers, M. Van Poucke, L. Ronsyn, L. Peelman. Vlaams Diergeneeskundiig Tijdschrift. October 2016:185-196. Quote: A Belgian population of ten breeds with a low to moderately low genetic diversity or which are relatively popular in Belgium, i.e. Bichon frise, Bloodhound, Bouvier des Flandres, Boxer, Cavalier King Charles spaniel, Irish setter, Papillon, Rottweiler, Golden retriever and Labrador retriever, was genotyped for all potentially relevant disease-causing variants known at the start of the study. In this way, the frequency was estimated for 26 variants in order to improve breeding advice. Disorders with a frequency high enough to recommend routine genotyping in breeding programs are (1) degenerative myelopathy for the Bloodhound, (2) arrhythmogenic right ventricular cardiomyopathy and degenerative myelopathy for Boxers, (3) episodic falling syndrome and macrothrombocytopenia for the Cavalier King Charles spaniel, (4) progressive retinal atrophy rod cone dysplasia 4 for the Irish setter (5) Golden retriever progressive retinal atrophy 1 for the Golden retriever and (6) exercise induced collapse and progressive rod-cone degeneration for the Labrador retriever. To the authors’ knowledge, in this study, the presence of a causal mutation for a short tail in the Bouvier des Flandres is described for the first time. ... The autosomal recessive disorder episodic falling syndrome (EFS) causes neurological episodes often triggered by stress, excitement or exercise. Symptoms occur at the age of three months to four years and become progressively worse. A frequency of 12.3% (Wt/Mt) carriers was found in 57 genotyped animals, which is very similar to the estimate of 12.9% carriers in a USA population (Gill et al., 2011). No homozygous mutant individuals were encountered (Table 3). The authors encourage routine genotyping in breeding dogs because of the high frequency.

Classification of involuntary movements in dogs: Paroxysmal dyskinesias. Mark Lowrie, Laurent Garosi. Vet. J. February 2017;220(1):65-71. Quote: Paroxysmal dyskinesias (PDs) are a group of hyperkinetic movement disorders characterised by circumscribed episodes of disturbed movement, superimposed on a background state in which such abnormality is absent. There is no loss of consciousness. Episodes can last seconds, minutes or hours, and the beginning and end of the movement disturbance is abrupt. Neurological examination is typically normal between episodes. PDs are associated with a broad spectrum of clinical presentations, encompassing various aetiologies. ... This review aims to synthesise a classification scheme for veterinary PDs by reviewing human systems and applying them to veterinary examples. However, it is anticipated that genetic advancement will greatly aid in future stratification and therapy for PDs in dogs. Therefore, classification systems should be viewed as works in progress that should be modified as necessary. ... However, biochemical and genetic markers are available for some PDs in dogs (notably canine epileptoid cramping syndrome [CECS] and episodic falling syndrome [EFS] of the Cavalier King Charles spaniel, respectively) and these have only served to confirm the suspicion of PD over epilepsy in these breeds. ... Certain breed-specific features can aid in achieving a definitive diagnosis. The work up for EFS in Cavalier King Charles spaniels, for example, involves genetic testing, whereas CECS in the Border terrier requires serological testing for gluten-specific antibodies. ... The first genetically mapped PD in companion animals was EFS in Cavalier King Charles Spaniels. ... Medications: Medications used in the management of PD have variable and often limited efficacy. In humans, carbamazepine is the drug of choice for kinesigenic dyskinesias and clonazepam for the non-kinesigenic forms. A major difference between PNKD and PKD in humans is that PNKD is relatively refractory to therapy. In dogs, successful treatment of PNKD has been reported, albeit uncommonly, with clonazepam, acetazolamide and fluoxetine. Acetazolamide was also very effective in the management of EFS in Cavalier King Charles spaniels. ... Highlights: • Paroxysmal dyskinesias are circumscribed episodes of disturbed movement without loss of consciousness. • Diagnosis is challenging; hence accurate identification is critical. • Three forms of paroxysmal dyskinesia exist: kinesigenic, nonkinesigenic and exertion-induced dyskinesia. • Paroxysmal dyskinesias are typically self-limiting and have a benign course.

Paroxysmal Dyskinesia in Border Terriers: Clinical, Epidemiological, and Genetic Investigations. Q.E.M. Stassen, L.L.E. Koskinen, F.G. van Steenbeek, E.H. Seppälä, T.S. Jokinen, P.G.M. Prins, H.G.J. Bok, M.M.J.M. Zandvliet, M. Vos-Loohuis, P.A.J. Leegwater, H. Lohi. J. Vet. Intern. med. August 2017:31(4):1123-1131. Quote: Background: In the last decade, a disorder characterized by episodes of involuntary movements and dystonia has been recognized in Border Terriers. Objectives: To define clinical features of paroxysmal dyskinesia (PD) in a large number of Border Terriers and to study the genetics of the disease. Animals: 110 affected and 128 unaffected client-owned Border Terriers. Methods: A questionnaire regarding clinical characteristics of PD was designed at Utrecht University and the University of Helsinki. Thirty-five affected Border Terriers underwent physical examination and blood testing (hematology and clinical biochemistry). Diagnostic imaging of the brain was performed in 17 affected dogs and electroencephalograms (EEG) between episodes were obtained in 10 affected dogs. A genomewide association study (GWAS) was performed with DNA of 110 affected and 128 unaffected dogs. Results: One hundred forty-seven questionnaires were included in the study. The most characteristic signs during episodes were dystonia, muscle fasciculations, and falling over. The majority of owners believed that their dogs remained conscious during the episodes. A beneficial effect of anti‐epileptic therapy was observed in 29 of 43 dogs. Fifteen owners changed their dogs’ diet to a hypoallergenic, gluten-free diet, and all reported reasonable to good improvement of signs. Clinical examinations and diagnostic test results were unremarkable. The GWAS did not identify significantly associated chromosome regions. Conclusions and Clinical Importance: The survey results and EEG studies provided further evidence that the observed syndrome is a PD rather than epilepsy. Failure to achieve conclusive results by GWAS indicates that inheritance of PD in Border Terriers probably is complex. ... Nevertheless, based on the considerations described above, focal epilepsy is less likely and the term CECS [canine epileptoid cramping syndrome] can be replaced by the descriptive term PD, which refers to a group of movement disorders characterized by recurrent episodes of hyperkinesia, altered muscle tone, or both.

International veterinary canine dyskinesia task force ECVN consensus statement: Terminology and classification. Sofia Cerda-Gonzalez, Rebecca A. Packer, Laurent Garosi, Mark Lowrie, Paul J. J. Mandigers, Dennis P. O'Brien, Holger A. Volk. J. Vet. Intern. Med. March 2021; doi: 10.1111/jvim.16108. Quote: Movement disorders are a heterogeneous group of clinical syndromes in humans and animals characterized by involuntary movements without changes in consciousness. Canine movement disorders broadly include tremors, peripheral nerve hyperexcitability disorders, paroxysmal dyskinesia, and dystonia. Of these, canine paroxysmal dyskinesias remain one of the more difficult to identify and characterize in dogs. Canine paroxysmal dyskinesias include an array of movement disorders in which there is a recurrent episode of abnormal, involuntary, movement. ... Dystonic movements described in animals involve flexion of the limbs such as canine epileptoid cramping syndrome or Chinook dyskinesia, or other postures such as the “deer stalking” in Cavalier King Charles spaniels. ... In this consensus statement, we recommend standard terminology for describing the various movement disorders with an emphasis on paroxysmal dyskinesia, as well as a preliminary classification and clinical approach to reporting cases. In the clinical approach to movement disorders, we recommend categorizing movements into hyperkinetic vs hypokinetic, paroxysmal vs persistent, exercise-induced vs not related to exercise, using a detailed description of movements using the recommended terminology presented here, differentiating movement disorders vs other differential diagnoses, and then finally, determining whether the paroxysmal dyskinesia is due to either inherited or acquired etiologies. ... Table 4. Etiological classification of canine paroxysmal dyskinesia: Inherited or presumed inherited (primary) paroxysmal dyskinesia: Episodic hypertonicity in Cavalier King Charles Spaniels. ... Table 5. Breed-related paroxysmal dyskinesias: Colloquial name(s): Episodic falling syndrome; Primary affected breed: Cavalier King Charles spaniel; Mode of inheritance: Autosomal recessive; Trigger: Exercise, excitement, stress; Duration (min): <1 to several minutes; Progression: Improve/stabilize with age; Similarity with human disorder(s): Paroxysmal dyskinesia. ... Table 6. Known genetic mutations for canine movement disorders: Movement disorder: Paroxysmal dykinesias; Subtype or breed: Cavalier King Charles spaniel; Mutation: BCAN; Genetic test available?: Yes, for Cavalier King Charles spaniel. ... This consensus statement represents a starting point for consistent reporting of clinical descriptions and terminology associated with canine movement disorders, with additional focus on paroxysmal dyskinesia. With consistent reporting and identification of additional genetic mutations responsible for these disorders, our understanding of the phenotype, genotype, and pathophysiology will continue to develop and inform further modification of these recommendations.

Canine paroxysmal dyskinesia—a review. Paul J. J. Mandigers, Koen M. Santifort, Mark Lowrie, Laurent Garosi. Frontiers Vet. Sci. July 2024; doi: 10.3389/fvets.2024.1441332. Quote: Paroxysmal dyskinesias (PDs) are a group of involuntary, hyperkinetic movement disorders that recur episodically and may last seconds to hours. An important feature of PD is that there is no loss of consciousness during the episode. Using a clinical classification, three main types of PDs have been distinguished in canine PD: (1) paroxysmal kinesigenic dyskinesia (PKD) that commences after (sudden) movements, (2) paroxysmal non-kinesigenic dyskinesia (PNKD) not associated with exercise and can occur at rest, and (3) paroxysmal exertioninduced dyskinesia (PED) associated with fatigue. Canine PDs are diagnosed based on the clinical presentation, history, and phenomenology. For the latter, a video recording of the paroxysmal event is extremely useful. An etiological classification of canine PDs includes genetic (proven and suspected), reactive (drug-induced, toxic, metabolic, and dietary), structural (neoplasia, inflammatory, and other structural causes), and unknown causes. In this review, an overview of all reported canine PDs is provided with emphasis on phenotype, genotype, and, where possible, pathophysiology and treatment for each reported canine PD.  Genetic PDs: Cavalier King Charles Spaniel/episodic falling syndrome: Episodic falling syndrome (EFS) was first described in 1983. Affected dogs present themselves with progressive hypertonicity of the limbs leading to a characteristic “deer-stalking” or “praying” position. Other clinical signs may include facial muscle stiffness, stumbling, a “bunny-hopping” gait, arching of the back, and vocalization (Supplementary Video S1). The episodes, triggered by exercise, stress, apprehension, or excitement, last from less than 1 min to several minutes. It is the first PD in which the causative mutation was identified. It affects young dogs (up to 4 years) and is caused by a mutation in the brevican gene (BCAN). This gene encodes a brain-specific protein of the extracellular matrix proteoglycan complex. The abnormally formed protein results in a disrupted axonal conduction/synaptic stability. The mode of inheritance is autosomal recessive. Although all CKCS fur color variants can be crossed among each other, EFS was predominantly seen in the Ruby and Black and Tan fur variants, as the mutated allele had a higher frequency in these fur colors. Interestingly, EFS improves with age which might suggest that in time compensatory pathways may lead to a resolution of the abnormally formed protein (9, 18). For this reason, if affected CKCS only have a low frequency of these episodes, the advice could be to avoid triggers and show some hesitance in medical treatment. Affected CKCS have been treated with both clonazepam and acetazolamide (17). This PD can be classified as a PNKD.