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Review

Idiopathic headshaking: Is it still idiopathic? Kirstie Pickles *, John Madigan, Monica Aleman Department of Veterinary Medicine and Epidemiology, University of California Davis, CA 95616, USA

A R T I C L E

I N F O

Article history: Accepted 27 March 2014 Keywords: Headshaking Head flicking Trigeminal nerve Trigeminal neuralgia Trigeminal neurophysiology

A B S T R A C T

The clinical syndrome of equine idiopathic headshaking (HSK) was first described in the veterinary literature over 100 years ago, and the disorder continues to be a cause of substantial distress for the horse, frustration for the owner and therapeutic challenge for the veterinarian. This review presents a summary of the current knowledge of clinical signs, signalment, aetiopathogenesis, anatomy, diagnosis and treatment of idiopathic HSK. Recent advances in understanding the pathogenesis of the disease will be discussed with reference to human trigeminal neuralgia, along with the implications this may have for potential therapies. © 2014 Elsevier Ltd. All rights reserved.

Introduction Idiopathic headshaking (HSK) is a spontaneously occurring disorder consisting of violent head flicks that predominantly affects mature geldings (Lane and Mair, 1987; Madigan and Bell, 2001; Mills et al., 2002). Severely affected horses may sustain significant selfinflicted trauma and appear to have compromised welfare. Involvement of the trigeminal nerve in HSK has long been suspected (Williams, 1897, 1899), and this has been recently confirmed (Aleman et al., 2013), although because an apparent cause has not yet been identified the term idiopathic continues to be used. Current therapeutic options are limited by our incomplete understanding of the aetiopathogenesis of HSK and humane euthanasia may be required in unremitting cases. The clinical signs of HSK are suspected to result from trigeminal neuropathic pain and the disease appears to share some similarities with human trigeminal neuralgia (HTN) (Aleman et al., 2013). This review details existing clinical and diagnostic data pertaining to HSK, discusses HSK as a possible animal model of human trigeminal neuralgia and provides a comprehensive summary of current treatment options. Clinical signs Appearance of clinical signs Affected horses, colloquially termed ‘headshakers’, exhibit violent, usually vertical, shakes, flicks, or jerks of the head, in the absence of any apparent physical stimulus. Other clinical signs include snorting, an ‘anxious’ facial expression (Fig. 1) and muzzle rubbing, which

* Corresponding author. Tel.: +44 781168 6833. E-mail address: [email protected] (K.J. Pickles).

can be so intense that horses strike at their nose with their thoracic limbs. HSK can be so severe that the horse inflicts considerable self-trauma (abrasions to muzzle, limbs) and is dangerous to handle and ride. A full range of clinical signs and their prevalence is listed in Table 1. Some horses appear to be more severely affected than others, and clinical signs may be intermittent or continuous. If severe, HSK may impair the horse from performing simple daily life activities such as eating. In addition to the reported signs, we have observed lip smacking and nose licking in a few horses. Progression of clinical signs has been reported anecdotally (Lane and Mair, 1987; Newton et al., 2000; Mills et al., 2002) but a longitudinal study of HSK severity has not been published. Indeed, there is no agreed methodology for grading severity of clinical signs, which would be beneficial for more accurate monitoring of the disease, treatment efficacy and for comparison of published studies. Seasonality Seasonality of clinical signs is reported in approximately 60% of HSK horses while the remainder exhibit constant or erratic episodes (Madigan and Bell, 2001; Mills et al., 2002) (Table 1). Some headshaking recurs within the same few calendar weeks each consecutive year (Madigan et al., 1995). A greater proportion of geldings than mares are reported to be affected seasonally (Mills et al., 2002). In a largely US population of HSK horses, the majority (91%) of horses with seasonal HSK developed signs in the spring and early summer and these ceased in late summer and fall, although a small proportion (4%) were symptomatic in the fall and the horses stopped HSK in the spring (Madigan and Bell, 2001). In contrast, the majority (43%) of UK horses with seasonal HSK are symptomatic in spring, summer and autumn, 39% in spring and summer, 14% in summer alone, 3% in summer and autumn, 1% in winter and spring and less than 1% in spring only (Mills et al., 2002). These reported seasonal

http://dx.doi.org/10.1016/j.tvjl.2014.03.031 1090-0233/© 2014 Elsevier Ltd. All rights reserved.

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triggered by wind or rain (Mills et al., 2002) or a sharp, loud sound such as metal on metal contact or loud clapping. Auditory stimulation such as a high note, a loud noise, or a vibration has also been reported as a rare inciting cause of HTN patients (Henderson, 1967). The mechanism by which sound can influence the trigeminal nerve is unknown. Increase in exercise intensity frequently precipitates clinical signs (Lane and Mair, 1987; Madigan and Bell, 2001; Newton et al., 2000). The reason for this is unknown but increased autonomic activity and air currents over the muzzle are possible stimulatory factors. Signalment Frequency and distribution

Fig. 1. Clinical signs of idiopathic headshaking: Note the anxious expression of the horse and proximity to the wall as this horse has been rubbing his nose.

presentations appear to indicate some geographical variation of possible triggering events in HSK phenotype. Other influences HSK behaviour can also vary in response to weather patterns and exercise (Lane and Mair, 1987; Madigan and Bell, 2001; Mills et al., 2002) (Table 1). Horses with severe clinical signs during bright sunny days and with a reduction of HSK at night are termed ‘photic headshakers’ (Madigan et al., 1995). In other horses, HSK may be

The prevalence of HSK is reported to be 1–1.5% (Slater, 2013). There have been reports of HSK in many countries including the USA, Canada, the UK, Germany, Australia, and New Zealand. Anecdotally, idiopathic HSK appears to have a worldwide geographical distribution. Age HSK can occur at any age but is primarily a disease of adult horses with median (range) reported ages of 8 (4–17) years (Newton et al., 2000), 9 (1–30) years (Madigan and Bell, 2001), 9.5 (4–28.5) years (Mills et al., 2002), and 10 (5–16) years (Mair, 1999). The median age of first onset of HSK is reported as 6 years with 39% developing signs of HSK aged 5 years or younger, 42% starting at 5–10 years, 13% at 10–15 years, 5% at 15–20 years and 4% aged over 20 years (Mills et al., 2002). Sex

Table 1 Clinical signs exhibited by horses with idiopathic headshaking and their reported prevalence. Clinical sign Shaking or flipping the head in a vertical plane Acting as if an insect had flown up the nose Muzzle rubbing Snorting ‘Flips’ upper lip Strikes at face with foot Anxious expression Rubs nose on ground while stationary Rubs nose on ground while moving Horizontal headshaking Rotatory headshaking Sensitive muzzle Staring into space Panic following staring episodes Submerging muzzle on water Headshakes at rest Headshakes at rest only Headshakes at exercise only Headshaking increases when excited Exercise precipitated headshaking Headshaking at rest or exercise Headshaking only when ridden Headshaking associated with bright, sunny days Headshaking reduced at night Seeks shade in environment Avoidance of light Headshaking improved indoors Headshaking improves on rainy days Headshaking improves on windy days Headshaking worse on windy days Seasonality of headshaking signs

Percentage of horses (%) 891, 922, 794 881, 722 751, 792, 604 641, 732, 514 722 632, 423 611 462 442, 453 252, 323, 74 74 132 22, 193 133 32 412 41, 24 323, 564 512 411 551, 424 101 521, 642 521, 742 301, 62 353 772 582 222 222 591, 642

References with number of horses in the study in parentheses: 1 Madigan and Bell, 2001 (109); 2 Mills et al., 2002 (254); 3 Madigan and Bell, 1998 (31); 4 Lane and Mair, 1987 (100).

Geldings consistently appear to be over-represented comprising 71.5% of cases (odds ratio [OR] 2.16) compared to 26.5% mares and 2% stallions in a study of mostly US horses (Madigan and Bell, 2001), and 70% and 63%, respectively, in UK studies (Lane and Mair, 1987; Mills et al., 2002). Geldings are also reported to be more frequently seasonally affected (Mills et al., 2002). Breed and discipline All breeds appear susceptible. A case control study reported Thoroughbreds to be over-represented comprising 41% (OR 3.21) in a series of 109 cases (Madigan and Bell, 2001), however other studies show that all breeds are equally affected (Mills et al., 2002). HSK horses are used in most equine disciplines although horses used in lighter activities appear most frequently affected with 43% of 109 cases used for pleasure riding (Madigan and Bell, 2001) and 91% of 254 horses with HSK used for general purpose riding (Mills et al., 2002). Conversely, racehorses may be under-represented comprising only 2% of 100 cases (Lane and Mair, 1987). Aetiopathogenesis Involvement of the trigeminal nerve Clinical signs of HSK may reflect trigeminal neuropathic pain. Surprisingly, although ‘neurosis of the infraorbital portion of supermaxillary division of the trifacial nerve’ was proposed in initial reports of HSK over 100 years ago (Williams, 1897, 1899), confirmation of trigeminal involvement has only recently been definitively identified (Aleman et al., 2013, 2014). These recent studies demonstrated differences in the threshold for activation of the infraorbital nerve, a branch of the maxillary division of the trigeminal nerve,

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between control and HSK horses, with affected horses having significantly lower stimulus thresholds (≤5 mA) than control horses (≥10 mA). Interestingly, a horse with seasonal HSK tested (only) during a time of remission showed a threshold for activation similar to control horses, suggesting that the threshold of the nerve is malleable. Once a sensory action potential was triggered, there were no differences in all neurophysiological parameters measured, including conduction velocity. Additionally, there were no differences between left and right sides demonstrating bilateral involvement of the trigeminal nerve in affected horses. Given the proven involvement of the trigeminal nerve in the pathophysiology of the disorder, the term ‘trigeminal-mediated HSK’ might be a more accurate term for this disorder. The cause of the aberrant trigeminal nerve activity (‘hypersensitivity’) in equine HSK remains elusive. Despite the predilection of equine herpesvirus-1 for latency in the trigeminal ganglion, this virus does not appear to be involved in the pathogenesis of HSK (Aleman et al., 2012). Some clinical similarities appear to exist between HSK and HTN, a debilitating cause of facial pain in people. Sufferers of HTN report intermittent or continuous burning, itching, tingling, tickling, or electric-like pain originating in area innervated by the trigeminal nerve (Nurmikko and Eldridge, 2001), which appear to equate well to the observed signs displayed by horses with HSK. Unlike equine HSK, however, HTN patients usually have unilateral clinical signs (Nurmikko and Eldridge, 2001) and focal compression and demyelination of the trigeminal nerve root entry zone are frequently documented (Devor et al., 2002). The limited pathological studies undertaken in horses with HSK to date have failed to find any pathological abnormalities (Newton, 2001; Aleman et al., 2013). Additionally, such demyelination slows trigeminal nerve conduction velocity in patients with HTN, which is not present in horses with HSK (Aleman et al., 2013). As HSK horses can go into spontaneous remission, some after many years of HSK, it appears that the aberrant trigeminal nerve activity might be reversible, rather than the result of permanent damage. However, long-term studies to investigate this assumption have not been performed. Together, these findings suggest functional rather than structural alterations in the trigeminal nerve in equine HSK (but this assumption requires validation). The reason why some horses enter remission, which may last from weeks to years, is unknown. The rate at which horses enter long-term remission appears low with Madigan and Bell (2001) stating that 5% of 109 HSK horses had ceased headshaking for more than 1 year. One HSK horse in remission has been observed to exhibit recurrence of clinical signs shortly after receiving an electric shock to the muzzle (J. Madigan, personal communication). Some authors argue that the paroxysmal nature of HTN pain is inconsistent with compression-induced ectopic impulses at the site of injury and that spontaneous discharges arising from select neurons whose threshold for firing has been altered is a more plausible explanation (Nurmikko and Eldridge, 2001). This hypothesis is comparable with that reported in horses with HSK (Aleman et al., 2013). As such, HSK may be useful as an animal model of studying a naturally occurring trigeminal nerve disorder with altered threshold activity. Dorsal root ganglion cells have been shown to possess properties that (in certain circumstances) can lead to this type of spontaneous firing activity (Amir et al., 1999). Increase in subthreshold oscillations in the resting membrane potential of a subpopulation of A neurons (Liu et al., 2000) leads to increased spike activity and subsequent cross-excitation of adjacent hyperexcitable C fibres (Amir and Devor, 2000). A nociceptive signal of pain results if sufficient neurons are recruited into this spreading cluster of discharging cells (Amir and Devor, 2000). Inherent cell self-quenching mechanisms are believed to cause the abrupt cessation of such signals (and thus pain). HTN patients with continuous ectopic discharge and unre-

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lenting pain may have central sensitisation or progressive damage to the central terminals of trigeminal afferents (Burchiel and Slavin, 2000). It has been postulated that the photic trigger to clinical signs in some horses with HSK is similar to the human photic sneeze (Madigan et al., 1995) in which persistent photic stimulation via the optic nerve leads to a tickling sensation in the nasal mucosa (Whitman and Packer, 1993). The neural pathway of this phenomenon could be the result of intense light stimulation of the optic nerves causing cross-activation of the maxillary branch of the trigeminal nerve (Everett, 1964). A second theory called ‘parasympathetic generalisation’ postulates that adjacently located parasympathetic branches are co-activated (Everett, 1964). Similar neural pathways could be involved in causing irritating sensations and subsequent HSK behaviour in horses triggered by bright light (Madigan et al., 1995). The clinical signs of photic HSK are identical to those of non-photic HSK (Newton et al., 2000; Madigan and Bell, 2001) and therefore multiple triggers appear to activate the same end trigeminal response. Indeed, we have observed horses in which HSK is triggered by sound (metal sound, clap) or eating (hard carrots, fibrous hay) and with a worsening of headshaking following a diagnostic nasal swab or when food is in contact with the nose (Aleman et al., 2014). Other factors Exercise is a stimulus for HSK activity in some horses (Lane and Mair, 1987; Mair and Lane, 1990; Madigan et al., 1995). The reason for this is unclear but perhaps increased air currents over the nose cause allodynia. The over-representation of geldings is also puzzling. Lack of testosterone-induced negative feedback of gonadotropins was investigated as a hypothesis for this (and the seasonality of clinical signs) but was not upheld (Pickles et al., 2011). Seasonal fluctuations in pasture nutritive value, particularly improved grassland, might offer an alternative explanation for the seasonality of HSK clinical signs and investigation of such an association is warranted. Pathological causes of HSK have been determined in a small number of cases and include middle and inner ear infection, temporohyoid osteoarthropathy, ear ticks (Otobius megnini), ear mites (Trombicula autumnalis), guttural pouch disorders, periapical dental osteitis, other dental problems (e.g. wolf teeth abnormalities), allergic rhinitis, equine protozoal myelitis (EPM), vasomotor rhinitis, ocular disorders (cysts, masses), intranasal masses, sinusitis, nuchal crest avulsion, apparent neck pain, inappropriate bridle, rider ineptitude, and behaviour disorder (Cook, 1979, 1980, 1992; Kold et al., 1982; Lane and Mair, 1987; Mair and Lane, 1990; McGorum and Dixon, 1990; Mair, 1994; Moore et al., 1997; Stephenson, 2005; Berger et al., 2008; Voigt et al., 2009; Fiske-Jackson et al., 2012). It is important to rule out any pathological disorder before a clinical diagnosis of idiopathic HSK is made. In these idiopathic cases, there is a lack of apparent anatomical and pathological findings. Trigeminal nerve anatomy The trigeminal complex is formed of peripheral components, namely, the trigeminal nerve, trigeminal ganglion, three main branches (ophthalmic, maxillary, mandibular [Fig. 2], and subsequent branches), and central components (spinal tract and nuclei of the trigeminal complex within the brainstem). The spinal tract of the trigeminal complex might extend up to the second cervical spinal cord segment. The nerve has sensory and motor components and is the largest of all cranial nerves. The sensory components include the ophthalmic, maxillary, and mandibular nerves (De Lahunta and Glass, 2009). The mandibular nerve also has motor function. The trigeminal ganglion contains sensory cell bodies for pain

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Fig. 2. Peripheral components of the trigeminal complex. Ophthalmic nerve (OPH in green), maxillary nerve (MAX and its branch infraorbital nerve [IO], in yellow), mandibular nerve (MAN in red), and trigeminal ganglion (oval brown structure). Not all branches from each nerve are shown. Figure not drawn to scale.

and temperature modalities of all three sensory nerves of the trigeminal nerve (De Lahunta and Glass, 2009). The cell bodies of neurons of proprioceptive modalities are not located in the trigeminal ganglion but in nuclei within the brainstem (De Lahunta and Glass, 2009). The motor part of the mandibular nerve is ventral to the trigeminal ganglion. The ophthalmic nerve is the smallest of the three sensory nerves and runs lateral to the cavernous sinus. The ophthalmic nerve enters the orbital fissure along with the oculomotor, trochlear, abducens, and sympathetic nerves to the eye. The ophthalmic nerve gives rise to the lacrimal, frontal, nasociliary, and ethmoidal nerves (Budras et al., 2009). The maxillary nerve emerges from the round foramen and continues into the maxillary foramen and infraorbital canal as the infraorbital nerve. The maxillary nerve has several branches including the zygomaticofacial, pterygopalatine, major palatine, minor palatine, caudal nasal, and infraorbital nerves (Budras et al., 2009). The caudal nasal nerve has been commonly referred to as the ethmoidal nerve. However, these nerves are distinct structures arising from different branches of the trigeminal nerve as explained previously. The mandibular nerve gives rise to (among others) the masseteric, temporal, pterygoid, tensor tympani, tensor veli palatine, mylohyoid, auriculotemporal, buccal, lingual, and mental nerves (Budras et al., 2009). The signs of apparent facial discomfort displayed by affected horses appear to be mainly localised to the muzzle/nose area. The maxillary nerve is sensory to the lower eyelid, maxillary teeth, upper lip, maxillary sinus, and nose. Attempts to diagnose the disorder have been made by local anaesthesia of the infraorbital/maxillary nerve (Mair, 1999; Newton, 2001; Roberts et al., 2013) (Fig. 3) (see discussion later).

Diagnosis Detailed history and observation of headshaking Fig. 3. Maxillary nerve block. Image showing electrode placement for electrophysiology study at the level of the maxillary nerve. Note the orange electrode depicts the site for maxillary nerve block, caudal and ventral to the orbit.

Table 2 Diagnostic questions to ask during detailed history taking from an owner of a horse with suspected idiopathic headshaking. Question Signalment Age of onset of clinical signs Type of headshaking activity: vertical, horizontal, rotatory Frequency: how many headshakes per minute, hour, day, week Occurrence of signs: day vs. night, sunny vs. windy day, etc. Seasonality: month of onset ± cessation each year Association with exercise: yes or no, under saddle or lunge line Any events associated or concurrent to headshaking episodes e.g. bright light, feeding, sound Any other concurrent ill health/clinical signs suggestive of other disease

A diagnosis of ‘idiopathic’ HSK is based on clinical evaluation of a specific phenotype of ‘headshake’, seen as a rapid downward jerk of the nose followed by upward flinging of the head, plus exclusion of other diseases. A detailed history should be taken from the owner (Table 2) and a diary of daily weather patterns, the horse’s management, exercise regimen and HSK events is very helpful. The diagnostic process for evaluation of a horse with headshaking is detailed in Table 3. The horse should be observed at a distance and close at hand for HSK behaviours and the identification of any triggers. The horse should be watched wearing a bridle and bit if appropriate and under saddle if HSK occurs only when ridden. It is important in such cases to exclude problems associated with the tack, rider, or behaviour of the horse. However, the horse should not be ridden as part of the evaluation if HSK is so violent that riding is unsafe. It may also be useful to review video recordings, particularly if HSK is associated with specific weather or conditions that are not present when the horse is examined.

Table 3 Diagnostic process for the evaluation of a horse with suspected idiopathic headshaking (HSK). PE, physical examination; NAD, nothing abnormal detected; URT, upper respiratory tract; GP, guttural pouches. Diagnostic process Signalment and history Observation of headshaking Full PE including ophthalmoscopy, otoscopy and oral examination Endoscopy of URT including GP Radiography of the head ±Computed tomography, magnetic resonance imaging ±Infraorbital/maxillary nerve anaesthesia

Findings supportive of HSK Adult gelding, possible seasonality of clinical signs, worsens with exercise Rapid downward jerk of the nose followed by upward flinging of the head NAD which could explain headshaking NAD which could explain headshaking NAD which could explain headshaking NAD which could explain headshaking Improvement of headshaking

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Physical examination and ancillary diagnostic aids

Treatment

Our own routine evaluation includes ophthalmic, otoscopic and oral examinations, upper airway endoscopy including guttural pouches, and head radiography. Computed tomography (CT) and magnetic resonance imaging are useful to rule out other disorders of bone and soft tissue of the head. We have not observed abnormalities on CT studies of horses with idiopathic HSK. Local anaesthesia of the infraorbital nerve is used by some clinicians to aid diagnosis but reported success rates of this procedure are low. In one study, 3/19 horses improved, 8/19 horses remained unchanged and 8/19 horses were worse following infraorbital anaesthesia with 12 mL 2% mepivacaine (Mair, 1999), while another study reported a 50% improvement in only 1/8 horses following 2–3 mL 2% mepivacaine (Newton et al., 2000). The low volumes of local anaesthetic used in these studies might be partly responsible for the poor response. On the other hand, if more volume of anaesthetic is infiltrated, there is a risk of anaesthetising other nerves in the vicinity. Bilateral anaesthesia of the posterior ethmoidal nerve (maxillary nerve, Fig. 3) appears to have reasonable diagnostic value with a reported improvement in 13/17 (Newton et al., 2000) and 23/27 horses with HSK (Roberts et al., 2013). These studies performed this procedure at a level below the zygomatic arch by infiltrating 5 mL of 2% mepivacaine at a depth of 5 cm. However, nerve conduction studies in HSK and healthy horses have demonstrated that the maxillary nerve is located at an approximate depth of 6–7 cm (Aleman et al., 2013, 2014). Further, due to the size and depth of the nerve, diffusion of the anaesthetic might require time for full effect (Newton et al., 2000). The horse must be physically and chemically restrained to perform both these local anaesthetic techniques safely. Video recording pre- and post-nerve block is recommended to assess any response in a more objective manner. Possible complications of these procedures are common (Mair, 1999; Newton et al., 2000) and include haematoma, worsening of HSK, infection, neuritis, and painful neuroma formation. It is important to remember that a positive response to the procedure is not specific for a diagnosis of HSK as all areas innervated by the nerve will be anaesthetised and therefore any other pathology with trigeminal involvement, e.g. dental pain, will also respond. As such, information attained from regional neural anaesthesia should be used in conjunction with all other findings. Recently, we reported a horse with idiopathic HSK (a diagnosis further supported by electrodiagnostic testing) which continued to have maxillary nerve conduction following anaesthesia of the maxillary nerve (Aleman et al., 2014). This finding raises the question of the efficacy of nerve anaesthesia procedures to completely ablate sensory nerve conduction. Neurophysiology studies of the trigeminal nerve and observation of a reduced threshold for nerve activation is diagnostic for trigeminal mediated HSK (Aleman et al., 2013) (Figs. 4A and B); however such studies are invasive and require general anaesthesia which limit their clinical use. Such neurophysiological investigation provides objective and quantitative data and has the potential to be used to accurately monitor treatment success. HTN is similarly diagnosed by exclusion of other pathology and a positive response to treatment with carbamazepine (Nurmikko and Eldridge, 2001). Quantitative sensory testing provides non-invasive assessment and measurement of sensory nerve function by quantifying the amount of physical stimulus required for sensory perception to occur (Walk et al., 2009). This procedure is useful in HTN patients to accurately map areas of altered sensory perception but it appears to be an insensitive tool in the horse (K. Pickles et al., unpublished observations).

Since the aetiology of HSK is unknown, current treatments are neither specific nor curative so the majority of horses with HSK are managed (which is not always possible) rather than cured. The high failure rate of many HSK treatments is unsurprising given that they have no effect on correcting the abnormal trigeminal neurophysiology. Given that some horses go into remission, the aberrant activity of the trigeminal nerve might be reversible. Future treatments capable of such manipulation will likely hold the key to successful treatment of HSK. There are few scientific efficacy trials of HSK treatments. This is compounded by the difficulty in objective assessment of the condition and any treatment response, the phenomena of spontaneous and seasonal remission and placebo effect. A summary of the available evidence is presented and summarised in Table 4; however it should be remembered that, for the majority of these drugs, there are no pharmacokinetic and safety data in the horse.

Environmental management Avoidance of known triggers may be helpful such as riding at night or in an indoor arena if light is a trigger. However, for most owners such management is impractical, particularly for competition horses.

Nose nets and face masks Nose nets (Fig. 5) are one of the most successful therapies for HSK and are now permitted at some equestrian competitions. Approximately 75% of owners reported some improvement in HSK using either a full net (covering the muzzle and upper and lower lips) or a half net (covering only the nostrils and upper lip) (Mills and Taylor, 2003). A 50% or greater improvement was noted by two-thirds of owners and a 70% or greater improvement by one-third. Half nets appeared to be significantly better at controlling ‘bee up the nose’ behaviour. Use of nets might be most successful early on in the disease as horses >10 years old are reportedly less likely to show a 50% or greater improvement in ‘nose flipping’ and ‘HSK at exercise’. More recently, a study of over 100 HSK horses found that >50% derived some relief from wearing nose nets, although full resolution of HSK was rare (K. Pickles et al., unpublished observations). Some HSK horses that do not respond to a traditional nose net improve with the use of soft rope plaits, or a similar device, that attaches to the noseband or browband (K. Pickles et al., unpublished observations). The mechanism by which nose nets improve HSK is unknown. They might act to reduce aversive stimulation of hyperaesthetic areas or, alternatively, the constant presence of the net might work by adjacent receptor field inhibition or receptor adaptation of the contact area (Raj et al., 1999). Perhaps the sensory input is altered or inhibited by applying a different type of stimulus? Face masks are similarly effective at reducing HSK in >50% of horses (K. Pickles et al., unpublished observations). Horses with photic HSK benefit from fly masks with ultraviolet blocking sun shade (e.g. Guardian Mask) (Madigan et al., 1995), whereas tinted contact lenses do not appear useful in these horses (Newton et al., 2000).

Medication All medications listed have potential adverse effects and polypharmacy should be avoided. Governing sport federations should be consulted regarding regulations and withdrawal times for the use of drugs in competing or show horses. It has to be emphasised that

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A

B Fig. 4. Sensory nerve conduction study. (A) Stimulating unit (S) located in the maxillary gingival mucosa and recording electrodes (pair per site, labelled as A1, A2, A3, A4). A1, infraorbital nerve; A2, maxillary nerve; A3, spinal tract of trigeminal complex; A4, cortical somatosensory; G, ground electrode; T, temperature probe. (B) Sensory nerve action potentials recorded in a horse with idiopathic headshaking at areas A1, A2, A3, and A4. Note the low stimulus intensity at 2.5 milliamperes (mA), divisions: 5 milliseconds (ms) per horizontal division, variable amplitude in microvolts (µV) per vertical divisions as indicated, N, average of 1000 responses.

pharmacokinetic and safety studies for most of the following drugs are not available. Cyproheptadine Cyproheptadine (Pericatin, Auden McKenzie) is a first generation antihistamine with additional anticholinergic, antiserotonergic, calcium channel blocking and local anaesthetic activity (Lowe et al., 1981) used to treat human vascular headaches. There are no avail-

able data on the bioavailability or pharmacokinetics of cyproheptadine in horses. Reports of cyproheptadine treatment of HSK are conflicting. Two UK studies found no improvement with use of cyproheptadine (Mair, 1999; Newton et al., 2000), however Madigan and Bell (2001) reported that 70% of 61 horses with HSK in the USA treated with 0.3 mg/kg orally twice daily, improved moderately to greatly within 1 week of commencing therapy. Additionally, recurrence of clinical signs occurred within several days of cessation of therapy (Madigan and Bell, 2001).

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Table 4 Dosage guidelines, evidence of success and reported side effects of treatments used in idiopathic headshaking (HSK). N/A, not applicable; PO, per os (orally). Treatment

Dose

Nose nets

N/A

Face mask Cyproheptadine

N/A 0.3 mg/kg PO twice daily

Carbamazepine

2–8 mg/kg PO 2–4 times daily

Cyproheptadine + carbamazepine

as above

Antihistamines Fluphenazine Phenobarbitone

Hydroxyzine: 0.8 mg/kg PO twice daily 50 mg IM, repeat every 1–4 months 3–6 mg/kg PO twice daily

Gabapentin

5–20 mg/kg PO once or twice daily

Corticosteroids

Not reported

Sodium cromoglycate eye drops Melatonin Magnesium Chiropractic therapy

1 drop/eye four times daily 15–18 mg PO once daily at 17:00 h 10–20 mg PO once daily N/A

Homeopathy Acupuncture Fly control Infraorbital neurectomy/sclerosis

N/A N/A N/A N/A

Platinum coil implantation

N/A

a b c d e f g h i j k l

Evidence of success Reduction of clinical signs in >70% of 36 seasonal HSK horsesa and >50% of 110 HSK horsesb Reduction of clinical signs in >50% of 83 HSK horsesb 70% of 61 headshakers improved moderately to greatly within 7 daysc; no improvement in five horsesd and three horses (one received only 0.2 mg/kg)e Successful in 88% of cases but results were unpredictable at pre-defined dose ratese; decreased HSK in 2/9 horsesb 80–100% improvement in 80% of 12 cases within 3–4 dayse General antihistamine use decreased HSK in 12/36 horsesb Improvement in 7/16 horsesg Improvement in reducing distress of severely affected horsesi Anecdotal variable success; no response in one severely HSK horsei 17/31b and 3/20c horses improved; dexamethasone pulse therapy had no effect in 20 horsesj Successful in three (atypical) seasonal headshakersk Improvement 2/7c and 8/17b horses Improvement in 25/58 horsesb 1/28 horses improved, 4/28 slight improvementc; partial improvement 4/50 horsesa 6/93 horses improved, 29/93 partial improvementa 4/25 horses improved, 6/25 slight improvementc 18/109b and 3/109 horses improvedc Not recommendedd Salvage procedure only, success in approximately 50% including multiple surgeriesl

Reported side effects Irritated by mask, panicb Spookiness, reduced visionb Mild lethargy, drowsiness, anorexiab,f None None Sedationb Extrapyramidal effectsh Mild sedation common Sedation None None May not shed winter coatb None None None None None Recurrence of HSK, severe pain and self-traumad Recurrence of HSK, muzzle rubbing and self-trauma (63%)l

Mills and Taylor (2003). K. Pickles et al., unpublished observations. Madigan and Bell (2001). Mair (1999). Newton et al. (2000). Madigan et al. (1995). P. Smith and J. Madigan, unpublished observations. Baird et al. (2006). Aleman et al. 2014. Tomlinson et al. (2013). Stalin et al. (2008). Roberts et al. (2013).

More recently, an international study of over 100 HSK horses found that cyproheptadine reduced HSK in 48% of horses (K. Pickles et al., unpublished observations). Side effects of cyproheptadine treatment included lethargy, drowsiness and anorexia and were reported in 50% of horses (Madigan et al., 1995; K. Pickles et al., unpublished observations). Carbamazepine Carbamazepine (Tegretol, Novartis) is an anticonvulsant which stabilises voltage-gated sodium channels and is the pharmaceutical treatment of choice for HTN. Newton (2001) reported that 4 mg/ kg carbamazepine given four times daily was successful in treating HSK, although increasing the dose was necessary in some cases to maintain this response. Carbamazepine has proved much less efficacious when used by the authors reducing HSK in only 2/9 horses (K. Pickles et al., unpublished observations). Additionally, many owners find the frequent administration schedule problematic. Carbamazepine used in combination with cyproheptadine reduced HSK in 88% of horses (Newton et al., 2000), although the number of horses treated was low. There is wide individual variability between horses in the pharmacokinetics of this drug (Newton, 2001), which may explain treatment failure in some horses. Obtundation, lethargy and

Fig. 5. Nose net covering nose and lips.

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drowsiness are frequent side effects (K. Pickles et al., unpublished observations). Antihistamines Antihistamines may improve HSK in some horses although response is variable. Madigan and Bell (2001) reported only 1/16 horses with HSK responded positively to antihistamine therapy however, more recently, 12/36 owners reported antihistamine use decreased HSK behaviour (K. Pickles et al., unpublished observations). The choice of antihistamine did not appear to affect outcome. Mild drowsiness was reported in many horses with treatment (K. Pickles et al., unpublished observations). Fluphenazine Fluphenazine is an antipsychotic drug which acts by blocking central dopamine receptors. Fluphenazine is reported to have improved HSK in 7/16 horses (P. Smith and J. Madigan, unpublished observations) however fluphenazine treatment should not be undertaken lightly as severe extrapyramidal effects have been reported in some horses (Baird et al., 2006). A new vial should always be used for each individual treatment. Phenobarbitone Phenobarbitone has been used, with some success, to treat extremely severe HSK where the horse is particularly distressed (Aleman et al., 2014). Mild sedation is a common effect of the treatment. Gabapentin Gabapentin is an antiepileptic drug used for the treatment of HTN. Its mechanism of action is unclear but is thought to involve the α-subunit of voltage-gated calcium channels (Maneuf et al., 2006). Anecdotal empirical use of gabapentin for the treatment of HSK reports variable success. Recent pharmacokinetic studies report poor oral bioavailability (16%) in the horse (Terry et al., 2010). There is potential for using newer drugs for neuropathic pain such as pregabalin, however no equine pharmacological data currently exist for these drugs. Corticosteroids Madigan and Bell (2001) reported 3/20 horses responded to corticosteroid treatment. More recently, approximately 50% of 31 owners reported improvement in HSK following oral or intramuscular corticosteroid use (K. Pickles et al., unpublished observations). However, these results must be interpreted cautiously since the study was based on an owner survey and a placebo effect could not be ruled out. Dexamethasone pulse therapy has been used in the treatment of human neuropathic pain but its use in HSK did not result in improvement (Tomlinson et al., 2013). Sodium cromoglycate eye drops Sodium cromoglycate stabilises mast cell membranes preventing the release of histamine and other mediators. Sodium cromoglycate eye drops have been used successfully in three horses with seasonal HSK that also showed excessive tear production and photophobia (Stalin et al., 2008). These findings support an allergic condition in this group of horses although the horses were previously treated with ophthalmic dexamethasone with no response.

Melatonin The neurohormone melatonin is a universal photoperiodic hormone signal which plays an important role in reproductive performance, particularly in seasonal breeders, causing inhibition of gonadotropin-releasing hormone-stimulated calcium signalling (Srinivasan et al., 2009). Melatonin also modulates pain (including neuropathic pain) and has various anti-nociceptive effects including activation of opioid receptors, inhibition of pro-inflammatory cytokine production, modulation of gamma-aminobutyric acidA receptor function and acting as a free radical scavenger (Ambriz-Tututi et al., 2009). Melatonin receptors are present in the trigeminal ganglion and trigeminal nucleus of mammals (Weaver et al., 1989) and melatonin has been shown to attenuate an inducible model of trigeminovascular nociception in rats (le Grand et al., 2006). Manipulation of the photoperiod with melatonin has been reported to improve seasonal HSK in 2/7 and 8/17 horses (Madigan and Bell, 2001; K. Pickles et al., unpublished observations). Therapy is most successful when melatonin is started before the onset of spring for those horses with seasonal HSK where signs begin in the spring and cease in late autumn and winter. For successful photoperiod manipulation, the dose must be given promptly at 17:00 h each day. Some horses might require treatment all year round while others are able to cease melatonin therapy for several winter months. Due to manipulation of the photoperiod, approximately 40% of treated horses do not shed their coat and require clipping (K. Pickles et al., unpublished observations). Nutritional supplements A plethora of nutritional supplements have been used in an attempt to manage HSK. Over 40% of owners have tried feeding supplements for the treatment of HSK with approximately 35% of these perceiving an improvement (Mills et al., 2002). Very few nutritional supplements that claim to alleviate HSK have been subject to scientific validation. No improvement in HSK was observed in a randomised, blinded, crossover study of a feed supplement containing calcined magnesite, products of tubers, roots and aromatic or appetising herbs, methylsulfonylmethane and glutamine peptide (Talbot et al., 2013). Interestingly, in the latter study, owners thought there was an improvement with both the supplement and the placebo emphasising the placebo effect in interpretation of ownerreported response to treatment. Magnesium Magnesium increases the threshold for nerve firing, thereby increasing the stimulus required for depolarisation (Fawcett et al., 1999). Magnesium therefore appears to be a rational therapy given the reduced activation threshold of the trigeminal nerve in HSK horses (Aleman et al., 2013). However, optimal serum magnesium concentrations are unknown, and the best way to achieve these concentrations is also unknown as indeed is whether this can be achieved via oral supplementation. Approximately 40% of 58 owners reported improvement in HSK following oral supplementation with 10–20 g of magnesium daily (K. Pickles et al., unpublished observations). We recommend measuring plasma ionised magnesium before supplementation and 2 weeks after the initiation of supplementation to avoid possible toxicity although side effects appear rare (K. Pickles et al., unpublished observations). Alternative therapies Chiropractic or acupuncture treatment of HSK are tried by approximately one-quarter of owners, however over 90% of those treated show a complete lack of response (Madigan and Bell, 2001;

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Mills et al., 2002). Homeopathy has been used by 38% of owners with approximately one-third of these considering their horse partially improved (Mills et al., 2002). Fly-control measures are commonly used, with 100% application in one study; however these yielded improvement in only 2% of HSK horses (Madigan and Bell, 2001). More recently, 25% of owners reported some reduction in HSK with fly control (K. Pickles et al., unpublished observations). Surgery The use of infraorbital neurectomy for the treatment of HSK was included in the first report of HSK in the veterinary literature (Williams, 1897); however response to this procedure is poor with high post-surgical complication rates and its use is therefore contraindicated (Mair, 1999). Sclerosis of the posterior ethmoidal nerve has also been discontinued due to the high rate of recurrence of HSK (Newton et al., 2000). More recently, the application of platinum coils to provide compression of the caudal infraorbital nerve (with or without laser cautery of the nerve) has been described as a salvage procedure for HSK horses unresponsive to medical therapy (Roberts et al., 2009, 2013). An overall success rate of approximately 50% has been reported, although multiple surgeries were required in a substantial proportion of the horses due to HSK recurrence. Postoperative nose rubbing with possible self-trauma and increased severity of HSK was reported in 63% of horses. While these adverse effects were usually temporary, four horses had to be euthanased due to their severity and/or non-resolution. This procedure should therefore only be contemplated in horses for which euthanasia is the only other option (Roberts et al., 2013). Conclusions Idiopathic HSK remains poorly understood. Recent advancement in our understanding of the disease has established a clear role for the trigeminal nerve such that we believe the term idiopathic HSK should now be superseded by ‘trigeminal-mediated HSK’. While the identification of abnormal trigeminal nerve physiology in HSK horses has been a significant step forwards, the underlying cause of this decreased activation threshold remains elusive. While current evidence suggests a functional abnormality, detailed descriptions of morphometric and histochemical features of the trigeminal complex in affected horses are warranted. Current treatments have poor efficacy for many HSK horses. It is hoped that further clarification of the pathophysiology will hold the key to more rational treatments and thus improve the welfare of HSK horses. Conflict of interest statement None of the authors of this paper has a financial or personal relationship with other people or organisations that could inappropriately influence or bias the content of the paper. References Aleman, M., Pickles, K.J., Simonek, G., Madigan, J.E., 2012. Latent equine herpesvirus-1 in trigeminal ganglia and equine idiopathic headshaking. Journal of Veterinary Internal Medicine 26, 192–194. Aleman, M., Williams, D.C., Brosnan, R.J., Pickles, K.J., Berger, J., LeCouteur, R.A., Holliday, T.A., Madigan, J.E., 2013. Sensory nerve conduction and somatosensory evoked potentials of the trigeminal nerve in horses with idiopathic headshaking. Journal of Veterinary Internal Medicine 27, 1571–1580. Aleman, M., Rhodes, D., Williams, D.C., Guedes, A., Madigan, J.E., 2014. Sensory evoked potentials of the trigeminal nerve for the diagnosis of idiopathic headshaking in a horse. Journal of Veterinary Internal Medicine 28, 250–253. Ambriz-Tututi, M., Rocha-González, H.I., Cruz, S.L., Granados-Soto, V., 2009. Melatonin: A hormone that modulates pain. Life Sciences 84, 489–498.

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