Syringomyelia in the Cavalier King Charles Spaniel - Diagnosis and Treatment of Central Neuropathic Pain

Syringomyelia and Chiari-like malformation is a hereditary and incurable neurological disease comp lex in the Cavalier King Charles Spaniel (CKCS). The suggested mode of inheritance is polygenic with variable penetrance. Chiari-like malformation (CM) is a developmental skull anomaly characterised by occipital bone hypoplasia and secondary reduced volume of the caudal cranial fossa. This results in caudal cranial fossa overcrowding characterised by a volume mismatch between the reduced intracranial volume and increased cerebellar volume, which leads to cerebellar indentation and partial herniation into the foramen magnum. The consequence of the overcrowding and cerebellar herniation is a subarachnoidal stenosis that alters the pressure and flow dynamics of the cerebrospinal fluid.

Syringomyelia (SM) is defined as a fluid-filled cavity (syrinx) in the spinal cord parenchyma. The CM/SM complex was originally described in 2000 by Rusbridge et al.¹ The causal relationship between CM and the development of SM is still controversial. It has been suggested that the syrinx formation is a result of pressure differences between the spinal cord parenchyma and the subarachnoidal space. The cerebrospinal fluid transport is pulsatile and synchronous with the cardiac rhythm. The CM/SM patient has an increased systolic cerebrospinal fluid pressure due to cerebellar prolapse and secondary subarachnoidal stenosis. The result is a sucking effect that facilitates transport of cerebrospinal fluid from the subarachnoidal space into the spinal cord parenchyma. This vicious circle induces the syrinx formation. The cross-sectional increase in the syrinx area enlarges the overall cross -section of the spinal cord. As a consequence, the subarachnoidal space is reduced and the systolic pulsatile pressure of cerebrospinal fluid increases accordingly.² SM is also seen in other breeds, often secondary to trauma, inflammation or intervertebral disc degeneration but never with concurrent CM.

Prevalence

The prevalence estimation of SM in CKCS is challenging since the definitive diagnosis requires magnetic resonance imaging (MRI) confirmation. In addition, it is important to stress that CKCS with MRI confirmed SM can be asymptomatic. A retrospective British/Dutch study on asymptomatic CKCS has shown an age­ dependent increase in the prevalence of asymptomatic SM from 25% to 70% in CKCS between 12 and 72 months of age.³ In Danish CKCS the prevalence of symptomatic SM is 15%.⁴

Symptoms

The clinical manifestation of SM includes characteristic behavioural changes; these are presumably associated with central neuropathic pain. Central neuropathic pain is defined as ‘pain caused by a lesion in the central somatosensory nervous system’ by the International Association for the Study of Pain and is characterised by allodynia (pain as a result of non-noxious stimuli) and hyperalgesia (increased pain sensation as a result of noxious stimuli). Some cases also present with neurological symptoms (e.g., proprioceptive or lower motor neuron deficits). The most prevalent clinical signs are: intermittent spontaneous or evoked scratching; reluctance to be touched in the head and neck region; and, in severe cases, paroxysmal pain manifestations with vocalisation, intense scratching, rubbing and circling on the ground floor. The scratching is uni- or bilateral and is directed at the head, ears, neck, shoulders, axillae, chest or ventral abdomen. Phantom scratching, a reflex without skin contact, can also be seen and is indicative of dysaesthesia (an unpleasantly abnormal sensation). Factors that aggravate the scratching are collars and harnesses, excitement and stressful situations. Some dogs are reluctant to wear collars or harnesses. Others resist being groomed or touched on the neck, ears and other extremities. In most cases one also finds a history of sleeping difficulties, restlessness, hypersensitivity to noise, sunlight and wind and reduced contact with the owner, other dogs and other people.⁵ In humans, the SM-associated damage to nociceptive and other sensory pathways of the spinal cord causes pain and is a prominent feature in 50–90% of adult patients. The pain phenomena are classified as central, neuropathic pain, and the patients report neck and back pain or dysaesthesia characterised by burning pain, hyperaesthesia and pins and needles.⁶

Diagnosis

Diagnosis should ideally be based on a thorough anamnesis with the owner’s description of one or more of the above symptoms, a clinical examination to rule out dermatological conditions (e.g., ectoparasites, dermatitis and allergy) and otitis externa as a ca use of the scratching, and a neurological examination to rule out other neurological differential diagnosis; here an MR scan of the neurocranium and cervical spinal cord is recommended. The characteristic MRI findings are cerebellar indentation or partial herniation and SM. SM has a predilection for the cervical spinal cord segments C2-C4 (75% of cases), but dogs with cervical SM also present with thoraco-lumbar (76%) or lumbar SM (49%). The clinical manifestations of SM and the degree of pain are linked to the syrinx diameter relative to that of the spinal cord and the potential asymmetrical syrinx distribution as directed towards the dorsal horns of the spinal cord. The greater the syrinx to spinal cord ratio and the more asymmetrical distribution on the transverse images, the more severe are the symptoms and signs of pain.⁷ In addition to CM and SM, the MR images often reveal concomitant kinking curvature of the spinal cord in the cranio-cervical junction, ventriculomegaly and otitis media with effusion. The clinical significance of these findings is subject to continuous debate.

Treatment

The pathophysiology of chronic pain is complex and the treatment is significantly different from the traditional treatment options for acute inflammatory pain in veterinary patients. The mechanisms involved in central neuropathic pain, and thus the core treatment targets, are primarily receptors of the dorsal horn and higher pain centres (e.g., the somatosensory cortex, periaqueductal grey and limbic systems). The aim is to identify the pain mechanisms responsible for the clinical signs, to define the treatment targets and obtain the best possible analgesia with a minimum of adverse drug reactions. There are no published, evidence-based protocols on the treatment of central neuropathic pain in dogs with CM and SM. The following protocol is based on the author’s personal experience combined with recommendations from published data on central neuropathic pain and treatment protocols in human patients.

Pregabalin (PGN) is a structural gamma-aminobutyric acid (GABA) analogue with anticonvulsant and analgesic properties. The primary target of PGN is the a2-δ-subunit of the voltage-gated calcium channels in the central nervous system. The analgesic effect of PGN is mediated through the inhibition of voltage-gated calcium channel function by a reduction in anterograde a2-δ-subunit trafficking and impairment of upregulation of synaptic expression and inhibition of synaptic excitatory neurotransmitter (glutamate) release in the dorsal root ganglia and dorsal horn. In addition, PGN enhances the expression of excitatory amino acid transporters (EAAT3) in neuronal plasma membranes. This leads to increased inactivation and reduction of the extracellular concentration of glutamate. A third target site is the spinal cord KATP potassium channel. PGN activates the potassium channel, and the prolonged opening results in neurotransmitter release inhibition (primarily substance P) and modulated neuronal excitability.⁸ The pharmacokinetics of PGN after PO administration (4 mg/kg) has been investigated in six adult Labrador /Greyhound dogs.⁹ The reported maximal plasma concentration, C_max was 7.15 (4.6–7.9 ) µg/ml and the time for C_max to occur, T_max was 1.5 (1.0–4.0) hours. Elimination half-life (T½el) was 6.9 (6.21–7.4) hours. No adverse effects were seen. Yet, to date, the available clinica l research data on the usage of PGN in canine patients with chronic pain is very sparse. One prospective cohort study on long-term outcome in 48 CKCS has shown improvement or the status quo maintained in 12/ 48 (25 %) of dogs treated with PGN (2–4 mg/kg PO q8h), gabapentin and/or intermittently carprofen.¹⁰ The recommended anticonvulsant PGN dosage for canine patients is 2–4 mg/kg q8–12h. For the treatment of neuropathic pain, we have anecdotal reports and personal experience with a dosage regimen of 2–10 mg/kg (and titrated to effect up to 30 mg/kg) q12h. In human patients with different causes of neuropathic pain, PGN has been found effective in several randomized, double-blind, placebo-controlled clinical trials.

NSAIDs as an add-on to the multimodal protocol will reduce the peripheral micro-inflammation caused by the scratching. In case of an insufficient analgesic effect, add-on with an opioid (e.g., tramadol 1–4 mg/ kg PO q4–8h) or with the tricyclic antidepressants clomipramine or amitriptyline (1–2 mg/kg PO q24h) may improve the analgesic effect and reduce the scratching in most patients.

Routine follow-up on the effect of the multimodal treatment regimen is imperative. Owners must observe their dogs on a daily basis and report on predefined parameters, including reduction in scratching events during the day, potential side effects (primarily ataxia and sedation) and general quality of life. This enables the veterinary surgeon to evaluate continuously the success of the treatment continuously. The prognosis is guarded and treatment effect varies between individuals, depending on co-morbidities. Twenty percent of CKCS with symptomatic SM will be euthanized due to non­sufficient treatment effects and severe pain manifestation, which results in a markedly reduced quality of life.^4,10

References

1.  Rusbndge C, MacSweeny JE, Davies JV, Chandler K, Fitzmaurice SN, Dennis R, et al. Syringohydromyelia in Cavalier King Charles spaniels. Journal of the American Animal Hospital Association. 2000;36(1):34–41.

2.  Greitz D. Unraveling the riddle of syringomyelia. Neurosurgical Review. 2006;29(4):251–263; discussion 64.

3.  Parker JE, Knowler SP, Rusbridge C, Noonnan E, Jeffery ND. Prevalence of asymptomatic syringomyelia in Cavalier King Charles spaniels. The Veterinary Record. 2011;168(25):667.

4.  Thorner MS, Stougaard CL, Westrup U, Madry M, Knudsen CS, Berg H, et al. Prevalence and heritability of symptomatic syringomyelia in cavalier King Charles Spaniels and long-term outcome in symptomatic and asymptomatic littermates. Journal of Veterinary Internal Medicine. 20152, 9(1):243–250.

5.  Rutherford L, Wessmann A, Rusbridge C, McGonnell IM, Abeyesinghe S, Burn C, et al. Questionnaire-based behaviour analysis of Cavalier King Charles spaniels with neuropathic pain due to Chiari-like malformation and syringomyelia. Veterinary Journal. 2012;194(3):294–298.

6.  Todor DR, Mu HT, Milhorat TH. Pain and syringomyelia: a review. Neurosurgical Focus. 2000;8(3):E11.

7.  Rusbndge C, Carruthers H, Dube MP, Holmes M, Jeffery ND. Syringomyelia in cavalier King Charles spaniels: the relationship between syrinx dimensions and pain. The Journal of small animal practice. 2007;48(8):432–436.

8.  Kremer M, Sa/vat E, Muller A, Yalcin I, Barrot M. Antidepressants and gabapentinoids in neuropathic pain: Mechanistic insights. Neuroscience. 2016;338:183–206.

9.  Salazar V, Dewey CW, Schwark W, Badgley BL, Gleed RD, Horne W, et al. Pharmacokinetics of single-dose oral pregabalin administration in normal dogs. Vet Anaesth Analg. 2009;36(6):574-80.

10.  Plessas IN, Rusbridge C, Driver CJ, Chandler KE, Craig A, McGonnell IM, et al. Long-term outcome of Cavalier King Charles spaniel dogs with clinical signs associated with Chiari-like malformation and syringomyelia. The Veterinary Record. 2012;171(20):501.