The association between Chiari-like malformation, ventriculomegaly and seizures in cavalier King Charles spaniels

The association between Chiari-like malformation, ventriculomegaly and seizures in cavalier King Charles spaniels

The Veterinary Journal 195 (2013) 235–237 Contents lists available at SciVerse ScienceDirect The Veterinary Journal journal homepage: www.elsevier.c...

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The Veterinary Journal 195 (2013) 235–237

Contents lists available at SciVerse ScienceDirect

The Veterinary Journal journal homepage:

Short Communication

The association between Chiari-like malformation, ventriculomegaly and seizures in cavalier King Charles spaniels C.J. Driver ⇑, K. Chandler, G. Walmsley, N. Shihab, H.A. Volk Department of Veterinary Clinical Sciences, Royal Veterinary College, Hawkshead Lane, Potters Bar, Herts AL9 7TA, UK

a r t i c l e

i n f o

Article history: Accepted 20 May 2012

Keywords: Chiari-like malformation Ventriculomegaly Epilepsy Cavalier King Charles spaniel

a b s t r a c t Cavalier King Charles spaniels (CKCSs) with Chiari-like malformation (CM) and associated seizures are frequently diagnosed with idiopathic epilepsy. There could be an association between ventriculomegaly (V) or caudal fossa overcrowding (CCFP) and seizures. A retrospective case-control study was performed using MRI to investigate the possible association between these morphological abnormalities and seizures. Seizure semiology and, where possible, electroencephalographic (EEG) abnormalities were documented. Eighty-five CKCS with CM were included, 27 with seizures. There was no association between V or CCFP and seizures (P = 0.10 and 0.71, respectively). Seizures were classified as having partial onset in 61% of individuals in the study population (95% CI 42.41–76.43%). Another cause of recurrent seizures in CKCS (such as familial epilepsy) is suspected, as previously reported. Ó 2012 Elsevier Ltd. All rights reserved.

Chiari-I malformations (CMs) in children are congenital anomalies associated with hypoplasia of the bones of the posterior fossa (Nishikawa et al., 1997). They result in compression of neural tissue, most commonly causing pain and seizures. It has been suggested that CM has a role in epileptogenesis (Parmeggiani et al., 1999). There is currently no evidence in the human literature to suggest volume overcrowding is associated with seizures. The analogous canine condition is prevalent in Cavalier King Charles spaniels (CKCSs) and is often associated with syringomyelia and neuropathic pain (Rusbridge and Knowler, 2003). In a previous report of CM in CKCS, 32% of the study population had seizures (Lu et al., 2003). There is a heritable basis for idiopathic epilepsy in CKCS, but affected dogs are unrelated to dogs with occipital bone hypoplasia (Rusbridge and Knowler, 2004). In CKCS with CM, ventriculomegaly is associated with overcrowding of the caudal fossa and syrinx dimensions (Driver et al., 2010), possibly as a result of altered cerebrospinal fluid (CSF) flow dynamics. A unifying theory associating CM, hydrocephalus and syringomyelia with reduced venous drainage from the central nervous system has been proposed in humans (Williams, 2008). Hydrocephalus has previously been associated with seizures in dogs (Simpson, 1989). Rusbridge et al. (2006) postulated that progressive ventriculomegaly in CKCS with CM could be associated with seizures. Conversely, a separate study found the presence of neurological signs correlated poorly with morphological abnormalities including the degree of cerebellar herniation, the relative size of the cerebellum, the size of the lateral ventricles and the ⇑ Corresponding author. Tel.: +44 1707 666633. E-mail address: [email protected] (C.J. Driver). 1090-0233/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.

proportion of the foramen magnum occupied by the spinal cord (Lu et al., 2003). Therefore, it is unclear whether the presence and severity of CM and ventriculomegaly should be considered incidental in CKCS with CM that present with seizures. The primary aim of this study was to use MRI to measure cranial volumes on MRI and investigate possible associations between morphologic abnormalities in CKCS with CM and seizures. The secondary aim was to describe the seizure semiology and electroencephalographic (EEG) findings obtained from CKCS with CM. A search of electronic medical records from November 2005 to 2010 at the Royal Veterinary College was performed to identify CKCS with full cranial MRI consistent with CM (cerebellar indentation and herniation into the foramen magnum) for which T2weighted transverse and mid-sagittal MRI scans of the brain were available. Dogs were excluded if there were abnormalities on routine complete blood count, serum biochemical profile, bile acid stimulation test, cerebrospinal fluid analysis, or if there were MRI lesions other than CM that may have been associated with seizures. Data collected included age when scanned, presenting clinical complaint and in some cases, seizure semiology. Dogs were grouped by the presence or absence of seizures at presentation. Seizures were classified on the basis of owner description as in Berendt and Gram (1999). When possible, EEG was performed under light sedation with 0.005 mg/kg medetomidine hydrochloride (Animalcare) using a digital EEG unit (Trackit, Lifelines). A total of 16 platinum needle electrodes, including a ground, were used to record the EEG. An electrocardiogram (ECG) was obtained by using a base-apex electrode configuration. Each dog was assigned a study number so that an observer (CD), masked to the dog’s age and any history of seizures, could make


C.J. Driver et al. / The Veterinary Journal 195 (2013) 235–237

Table 1 Seizure classification by onset, type and subtype (Berendt and Gram, 1999). Seizure type

Number (%)

Partial onset Generalised onset Partial seizures Simple partial Complex partial Partial seizures with secondary generalisation Generalised tonic–clonic Generalised tonic Generalised atonica Generalised

17 (61) 11 (39) 10 (36) 5 (50) 5 (50) 7 (25) 13 (46) 3 (11) 2 (7) 11 (39)

a Canine patients with atonic seizures had normal cardiac evaluation including 24-h electrocardiographic halter monitor.

measurements. Suitable MRI series were exported to commercially available medical image software (Mimics 10.11, Materialise) and accurately measured in three dimensions, as previously described (Driver et al., 2010). The percentage volumes of parenchyma within the caudal cranial fossa (CCFP) and the ventricle size relative to total brain volume (V) were recorded. Statistical analysis was performed with a commercial software package (SPSS for Windows v17.0, SPSS). The Shapiro–Wilk W test was used to assess for normality in datasets (CCFP, V, age). Means and standard deviations were calculated for normally distributed continuous data, and medians and ranges were determined for non-parametric data. Independent sample t tests or Mann–Whitney U tests were used for statistical evaluation. Two-tailed tests were used in all cases and P < 0.05 considered significant. Eighty-five CKCS were included. They presented with histories of seizures (n = 27), peripheral vestibular disease (n = 3) and neuropathic pain (n = 55). There were 27 dogs in group 1 (seizures) and 58 dogs in group 2 (control). There were no statistically significant differences between group 1 and 2 for CCFP (89.83 ± 2.37% vs. 89.66 ± 1.80%; P = 0.71), V (4.63%, 1.00–14.7% vs. 5.813%, 0.88– 33.9%; P = 0.10) or age (4.48 ± 2.92 years vs. 4.48 ± 2.73 years; P = 0.99). Seizure classification is summarised in Table 1. Seizures were classified as having partial onset in 17 individuals (61% of the study population, 95% CI 42.41–76.43%). EEG was performed in four dogs with seizures and was found to be abnormal in three cases; findings are summarised in Table 2. Our results suggest that there is no difference in ventricle size or caudal fossa overcrowding between CKCS with CM and seizures and those with CM and other clinical signs but not seizures. This supports previous evidence that morphological abnormalities are not be associated with individual clinical signs (Lu et al., 2003). There could therefore be another source of epileptogenesis in this subset of dogs. In humans with posterior fossa malformations, the two risk factors identified for epilepsy are familial antecedents for epilepsy and the involvement of the cerebellum in the malformation (Parmeggiani et al., 1999). As there is a heritable basis for idiopathic epilepsy in CKCS (Rusbridge and Knowler, 2004), the former might be considered in these dogs. Another suspected cause

of seizures and focal paroxysmal abnormalities in humans with CM is cerebral microdysgenesis (Elia et al., 1999), which remains to be investigated in dogs. The EEG abnormalities described in this report are similar to those found in a small series of humans with CM, where paroxysmal abnormalities were mainly located over the frontal and temporal regions rather than in the cerebellum (Elia et al., 1999), suggesting they were not correlated with CM. However, there is a role for the cerebellum in epileptogenesis or seizure inhibition that has been demonstrated in animals (Dow, 1988). Lesions of the cerebellum such as ganglioglioma can cause seizures (Harvey et al., 1996). Rhythmic output from the cerebellum may contribute to the maintenance of generalised petit mal seizures (Kandel and Buzsaki, 1993). Conversely, several subcortical structures including the cerebellum influence the susceptibility of the forebrain to seizures by modulating the threshold for seizure initiation (Gale, 1992). As EEG electrodes were not routinely placed over the cerebellum in the cases included in the study, the possibility of paroxysmal electrical activity originating in the cerebellum of CKCS with CM could not be excluded. Therefore, it is possible that there a subset of CKCS in which epileptogenesis occurs in the cerebellum, as previously postulated in a small group of human patients (Elia et al., 1999). Sixty-one per cent of dogs in the present study had seizures that were classified as partial onset, which is similar to findings in previous studies in the general canine population (Berendt and Gram, 1999). This is the first report of seizure semiology of dogs with CM and epilepsy. Similarly, small case series in humans with CM and epilepsy reported a predominance of partial seizures, typically with secondary generalisation (Elia et al., 1999; Granata and Valentini, 2011). In our study, two CKCS experienced unusual acute onset, brief generalised atonic seizures. These were similar to ‘drop’ seizures associated with Chiari-I in children, which are believed to originate in the cerebellum (Pandey et al., 2001). These ‘drop’ seizures are paroxysmal attacks of collapse with or without loss of consciousness, abnormal extensor posturing and varying degrees of respiratory compromise, that are commonly associated with structural lesions of the cerebellum. ‘Drop’ seizures are often misdiagnosed as epilepsy in children with CM (Granata and Valentini, 2011). Further study is required to evaluate this association in dogs. There are limitations to this retrospective study. A control group of CKCS without CM could not be recruited as the disease is almost ubiquitous in this breed (Cerda-Gonzalez et al., 2009). We therefore investigated the relationship of individual morphometric abnormalities associated with CM and the presence of recurrent seizures. Additionally, a larger sample size might have provided enough statistical power to demonstrate statistically significant differences between the two groups. 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.

Table 2 Results of electroencephalography studies in three CKCS.



Seizure semiology

EEG report

Case 1

1 year; female spayed

Case 2 Case 3

11 months; male neutered 6 years; male neutered

Complex partial seizures; repetitive fly catching Generalised tonic seizures Complex partial seizures

Generalised spike-wave activity, more severe in the right fronto-temporal regionsa. There was further spike activity with underlying delta activity on waking (bifrontal, worse on the right) Generalised inter-ictal spike waves, mostly observed from the fronto-temporal regions Transient sharp waves during sleep in the rostral cortical regions particularly in the frontocentral areas. After reversal of sedation, further rhythmic sharp wave activity, which was often associated with witnessed seizure-like episodes

The generalised spike wave activity recorded may reflect the poor spatial resolution of EEG in detecting an epileptic seizure focus in non-superficial cerebral tissue.

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Acknowledgements The authors would like to acknowledge the dogs and dog owners that participated in this study and the veterinarians who referred them to us. The authors would also like to thank the various CKCS health clubs for their continuous support for the investigation of these conditions. Finally, the authors also would like to thank the Clinical Investigation Centre of the Royal Veterinary College and its research office for assessing the manuscript according to the Royal Veterinary College’s code of good research practice (Authorisation Number – VCS_00244).

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