Spontaneous late-onset myoclonic epilepsy in cats: 15 cases (2015–2023)

Abstract

Objectives

The aim of this study was to describe spontaneous late-onset myoclonic epilepsy (SLOME) in older cats.

Methods

A retrospective, two-centre study was conducted on cats diagnosed with spontaneous (non-audiogenic) head myoclonus between 2015 and 2023.

Results

A total of 15 cats were included. Breeds included domestic shorthair (11/15, 73%) and one each (7%) of domestic longhair, Somali, Burmese and Russian Blue. Of the 15 cats, eight (53%) were castrated males and seven (47%) were spayed females. All cats were older, with a median age at presentation of 13.2 years (range 8.9–17). The median duration between the first episode and presentation was 5.5 months (range 1–24). All cats (15/15, 100%) presented with spontaneous, non-audiogenic myoclonus of the head, some of which had additional thoracic limb (3/15, 20%) or full body (1/15, 7%) involvement. Myoclonus frequency was progressive, with multiple daily or weekly episodes in half of the population (7/15, 47%). Two cats (2/15, 13%) had concurrent generalised tonic–clonic seizures. Eight cats (53%) had advanced imaging that was normal in all but three (37%) cats with concurrent brain atrophy, otitis media/externa and a pituitary mass. A diagnosis of SLOME was made in all cats. Levetiracetam (7/15, 47%) and phenobarbital (1/15, 7%) were administered, and all cats had a positive response, displaying either resolution or significant reduction in frequency of the myoclonus at a median follow-up time of 128 days (range 30–300).

Conclusions and relevance

SLOME is a novel epileptic seizure phenotype prevalent in older cats, unrelated to audiogenic triggers, and occasionally accompanied by generalised tonic–clonic seizures. Levetiracetam could result in dramatic improvement.

Introduction

Myoclonus is a sequence of repeated, variably rhythmic, brief, shock-like jerks resulting from the sudden involuntary contraction or relaxation of one or more muscles, which generates movement of the affected body part (eg, the head). ¹

In humans, the most recent classification of myoclonus is based on clinical, aetiological and neurophysiological factors. ² Clinically, myoclonus can be classified based on topography (focal, multifocal, segmental, generalised), rhythmicity (rhythmic or arrhythmic), status of occurrence (at rest, during an action or while maintaining a posture) and provocation (reflex when triggered by a stimulus or spontaneous). ² Aetiologically, myoclonus can be physiological (eg, sleep jerks), essential (eg, idiopathic), epileptic, symptomatic or secondary (eg, due to underlying neurological disease) or psychogenic. ² Neurophysiologically, myoclonus can be cortical, cortical–subcortical, subcortical–non-segmental, segmental or peripheral. ²

In veterinary neurology, no such in-depth classification of myoclonus exists. Generally, myoclonus is considered to be epileptic or non-epileptic. ³ Myoclonic seizures have been reported in juvenile myoclonic epilepsy, such as in Rhodesian Ridgeback dogs with a DIRAS1 gene mutation – with or without accompanying absence seizures^4,5 – and in Beagles and Wirehaired Dachshunds with Lafora disease caused by an EPM2B gene mutation.^{6 –8} Myoclonus has also been recently described in older Retriever dogs, speculated to represent late-onset myoclonic seizures. ⁹ A more focal myoclonus (ie, predominantly the head) has also been described in old Cavalier King Charles Spaniels,^10,11 which is less pharmacoresponsive in the long term and likely associated with a neurodegenerative process. ¹¹ Symptomatic myoclonus, of unknown epileptic or non-epileptic origin, has also been reported in dogs with lymphoproliferative central nervous system disease, ¹² meningoencephalomyelitis of unknown origin,^13,14 sepsis (auricular myoclonus) ¹⁵ or as a pharmacological adverse effect.^{16 –18} Non-epileptic segmental myoclonus has been historically considered the hallmark of distemper in dogs and has been associated with lower motor neuron damage. ¹⁹ Recently, the cervical spasms manifested in dogs with severe cervical hyperaesthesia or cervical myelopathy were suspected to represent spinal myoclonus. ²⁰

Other than generalised tonic–clonic (GTC) seizures, other epileptic seizure phenotypes have been recognised in cats. Feline temporal lobe epilepsy (FTLE), previously called feline partial cluster seizures with orofacial involvement (FEPSO), has a characteristic phenotype and is most commonly associated with limbic encephalitis. ²¹ Another recognised phenotype is feline audiogenic reflex seizures (FARS). ²² In FARS, cats manifested audiogenic reflex myoclonic seizures, some of which were accompanied by GTC or absence seizures. ²² In all cases, the myoclonic seizures were triggered by audiogenic stimuli, although some seizures occurred without a trigger. ²²

We have identified a population of cats with suspected spontaneous late-onset myoclonic epilepsy (SLOME) manifested as spontaneous non-audiogenic myoclonic seizures occasionally accompanied by GTC seizures that responded to levetiracetam. The aim of this study was to describe the semiology, MRI findings, treatment and outcome in cats with SLOME.

Materials and methods

This was a retrospective, observational, two-centre, case-series study conducted between January 2015 and December 2023. Ethical approval was granted by the Royal Veterinary College Social Sciences Research Ethical Review Board (URN: SR2023–0163).

Search terms included the following: myoclon* or jerk, and, cat or feline. The inclusion criteria consisted of complete medical records, clinical features consistent with head or body myoclonus and lack of a reflex trigger. The exclusion criteria included clinical records that did not clearly describe myoclonus and reflex myoclonus (eg, audiogenic or photogenic).

Complete medical records consisted of signalment, presenting complaints, clinical, neurological and clinicopathological findings. MRI, CT, cerebrospinal fluid (CSF) analysis findings, other diagnostic test results and video recordings were obtained when available. All neurological examinations were performed by a board-certified neurologist or a neurology resident under the direct supervision of a board-certified neurologist. MRI was performed with a high-field magnet (Intera 1.5T; Philips Healthcare), and it included a minimum of transverse and sagittal T2-weighted, transverse fluid attenuation inversion recovery, and transverse and sagittal T1-weighted pre- and post-contrast (gadopentetate dimeglumine 0.1 mmol/kg IV bolus) images. CT used a multi-slice scanner (320-slice Aquilion ONE Genesis Edition; Canon Medical Systems).

Follow-up was conducted in two stages: short term, based on telephone call or clinical re-examination records, and long term, where a questionnaire regarding outcome and follow-up was sent to the owners.

A descriptive statistical analysis was performed using standard statistical software (SPSS Statistics 26; IBM). Data were assessed for normal distribution using the Shapiro–Wilk test for normality. Non-normally distributed numerical variables were presented as median, interquartile range (IQR) and range, while categorical variables were summarised as counts and percentages.

Results

A total of 24 cats with myoclonus were identified, 15 of which met the inclusion criteria. Breeds represented were domestic shorthair (11/15, 73%) and one each (1/15, 7%) of domestic longhair, Burmese, Russian Blue and Somali. Of the 15 cats, eight (53.3%) were castrated males and seven (47%) were spayed females. All cats were older, with a median age at presentation of 13.2 years (range 8.9–17, IQR 11.3–14.9). The median body weight at presentation was 4.2 kg (range 3.2–5.8, IQR 3.4–4.8). The median duration between the first episode and presentation was 5.5 months (range 1–24, IQR 5–24). Two cats were genetically related as mother and daughter.

In 8/15 (53%) cats, myoclonus was the main presenting complaint; the other 6/15 (40%) cats were referred because of a different complaint and myoclonus was diagnosed incidentally. These cats were presented because of GTC seizures (2/15, 13%) and one each (1/15, 7%) of acute progressive lateralised vestibular signs and Horner syndrome, acute Horner syndrome alone, subacute progressive head pressing and pacing, anorexia and lethargy after hypophysectomy to treat acromegaly, and upper respiratory signs. In all cats that presented with other clinical or neurological signs, myoclonus had been present for more than 5 months before the onset of these signs; therefore, myoclonus was considered an incidental finding.

Other than the head myoclonus, neurological examination was abnormal in 3/15 (20%) cats. Abnormal findings included one each (1/15, 7%) of right-sided Horner syndrome, right-sided central vestibular syndrome along with Horner syndrome, and diffuse forebrain characterised by disorientation, pacing, head pressing and getting stuck in corners.

Paroxysmal episodes were confirmed as myoclonus in all cats, based on clinical observation (15/15, 100%) or video assessment (8/15, 53%). Although all cats remained conscious during the episodes, myoclonus persisted despite attempts of distraction. No audiogenic, photogenic or other triggers were identified in any of the cats, and none of the episodes were accompanied by autonomic or post-ictal signs. In all cats, myoclonus affected the head (15/15, 100%). Additional involvement of the thoracic limbs was observed in 3/15 (20%) cats, and full-body involvement in 1/15 (7%). In almost half of the cases (7/15, 47%), the frequency of head myoclonus was reported as progressive. The duration of individual episodes was less than 1 min in all cats (15/15, 100%). Episodes occurred multiple times a day in 6/15 (40%) cats, multiple times per week in 4/15 (27%) cats, while the frequency was uncertain in the remaining cases because of insufficient history.

Two cats (13%) had concurrent GTC seizures. In one of these cats, head myoclonus began 3–4 months before the onset of GTC seizures. In the other, head myoclonus and GTC seizures appeared at the same time and occurred interchangeably.

Haematology was normal in 13/15 (87%) cats and abnormal in 2/14 (13.3%) cats, including stress leukogram in one cat and mild anaemia in another. Serum biochemistry was within normal limits in the majority of cats (14/15, 93%) and abnormal in 1/15 (7%), which showed hypercholosterolaemia (4.7 μmol/l, reference interval 2.2–4). Urinalysis and total thyroxine (TT4) were performed in 3/15 (20%) cats and were within normal limits. Two cats (14%) had been previously diagnosed with hyperthyroidism and TT4 was not performed at the time of referral.

MRI of the head was performed in 6/15 (40%) cats, of which 4/6 (70%) revealed a normal brain. One cat had diffuse cerebrocortical atrophy, likely age-related, and another cat had a pituitary mass. Two cats (14.3%) had a CT scan of the head, which revealed middle ear effusion and evidence of otitis externa and media in one cat, whereas it was normal in the other. In 4/15 (27%) cats, cerebellomedullary cisternal CSF analysis was performed and was within normal limits. Serology for LGI1 antibodies was performed on 3/15 (20%) cats and was negative. Serology for infectious diseases was performed in some cats and was negative for all: ELISA for feline immunodeficiency virus and feline leukaemia virus antigen (3/15, 20%), indirect fluorescent antibody (IgG and IgM) for Toxoplasma gondii (1/15, 7%) and for feline coronavirus (1/15, 7%).

A diagnosis of SLOME was made for all cats. Of them, two (13%) had accompanying GTC seizures and a normal MRI of the brain. Three cats presented for more acute/subacute signs and were diagnosed with otitis externa/media (Horner syndrome: 1/15, 7%), pituitary mass (diffuse forebrain signs: 1/15, 7%) and suspected otogenic meningoencephalitis (central vestibular syndrome and Horner syndrome, no advanced imaging performed; however, the cat improved with antibiotics: 1/15, 7%). Other comorbidities included hyperthyroidism (2/15, 13%), upper respiratory tract disease (1/15, 7%) and hypertrophic cardiomyopathy (1/15, 7%).

Nine cats (60%) were treated with antiseizure drugs to treat myoclonus. Levetiracetam (20–25 mg/kg PO q8h [in two cats q12h and in one cat 10 mg/kg q8h]) was given to 7/15 (47%); all cats had a dramatic positive response to levetiracetam, with myoclonus ceasing or a seizure frequency decrease of 50% or greater from multiple per day to a frequency of a few episodes per week, at a median follow-up time of 128 days (range 30–300, IQR 63.7–264.7). In one cat, myoclonus recurred after 1 year on levetiracetam; phenobarbital (2.5 mg/kg PO q24h) was then added, resulting in cessation of the myoclonic episodes during a 6-month follow-up period. In one cat that also had GTC seizures, phenobarbital (2.5 mg/kg PO q12h) was given as the initial treatment after diagnosis and both GTC seizures and myoclonus resolved during a 4-month follow-up period. In the other cat with GTC seizures, the latter were controlled under administration of levetiracetam during a 1-month follow-up period. Two cats were treated with the antibiotic amoxicillin/clavulanic acid (20 mg/kg PO q12h) for otitis externa/media and suspected otogenic meningoencephalitis. In these cats, the additional neurological signs resolved after antibiotic treatment. The owners declined antiseizure medication, and the myoclonus episodes persisted throughout the 1-month follow-up period. The cat with the pituitary mass received only palliative treatment with prednisolone (1 mg/kg PO q24h) and was euthanased shortly after discharge.

For the cats still alive at the time of writing, long-term follow-up was obtained via an owner questionnaire (9/15, 60%). Five cats had been euthanased for non-neurological reasons. Of the questionnaires sent, the response rate was low (3/9, 33%), with a median follow-up duration of 953 days (range 470–1650). In all cases, myoclonus persisted and occurred sporadically throughout the day. Although the cats appeared to be conscious during the episodes, they could not be distracted out of them. No cat was reported as being lethargic, confused or disoriented during the episodes. Only one cat was treated with levetiracetam, which markedly reduced the frequency of the episodes; the remaining cats received no treatment. One cat developed GTC seizures, and another was suspected to have signs consistent with dementia.

Discussion

This study describes SLOME as a novel phenotype of suspected epileptic seizures in older cats that is responsive to levetiracetam. SLOME may consist of a spontaneous alternative phenotype form of FARS as it shares similarities; however, it differs as it is not triggered by audiogenic stimuli and is not often accompanied by GTC seizures.

In cats, FARS is the most reported cause of myoclonus in cats. ²² It is a geriatric epileptic syndrome characterised by myoclonus triggered by high-pitched noises, frequently followed by GTC and occasionally by absence seizures. ²² Although all cats in FARS have audiogenic seizures, 20% and 8% may manifest spontaneous myoclonus or GTC seizures, respectively. ²² Most cats responded to withdrawal of the audiogenic reflex (75%), ²² and a reduction of 50% or more in the number of myoclonic seizure days was seen in all patients treated with levetiracetam in a single clinical trial. ²³ In the cats from our study with SLOME, no audiogenic triggers were reported – as per the inclusion criteria – and myoclonus was spontaneous in all cases, mainly affecting the head. Only a few cats with SLOME (13%) had accompanying GTC seizures. In 40% of cases, myoclonus was not the main presenting complaint. It can be speculated that owners may perceive this as a less dramatic sign compared with GTC seizures and therefore may not seek immediate veterinary attention. None of the cats with SLOME exhibited signs of cognitive dysfunction or deafness, in contrast to what has been reported in FARS. However, similar to FARS, all cats treated with levetiracetam showed a marked reduction or complete cessation of myoclonic seizures. Notably, in one cat, after 1 year of successful management with levetiracetam, a progressive increase in daily myoclonus frequency led to the introduction of phenobarbital, which subsequently stopped the episodes. Interestingly, the biological mother of one cat exhibited the same semiology as her daughter, raising the possibility of a genetic component.

A progressive geriatric myoclonus has been reported in middle-aged and older Cavalier King Charles Spaniels.^10,11 In this breed, myoclonus was spontaneous, mainly affecting the head with variable involvement of the thoracic limbs and usually accompanied by rapid blinking. ¹⁰ In some cases, presence of GTC seizures was variable (15–69%).^10,11 Progressive behavioural changes suggestive of cognitive decline were common. ¹¹ Levetiracetam initially led to a reduction in episodes; however, in one cohort of dogs, myoclonus tended to progress over time despite treatment, suggesting a potential underlying neurodegenerative process. ¹¹ Cats with SLOME share some similarities with Cavalier King Charles Spaniels with myoclonus, as both conditions involve geriatric animals exhibiting primarily head-focused myoclonus. However, in our feline cohort, the myoclonus was not accompanied by the characteristic blinking observed in Cavalier King Charles Spaniels. In addition, the cats in our study responded well to levetiracetam during the period examined, and the condition was not progressive in almost half the population. Another comparable canine syndrome is myoclonus in geriatric Retriever breeds. ⁹ In that study, five dogs exhibited head myoclonus, often involving the limbs or entire body, with one dog also experiencing GTC seizures. ⁹ All responded to levetiracetam. ⁹ None of these studies included electroencephalographic testing to confirm an epileptic origin for the myoclonus;^{9 –11} however, myoclonic epilepsy was suspected owing to the response to levetiracetam and the presence of GTC seizures in some cases.

Inherited myoclonic epilepsy associated with degenerative encephalopathies has been rarely reported in feline veterinary literature. Neuronal ceroid lipofuscinosis is the most commonly reported disease associated with myoclonus in cats.^{24 –26} In such cases, the manifestation of myoclonus would be expected at a younger age. Lafora disease, a commonly reported myoclonic epilepsy in dogs that manifests at an older age, ⁷ has only been reported in two feline pathological case reports.^27,28 In one of them, neurological signs were not described; ²⁷ however, the other documented signs such as ‘tremors’ and ‘bobbing’ of the head and body, which could possibly represent myoclonus.

An overall frequent type of myoclonus in cats throughout the literature is drug-induced myoclonus. Myoclonus has been reported in cats treated with chemotherapy (eg, chlorambucil PO), ²⁹ analgesics (eg, gabapentin PO) ³⁰ and general anaesthetics (eg, etomidate IV). ³¹ In addition, myoclonus has been reported after epidural or subarachnoid injection of opioids and topical anaesthetic (eg, morphine and bupivacaine). ³² In humans, there is strong evidence of drug-induced myoclonus associated with intravenous anaesthetics (etomidate), cephalosporins (ceftazidime, cefepime), fluoroquinolones (ciprofloxacin), selective serotonin reuptake inhibitors (citalopram, escitalopram, paroxetine, sertraline), tricyclic antidepressants (amitriptyline), glutamate antagonists (amantadine), atypical antipsychotics (clozapine, quetiapine), antiseizure medications (carbamazepine, oxcarbazepine, phenytoin, gabapentin, pregabalin, valproate), pure opioid agonists (fentanyl, morphine), bismuth salts and mood stabilisers (lithium). ³³ Drug-induced myoclonus is speculated to have different pathophysiology depending on the drug; however, most of them have been postulated to be associated with serotonin syndrome. ³³ Drug-induced myoclonus tends to be reversible after withdrawal of the causative drug. ³³ Therefore, it is important when confronting myoclonus in cats to consider recent, previous or current medications administered and drug-induced myoclonus.

The limitations of this study include its retrospective design, the small number of cases and the absence of electroencephalographic evaluation to confirm the epileptic origin of the myoclonus.

Conclusions

SLOME is a spontaneous form of geriatric myoclonic epilepsy in cats that responds well to levetiracetam. Early recognition and treatment may improve quality of life, reduce the risk of progression to GTC seizures and offer therapeutic benefit with minimal side effects.