Abstract
Objectives
Hypertensive encephalopathy in cats is an important entity but is underestimated in clinical practice. This could be explained, in part, by non-specific clinical signs. The objective of this study was to characterise the clinical manifestations of hypertensive encephalopathy in cats.
Methods
Cats with systemic hypertension (SHT) recognised by routine screening, associated with underlying predisposing disease or a clinical presentation suggestive of SHT (neurological or non-neurological), were prospectively enrolled over a 2-year period. Confirmation of SHT was based on at least two sets of measurements of systolic blood pressure >160 mmHg by Doppler sphygmomanometry.
Results
Fifty-six hypertensive cats with a median age of 16.5 years were identified; 31 had neurological signs. In 16/31 cats, neurological abnormalities were the primary complaint. The other 15 cats were first presented to the medicine or ophthalmology service, and neurological disease was recognised based on the cat’s history. The most common neurological signs were ataxia, various manifestations of seizures and altered behaviour. Individual cats also showed paresis, pleurothotonus, cervical ventroflexion, stupor and facial nerve paralysis. In 28/30 cats, retinal lesions were detected. Of these 28 cats, six presented with a primary complaint of visual deficits, and neurological signs were not the primary complaint; nine presented with non-specific medical issues, without suspicion of SHT-induced organ damage; in 13 cats, neurological issues were the primary complaint and fundic abnormalities were detected subsequently.
Conclusions and relevance
SHT is common in older cats and the brain is an important target organ; however, neurological deficits are commonly ignored in cats with SHT. Gait abnormalities, (partial) seizures and even mild behavioural changes should prompt clinicians to consider the presence of SHT. A fundic examination in cats with suspected hypertensive encephalopathy is a sensitive test to support the diagnosis.
Introduction
Systemic hypertension (SHT) is a well-recognised problem in elderly cats with predisposing diseases, particularly chronic kidney disease (CKD), hyperthyroidism and, more rarely, hyperaldosteronism. Idiopathic hypertension is diagnosed when no predisposing disease is recognised and accounts for up to 40% of cases.1–4 Despite the general recommendation to routinely measure blood pressure (BP) in cats at risk for SHT, it often remains undiagnosed until cats present with severe target organ damage (TOD) and an associated guarded prognosis regarding complete recovery.5,6 The eyes, central nervous system (CNS), kidneys and cardiovascular system are known target organs of SHT.5–11 Hypertensive retinopathy is the most common clinically diagnosed manifestation of SHT-induced TOD.5,6 Hypertensive encephalopathy is less commonly reported. In one study, neurological signs were recognised by the owners in only 5/24 cats with SHT-induced TOD before the initial presentation, and an additional six cats had developed neurological signs in the further course of hypertensive disease. 5 In a second retrospective study of 69 cats, neurological signs were the primary complaint in seven cats, neurological abnormalities were identified in the initial clinical examination in 14 cats and neurological abnormalities developed in the further course of the disease in an additional six cats. 6 These studies imply that although the incidence of hypertensive encephalopathy in feline SHT is rather high (29–46%), its associated clinical signs are only recognised as a presenting complaint in 10–20% of cases. In addition to hypertensive encephalopathy, ischaemic myelopathy associated with SHT has been described. 12
Neurological signs attributed to hypertension in cats are various and include seizures, changes in mentation (lethargy, stupor, coma), vestibular dysfunction (head tilt, vestibular ataxia, abnormal nystagmus) and less common behavioural changes (disorientation, polyphagia, abnormal vocalisation, photophobia, frequent blinking, head pressing), tremors, sudden collapse, cervical ventroflexion, episodes of dragging the pelvic limb(s), decorticate posturing of one or both thoracic limbs, (temporary) cerebellar ataxia, ambulatory/non-ambulatory paresis, (isolated) cranial nerve deficits and acute blindness (presumed cortical in nature).5,6,10,12–16
We hypothesised that the occurrence of hypertensive encephalopathy often remains unsuspected and therefore undiagnosed owing to the subtlety of some neurological signs, as opposed to the often acute and dramatic retinal manifestations. Therefore, the aim of this study was to evaluate the clinical occurrence of hypertensive encephalopathy and to characterise its different manifestations in cats.
Materials and methods
Animals
Between March 2019 and January 2021, cats presented to the Small Animal Clinic, at the Vetsuisse Faculty of the University of Zurich, with a clinical complaint potentially caused by STH or predisposing for SHT, and subsequently confirmed SHT, were prospectively enrolled. This comprised cats with: (1) impaired vision or blindness; (2) neurological deficits; (3) predisposing diseases such as CKD and/or hyperthyroidism; and (4) age >10 years.
In all cats, a routine complete blood count and biochemical profile, including thyroxine (T4) levels and urinalysis, were performed. In cats with low serum potassium (<3.8 mmol/l), an abdominal ultrasound to assess the adrenal glands was performed.
Diagnosis of CKD was based on serum creatinine above the reference interval (RI; >163 µmol/l) in non-dehydrated animals with or without clinical signs such as weight loss, polyuria/polydipsia or irregular kidney size or surface on abdominal palpation. Hyperthyroidism was diagnosed if the concentration of serum T4 exceeded the RI (>3.3 µg/dl). Hypokalaemic cats with an adrenal mass on abdominal ultrasound and elevated serum aldosterone were diagnosed with primary hyperaldosteronism. If no underlying disease was identified, SHT was classified as primary or idiopathic.
Blood pressure measurement
Indirect systolic BP measurements were obtained with Doppler sphygmomanometry (Parks Device 811B) using a standard protocol in a quiet environment and away from other animals. Predefined cuff sizes were chosen after measuring the limb circumference (Table 1). The cats were allowed to acclimate to the measurement room for 5–10 mins before BP measurement was attempted, and measurements were only taken when the cat was calm and motionless. The cats were gently restrained in a comfortable position, in ventral recumbency without sedation. The cuff was placed on a limb or the tail, based on the cat’s preference. All BP measurements were performed by a single, well-trained investigator (LM). The average of five subsequent BP measurements was obtained after the plateauing of BP measurements. The inclusion criterion was an average BP of >160 mmHg.
Choice of cuff size for measuring blood pressure in cats
Neurological examination
A complete neurological examination was performed in every cat by a trained neurologist.
Imaging
MRI was discussed with the owners and a brain MRI (Philips Ingenia 3T, eight-channel small extremity coil) was performed under general anaesthesia after considering the risks and benefits for each individual cat. The protocol used for the individual cats was based on the preference of the radiologist in charge and consisted of at least a transverse T2-weighted (T2W), fluid-attenuating inversion recovery and T2*W, sagittal and dorsal T2W, diffusion-weighted and three-dimensional T1-weighted pre- and postcontrast sequences.
Treatment
Antihypertensive treatment was started as a monotherapy in all cats. Cats were treated either with amlodipine (0.625 mg q24h in cats weighing <4 kg, 1.25 mg q24h in cats weighing >4 kg) or with telmisartan (1.5 mg/kg q24h). BP was monitored after 24 h, and the same treatment was continued. BP measurement was repeated after 8 h and, in case of insufficient response (BP continued to be >160 mmHg), either telmisartan (+1.5 mg/kg q24h) was added in those cases started on amlodipine or in those cases started on telmisartan, amlodipine (+0.625 mg) was added.
Follow-up
At the time of writing, every owner had been contacted by telephone. Questions to determine actual clinical status, death or euthanasia were included. The time between the first presentation and last follow-up or death was noted.
Results
Animals, fundoscopy and presenting complaint
SHT was diagnosed in 56 cats; neurological deficits were identified in 31/56. Fourteen cats were also included in a previous prospective study evaluating the reliability of a fundic examination by a non-ophthalmology-trained veterinarian. 17
Age, median systolic BP and causes of hypertension for all 56 hypertensive cats examined in the study period are provided in Table 2. The study population (ie, cats with neurological abnormalities) consisted of 31 cats. Of these, nine had been presented to the medicine, 16 to the neurology and six to the ophthalmology service, respectively. Breeds included domestic shorthair (n = 21), British Shorthair (n = 4), Persian (n = 2), Siamese (n = 2), Burmese (n = 1) and Chartreux (n = 1). Eighteen of the cats were spayed females and 13 were castrated males. An ophthalmological examination was performed in 30 cats, and retinal lesions were detected during fundoscopy in 28/30 cats. Of these 28 cats, six were primarily presented because of visual deficits and/or mydriasis, and neurological signs were not a primary complaint; 13/28 cats had been presented because of neurological abnormalities as the primary complaint, and fundic abnormalities were detected subsequently; in 9/28 cats, hypertension was found without a primary complaint of any TOD, but fundic abnormalities were subsequently found in all nine. These nine cats were first presented to the medicine service with non-specific complaints of anorexia, apathy, weight loss, intestinal or urological signs. Fundic lesions were not found in two cats, and no fundic examination was performed in one cat presented with a primary neurological complaint.
Blood pressure (BP), age and cause of systemic hypertension (SHT) in 56 cats and in subgroups of cats with associated neurological signs
Presented with primary medical (n = 9) or ophthalmological complaint (n = 6)
Systolic BP with Doppler sphygmomanometry
CKD = chronic kidney disease
Cats with neurological signs as the primary concern
The neurological signs of all 31 cats are summarised in Table 3. In 16/31 cats, neurological signs were the primary presenting complaint. Twelve of these 16 cats showed ataxia. Six of these 12 cats had vestibular signs (head tilt, n = 4; abnormal nystagmus, n = 3; walking in circles, n = 2; falling to one side, n = 2; positional strabismus, n = 1). The other six cats had non-vestibular but suspected cerebral (proprioceptive) ataxia; of these, three were blind, which was considered a factor contributing to the ataxia.
Neurological abnormalities in 31 cats with systemic hypertension
Four cats showed various expressions of altered behaviour: hiding (n = 2); disorientation (n = 2); sleeping in unusual locations (n = 1); increased and inappropriate vocalisation (n = 1, euthyroid); and increased appetite (n = 1, euthyroid).
Three cats presented with generalised seizures, and three cats showed variable paresis: hemiparesis (n = 1), hemiplegia (n = 1) and tetraparesis (n = 1). Two cats showed pleurothotonus, two ventroflexion (one hypokalaemic due to hyperaldosteronism, one with tetraparesis), one stupor and one right-sided facial nerve paralysis (without vestibular signs). 16
Based on the presenting neurological abnormalities, the neuroanatomical localisations in these cats were the telencephalon (n = 16), vestibular system (n = 6), craniocervical spinal cord (n = 3) and facial nerve (n = 1). In this group, the neurological abnormalities could not all be attributed to a single neuroanatomical location (ie, the neurological examination implied multifocal lesions).
Cats without neurological signs as primary concern
In the other 15 cats, neurological deficits were recognised only after thorough expansion of the clinical history. Six of these 15 cats had demonstrated seizures. In three cats, these were infrequent generalised seizures of short duration. Three cats had focal seizures, specifically intermittent twitching of the face (n = 2) and intermittent twitching of the thoracic wall (n = 1). In five cats, altered behaviour, such as increased and inappropriate vocalisation (n = 3, all euthyroid), hiding (n = 1), disorientation (n = 1) and inappropriate urination (n = 1), had been observed. Three cats had shown ataxia, all of which were considered of vestibular origin; of these, one showed intermittent and infrequent tilting to one side and occasional falling from the scratching tree. One cat had shown intermittent paraparesis. Neurological complaints had been present in some of these cats for >6 months.
Based on the neurological abnormalities, affected neuroanatomical localisations in these cats were the telencephalon (n = 12), the vestibular system (n = 2) and the spinal cord (n = 1). In this group, the neurological abnormalities could seemingly be attributed to one main neuroanatomical location.
Imaging findings
MRI of the brain was performed in 4/31 cats, three of which had a primary neurological complaint. Three cats showed increased signal intensity within the white matter on T2W images of the cerebrum (Figure 1).
Fifteen-year-old male neutered domestic shorthair cat with severe hypertension and vasogenic oedema. (a–d) Transverse images (3 T) at the same level. (a) Marked, diffuse T2-weighted (T2W) hyperintensity (white arrows) is evident, involving the white matter of the cerebral hemispheres. (b) This region is hypointense in a T1-weighted postcontrast sequence. (c) Diffusion-weighted imaging (B value 1000) demonstrates low signal (high diffusion) in the regions that are hyperintense on T2W images, while (d) it shows high values on the apparent diffusion coefficient map, consistent with unrestricted diffusion owing to vasogenic oedema
Microbleeds were not observed. In one cat, no abnormalities were detected; its neurological signs were intermittent facial twitching and ear flicking, which were interpreted as a partial seizure. In view of the unremarkable MRI, a diagnosis of cryptogenic epilepsy was made; however, all abnormalities disappeared after normalisation of the elevated BP, indicating MRI-negative hypertensive encephalopathy.
Treatment
Amlodipine was used as a single hypertensive medication in 39 cats, including 22/31 neurological cats. Amlodipine dosage at discharge ranged from 0.625 mg/cat/day to 5 mg/cat/day (median 1.25). Telmisartan (1–2 mg/kg/day) was used as a single hypertensive drug in six cats (median 2 mg/kg/day), including four cats with neurological signs. A combination of amlodipine and telmisartan was used in 11 cats, including four cats with neurological signs. The amlodipine dosage ranged from 0.625 mg/kg/day to 2.5 mg/kg/day (median 0.625 mg/kg/day) in this group, combined with 1–3 mg/kg/day telmisartan (median 1.5 mg/kg/day).
Follow-up
Follow-up information was available for 25/31 cats with neurological signs. The other 6/31 cats were lost to follow-up.
In 15/25 cats, the neurological signs resolved completely under antihypertensive treatment after a mean of 60 days (range 8–199), including cats with severe seizures, hemiplegia or stupor. These 15 cats were discharged with amlodipine monotherapy (n = 11; median dosage 1.25 mg/cat/day [mean 1.02; range 0.625–1.25), telmisartan monotherapy (n = 1; dosage 2 mg/kg q24h) or combined amlodipine–telmisartan therapy (n = 3; amlodipine 0.625 mg/cat q24h and telmisartan 1.5 mg/kg q24h [n = 1]; amlodipine 0.625 mg/cat q24h and telmisartan 1.5 mg/kg q12h [n = 1]; and amlodipine 2.5 mg/cat q24h and telmisartan 2 mg/kg q24h [n = 1]). Two of these cats with an initial full recovery were euthanased due relapsing neurological signs 3.5 and 9 months after discharge, respectively.
A partial response was observed in 8/25 cats. Remaining neurological signs included mild ataxia (n = 3), facial twitching (n = 2), vocalisation (n = 1) and mild behavioural changes (n = 1).
These eight cats had been discharged with amlodipine monotherapy (n = 4; median 1.56 mg/kg/day [mean 2.34; range 1.25–5]), telmisartan monotherapy (n = 3; mean 1.5 mg/kg q24h [range 1–2]) or amlodipine and telmisartan combination therapy (n = 1; amlodipine 0.625/cat q12h and telmisartan 1 mg/kg q24h).
No response to the initial treatment was observed in two cats (seizures and behavioural changes), and both were euthanased 4 and 6 days after discharge, respectively, at the owners’ requests. Both cats were discharged with amlodipine (0.625 and 1.25 mg/cat/day) monotherapy. Neither of these two cats had an MRI or post-mortem examination to confirm hypertensive encephalopathy.
Regarding long-term analysis and survival, 14/25 cats were still alive at the time of writing, after a median of 445.5 days (range 58–793) of starting treatment for hypertension.
One blind cat died after falling from a balcony and 10 were euthanased, four because of poorly controlled SHT (as stated above) and six for reasons not associated with SHT.
Discussion
Even though the CNS has long been recognised as an important target organ for hypertensive damage in cats, only few studies have characterised the associated specific neurological signs, which was the goal of this study. Several general findings, confirming those of previous reports, are worth mentioning. First, a relatively large number of cats enrolled in a relatively short period underscores the importance of SHT in cats. 15 Second, the number of hypertensive cats with neurological signs was relatively high at 55%. Third, neurological complaints were the reason for presentation in only around half of the cats with neurological signs, similar to previous studies. Furthermore, the neurological signs were quite variable. Finally, clinical neurological signs were reversible or partly reversible in 92% of cases, including cats with severe seizures and stupor. From our perspective, the latter three points are the most important. A multitude of neurological signs had been present before the cats were finally presented with an acute and severe TOD. Neurological abnormalities had apparently been ignored owing to intermittent occurrence, subtle manifestations or the misinterpretation of signs. In contrast to the often irreversible retinal blindness, even severe neurological abnormalities are seemingly reversible.
The most common neuroanatomical location of CNS damage was the forebrain. The corresponding clinical signs were variable, with seizures, altered behaviour, (suspected) cerebral ataxia, (probably at least some) paresis and pleurothotonus.
The second most common location was the brainstem. The corresponding clinical signs were (central) vestibular signs, including vestibular ataxia, (probably at least some) paresis and stupor.
An additional suspected location was the spinal cord, as two cats showed paresis only, without any additional signs indicative of a forebrain or brainstem lesion.
There are similarities and dissimilarities in hypertensive encephalopathy between species. Humans may have a condition called posterior reversible encephalopathy syndrome, which manifests in seizures owing to prosencephalic white matter oedema.18–21 The same brain region is affected in hypertensive cats, described with acute BP elevation >30 mmHg or a sustained BP elevation >180 mmHg. 20 The mechanisms underlying cerebral oedema formation are thought to be arteriolar vasoconstriction and disruption of the blood–brain barrier with subsequent vasogenic edema.13,14,18,20 Compensatory cerebral arteriolar vasodilation exacerbates cerebral oedema. Chronic SHT may lead to damage of the endothelium, with release of inflammatory cytokines further increasing permeability and oedema.14,19 In contrast to dogs and humans, lacunar infarction and intracerebral haemorrhage are not always present in cats. 18 In fact, arterial hyalinosis and arteriosclerosis were a consistent finding within oedematous areas seen on neuropathology in hypertensive cats.14,18 This difference is thought to be due to a different vascular supply of the brain by the maxillary artery (after branching from external carotid artery), while in dogs cerebral perfusion is supplied by the basilar and internal carotid arteries.13,18
The gold standard method of diagnosing cerebrovascular disease in veterinary medicine is considered to be MRI. 20 To identify areas of restricted diffusion (ie, cytotoxic oedema), diffusion-weighted imaging is applied, which uses paired dephasing and rephrasing gradients. 20 In 3/4 cats, abnormalities in line with a previous report were found. 20 In an additional cat without MRI abnormalities, SHT as the cause of the partial seizures was supported by the disappearance of the seizures under antihypertensive treatment. Clinical signs differ with the size and location of the CNS damage.
Besides the brain, SHT can also lead to ischaemic myelopathy of the cranial cervical spinal cord resulting in cervical ventroflexion and tetraparesis/tetraplegia with intact nociception. 12 In this study, four cats showed variable degrees of paresis. In one of these cats, paraparesis occurred even while under antihypertensive treatment for retinal TOD, underlining the importance of monitoring BP regularly even in cats already treated for SHT, as adjustment of the therapy may be needed in the course of the disease.
As described, clinical signs due to SHT may be variable and sometimes quite subtle. The diagnosis is confirmed with repeated BP measurements, and there can be subsequent resolution of signs in 60% and improvement of neurological signs in 23% with appropriate antihypertensive treatment. 17 Furthermore, the diagnosis of concomitant ocular abnormalities helps to strengthen the diagnosis of hypertensive TOD to the brain, as 28/30 (93%) cats in this study also had ocular damage.
A hypertensive study population is biased toward the specialty where a case is referred to. Likewise, in the studies by Littman 5 and Maggio et al, 6 cats were biased toward ocular TOD. In the present study there may have been a bias toward neurological TOD. Although we attempted to enrol every cat with SHT presented to any specialty service of our hospital, some cats with primary ophthalmological TOD may have been missed.
Symmetric dimethylarginine is not part of the routine work-up at our clinic and was not performed in most of the cats included in the study. Therefore, we might have missed International Renal Interest Society stage 1 renal failure as an underlying cause of hypertension.
If MRI is the gold standard method to diagnose hypertensive encephalopathy, the diagnosis was only confirmed in 10% of the cases in this study. In contrast, it may be argued that the general anaesthesia required for MRI is risky in older cats and that a normal MRI does not rule out small, hypertension-induced lesions. Therefore, in veterinary medicine, neurological abnormalities might be presumptively diagnosed as related to hypertension purely based on BP measurements, fundic examination and observation of the neurological improvement under appropriate treatment. 17 Advanced imaging may be limited to those with persistent clinical abnormalities.
Although a treatment protocol was initially defined, issues with the availability of medication and compliance led to variations in treatment. Therefore, we cannot draw conclusions about the effectiveness of the different antihypertensive drugs used in this study on the resolution of neurological signs.
Conclusions
In older cats, damage to the brain secondary to SHT is common but may remain undetected in many cases. This is likely due to the observation that associated clinical signs are variable and sometimes subtle, occurring only intermittently, as well as the lack of awareness or misinterpretation of clinical signs. Hypertensive encephalopathy should be strongly suspected with repeated BP measurements and subsequent resolution of signs with appropriate antihypertensive treatment. Furthermore, the diagnosis of concomitant ocular abnormalities helps to strengthen the diagnosis of hypertensive TOD to the brain, as 28/30 (93%) cats in this study also had ocular damage. BP measurement in elderly cats with or without suspected TOD damage should be routine.
Footnotes
Acknowledgements
The authors thank Nadja Wolfer for her contribution to the figure design and figure legend.
Author note
The results of this study have been presented as an abstract at the 31st ECVIM-CA online congress.
Conflict of interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
This study was, in part, funded by the Swiss Association for Small Animal Medicine, Hunenberg, Switzerland.
Ethical approval
The work described in this manuscript involved the use of non-experimental (owned or unowned) animals. Established internationally recognised high standards (‘best practice’) of veterinary clinical care for the individual patient were always followed and/or this work involved the use of cadavers. Ethical approval from a committee was therefore not specifically required for publication in JFMS. Although not required, where ethical approval was still obtained, it is stated in the manuscript.
Informed consent
Informed consent (verbal or written) was obtained from the owner or legal custodian of all animal(s) described in this work (experimental or non-experimental animals, including cadavers) for all procedure(s) undertaken (prospective or retrospective studies). No animals or people are identifiable within this publication, and therefore additional informed consent for publication was not required.
