Introduction

Narcolepsy is a sleep disorder affecting ∼1 in 2000 humans in the United States and Europe.¹ The disease is characterized by hypersomnia often associated with cataplexy and other clinical manifestations including sleep paralysis, hypnagogic (at sleep onset) hallucinations, and disturbed nighttime sleep.¹ A diagnosis of narcolepsy in humans is generally based on history and clinical symptoms and can be confirmed with overnight polysomnography and sleep latency tests.¹ The presence of cataplexy is pathognomonic of the disease.¹ The pathophysiology of narcolepsy is related to deficits in the hypocretin/orexin system, which is involved in various hypothalamic functions including food intake, energy homeostasis, autonomic functions, and sleep and wake control.^1–3 Hypocretin 1 and 2 (also named orexin A and B) are neuropeptides produced by a specific group of neurons located in the lateral hypothalamus which project to monoaminergic, cholinergic (wake-promoting) and GABAergic (sleep-promoting) pathways in the mesencephalon, pons, basal forebrain, cerebral cortex, and spinal cord.⁴ Narcolepsy in humans is classified as primary (when not associated with any concurrent cerebral disease) or symptomatic/secondary (when occurring as a consequence of another cerebral pathology). Primary narcolepsy in humans can be caused by loss of hypocretin-producing neurons with subsequent reduced production of hypocretin (type 1 narcolepsy), or be associated with normal cerebrospinal fluid (CSF) hypocretin levels and an unclear pathophysiology (type 2 narcolepsy).¹ Although familial forms exist, in humans, primary narcolepsy is more frequently sporadic and attributed to a combination of genetic and environmental factors with possible immunogenic triggers.¹ Primary narcolepsy/cataplexy has been thoroughly investigated in dogs as a natural model of the human disease.^2,5–8 Familial forms have been described in Doberman pinschers, Labrador retrievers, and dachshunds and associated with an autosomal recessive mode of inheritance.⁶ Breed-related mutations in the hypocretin receptor-2 gene have been detected, causing reduced expression of hypocretin receptor-2.^2,6 In these dogs, the hypocretin 1 level in the CSF was normal.⁷ The same study determined that the detection of hypocretin 2 in CSF was only possible in CSF samples of >5 mL, and reliable in samples of >10 mL, limiting the ability to diagnostically measure the hypocretin 2 level in a clinical setting.⁷ Sporadic forms of primary narcolepsy are also reported in dogs, with a later onset compared with familial forms and consistently low hypocretin levels in CSF, as in human type 1 primary narcolepsy.⁶ Unlike primary narcolepsy, in symptomatic narcolepsy, the clinical signs occur as a consequence of another cerebral disease.^9,10 In a large review of 116 cases of symptomatic narcolepsy in humans, inherited disorders (34%), tumors (29%), and head trauma (16%) were the most common causes, whereas only 4 cases (3%) were diagnosed with encephalitis.¹⁰ The hypothalamus was by far the most commonly affected structure with 70% of cases, whereas the brainstem was represented in only 9%.¹⁰ In veterinary literature, published cases of clearly symptomatic narcolepsy are limited to a recently described dog with a pituitary mass and a normal hypocretin 1 level in the CSF.¹¹ One puppy with narcolepsy and distemper encephalitis was also previously reported, although the possibility that that dog had two concurrent diseases could not be excluded.¹²

Herein we report a case of symptomatic narcolepsy/cataplexy in a dog with brainstem meningoencephalitis of unknown origin (MUO) diagnosed following previously reported criteria.¹³ The narcolepsy/cataplexy resolved with appropriate immunosuppressive treatment for MUO.

Case Report

A 4 yr old, intact female cocker spaniel was presented with a 48 hr history of acute-onset progressive lethargy/hypersomnia, vestibular signs. and cataplexy episodes. The hands-off examination revealed an obtunded mental status, left head tilt, and vestibular ataxia with the tendency to fall to the left. The hands-on examination triggered a narcolepsy-cataplexy episode with sudden unresponsiveness and loss of tone and areflexia in all four limbs. Bilateral miosis, convergence-retraction nystagmus, and absent vestibulo-ocular and gag reflexes were evident during the episode. The heart rate was 50 beats per min and systolic blood pressure was 220 mm Hg. The neurolocalization was multifocal intracranial, affecting the mesencephalon, the medulla oblongata, and the hypothalamus (given the narcolepsy/cataplexy). The dog continued to rapidly alternate between hyperexcitement and narcolepsy-cataplexy episodes despite intravenous administration of 0.5g/kg mannitol^a. Electrocardiography during the episodes did not reveal any abnormality aside from the bradycardia. Between the narcolepsy-cataplexy episodes, blood pressure, and heart rate were normal.

Hematology and serum biochemistry profiles including electrolytes were unremarkable. High field MRI^b of the brain revealed an ill-defined, mildly contrast-enhancing^c intra-axial lesion, hyperintense in T2-weighted and fluid-attenuated inversion recovery sequences and isointense in T1-weighted sequences, infiltrating the mesencephalic tegmentum, the pons, and the rostral medulla oblongata (Figures 1A, B). CSF analysis revealed mild mononuclear pleocytosis (white blood cells: 8/µL, reference range 0–5/µL; red blood cells: 0/µL, reference range 0–250/µL; total protein: 0.13 g/L, reference range 0.00–0.35 g/L). Polymerase chain reaction testing for Toxoplasma gondii, Neospora caninum, and canine distemper virus in CSF were negative. The CSF hypocretin level could not be measured as a result of the paucity of remnant CSF following routine analyses as well as the inability to find a laboratory that would perform the test. Thoracic radiographs and abdominal ultrasound were unremarkable. A presumptive diagnosis of MUO was made based on previously published criteria.¹³

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Immunosuppressive treatment with prednisolone^d (1 mg/kg q 12 hr) and cytosine arabinoside^e (50 mg/m² subcutaneously q 12 hr for 2 days) was started. During hospitalization, narcolepsy-cataplexy episodes could still be repeatedly triggered by offering food (Figure 2; Supplementary Video I); however, they gradually decreased in frequency, duration, and ease of triggering and finally subsided along with all the other clinical signs over 3 wk. The immunosuppressive treatment was tapered following a previously reported protocol.¹⁴ Prednisolone was administered at 1 mg/kg q 12 hr for 4 wk, 1 mg/kg q 24 hr for 6 wk, 0.5 mg/kg q 24 hr for 6 wk, and then at 0.25 mg/kg q 24 hr for 6 wk, q 48 hr for 6 wk, and then q 72 hr for 6 wk before finally being discontinued. Cycles of cytosine arabinoside 50 mg/m² subcutaneously q 12 hr for 2 days were administered every 3 wk for four times, every 4 wk for four times, and then every 5 wk for four times. At that stage, after 12 mo of treatment, as a result of a shortage in distribution of cytosine arabinoside by the producer, its administration was substituted with cyclosporine^f at the dose of 5 mg/kg q 12 hr. Cyclosporine was then gradually tapered over the following 12 mo to 2.5 mg/kg q 48 hr. Repeat MRI of the brain performed 24 mo after diagnosis revealed marked reduction in size of the lesion (Figures 1C, D). CSF analysis and repeated imaging of the thorax and abdomen were unremarkable. Given the presence of persistent MRI changes, although possibly not representing active encephalitis, the dog was continued on cyclosporine at the dose of 2.5 mg/kg q 48 hr for another 3 mo and then 2.5 mg/kg q 72 hr for another 3 mo before discontinuing that medication. There was no relapse of clinical signs over a 32 mo follow-up period from diagnosis. Apart from the initial polyuria and polydipsia, moderate interdigital and facial hypertrichosis, which resolved with tapering of the cyclosporine, was considered the only side effect of the treatment.

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Discussion

In this report, we described a case of symptomatic narcolepsy/cataplexy in a dog with brainstem MUO. The diagnosis of MUO was based on previously reported criteria and supported by both a clinical and imaging response to immunosuppressive treatment.¹³ The presence of episodes of sudden loss of muscle tone and areflexia in all four limbs, clearly and repeatedly triggered by offering food as a positive emotional stimulus, is characteristic of cataplexy.^1,5 The presence of cataplexy is considered pathognomonic for narcolepsy both in humans and in dogs.^1,5 The normal serum biochemistry and the absence of abnormalities on the electrocardiography at the time of the episodes in our case further rules out metabolic and cardiogenic causes of collapsing episodes. The occurrence of the clinical signs at the time of onset of the cerebral disease, together with the gradual resolution within 3 wk of starting appropriate treatment and the absence of recurrence over a 32 mo period, demonstrated the secondary nature of the narcolepsy/cataplexy in our case. Although symptomatic treatment for narcolepsy/cataplexy with, for example, imipramine, clomipramine, or venlafaxine is reported in dogs and could have been administered to alleviate the clinical signs, further treatment was considered unnecessary in our case given the rapid response to immunosuppression.⁵

As stated above, in a large review of 116 cases of symptomatic narcolepsy in humans, inherited disorders (34%), tumors (29%), and head trauma (16%) were the most common causes, whereas only 4 cases (3%) were diagnosed with encephalitis.¹⁰ These 4 cases were all associated with encephalitis lethargica, a widespread epidemic disease that occurred particularly between 1918 and 1925, and to a lesser extent until 1940.^10,15 Encephalitis lethargica was primarily characterized by lethargy, sleep-cycle disturbances, ophthalmoplegia and extrapyramidal signs, and was suspected to have an infectious or immune-mediated etiology.¹⁵ The primarily affected area was located between the caudal thalamus and rostral mesencephalon; however, other areas of the brain were affected on histopathology.¹⁵ Although some similarities between our case and the clinical signs and lesion location associated with encephalitis lethargica were detected, extrapyramidal signs were not present in our dog. Considering also the epidemic nature of encephalitis lethargica in humans, attempts to create a parallel with this condition would be too speculative. Another form of encephalitis, anti-Ma2–associated encephalitis, has been described in humans as a possible cause of narcolepsy.¹⁰ Anti-Ma2–associated encephalitis is reported to be a paraneoplastic syndrome, with underlying neoplasia detected in 90% of cases.¹⁶ Neurological signs precede the detection of the neoplasia in 62% of cases.¹⁶ In the case we described, no evidence of underlying neoplasia was detected at presentation or on repeated diagnostic investigations 24 mo later.

In human cases of symptomatic narcolepsy, the hypothalamus is by far the most commonly affected structure with 70% of cases, whereas the brainstem is represented in only 9%.¹⁰ Of seven cases with isolated cataplexy (without concurrent narcolepsy), three had a lesion affecting the mesencephalon (tegmentum and periaqueductal gray matter) or the pontomedullary region.¹⁰ Lesions in these areas probably affect the projection pathways of the hypocretin/orexin system, thereby likely sparing the production of these neuropeptides. The hypocretin-producing hypothalamic neurons project onto many mesencephalic and pontine monoaminergic and cholinergic nuclei involved in sleep and wake control. The monoaminergic nuclei involved in this system include the noradrenergic locus coeruleus, the serotonergic dorsal raphe nucleus, the histaminergic tuberomammillary nucleus, the dopaminergic periaqueductal gray matter, and the glutamatergic parabrachial nucleus, which fire rapidly during wakefulness and slowly or minimally during slow-wave and rapid eye movement (REM) sleep, respectively.¹ Conversely, the cholinergic nuclei, including the pedunculopontine and laterodorsal tegmental nuclei of the pons, are active during wakefulness but even more so during REM sleep, although they remain silent in slow-wave sleep.¹ The muscle paralysis of cataplexy is induced by the activation of circuits in the pons following signals relayed through the medial prefrontal cortex and amygdala as a consequence of strong, generally positive, emotions.¹⁷ Although both nearly cease their discharge during REM sleep, in narcoleptic dogs, only the noradrenergic neurons in the locus coeruleus interrupt their activity during cataplexy attacks, whereas the serotoninergic neurons in the nucleus of the dorsal raphe continue to discharge to the level seen in non-REM sleep.¹⁷ Histaminergic nuclei continue to be active during cataplexy, at a level similar to or even greater than that in quiet wakefulness.¹⁷

In the previously described case of symptomatic narcolepsy/cataplexy in a dog with a pituitary mass, the authors of that report already suggested a possible association between the mesencephalic component of the lesion and the occurrence of narcolepsy/cataplexy.¹¹ This assumption was based on the normal hypocretin level in the CSF and the decreased caudal extension of the mass with reduced mesencephalon compression on recheck MRI following resolution of the narcolepsy/cataplexy episodes.¹¹ However, as a result of the extension of the mass markedly compressing also the diencephalon, this association remained speculative. In our dog, the presence of a focal lesion affecting the mesencephalon, pons, and rostral medulla oblongata and grossly sparing hypothalamic structures can support the previously suggested association between diseases caudal to the diencephalon and the occurrence of narcolepsy/cataplexy in dogs. Comparing the lesions described in both our and the previous report of symptomatic narcolepsy/cataplexy in a dog, it appears that pathology of the rostral mesencephalon might play a role in the occurrence of these specific clinical signs in dogs. This can also be supported by the described location of the primary lesion in people with encephalitis lethargica.¹⁵ Evaluation of the CSF hypocretin level could have helped to better define the pathophysiology of the narcolepsy-cataplexy episodes in our case; however, as stated above, this was unfortunately not possible as a result of a paucity of remnant CSF following routine analyses and also an inability to find a laboratory that would perform the test.

The cardiovascular changes appearing only in association with the cataplexy episodes were of particular interest at the time of diagnosis. Although bradycardia associated with hypertension and brainstem dysfunction at the time of presentation suggested the possibility of Cushing’s reflex, no signs of increased intracranial pressure were detected on MRI. The neuroanatomical pathways of sleep-wake control and autonomic nervous system regulation are closely connected. Hypocretin neurons project to many autonomic nervous system regulation centers including periaqueductal gray matter and the nucleus of the solitary tract.¹⁸ Moreover, they are located in the lateral part of the hypothalamus, which also contains autonomic nervous system neurons projecting to the lateral medulla and the intermediolateral gray matter column of the spinal cord.¹⁸ Heart rate and blood pressure normally vary according to the different phases of sleep as a result of increased parasympathetic activity during the non-REM phase and increased sympathetic activity during REM sleep.^18,19 In the REM phase, blood pressure and heart rate may fluctuate significantly, with blood pressure being potentially higher than during the waking state.¹⁸ In human patients with type 1 primary narcolepsy, autonomic changes affecting energy metabolism, cardiovascular activity, gastrointestinal motility, erectile function, and pupillary function are well reported; however, specific descriptions of the cardiovascular changes are conflicting.^18,19 Nevertheless, increased blood pressure as a result of raised sympathetic tone with secondary decreased heart rate, compatible with what we reported in our case, has been specifically described during cataplexy attacks in humans.²⁰ Considering their waxing and waning course in association with the narcolepsy-cataplexy episodes, we suspect that the cardiovascular changes described in our case were also associated to the hypocretin/orexin system dysfunction and cholinergic/monoaminergic imbalance.

Conclusion

We described a case of symptomatic narcolepsy/cataplexy in an adult dog secondary to brainstem MUO. Narcolepsy/cataplexy can present as a sign of an underlying structural brain pathology affecting the brainstem in dogs and resolve with appropriate treatment of the primary lesion. Cardiovascular changes can occur in association with the narcolepsy-cataplexy episodes.