History
A 6-year-old 32.4-kg intact male Golden Retriever was presented with a 6-week history of bilateral protruding third eyelid. Hematology, biochemistry, and thyroid profile were normal. Worsening of the third eyelid protrusion and gray discoloration of the tongue were observed after periods of rest and resolved with exercise. Physical examination was unremarkable. Neurological examination showed intermittent obtundation, mild generalized proprioceptive ataxia without obvious tetraparesis, and left lateralizing postural reaction deficits. Bilateral miosis, third eyelid protrusion and lower eyelid ptosis, reduced left nostril sensation, absent left menace response, and subjectively reduced sensation on the left side of the body were present.
Assessment
Anatomic diagnosis
The proprioceptive ataxia with left lateralizing postural reaction deficits, intermittent obtundation, absent left menace response, reduced left nostril sensation, and diminished sensation on the left side of the body localized the lesion to the right prosencephalon (Table 1). The bilateral miosis, third eyelid protrusion, and mild ptosis of the lower eyelids were suggestive of bilateral oculosympathetic dysfunction (Horner syndrome). The exacerbated third eyelid protrusion during periods of rest further suggested autonomous nervous system imbalance. Denervation supersensitivity of affected blood vessels causing vasoconstriction was a possible explanation of the intermittent gray discoloration of the tongue.
Anatomical localisation of neurological signs.
| Neurological sign | Possible locations of lesion |
|---|---|
| Proprioceptive ataxia in thoracic and pelvic limbs | Forebrain, brainstem, C1-C5 spinal cord, or C6-T2 spinal cord (pelvic limbs > thoracic limbs) |
| Postural reaction deficits in left thoracic and pelvic limbs | Right forebrain, left brainstem, left C1-C5 spinal cord, or left C6-T2 spinal cord |
| Obtundation | Forebrain or brainstem (ascending reticular activating system) |
| Absent left menace response | Left retina, left optic nerve, optic chiasm, right optic tract, right forebrain, or left cerebellum |
| Reduced left nostril sensation | Left trigeminal nerve (ophthalmic and maxillary nerves), left trigeminal ganglion, left brainstem, or right forebrain |
| Horner syndrome (miosis, third eyelid protrusion, mild ptosis of lower eyelid) | Hypothalamus (first-order neuron); brainstem and lateral funiculus of the spinal cord (lateral tectotegmentospinal tract); intermediolateral horn of the gray matter of the first three thoracic spinal cord segments (second-order neuron); cranial mediastinum, brachial plexus, and vagosympathetic trunk in cervical region (preganglionic fibers); cranial cervical ganglion (third-order neuron); postganglionic fibers traveling through or medial to tympanic bulla, coursing intracranially via the tympano-occipital fissure and carotid canal and then ventral to trigeminal ganglion and extracranially through the orbital fissure into the orbit. |
Likely location of the lesions
The above-described neurological deficits suggested a right-sided prosencephalic lesion with possible bilateral involvement of the diencephalon and, more specifically, the hypothalamus. Alternatively, a multifocal lesion localization involving the right prosencephalon and bilateral peripheral oculosympathetic pathway was considered.
Etiologic diagnosis
Considering the persisting nature of insidious-onset lateralizing forebrain neurological deficits, in a 6-year-old Golden Retriever, the main differential diagnosis was neoplasia. Inflammatory disease such as meningoencephalitis of unknown origin (presumed immune-mediated) or infectious meningoencephalitis was possible but deemed less likely based on the 6-week nonprogressive history. A cerebrovascular accident was unlikely based on the presence of chronic nonimproving signs. There was otherwise no history of trauma, exposure to toxins, or metabolic disturbances. Idiopathic disease was considered as a possible cause of Horner syndrome but not for the lateralizing prosencephalic signs. Late-onset neurodegenerative disease is possible in dogs, but the lateralizing neurolocalization is uncharacteristic. Finally, brain malformations seemed unlikely, considering the age and lack of previous neurological or behavioral signs.
Diagnostic Test Findings
MRI was performed with 1.5-T permanent MRI scanner (1.5T SIGNA HDe; GE Healthcare). Transverse, dorsal, and sagittal T2w images, transverse FLAIR, T2*GRE, and pre- and postcontrast (Dotarem; 0.2 mL/kg, IV) T1w images of the head were obtained. Dorsal STIR images of the cervicothoracic vertebral column were also acquired.
MRI revealed a smaller right prosencephalon, with irregularly organized small gyri, erratic and incomplete sulcation, increased thickness of the occipital bone, and malposition of the flax cerebri and osseous tentorium cerebelli to the right (Figure 1). The right lateral ventricle was enlarged and distorted, extending toward an adjacent infolding of the temporoparietal cortex (Figure 2). There was a T2w hyperintense, T1w hypointense, FLAIR isointense space between a smaller right thalamus and medial temporal lobe. The signal intensity of the brain was normal with no pathologic contrast enhancement. The cervicothoracic vertebral column was unremarkable. Based on the above, a right-sided congenital malformation of the brain was diagnosed.
Brain MRI of a 6-year-old Golden Retriever with bilateral Horner syndrome and left-sided proprioceptive deficits, absent menace response, and nostril sensation. Transverse T2w MRI images at the level of the frontal lobes (A), head of caudate nuclei (B), interthalamic adhesion (C), rostral colliculi (D), pons (E), and rostral medulla oblongata (F). The right telencephalon and diencephalon are reduced in size. The right cerebral gyri are small and irregularly organized, and sulcation is erratic and incomplete. A significantly smaller or absent right crus cerebri can be appreciated, which causes asymmetry of the ventral mesencephalon (D). There is increased thickness of the right occipital bone (F) and malposition of the falx cerebri (B, C, D, E, F) and tentorium cerebelli (E, F) to the right side. Notice the T2w hyperintense area (suspected ex-vacuo) between the right diencephalon and medial temporal lobe (C).
Citation: Journal of the American Veterinary Medical Association 261, 9; 10.2460/javma.23.04.0196
Dorsal brain MRI T2w images demonstrating marked asymmetry of the cerebral hemispheres caused by anomalous and incomplete development of the right side. The right cerebral gyri appear smaller and irregularly arranged (A, B, C, D) with a decreased number of sulci that appear enlarged (A, B, C). There is an infolding of the right temporoparietal cortex characterized by an agglomeration of widened but incomplete sulci that extends toward the right lateral ventricle (B).
Citation: Journal of the American Veterinary Medical Association 261, 9; 10.2460/javma.23.04.0196
Orthogonal thoracic radiographs and cisternal CSF analysis were unremarkable. Sympathomimetic pharmacological testing with ocular application of 1% phenylephrine resulted in bilateral mydriasis and normal position of the third eyelids well within 20 minutes. This result indicated denervation supersensitivity and localized the lesion to the third-order neuron bilaterally. This supported our hypothesis that the brain malformation was unrelated to the recent development of bilateral Horner syndrome but could instead explain all other neurological deficits.
Comments
Prior to investigations, the suspicion of a single intracranial lesion justifying both the lateralizing prosencephalic deficits and bilateral Horner syndrome was raised. Surprisingly, an asymmetrical right-sided malformation of the brain was detected. This anomaly of cerebral development was congenital, whereas the bilateral Horner syndrome was a recent occurrence. No ataxia or other neurological signs were initially reported, but long-term clumsiness with intermittently strange behavior were mentioned by the owner when repeating the anamnesis. Considering the high prevalence of idiopathic Horner syndrome in this breed, the lack of any other pathology involving the oculosympathetic pathway, and the suspected denervation supersensitivity on pharmacological testing indicating a third-order neuron involvement, the presumptive diagnosis of bilateral idiopathic Horner syndrome was reached.
Horner syndrome is caused by dysfunction of the oculosympathetic pathway and is characterized by miosis, enophthalmos, protrusion of the third eyelid, and ptosis.1,2 The sympathetic innervation of the eye consists of a 3-neuron pathway. The central or first-order neuron is found in the hypothalamus, the preganglionic or second-order neuron in the intermediolateral horn of the gray matter of the first 3 thoracic spinal cord segments (T1-T3), and the postganglionic or third-order neuron in the cranial cervical ganglion.1 Underlying causes include ischemic myelopathy, otitis media/interna, trigeminal neuritis, CNS inflammation, neoplasia, intervertebral disk disease, trauma, cervical surgery, and intrathoracic tube placement.2
An idiopathic etiology was reported in 28% of cases with Horner syndrome, and 49% are Golden Retrievers (2.6% breed prevalence).1,3 The age at presentation is 5 to 8 years,1 and bilateral involvement can occur in 6%.3 The underlying pathogenesis remains unclear, and a presumptive diagnosis is reached by exclusion of other possible causes.3 Assessing the integrity of the oculosympathetic pathway is sometimes necessary and involves imaging of the head, cervical vertebral column, brachial plexus, and thorax. This can be achieved with 1 or more imaging modalities such as MRI, CT, and/or radiography.1 Additional diagnostic steps are required in selected cases and include sampling of identified lesions, CSF analysis, and infectious diseases screening.1,3 Accurate neurolocalization and strong clinical reasoning are essential in interpreting imaging findings. There is no specific treatment, but prognosis is good, relapses are unlikely, and recovery can take up to 15 weeks.1,2 Our patient had improved at 10 weeks after diagnosis and fully recovered at 6 months. This further supported our hypothesis of idiopathic Horner syndrome unrelated to the underlying brain malformations.
Pharmacological testing aided reaching a diagnosis in our case. Ocular application of diluted phenylephrine (0.1% or 1%), a direct sympathomimetic drug, is expected to resolve clinical signs of idiopathic Horner syndrome within 20 minutes.1 The same effect is not observed in the normal eye, and thus assessing both eyes is useful for comparison purposes.1,3 This rapid response occurs secondarily to denervation supersensitivity. The lack of endogenous presynaptic release of norepinephrine from the affected postganglionic neuron increases the sensitivity of the postsynaptic membrane, which results in a much faster response despite using diluted phenylephrine.1–3 A good correlation between the site of confirmed lesions and pharmacological localization is generally expected.2 Pharmacological testing can predict the site of the lesion in 79% of cases.3 Most Golden Retrievers with idiopathic Horner syndrome (80%) are localized as postganglionic, and only 20% are localized as preganglionic.2
Congenital malformations of the brain are structural anomalies divided into primary and secondary categories and are present at birth.4 Primary congenital malformations are the result of genetic mutations, while secondary malformations occur due to teratogenic factors including prenatal infections, toxins, hypothyroidism, trauma, vitamin deficiencies, and others.4 An ontogenetic morphological classification groups congenital CNS malformations into defects of neural tube closure, defects of forebrain induction, neuronal migration disorders and sulcation defects, disorders of proliferation or size, encephaloclastic defects, and congenital hydrocephalus and cysts.4 In our case, considering the erratic anatomical arrangement and incomplete development of only 1 side of the brain, a secondary defect disturbing the process of neuronal migration, sulcation, and development was suspected, but other etiopathogenetic hypotheses cannot be ruled out. The suspected depletion of the right cortical neuronal cell population and subsequent reduction of its descending projection fibers could explain the severely hypoplastic ipsilateral crus cerebri. Although neurological impairment is often evident from a young age, some developmental anomalies remain subclinical or asymptomatic.5
In summary, this unexpected case of bilateral idiopathic Horner syndrome emphasizes the importance of detailed anamnesis and its impact on differential diagnoses. Furthermore, our presumptive diagnosis was possible to reach with application of clinical reasoning when MRI findings were interpreted and with supportive evidence of pharmacological testing. This diagnostic step demonstrated its usefulness by indicating a third-order neuron lesion and thus ruling out a connection with the brain malformation.
Acknowledgments
The authors have nothing to declare.
References
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Lockhart RL, Tzouganakis I, Tsvetanova A, Smith KM, Smith PM. The diagnostic yield of advanced imaging in dogs with Horner’s syndrome presenting with and without additional clinical signs: a retrospective study of 120 cases (2000-2018). Vet Ophthalmol. 2022;25(suppl 1):51-59.
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Higgins R, Oevermann A, Vandevelde M. Veterinary Neuropathology: Essentials of Theory and Practice. Wiley-Blackwell; 2012.
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