Hypertensive nonobstructive hydrocephalus as main magnetic resonance imaging feature in a dog with disseminated choroid plexus carcinomatosis

Abstract Obstructive or nonobstructive hypertensive hydrocephalus is reported in choroid plexus tumors. Choroid plexus tumors typically present as T2‐weighted hyperintense intraventricular masses with occasional cerebrospinal fluid‐drop metastasis. Acquired neoplastic nonobstructive hydrocephalus without visible mass lesion in magnetic resonance imaging is not reported in dogs. A 4.5‐year‐old Rhodesian Ridgeback presented with reduced mental status, unilaterally absent pupillary light reflex, and neck pain. Magnetic resonance imaging revealed a nonobstructive hydrocephalus and widened lumbar subarachnoid space with no evidence of a primary mass lesion. Postmortem examination confirmed a disseminated choroid plexus tumor affecting the ependyma and choroid plexi of all ventricles and the cerebral and lumbar subarachnoid space. Disseminated choroid plexus carcinomatosis should be considered as a possible cause of hypertensive hydrocephalus even in absence of a primary mass.

sometimes forming cyst-like structures. 3,4 Obstructive hydrocephalus is commonly associated to the presence of intraventricular masses obstructing cerebrospinal fluid (CSF) pathway; however, nonobstructive hydrocephalus is also postulated as possible concomitant phenomenon. Presence of ventricular system dilatation is evidenced caudal to the primary mass lesion more often in benign than malignant CPT. 4 The choroid plexus of the fourth, the third and lateral ventricles are described as predilection sites for location of the primary tumor. [4][5][6][7] Signal intensity of the tumoral extension by means of meningeal carcinomatosis and/or CSF-drop metastasis are reported as multifocal predominantly T2W hyperintense and markedly contrast-enhancing lesions adjacent to the subarachnoid space or ventricular system. 4,8 In the present case report, we describe a dog affected by primary disseminated leptomeningeal choroid plexus carcinomatosis causing a hypertensive nonobstructive hydrocephalus as main imaging feature, without detectable primary mass over repeated MRI examinations. The clinical examination revealed a body condition score 3/9. In the neurologic examination a reduced mental status, subjectively calmer demeanor, normal gait, low carried head posture, mild orthostatic tremor in the pelvic limbs and reduced proprioception of both hind limbs were detected. The pupils were mildly anisocoric with mild mydriasis in the left eye as well as absent menace response and pupillary light reflex on the left. Therefore, the neuroanatomical localization was defined multifocal intracranial and lumbar spinal cord. In the ophthamoligic examination there was severe bilateral papilledema MRI of the brain and lumbar spine was performed (Table S1) under general anesthesia using a 3 Tesla magnet (Philips Ingenia, Philips AG, Zurich, Switzerland).

| CASE PRESENTATION
Post-contrast T1W sequences were acquired after intravenous administration of gadolinium-based contrast agent (Omniscan, GE Healthcare AG, Opfikon, Switzerland; 0.1 mmol/kg). The dog was presented to the emergency service 112 days after initial presentation because of focal facial seizures, disorientation, circling, hyperthermia, pain within the neck region, and hypersalivation.
A second MRI-study was performed, using the same protocol as the initial scan (Table S1). The VPS was in situ. A regression of the diagnosed hydrocephalus with a mild ventricular asymmetry was evident ( Figure 3A-C). Additionally, multifocal, T2W, and FLAIR hyperintense intraaxial lesions within the left thalamic region, piriform lobes, cingulate gyri, parahippocampal gyri, and pons were present ( Figure 4A-C).
After contrast-medium injection, a marked, diffuse, extensive, ventrally distributed leptomeningeal enhancement was present.  neoplasia within all ventricles and in the cerebral subarachnoid space with low cellularity and papillary structure with multifocal multilayered papillae. The neoplastic cells were round to columnar with welldefined cell borders and moderately abundant eosinophilic cytoplasm.
The nuclei were round, basally located with indistinct nucleoli. Mild anisocytosis and anisokaryosis were present, whereas no mitoses were detected. The adjacent neuropil showed decreased eosinophilia, moderate vacuolization, and mild gliosis within the gray and white matter, as well as activated astrocytes and myelinophages in dilated myelin sheaths ( Figure 5A-D). Furthermore, mild lymphoplasmacytic encephalitis surrounding the changes described above, as well as mildly dilated lateral ventricles (hydrocephalus internus) were noted. Similar histopathological changes were found within the subarachnoid space at the level of L4-L5 spinal cord segments. Immunohistology of the brain showed that the majority of the neoplastic cells expressed vimentin.
Multifocally, the neoplastic cells were immunolabeled by pancytokeratin ( Figure 6A-C). Although the diffuse carcinomatosis was identified as etiology in histopathology, a clear pathophysiologic mechanism for the nonobstructive hydrocephalus could not be identified neither in MRI nor in histopathology. Hypertensive, nonobstructive hydrocephalus can occur because of impaired CSF absorption, such as in aquaporin dysregulation or villous atrophy, or because of overproduction. 4,13,14 In CPT, increased production of CSF because of hypersecretory neoplastic cells has been postulated as a possible cause or contributing factor to the hydrocephalus formation. [15][16][17][18] Up to 300 mL/day of CSF-like fluid were removed from VPS site in the presented case. Although we cannot state that the drained fluid is uniquely CSF with certainty, because of the transparent macroscopic appearance and amount, we speculate that most of it would have been CSF. If so, this would have been considered a highly increased CSF production, as the reported CSF production rate in the dog is approximately 68 mL/day 19 ; a mild amount of superficial wound secretion adding to the measured drained volume cannot be ruled out. Therefore, a CSF overproduction or a combination of overproduction and reduced absorption are speculated to be more likely mechanisms than reduced absorption alone. Furthermore, the concomitant meningoencephalitis in the later stages of disease course could have contributed to the persistence of the hydrocephalus. As described in literature, sterile or infectious inflammatory processes can lead to leptomeningeal protein precipitation or deposition of blood clots or fibrotic changes of the arachnoid villi, impairing therefore the CSF absorption. 4,13,20 The dog received long-term cyclosporine for treatment of atopic dermatitis since puppyhood. In human medicine, cyclosporine is reported as a rare cause of intracranial hypertension, leading to secondary medication induced papilledema. 15 The pathomechanism of cyclosporine-induced hypertensive hydrocephalus in humans remains unclear. 21 Therapy discontinuation in such cases leads to clinical resolution. [21][22][23][24] Although not described in veterinary literature, an empiric clinical decision of discontinuing cyclosporine was made after the first MRI scan. No improvement was observed after cyclosporine discontinuation.
Long-term administration of cyclosporine increases the risk for bacterial and fungal infections in dogs and might well contribute to the shunt infection in this case. [25][26][27][28] Further, long-term administration of cyclosporine is associated with increased risk for development of neoplasia in dogs and humans. 29,30 However, CPTs have are linked to cyclosporine treatment in humans and dogs.
The papilledema was interpreted as a feature of increased intracranial pressure. However generalized microvasculopathy after longterm administration of cyclosporine is a possible contributing factor to hypertension 31 or optic neuropathy and optic disc swelling. 24,32 The presence of papilledema was identified bilaterally and asymmetrically in the ophthalmologic examination and only on the left side in the MRI examination. Targeted imaging of the optic nerve and disc are challenging to achieve in a field of view, slice thickness and reconstruction matrix intended for whole brain imaging. Spatial resolution and partial volume effects play an important role in identification of such small structures and might explain the abovementioned mismatch between ophthalmologic examination and MRI. Microcoils for ocular imaging could have been used to address these concerns. 33 The CSF analysis revealed a mild pleocytosis and a marked increase in protein concentration. Together with imaging findings this was interpreted as a nonspecific finding, likely related with impaired CSF flow. 34 Even though several studies describe exfoliation of cancer cells and spread through the ventricular and subarachnoid space 6 the sensitivity for detection of carcinomatous cells within the CSF is low, 1 with detection in only approximately 50% of the analyzed samples. 4 It is not uncommon, that MRI and CSF analysis do not lead to a definitive diagnosis and biopsy samples might be indicated for a confirmed diagnosis.