Neural stem cells restore myelin in a demyelinating model of Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease is a fatal X-linked leukodystrophy caused by mutations in the PLP1 gene, which is expressed in the CNS by oligodendrocytes. Disease onset, symptoms and mortality span a broad spectrum depending on the nature of the mutation and thus the degree of CNS hypomyelination. In the absence of an effective treatment, direct cell transplantation into the CNS to restore myelin has been tested in animal models of severe forms of the disease with failure of developmental myelination, and more recently, in severely affected patients with early disease onset due to point mutations in the PLP1 gene, and absence of myelin by MRI. In patients with a PLP1 duplication mutation, the most common cause of Pelizaeus-Merzbacher disease, the pathology is poorly defined because of a paucity of autopsy material. To address this, we examined two elderly patients with duplication of PLP1 in whom the overall syndrome, including end-stage pathology, indicated a complex disease involving dysmyelination, demyelination and axonal degeneration. Using the corresponding Plp1 transgenic mouse model, we then tested the capacity of transplanted neural stem cells to restore myelin in the context of PLP overexpression. Although developmental myelination and axonal coverage by endogenous oligodendrocytes was extensive, as assessed using electron microscopy (n = 3 at each of four end points) and immunostaining (n = 3 at each of four end points), wild-type neural precursors, transplanted into the brains of the newborn mutants, were able to effectively compete and replace the defective myelin (n = 2 at each of four end points). These data demonstrate the potential of neural stem cell therapies to restore normal myelination and protect axons in patients with PLP1 gene duplication mutation and further, provide proof of principle for the benefits of stem cell transplantation for other fatal leukodystrophies with 'normal' developmental myelination.

Acute motor and sensory polyganglioradiculoneuritis in a cat: clinical and histopathological findings.

Polyneuropathies can have a variety of clinical presentations and tend to be rare in cats. In this report we describe a 6-year-old domestic shorthair cat with an acute and rapidly progressive onset of lower motor neuron and sensory signs affecting the spinal and cranial nerves. Histopathological examination revealed moderate-to-severe multifocal inflammatory infiltrates at the ventral and dorsal nerve roots, and dorsal spinal ganglia at the level of the L4 and cauda equina. The type and severity of inflammation varied between nerve roots, being composed of mainly neutrophils in some and mainly lymphocytes and macrophages in others. Immunohistochemistry showed a combination of neutrophils, macrophages and lymphocytes infiltrating the nerve roots and ganglia. The majority of the lymphocytes were T lymphocytes; only a few B lymphocytes were seen. Neurons within the affected ganglia showed central chromatolysis and necrosis. Wallerian-like degeneration and demyelination were observed in the nerve roots. A sensory and motor polyganglioradiculoneuritis was diagnosed. An autoimmune process similar to the acute motor and sensory neuropathy subtype of Guillain-Barré syndrome in humans or an infection by an unidentified agent were considered most likely.

Cavernous sinus syndrome secondary to intracranial lymphoma in a cat.

Cavernous sinus syndrome is characterised by internal and external ophthalmoplegia and sensory deficits over the head due to combined deficits of the three cranial nerves (CNs) responsible for the eye movements and pupil function (CN III, IV, VI) and at least one branch of the trigeminal nerve (CN V). It has rarely been described in cats and may occur secondarily to inflammatory, infectious or neoplastic lesions within the region of the cavernous sinus on the ventral aspect of the calvarium. This report describes the clinical and magnetic resonance imaging findings in a 14-year-old domestic shorthair cat with neurological deficits compatible with cavernous sinus syndrome caused by presumptive extranodal lymphoma. Treatment with chemotherapy resulted in clinical and imaging remission. Identification of the neurological deficits in cavernous sinus syndrome allows accurate neuroanatomical localisation in order to target diagnostic imaging studies.

A protocol for the management of canine cerebrospinal fluid for the proteomic assessment of putative biomarkers.

Cerebrospinal fluid (CSF) is a potential source for disease-specific biomarkers that may assist in the staging and determining the prognosis of neurodegenerative conditions in animals. However, the validity of such putative biomarkers may be influenced by pre-analytical variables, including the procedures adopted to collect and store the CSF. This study assessed the effect of three handling practices on the stability of a panel of CSF proteins: clusterin (also known as apolipoprotein J), haptoglobin, cystatin C, and transthyretin (TTR). The three handling procedures for canine CSF were mimicked in the laboratory as follows: (1) storage in a refrigerator overnight (4 °C for 18 h); (2) carrying a sample in the pocket of a clinician (37 °C for 4h); and (3) mailing a sample to a remote laboratory for analysis (room temp for 48 h). The impact of these three scenarios on the concentrations of the selected proteins was assessed using Western blotting and compared to an aliquot of CSF that had been kept frozen. The level of clusterin was significantly reduced following 48 h at room temperature (P<0.05), while the concentration of the dimeric form of TTR increased following this handling procedure and also when held at 37 °C for 4h. A reducing agent prevented this increase at 37 °C. In conclusion, exposing CSF samples to various environmental conditions can significantly alter their protein content, a factor that must be considered in studies assessing potential biomarkers in canine CSF.

Evaluation of auditory function in a population of clinically healthy cats using evoked otoacoustic emissions.

Cats may demonstrate deafness due to a variety of aetiologies and the current preferred method for assessing auditory function is the brainstem auditory evoked response (BAER). The BAER has largely been replaced by otoacoustic emission (OAE) testing in human neonatal deafness screening as the equipment is more readily available, is cheaper and the test is less invasive and simpler. This is the first study to demonstrate that transient evoked OAEs (TEOAE) and distortion product OAEs (DPOAE) can be recorded in cats using commercially available equipment. Protocols for recording the emissions and analysing the results are given. DPOAE testing is suggested to be quicker in this population of healthy cats and shows promise in rapidly providing detailed information about auditory function at a variety of different frequencies.

Dorsal spinous process impingement syndrome ('kissing spine') in a cat: imaging appearance and surgical management.

Spinal pain is an important clinical presentation in feline patients, but the underlying causes can often be difficult to elucidate. Dorsal spinous process impingement syndrome ('kissing spine' or in human patients 'Baastrup syndrome') is a significant cause of spinal pain in equine and human patients and radiographically is characterised by a close approximation of adjacent spinous processes with reactive bone sclerosis affecting these spinous processes. In this report we describe the first reported case of dorsal spinous process impingement syndrome in a cat causing spinal pain, and successful surgical management of the syndrome. The affected cat presented at 5 years of age for evaluation of a 7-month history of progressive thoracolumbar pain. Radiographs revealed close approximation of the dorsal spinous processes of the seventh, eighth and ninth thoracic vertebrae (T7, T8 and T9), with associated reactive bone sclerosis. Surgical resection of the T8 dorsal spinous process resulted in complete resolution of the clinical signs with no evidence of recurrence 9 months after surgery.

Feline intracranial meningioma with skull erosion and tumour extension into an area of skull hyperostosis.

Skull hyperostosis is a frequently recognised feature of meningioma in feline and human patients, occurring at a frequency of around 4.5% of human cases. Evidence of osteolysis with extension of meningioma into, and in some cases through, the region of skull hyperostosis is much less commonly described in human patients. Here we present a 12-year-old cat with marked skull hyperostosis secondary to an intracranial meningioma, with magnetic resonance imaging and computed tomography evidence of tumour extension into the skull, centrally within the region of hyperostosis. Only a thin layer of bone was remaining between the mass and the extracranial region. Surgical resection of the region of skull demonstrating tumour invasion and the underlying mass resulted in good resolution of clinical signs and no post-surgical recurrence of meningioma within the 5 months follow-up period. Histopathological examination confirmed the mass to be fibroblastic meningioma.

Thiamine deficiency in a cat: resolution of MRI abnormalities following thiamine supplementation.

Thiamine (vitamin B(1)) is an essential component of a number of metabolic pathways and thiamine deficiency results in a progressive encephalopathy in both humans and animals. Confirming thiamine deficiency is problematic and relies on demonstrating reduced red blood cells transketolase activity, or indirect methods including urinary organic acid analysis and dietary analysis. The characteristic and selective vulnerability of different brain regions in carnivores has been demonstrated by magnetic resonance (MR) imaging in the dog and cat as an aid to diagnosis. A 2-year-old, female, domestic shorthair cat was presented with an acute onset of seizures and ataxia. MR imaging was consistent with thiamine deficiency and supplementation resulted in a progressive clinical improvement. Repeated MR imaging 4 days after starting thiamine supplementation revealed near complete resolution of the MR abnormalities. Repeated MR imaging following appropriate therapy may be useful to further confirm thiamine deficiency.

Imaging diagnosis--Canine meningioangiomatosis.

Meningioangiomatosis is a rare proliferative disorder of the central nervous system. It occurs sporadically in dogs and is characterized by a leptomeningeal plaque that extends from the subarachnoid space along the perivascular spaces into the adjacent parenchyma. We describe the clinical presentation, magnetic resonance (MR) imaging and neuropathologic characteristics of two additional dogs with meningioangiomatosis, and document involvement of the thoracolumbar spinal cord, a site not previously described for this condition. MR imaging findings were different from those previously described, most likely reflecting the degree of vascularity and collagen deposition. The MR imaging features of meningioangiomatosis are not specific.

The wobbly cat. Diagnostic and therapeutic approach to generalised ataxia.

PRACTICAL RELEVANCE: Generalised ataxia is one of the most common neurological presentations identified in cats in practice. The causes can be subdivided into three forms on the basis of the neuroanatomical diagnosis: cerebellar, vestibular and sensory (spinal or general proprioceptive) ataxia. The type of ataxia will determine the diagnostic procedures and select the differential diagnoses, and an accurate neuroanatomical diagnosis is therefore essential. The differential diagnosis list can then be further tailored on the basis of patient signalment, clinical presentation and progression. GLOBAL IMPORTANCE: Irrespective of the world region, most of the causes of generalised ataxia in the cat are similar and many have been identified for a number of years (cerebellar hypoplasia has been recognised since the late 19th century). However, it is the advent of new technology, in particular veterinary access to magnetic resonance imaging, which has resulted in particularly rapid advances in our understanding, investigation and management of these different forms of ataxia. AUDIENCE: This article introduces the classification of patients with ataxia on the basis of their clinical presentation, discusses the common differential diagnoses associated with each form, and briefly reviews the more important diseases from a clinical perspective. It is aimed at all veterinarians who treat cats.

Quadrigeminal cyst management by cystoperitoneal shunt in a 4-year-old Persian cat.

Quadrigeminal cysts represent intracranial cystic accumulations of cerebrospinal fluid within the arachnoid mater at the level of the quadrigeminal cistern. Quadrigeminal cysts are rare in cats, with only one previous report in the veterinary literature. A 4-year-old, male-neutered Persian cat was presented with a 1-year duration of initially episodic, but later progressive, obtundation and collapse. Magnetic resonance imaging of the brain revealed a quadrigeminal cyst with marked compression of the adjacent neural structures, cerebellar herniation and obstructive hydrocephalus. Cystoperitoneal shunt placement was performed after the cat became refractory to medical therapy and this resulted in return of normal neurological status. The improvement in the neurological deficits following placement of a cystoperitoneal shunt in this case appeared to be correlated with resolution of the secondary effects (in particular the obstructive hydrocephalus) rather than resolution of the quadrigeminal cyst. Cystoperitoneal shunt placement was an effective long-term treatment option for the management of the quadrigeminal cyst in this cat.

Increasing local levels of neuregulin (glial growth factor-2) by direct infusion into areas of demyelination does not alter remyelination in the rat CNS.

Glial growth factor-2 (GGF-2) is a neuronally derived isoform of neuregulin shown in vitro to promote proliferation and survival of oligodendrocytes, the myelinating cells of the CNS. Enhanced remyelination has been demonstrated in vivo following systemic delivery of human recombinant GGF-2 (rhGGF-2) in experimental autoimmune encephalomyelitis (EAE). However, it is uncertain whether this is the result of direct effects of rhGGF-2 on cells of the oligodendrocyte lineage or due to modulation of the immune or inflammatory response. If this enhanced remyelination was due to direct effects of rhGGF-2 on cells of the oligodendrocyte lineage then one would expect rhGGF-2 to induce a similar proremyelinating response in nonimmune, gliotoxin models of demyelination. Using a gliotoxin model of demyelination we were therefore able to ascertain the in vivo effect of rhGGF-2 following local CNS delivery in a model that is not confounded by the concurrent presence of an immune-mediated process. No significant alteration in the rate or character of remyelination was evident following local delivery as compared to controls, and indeed nor following systemic delivery in the gliotoxin model. The results of this study therefore indicate that both direct infusion and systemic delivery of rhGGF-2 do not alter remyelination in a nonimmune, gliotoxin model of demyelination. This suggests that the proremyelinating effects of systemically delivered rhGGF-2 in EAE are unlikely to be due to direct effects on the oligodendrocyte lineage, but may be mediated by rhGGF-2 inducing an environment more favourable to remyelination, possibly through modulation of the immune response.

Intraventricular tension pneumocephalus as a complication of transfrontal craniectomy: a case report.

OBJECTIVE: To report the diagnosis and surgical treatment of a case of intraventricular tension pneumocephalus in a dog after a transfrontal craniectomy for removal of a falx cerebri meningioma. STUDY DESIGN: Case report. ANIMAL: A 12-year-old spayed English springer spaniel. RESULTS: Intraventricular air and a fistula between the craniectomy site and ventricular system were identified by magnetic resonance imaging. Prompt repair of the dural defect using prosthetic dura mater resulted in immediate regression of the neurological signs and cerebral spinal fluid rhinorrhea. Magnetic resonance imaging repeated 8 weeks after surgery showed complete resolution of pneumocephalus. CONCLUSIONS AND CLINICAL RELEVANCE: Tension pneumocephalus is an uncommon but life-threatening complication of craniectomy that requires urgent diagnosis and treatment.