A4-year-old 16.2-kg (35.6-lb) neutered male working Cocker Spaniel with a 1-week history of left thoracic limb monoparesis was evaluated. The dog was reported to be historically blind in the left eye. Two weeks prior to presentation, the dog developed acute vomiting, anorexia, and pyrexia (40°C [104°F]). The dog was treated by the referring veterinarian for suspected pancreatitis with tramadol, metronidazole, sucralfate, and ranitidine. Investigations prior to the referral evaluation also revealed regenerative, hypochromic, microcytic anemia. After the dog was fed a hypoallergenic diet, a sample of its feces was positive for occult blood. At the referral evaluation, the dog was bright, alert, and responsive. Its mucous membranes were pink and moist with a capillary refill time < 2 seconds. Results of cardiac and respiratory auscultation were unremarkable. Abdominal palpation identified a small firm mass cranial to the bladder (approx 2 cm in diameter). Rectal examination findings were unremarkable, and rectal temperature was within reference range. A neurologic examination was performed.
What is the problem? Where is the lesion? What are the most probable causes of this problem? What is your plan to establish a diagnosis? Please turn the page.
Assessment Anatomic diagnosis
| Problem | Rule out location |
|---|---|
| Left thoracic limb monoparesis with weak flexor withdrawal reflex and reduced limb muscle tone | Left C6-T2 spinal cord segments, left C6-T2 nerve roots, left brachial plexus, or peripheral polyneuropathy (left suprascapular, musculocutaneous, radial, median, or ulnar nerves) |
| Delayed proprioception and weak withdrawal reflex in the left pelvic limb | Left L6-S1 spinal cord segments, left L6-S1 nerve roots, or left sciatic nerve |
| Diminished patellar reflexes bilaterally | L4-L6 spinal cord segments, L4-L6 nerve roots, or left and right femoral nerves |
Likely location of 1 lesion
Multifocal peripheral neuropathy affecting the left brachial plexus (or multiple peripheral nerves innervating the left thoracic limb), the left sciatic nerve, and both femoral nerves was suspected. A multifocal spinal cord lesion was considered less likely given the relative sparing of tail function, normal perineal reflex, and normal proprioception in the right pelvic limb.
Etiologic diagnosis—Differential diagnoses for chronic, progressive, multifocal, asymmetric peripheral neuropathy included neoplastic infiltration (eg, round cell tumor), infectious polyneuropathy (eg, protozoal infection), or sterile inflammatory polyneuropathy. Metabolic, degenerative, and paraneoplastic polyneuropathy were considered less likely given the asymmetric involvement of multiple peripheral nerves. The diagnostic plan included repeated clinicopathologic testing, urinalysis, abdominal ultrasonography, electromyography, and analysis of a CSF sample.
Diagnostic test findings—A CBC and serum biochemical analysis were performed prior to anesthesia for further investigations. The CBC revealed microcytic hypochromic regenerative anemia (Hct, 32.9% [reference interval, 37.3% to 61.7%]; mean corpuscular volume, 46.9 fL [reference interval, 61.6 to 73.5 fL]; and reticulocyte count, 230.6 × 109 reticulocytes/L), most consistent with iron deficiency. This was suspected to be the result of chronic blood loss, most likely of gastrointestinal tract origin. Activated partial thromboplastin and prothrombin times were not prolonged. Serum biochemical analysis identified a low plasma urea concentration (1.5 mmol/L; reference interval, 2.5 to 9.6 mmol/L), high alkaline phosphatase activity (245 U/L; reference interval, 23 to 212 U/L), and hypertriglyceridemia (3.84 mmol/L; reference interval, 0.11 to 1.13 mmol/L). Urinalysis revealed a urine specific gravity of 1.028 and 1+ granular casts. No proteinuria was detected.
The dog was anesthetized and abdominal ultrasonographya was performed to further investigate the firm mass in the caudal portion of the dog's abdomen that had been palpated during the physical examination. Ultrasonography revealed that the right pancreatic lobe was mildly heterogeneous and hypoechoic with hyperechoic surrounding fat and mesentery, findings that were potentially consistent with pancreatitis. A focal segment of jejunum had circumferential, eccentric thickening of the muscularis layer with a large, focal, eccentric, homogeneous, hypoechoic mass-like lesion arising from this layer (Figure 1). The surrounding mesenteric fat was markedly hyperechoic with a minimal volume of adjacent anechoic fluid. The appearance of the stomach, liver, spleen, kidneys, adrenal glands, and lymph nodes was unremarkable. On the basis of the ultrasonographic findings, an infiltrative neoplasm, such as lymphoma or mast cell tumor, was considered the most likely differential diagnosis. Granulomatous disease was considered an alternative but less likely diagnosis. Fine-needle aspirate specimens of the liver, spleen, and jejunal mass were collected.
Longitudinal (A) and transverse (B) abdominal ultrasonographic views obtained during investigation of a firm mass in the caudal portion of the abdomen of a 4-year-old Cocker Spaniel with a 1-week history of left thoracic limb monoparesis. Two weeks earlier, the dog developed acute vomiting, anorexia, and pyrexia. In panel A, a focal segment of jejunum within the mid-caudal portion of the abdomen has circumferential eccentric thickening of the muscularis layer (arrows), which is continuous with a focal, eccentric, large, homogeneous, hypoechoic mass-like lesion arising from the muscularis layer (arrowheads). In panel B, this same focal segment of the jejunum in transverse view has circumferential, vascularized thickening of the muscularis layer (arrows). In Doppler mode, the blue color between the submucosa and the muscularis layers is indicative of vascularization between the intestinal layers (arrowhead). The blue and red zone surrounding the cranial part of the muscular layer is a motion artifact.
Citation: Journal of the American Veterinary Medical Association 257, 10; 10.2460/javma.2020.257.10.1013
During the same anesthetic episode, electromyography was performed to further characterize the dog's suspected peripheral neuropathy. Electromyography revealed abnormal spontaneous myofiber activity in the left cranial tibial, left gastrocnemius, left and right quadriceps femoris, right supraspinatus, right infraspinatus, left palmar interosseous, left extensor carpi radialis, left flexor carpi ulnaris, and left triceps brachii muscles. These findings were most consistent with peripheral polyneuropathy involving both femoral nerves and the left sciatic nerve, right subscapular nerve, and left median, ulnar, and radial nerves. Samples of CSF were collected from both the lumbar cistern and cisterna magna. Additional diagnostic tests, such as peripheral nerve biopsy and MRI of the C6-T2 and L4-S1 spinal cord segments and nerve roots and left brachial plexus, were declined by the owner pending results of the cytologic examination of the fine-needle aspirate specimens. The dog recovered from anesthesia uneventfully.
Analysis of the cisternal CSF sample did not reveal any abnormalities. Analysis of the lumbar CSF sample revealed a high total protein concentration (54.2 mg/dL; reference interval, < 45 mg/dL) and mild mononuclear pleocytosis (6 WBCs/μL [reference interval, < 5 WBCs/μL] and 0 RBCs/μL). Cytologic examination of the lumbar CSF sample revealed macrophages and occasional unremarkable small lymphocytes.
Cytologic examination of the fine-needle aspirate specimens of the jejunal mass, liver, and spleen revealed a large number of atypical, large, round cells that were most consistent with a neoplastic population of lymphoid cells. These findings supported a diagnosis of multicentric lymphoma. The polyneuropathy was suspected to be secondary to infiltration of the affected peripheral nerves by neoplastic lymphocytes (neurolymphomatosis). A paraneoplastic polyneuropathy could not be excluded in the absence of histopathologic examination of peripheral nerve biopsy specimens, but was considered less likely given the dog's asymmetric peripheral nerve involvement. The owner declined further investigations or treatment and requested euthanasia. The dog did not undergo a postmortem examination in accordance with the owner's wishes.
Comments
Neurolymphomatosis is a rare condition that is defined as infiltration of nerve roots or peripheral nerves by neoplastic lymphocytes.1–5 In humans, clinical signs of neurolymphomatosis may include painful or nonpainful polyneuropathy, cranial neuropathy, and peripheral mononeuropathy.1 Neurolymphomatosis is rarely reported in the veterinary medical literature, and the clinical signs in affected animals may be nonspecific; the most common pattern of signs is single or multilimb lameness, muscle weakness, and monoparesis or plegia, depending on the nerves involved.5–8 For the dog of the present report, the clinical signs were acute (1 week's duration) and the left side of the body was initially most affected.
In humans, neurolymphomatosis has been associated most commonly with B-cell non-Hodgkin lymphoma; however, neurolymphomatosis associated with lymphoma of T-cell lineage has also been reported.1,9,10 Determination of the lymphoma cell lineage may affect prognosis and chemotherapeutic choices and would be recommended before starting treatment. In the case described in the present report, cytologic examination of the jejunal mass revealed neoplastic lymphocytes, but cell lineage was not confirmed by immunocytochemical analysis given the owner's decision not to treat the dog.
For the dog of the present report, the combination of clinical signs and the presence of an abdominal mass at the time of the referral examination were suggestive of a multifocal disease process, such as infection, inflammation, or neoplasia. The diagnosis of lymphoma and polyneuropathy was achieved on the basis of the results of neurologic examination, abdominal ultrasonography, cytologic examination of the parenchymatous organs affected by the lymphoid cells, and electromyography. Ultrasonographic findings contributed to the diagnosis, negating the need for advanced diagnostic imaging.
Antemortem diagnosis of neurolymphomatosis is typically made on the basis of detection of enlargement or enhancement of nerves and nerve roots on MRI images and examination of peripheral nerve biopsy specimens. In human medicine, MRI and fluoro-deoxyglucose positron emission tomography are the techniques of choice for detection of enlargement, nodularity, and enhancement of the peripheral nerves because CT often fails to detect these changes.11
Treatment of neurolymphomatosis in humans involves systemic chemotherapy, commonly including methotrexate, cytarabine, and rituximab.9 Use of intrathecal chemotherapy and localized radiotherapy has also been reported.9,10 The median survival time of humans with neurolymphomatosis is 10 months.2 In veterinary medicine, a survival time of 53 days was reported for a dog with T-cell neurolymphomatosis of the radial nerve that was treated with a combination of systemic radiotherapy and lomustine.8 Palliative treatment with prednisolone of a cat with neurolymphomatosis has also been attempted, with a similar reported survival time of approximately 2 months.12
For the dog of the present report, a paraneoplastic neurologic syndrome or polyneuropathy could not be ruled out but was considered less likely given the asymmetric peripheral nerve involvement. Paraneoplastic neurologic disorders are the result of an indirect effect of tumors on the nervous system or muscles without local invasion or metastasis, and are suspected to result from an autoimmune response to proteins common to the tumor and the peripheral nervous system or CNS (onconeural antigens).13–15 In humans, paraneoplastic neurologic syndromes develop in < 1% of people with a malignancy, with the most common syndromes including encephalomyelitis, limbic encephalitis, subacute cerebellar degeneration, opsoclonus myoclonus, sensory neuropathy, chronic intestinal pseudo-obstruction, Lambert-Eaton myasthenic syndrome, and dermatomyositis.15 The most frequently diagnosed malignancies associated with paraneoplastic neurologic disorders in humans are thymoma; lung, testicular, and gynecologic cancers; and, less frequently, lymphoma.14,15 In dogs, paraneoplastic neurologic disorders have been reported in association with mastocytoma, thymoma, small cell carcinoma, and lymphoma.13,15 Although rare, neurolymphomatosis should be considered as a differential diagnosis for dogs with chronic, progressive, peripheral mononeuropathy or polyneuropathy, with or without a known history of lymphoma elsewhere in the body.
Footnotes
Logiq S7, GE Healthcare, Chicago, Ill.
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