Introduction
Spirocerca lupi is a parasitic nematode of domestic dogs and wild canids that has been reported in tropical and subtropical regions.1–8 Dogs are the definitive hosts of the parasite and become infected by the ingestion of coprophagous beetles, which serve as intermediate hosts carrying the third larval stage. The larvae migrate through the walls of the gastric blood vessels and aorta and settle in the esophageal wall. During migration, the larvae mature into adults and, once in the target organs, promote the formation of granulomatous nodules that may undergo neoplastic transformation such as osteosarcoma and fibrosarcoma.2,9–12 The typical clinical signs of spirocercosis are related to the presence of esophageal nodules and include regurgitation, vomiting, dysphagia, and weight loss.11,13
Aberrant migration of S lupi has been reported in almost every thoracic organ, the gastrointestinal and urinary tracts, and the subcutaneous tissues.1,6,14–16 In the CNS, so far aberrant migration has been found only in the spinal cord, where the nematode has been identified in the extradural and intradural extramedullary spaces as well as within the spinal cord parenchyma. This results in acute nonsymmetrical paresis or paralysis involving the hind limbs or all 4 limbs.17–20 Without proper and immediate treatment, the nematode continues to migrate through the spinal cord parenchyma, causing further and often irreversible damage.17,18 S lupi is endemic in Israel,1,6,16,18 and intraspinal migration of the nematode is now considered one of the primary differential diagnoses for peracute, progressive, nonsymmetrical spinal paresis in dogs.
While dogs presenting with neurological clinical signs characteristic of intraspinal spirocercosis are seen commonly, a definitive diagnosis could be made only by necropsy until recently.17–20 PCR test for detection of S lupi has recently been established and is now considered the diagnostic tool of choice, with 86% sensitivity and 100% specificity.21
Doramectin, an antiparasitic derivative of ivermectin, is the drug of choice to both prevent and treat esophageal spirocercosis.1,12,22–25 The recommended protocol for esophageal spirocercosis is 400 µg/kg, 6 times in a 2-week interval followed by a monthly dose until resolution of esophageal granuloma. In another study, milbemycin oxime at 0.5 mg/kg, PO, on days 0, 7, and 28, then monthly for at least 2 months and 2.5% moxidectin and 10% imidacloprid combination at 2.5 and 10 mg/kg, respectively, given topically once a week for at least 12 weeks have shown therapeutic efficacy but with lower success rates than with doramectin.26 However, this protocol is not sufficient to abruptly kill the nematode and stop its destructive migration/movement through the spinal cord, as deterioration of clinical signs has been witnessed in dogs within days following a single dose of doramectin.17,18,20 The limited penetration of the drug through the intact blood-brain barrier (BBB) has been shown to prevent its potential adverse effect on the brain.27,28 Moreover, the decreased expression of P-glycoprotein in spinal cord endothelial cells, as compared to that in the brain, allows some doramectin penetration into the spinal cord even without blood–spinal cord barrier (BSCB) disruption.27,29 These findings support the safe administration of higher and more frequent doses of doramectin. In this study, we examined this more aggressive approach by evaluating the short- and long-term efficacy and safety of a frequent, high-dose doramectin treatment protocol in dogs definitively diagnosed with intraspinal S lupi.
Materials and Methods
Case selection
All dogs admitted to the Koret School of Veterinary Medicine Teaching Hospital or to the Tipul Nimratz emergency center during 2021 and 2022 with an acute onset of neurological signs and a positive PCR test for S lupi in CSF from either lumbar or cisternal puncture were recruited. Only dogs with complete medical records, including relevant medical history, physical and neurological examination, and CSF analysis, were included.
The targeted gene for PCR is a 270-pb fragment of the 18S gene of S lupi using primers Sl18S-F (5′-AAG CTC CGA CTT TTG GAC GA-3′) and Sl18S-R (5′-GTC ACT ACC TCC TCA TGC CG-3′) described in Rojas et al16 with sample preparation and DNA extraction as explained in Ruggeri et al.21 DNA from CSF was extracted using the QIAamp Fast DNA Stool Mini Kit (Qiagen) according to the manufacturer’s instructions and following the modifications specified by Ruggeri et al.21 Moreover, a real-time PCR targeting a 270-bp fragment of the 18S gene of S lupi was amplified using primers Sl18S-F (5′-AAG CTC CGA CTT TTG GAC GA-3′) and Sl18S-R (5′-GTC ACT ACC TCC TCA TGC CG-3′) with conditions as previously described.16
Treatment protocol
Medical treatment, which was initiated immediately upon admission on the basis of characteristic clinical signs, included doramectin at a dosage of 400 μg/kg, SC, q 24 h for a maximum of 3 consecutive days. Once a definitive diagnosis was made, doramectin was administered to complete the 3 consecutive days and was followed by the same dose once a week for an additional 6 weeks. Prednisone was given at a dose of 1 mg/kg, PO, q 24 h, tapered every 3 days for 10 days, and clindamycin was given at a dose of 12.5 mg/kg, PO, q 12 h, for 7 days to reduce the risk of secondary spinal cord infection. Physiotherapy and controlled exercise were recommended and initiated immediately.
Follow-up evaluations
Dogs were invited for follow-up neurological evaluation at 7 to 10 days and at 1 month of treatment. Long-term follow-up was conducted either by physical and neurological follow-up examination during a hospital visit or through telephone communication and evaluation of short videos taken by the owners.
Results
Animals
Eight dogs were enrolled in this study, including 6 males (5 neutered) and 2 females (2 spayed), with a median age of 3.5 years (range, 0.8 to 14 years) and a median body weight of 18 kg (range, 9.4 to 27 kg). Four dogs had received routine prophylactic treatment with doramectin (200 μg/kg, SC, q 2 to 6 months) prior to the onset of clinical signs, including 1 dog (case 5) that was treated 1 month before. Neurological abnormalities on presentation included asymmetrical paraparesis (3/8), hemiparesis (2/8), tetraparesis (1/8), paraplegia (1/8), and severe neck pain without neurological deficit (1/8). Moderate to severe hyperesthesia of the vertebral column was present in all dogs. Five dogs were treated by their referring veterinarians prior to admission. Mean time from onset of clinical signs to diagnosis and initiation of treatment was 61 hours (median, 60 hours; range, 12 to 168 hours). Signalment, clinical characteristics, and treatment details are shown (Table 1).
Signalment, prophylactic treatment, onset, neurological examination, and localization at presentation in dogs with intraspinal Spirocerca lupi infection (n = 8).
| Dog number | Signalment | Prophylactic treatment | Onset | Neurological examination | Localization | Duration of clinical signs* | First dose ** |
|---|---|---|---|---|---|---|---|
| 1+ | 4 y, X, NM, 15 kg | None | AP | Asym NA paraparesis L > R | T3–L3 | 168 h | 168 h |
| 2 | 8 y, NM, B, 16 kg | 3 mo before | AP | Severe cervical hyperesthesia | C6-T2 | < 12 h | 24 h |
| 3 | 6 y, X, NM, 9.4 kg | 6 mo before | AP | Paraplegia with DP | T3–L3 | < 24 h | 24 h |
| 4 | 14 y, X, SF, 25 kg | None | AP | Hemiparesis R > L | C6–T2 | 72 h | 48 h |
| 5 | 0.8, X, IM, 27 kg | 1 mo before | AP | Asym NA paraparesis R > L | L4–S1 | 48 h | 48 h |
| 6 | 1.3 y, NM, BC, 20 kg | None | AP | Asym paraparesis L > R | T3-L3 | 12 h | 12 h |
| 7 | 2 y, NM; X, 27 kg | None | AP | NA, tetraparesis | C1–C5 | 72 h | 72 h |
| 8 | 1.5 y, F, X, 16 kg | 3 mo before | AP | Hemiparesis R > L | C6–T2 | 72 h | 72 h |
+Humanely euthanized. *Time interval from onset of clinical signs to diagnosis. **Time interval from onset of clinical signs to administration of the first doramectin dose.
AP = Acute progressive. Asym = Asymmetrical. B = Beagle. BC = Border Collie. DP = Deep pain perception. F = Female. HL = Hind limb. L = Left. LH = Left hind limb. M = Male. NA = Nonambulatory. NF = Neutered female. NM = Neutered male. R = Right. RH = Right hind limb. X = Mixed breed. Y = Year old.
Neuroanatomic localization of the lesion was T3-L3 in 3 of 8 dogs, C6-T2 in 3 of 8, L4-S3 in 1 of 8, and C1-C5 in 1 of 8. CBC and chemistry profiles were unremarkable in all dogs, except for absolute eosinophilia in 2 (0.81 X 103 cells/µL and 1.26 X 103 cells/µL; reference range, 0 X 103 to 0.6 X 103 cells/µL; cases 1 and 5) and mild leukocytosis in 1 (15.6 X 103 cells/µL; reference range, 5.2 X 103 to 13.9.0 X 103 cells/µL, case 5; Table 1).
CSF collected through either cisternal or lumbar puncture was abnormal in all 8 dogs, with total nucleated cell count ranging between 4 to 1,000 cells/μL (median, 195 cells/μL; mean, 290 cells/μL; reference range, 0 to 5 cells/µL) in cisternal samples (8/8) and 600 to 1,900 cells/μL (median, 1,100 cells/μL; mean, 1,216 cells/μL; reference range, 0 to 5 cells/µL) in caudal lumbar samples (6/8). Mild blood contamination of the CSF sample was documented in 6 dogs (cases 1 to 6; Table 2). CSF cytology revealed the presence of eosinophils in all samples, representing 9% to 70% of nucleated cells in the slide. Protein levels were elevated (> 25 mg/dL) in 7 of 8 dogs tested and ranged between 30 to 246 mg/dL (median, 100 mg/dL; mean, 191.5 mg/dL, reference range, 0 to 25 mg/dL). All 8 dogs had a positive PCR test for S lupi in the CSF, with 7 of 8 positive results in cisternal samples and only 5 of 8 in lumbar samples. Spinal radiographs were performed in 5 of 8 dogs and revealed only a mild spondylitis at T10-T11 vertebra in 1 dog (case 6). In the same dog, a caudal mediastinal opacity was detected, indicating a possible esophageal granuloma of S Lupi at this site. Focal attenuation of the contrast columns at T8-T13 and T9-T13 spinal cord segments was evident in both dogs that underwent myelo-CT (cases 1 and 3; Table 1). Intramedullary hyperintensity spread over spinal cord segments C3-C4 on T2-weighted MRI images and a focal intramedullary T1W postcontrast enhancement was observed in 1 dog (case 8).
Clinical pathology findings and short- and long-term outcomes in dogs with intraspinal S lupi infection (n = 8).
| Dog No. | Cell count (cells/µl; 0–5) | CSF protein (mg/dL; 0–25) | Eosinophils (% in smear; 0) | FU 10 to 14 days | FU 6 to 56 months |
|---|---|---|---|---|---|
| 1* | 40C | 38C | 9C | NA | NA |
| 1,900L | 80L | ||||
| 2 | 220C | 38C | 10C | Normal | Normal (12 mo) |
| 1,900L | 47L | ||||
| 3 | 4C | 300L | 10L | Amb paraparesis | Mild LH paresis and ataxia (8 mo) |
| 600L | 33L | ||||
| 4 | 500C | 30C | 50C | Proprioceptive ataxia and amb paraparesis | Mild paraparesis R > L (6 mo) |
| 1,000L | 100L | ||||
| 5 | 220C | 677L | 30C | Amb paraparesis R > L | Mild proprioceptive ataxia on HL (42 mo) |
| 1,800L | 70L | ||||
| 6 | 170C | 65C | 70C | Proprioceptive ataxia on HL and LH monoparesis | NA |
| 800L | 100L | 70L | |||
| 7 | 1,000C | 246C | 70C | Proprioceptive ataxia and tetraparesis | Mild proprioceptive ataxia on HL (36 mo) |
| 8 | 170C | 61C | 40C | R-side hemiparesis | Mild proprioceptive ataxia on HL (56 m) |
*Humanely euthanized. CCSF samples from cisterna magna. LCSF samples from lumbar puncture.
Amb = Ambulatory. FU = Follow-up. HL = Hind limb. L = Left. LH = Left hind limb. R = Right. RH = Right hind limb.
As mentioned, treatment with doramectin was initiated upon presentation on the basis of characteristic neurological signs in all dogs. Seven of the included dogs received the first dose of doramectin between 24 and 72 hours from onset of clinical signs (cases 2 to 8), and 1 dog (case 1; Tables 1 and 2) received the first dose on day 7 of clinical signs. Following positive PCR test for S lupi, treatment was continued as described.
Outcome
All dogs were discharged 1 to 7 days (median, 3.5 days) from admission. In 7 of 8 dogs, no further deterioration of neurological signs was recorded after the initiation of treatment. These 7 dogs showed improvement at 10 to 14 days on follow-up examination. As shown (Table 2), 4 of them regained ambulation (cases 3, 5, 6, and 7); 1 dog, which initially presented with severe cervical hyperesthesia, was free of pain (case 2); and 1 dog was relieved of cervicothoracic hyperesthesia, but the ataxic gait remained (case 8). The last of these dogs (case 4) improved initially but temporarily relapsed upon tapering of prednisone. Temporary increase in prednisone dose for an additional week resulted in improvement of clinical signs in this dog.
One dog (case 1; Table 1), which was admitted 7 days after the initiation of acute progressive paraparesis, continued to deteriorate despite receiving the same treatment. At the 10-day follow-up examination, this dog became paraplegic and lost its deep pain perception and was euthanized at the owner’s request. Histopathological examination revealed intraspinal migration tracts spread along several mid- and caudal thoracic segments with intraparenchymal hemorrhages and local inflammation. An end-stage larval nematode was identified at the most cranial end of the migratory tract (Figure 1). All remaining 7 dogs were ambulatory but still ataxic at a 1-month follow-up evaluation (Table 2). Owners reported no adverse effects of the drug during treatment.
Cross section images of 2 spinal cord segments from a dog with intraspinal spirocercosis that was euthanized due to deterioration of T3-L3 neurological signs. A—Formalin-fixed spinal cord segment showing migratory tract and hemorrhages (white arrows) in a spinal cord segment adjacent to the one with the nematode. B and C—Low and high magnification of H&E-stained slides of the same spinal cord segment showing microhemorrhage (C; green arrow). D—Formalin-fixed spinal cord segment with the nematode within the spinal cord dorsal horn and the adjacent dorsal and lateral funiculus. E and F—Low and high magnification of H&E-stained slides showing a cross section through the nematode (black arrow) and necrotic tract (red arrow) infiltrated with inflammatory cells (red arrow).
Citation: Journal of the American Veterinary Medical Association 261, 3; 10.2460/javma.22.09.0401
Cross section images of 2 spinal cord segments from a dog with intraspinal spirocercosis that was euthanized due to deterioration of T3-L3 neurological signs. A—Formalin-fixed spinal cord segment showing migratory tract and hemorrhages (white arrows) in a spinal cord segment adjacent to the one with the nematode. B and C—Low and high magnification of H&E-stained slides of the same spinal cord segment showing microhemorrhage (C; green arrow). D—Formalin-fixed spinal cord segment with the nematode within the spinal cord dorsal horn and the adjacent dorsal and lateral funiculus. E and F—Low and high magnification of H&E-stained slides showing a cross section through the nematode (black arrow) and necrotic tract (red arrow) infiltrated with inflammatory cells (red arrow).
Citation: Journal of the American Veterinary Medical Association 261, 3; 10.2460/javma.22.09.0401
Cross section images of 2 spinal cord segments from a dog with intraspinal spirocercosis that was euthanized due to deterioration of T3-L3 neurological signs. A—Formalin-fixed spinal cord segment showing migratory tract and hemorrhages (white arrows) in a spinal cord segment adjacent to the one with the nematode. B and C—Low and high magnification of H&E-stained slides of the same spinal cord segment showing microhemorrhage (C; green arrow). D—Formalin-fixed spinal cord segment with the nematode within the spinal cord dorsal horn and the adjacent dorsal and lateral funiculus. E and F—Low and high magnification of H&E-stained slides showing a cross section through the nematode (black arrow) and necrotic tract (red arrow) infiltrated with inflammatory cells (red arrow).
Citation: Journal of the American Veterinary Medical Association 261, 3; 10.2460/javma.22.09.0401
A long-term follow-up evaluation at 6 to 36 months following onset of clinical signs was available for 6 of 7 dogs. Five dogs (5/6), which presented initially with nonambulatory para- or quadriparesis, were ambulatory with minimal ataxia and proprioceptive deficits in one or both hind limbs. No further deterioration of neurological signs or any other adverse effects of the treatment were recorded during the study.
Discussion
This study evaluated the efficiency of multiple frequent doses of doramectin in preventing additional neurological deterioration by the migrating S lupi. When compared to previously reported outcomes in untreated dogs or in dogs treated with a single dose of doramectin,17–20,30 our results highlighted the advantage of the protocol described herein. Dogs in our study exhibited high rates of survival and recovered from the intraspinal migration. Because most dogs are still alive presently, there is no pathological or histological evidence for the fate of the nematodes. Nevertheless, the fact that no deterioration of neurological deficits occurred after the first 3 days of treatment suggests that the consecutive doses of this anthelmintic drug abruptly stopped the nematode migration through the spinal cord parenchyma, thereby allowing healing processes to take place. Overall, 7 of the 8 dogs displayed improvement in clinical signs, which sustained for the duration of the study and up to 6 to 36 months following treatment.
Dogs included in this study were similar in age, body weight, and clinical characteristics to other reported cases of intraspinal S lupi.4,17–19 The reported population was young and of midsize to large breed and suffered from a sudden onset of asymmetrical paresis or lameness that progressed over 1 to 7 days. A typical clinical manifestation of intraspinal spirocercosis is the change in neuroanatomical localization during the disease’s course, which is explained by the continuous migration of the nematode along the spinal cord.18 This was not recorded in any of the presented dogs after the initiation of treatment. In all 8 dogs in this study, CSF cytology revealed a high percentage of eosinophils, as was previously reported for aberrant intraspinal migration of S lupi. However, as eosinophilic pleocytosis is found in other CNS pathologies,31–37 our dogs were diagnosed definitively by the positive PCR results.
Doramectin prevents the transmission of electrical impulses in the muscles and nerves of the nematode by amplifying the glutamate effects on a specific gated chloride channel.38 This drug is used to treat esophageal granulomas caused by S lupi and serves as a prophylaxis in endemic areas. The doses regularly used to treat esophageal granulomas are 400 to 600 μg/kg and the success rate of eliminating the granuloma is 62% to 100%.1,6,22,23,25,38 Subcutaneous doses of 400 μg/kg doramectin, which are commonly used to treat endoparasites in dogs, are given once a week or 2 weeks for 6 to 12 weeks to eliminate S lupi esophageal granulomas.6,23–25
Treating intraspinal migration of either larval or adult nematode is challenging due to the severe and often irreversible damage caused to the spinal cord tract and nerve cells. If the administered dose is not fatal to the nematode, its continued migration results in rapid neurological deteriorating, which is often noted within hours to days of the initial presentation.17–21,28 Following the initiation of the described protocol, only 1 out of 8 dogs deteriorated and a rapid improvement was observed in the remaining 7 dogs. Serum half-life of ivermectin and doramectin in dogs was reported to be 3 days following either oral or SC administration.39 The pharmacokinetics and peak concentration of doramectin or ivermectin in the CSF are unknown, but both drugs do not cross the BBB and only partially cross the BSCB.27 In a study conducted on a healthy llama that received an IV injection (500 µg/kg) of ivermectin, a very low CSF concentration (0.25 ng/mL) was measured despite very high concentrations (2,291 to 7,742 ng/mL; mean, 4,751 ng/mL) of the drug in the serum.40 In another study41 on a neurologically affected llama, higher concentrations of ivermectin (2.9 to 3.5 ng/mL) were measured in the CSF, which was attributed to the disrupted BBB of the inflamed CNS. These concentrations were still lower than those measured in the serum (1.4 to 16.4 ng/mL) of the same animal.41 The BSCB is more permeable to doramectin than the BBB due to lower expression of P-glycoproteins.27 Moreover, severe destruction of spinal cord blood vessels leading to microhemorrhages and focal inflammation was recorded in histological evaluation of spinal cords from dogs that died or were euthanized due to the progression and irreversible clinical signs.17,18,20 Similar findings were recorded in the 1 dog that was euthanized in this study (case 1; Tables 1 and 2; Figure 1). Due to the disrupted BSCB in the inflamed tissue around the nematode and the small blood vessel tares caused by the moving larvae through the spinal parenchyma, we anticipated that increasing the doramectin concentration in the blood by its repeated daily administration would result in increased doramectin concentration in CSF and in spinal cord parenchyma around the living nematode.
The actual blood and CSF concentrations of doramectin were not measured in this study. Nevertheless, the lack of deterioration in all but 1 dog suggests that the level reached in the CSF, spinal cord, or both was enough to prevent further movement of the nematode within the spinal parenchyma. The main clinical manifestation of doramectin adverse effects are hypersalivation, mydriasis, ataxia, blindness, seizures, coma, respiratory compromise, and death.42 However, none of the dogs in our study showed any of these signs. This supports the notion that the drug did not cross the BBB despite focal disruptions in the spinal cord. The relatively rapid improvement of neurological signs can be attributed to the fast diagnosis and initiation of suitable treatment, which combined antiparasitic therapy with steroids. The ongoing spinal cord injury caused by the penetration and movement of the nematode is accompanied by secondary injury and inflammation, which may benefit from the administration of steroids.18,43 Moreover, a dead nematode may provoke additional inflammatory response, further justifying the use of steroids.18,44 No spinal compression or instability occurs in cases of intraspinal S lupi migration; hence, there is no need for confinement. These dogs are encouraged to exercise, and physiotherapy is often initiated soon after the diagnosis is confirmed.44,45 The latter can further improve prognosis and recovery rates, similar to recovery from other spinal cord diseases.
A dose of 200 μg of doramectin/kg is administered SC once in 2 to 3 months as a routine preventive treatment for esophageal S Lupi in Israel.1,6 Four dogs in this study were treated regularly by this prophylactic dose every 2 to 6 months. However, this preventive treatment failed to prevent the migration of the nematode through the gastric blood vessels and into the spinal cord. Administration of 200 μg/kg every 2 to 3 months is probably not sufficient to maintain therapeutic blood concentration that prevents the nematode migration throughout this time interval. According to the literature, the blood concentration of doramectin peaks 3 days after SC injection and then drops over 25 days.1,6,39 In 1 dog, preventive therapy with doramectin was given 30 days before the occurrence of intraspinal migration. Therefore, if such cases reoccur, adjustment of the preventive treatment protocol in endemic areas should be considered.
Here, we tested the suggested treatment protocol on a relatively small group of dogs. Nevertheless, all were definitively diagnosed with intraspinal spirocercosis and favorable outcomes were observed in all but one. These results reinforce the importance of early diagnosis and treatment of intraspinal nematode migration to allow recovery. Diagnosis should be made on the basis of characteristic clinical presentation, eosinophilic pleocytosis in the CSF, and positive PCR test. When PCR is not available, exclusion of a compressive spinal cord lesion may be needed. Overall, in the dogs we studied, a high-dose, frequent doramectin protocol initiated upon diagnosis and combined with prednisone provided good to excellent long-term outcomes.
Acknowledgments
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors declare that there were no conflicts of interest with respect to the publication of this manuscript.
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