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BULLETIN No. 1*
Please Note: This is an online version of a printed newsletter.
INTRODUCTION
HISTORY
IDENTIFICATION AND DISTRIBUTION OF IXODES
HOLOCYCLUS
LIFECYCLE AND BIOLOGICAL VARIABILITY
ATTACHMENT AND ENGORGEMENT
ENVIRONMENTAL FACTORS
MORTALITY RATES
THE IMPORTANCE OF RESPIRATORY
COMPROMISE IN STAGING TICK PARALYSIS
TREATMENT OF TICK PARALYSIS
OTHER CONSIDERATIONS IN PATIENT MANAGEMENT
CONCLUSION
REFERENCES
INTRODUCTION
This is the first in a series of Bulletins from the National Tick Paralysis Forum convened in June 1998 as a Merial Australia initiative. These Bulletins will describe existing knowledge and update research data from various sources. The series is intended to provide veterinarians in practice with a reliable source of background information derived from researchers and clinical experts in the field of tick poisoning.
Ixodes holocyclus is a parasite of unique significance to Australia. Although a large amount of information has been published on tick poisoning it remains a confusing disease and it is hoped that the National Tick Paralysis Forum will facilitate development of both its understanding and treatment.
This Bulletin will provide a general review of the biology of Ixodes holocyclus and the disease it can cause. Future Bulletins will report the findings of research projects, including surveys of current veterinary treatment of clinical cases.
HISTORY
The first reports of this tick occurred in 1824 when Howell described the tick to be "buried in the flesh" and to "destroy either man or beast". Reading the headstones at Cooktown cemetery provides ample evidence of this tick's lethal potential.
The variability of clinical signs caused by Ixodes holocyclus us was first outlined by Stuart in 1894, who described dogs that developed "apparent immunity" as well as cases that developed clinical signs within a few hours of attachment. In humans, the first confirmed death due to tick poisoning was reported in 1912 (Cleland) when a large engorged tick caused flaccid paralysis in a child, progressing to asphyxiation. By 1921 Dodd had established a definitive link between Ixodes holocyclus and clinical disease in three dogs, showing that it took 5 to 6 days after attachment for clinical signs to develop with motor paralysis being the major neurological deficit.
IDENTIFICATION AND DISTRIBUTION OF Ixodes holocylus
The identity of this tick can be easily established by the darker brownish discolouration of the first and 4th pairs of legs (starting from the head) and by the ultraviolet fluorescence of the 3rd pair of legs (Atwell, 1998). More formal classification relates to the long mouthparts and the complete (anterior) anal groove (hence holocyclus = "full circle"). The legs "move" towards the mouthparts as the tick engorges and the degree of this distortion can be confusing. The colour of the male and female tick varies with time but most ticks seen on animals are grey or light blue with variations occurring as the tick engorges [NF: and perhaps it changes even more as it becomes gravid].
The tick is found on the eastern seaboard of Australia, from North Queensland to Northern Victoria (Lakes Entrance), generally in bush and scrubland. It is not always restricted to the immediate coastline and can be found a long way inland in suitable habitats, e.g. Bunya Mountains.
LIFECYCLE AND BIOLOGICAL VARIABILITY
This is a three-host tick with four distinct lifecycle stages: egg, larva (6 legs), nymph (8 legs) and adult (male and female). Other than the egg and male adult, each stage must engorge on a host before detaching into the immediate local environment, where they moult to the next stage or lay eggs. All three engorging stages can cause poisoning, however large numbers of nymphs and larvae are required to do so.
The development period for each stage is variable, governed primarily by temperature and humidity of the local microclimate, e.g. the period from the time of a larva hatching to moulting to the nymphal stage varies from 20 days, at a constant 27.5°C, to 40 days at ambient room temperatures.
Nymphs are very active 5-6 days after moulting from the larval stage, and readily attach at day 8, e.g. to a bandicoot host. Emergence of adult ticks from the nymphal stage varies from 20 days at 24-27°C, to 53-65 days at ambient room temperature with a low night temperature of 10°C. Dry environments prolong this period and can actually kill the nymph.
Adult female ticks are increasingly active up to 6-7 days after hatching and will readily feed at day 9. Adult males do not feed.
It seems that a temperature of 27°C associated with moist conditions (not too dry or too wet) is optimal for tick development.
ATTACHMENT AND ENGORGEMENT
Once on the skin, ticks quickly attach and then start to feed. Attachment is mainly at the anterior of the host (head, neck and front legs) but may occur at any site. The pattern of attachment in experimental dogs is similar, even when ticks are loaded on the backs of animals, suggesting a predilection for certain sites.
Ticks do not feed constantly but tend to feed, salivate and rest, repeating this cycle at variable intervals. In experiments, ticks feed slowly for the first 72 hours after attachment and then rapidly from 120 hours onwards. The engorgement process is marked at the end, with dramatic enlargement just prior to detachment. Feeding rates are affected by temperature and humidity. For example, in warm summer weather complete engorgement can take 6 days, while this can be as long as 21 days in winter (with a low night temperature of 6°C). Local irritation of the tick by the host can also alter the time of engorgement and detachment. This variability in engorgement rate may explain some of the variability in toxin secretion rate and time to onset of clinical signs following attachment.
Once the tick detaches, it lays 20-200 eggs per day over 16-34 days, and dies 1-2 days after egg laying is complete.
ENVIRONMENTAL FACTORS
The seasonality of the tick lifecycle is dependent on the temperature and moisture content of the immediate local environment. The length and peak of the season can vary from year to year and region to region determined primarily by local temperature and humidity levels. Death of ticks occurs in periods of heat and dryness thus the late summer heat reduces the frequency of exposure of hosts to ticks.
Although some areas will have ticks all year round, most experience a seasonal peak in late spring and early summer. There is often a cessation of clinical cases with colder winter weather as ticks are killed or their development suppressed. The warmth and moisture of spring then accelerates development and improves survival of ticks. There is also evidence to suggest that the toxicity of ticks may vary from one season to the next.
Secretion of Toxin
Toxin production follows a similar pattern to feeding, with slow secretion into tick saliva over the first 72 hours followed by rapid secretion from 120 hours onwards. Some ticks can secrete larger doses of toxin at an earlier stage.
Attached adult ticks are irritated by excessive handling, direct heat and light. There are however no data on the rates of toxin secretion following handling of ticks or with application of chemicals directly to ticks. Nevertheless, it is important for owners not to irritate the tick or stress the affected animal.
Once a tick is identified on an animal it can either be directly removed or killed in situ with an appropriate acaricide or with local freezing sprays. Various protocols are adopted by different veterinary practices, but there is no comparative data to suggest which technique is the best. The severe anaphylactic reactions that can occur when ticks are removed from humans have not been seen in dogs.
Time to onset of toxicity
Apart from the variable rate of toxin secretion, the main delay in onset of toxicity is probably in the entry of the toxin into the lymphatic system. This is thought to occur by passive movement down a concentration gradient from the attachment site to the nearest lymph vessel. Once in the lymph vessels movement to the venous system is rapid.
Recent studies (Masina et al 1999, M Fitzgerald, pers comm 1998) have shown that the toxin is much smaller than originally thought (approximately 50 amino acids with a molecular weight of about 6,000). The toxin is presumed to bind to other molecules such as protein. This may help to explain the lag phase in the effect of the toxin on the host, as transit time from the site of attachment to the venous system may be longer for larger molecules. (Stone et al 1979)
Another delay then occurs in movement of the toxin from the venous system into neuromuscular junctions (NMJ). Cooper (1976) showed that tick toxin took several hours to penetrate mouse NMJ preparations in vitro, and that subcutaneous injections of toxin took up to 12 hours to have their effect.
The observation that dogs continue to deteriorate after tick removal and treatment is probably explained by these delays in toxin transit. It is also possible that animals with ticks attached on the caudal half of the body may have a slower onset of clinical signs due to the longer transit time to the venous system.
These observations support the use of subcutaneous TAS (tick antiserum) at the site of attachment. While no studies to prove its effectiveness have been completed, the local application of TAS at the site of toxin entry may significantly reduce the amount of free toxin eventually entering the venous system.
Effect of temperature on toxicity
The effect of toxin in the animal is temperature dependent. Experimental and clinical cases have shown that a cool environment will reduce toxin effect, while higher temperatures will increase its effect. High temperatures can also increase respiratory effort, further decreasing effectiveness of an already compromised respiratory system. Paralysis can cause hypothermia especially with environmental exposure or treatment with various drugs. The signs of hypothermia may be indistinguishable from severe tick paralysis (M Fitzgerald, pers comm 1996). Shivering is very important in temperature control and may be impossible or restricted following neuromuscular blockade. Thus it is a cool rather than very cold environment that benefits the outcome of the case.
Tick Toxicity and Host Immunity
Tick toxicity and host immunity also determine the rate and severity of tick paralysis in domestic animals.
(i) There seems to be a threshold quantity of toxin necessary to cause clinical signs (Ross, 1935), i.e. there is a critical level of toxin for each host animal.
(ii) Saliva of "older and bigger" ticks is the most toxic and older ticks have more capacity to produce toxin from their larger salivary gland mass (Koch, 1967).
Host immunity is also variable and apparently short lived; even serum producing animals with multiple tick exposures will occasionally become paralysed. Inducing immunity experimentally takes approximately 20 weeks of repeated single tick exposures. This can be accelerated using 7-8 ticks and peaks at 11-15 ticks.
Once ticks are detached, the antibody level declines quickly over 8-9 weeks. It can be reactivated to highly protective levels once a burden of approximately 5 ticks can be tolerated (Stone and Wright, 1980).
Toxin and Tick Antiserum
Tick antiserum (TAS) is believed to quickly neutralise free toxin in circulation. It is not known how long it takes to penetrate the neuromuscular junction or whether toxin bound there can be neutralised or displaced. The apparent slow clinical response following TAS administration could be because of time taken for TAS to penetrate such sites, and because of the "lag phases" outlined previously. The fact that local paralysis can occur at the site of attachment means passive spread of toxin to local NMJ's occurs before systemic circulation of toxin. The use of subcutaneous TAS should help neutralise toxin in the lymphatic system in such cases.
The psychosomatic effects of hospitalisation, separation anxiety and clinic procedures that are associated with stress may further influence the time taken to respond to treatment with TAS.
MORTALITY RATES
Information from a veterinary practice in northern NSW gathered over 23 years indicated mortality rates of dogs with tick paralysis to be 5% (D Johnston, pers comm, 1998). The average mortality rate was 3.6%. All dogs were treated for tick paralysis using a similar protocol during the observation period but mortality varied markedly with seasons.
THE IMPORTANCE OF RESPIRATORY COMPROMISE IN STAGING TICK PARALYSIS
The stages of tick paralysis have been designated from 1 to 5 (least to most severe) by Ilkiw & Turner (1988). This system concentrates on the severity of gait abnormalities.
The cardiovascular and respiratory complications of tick toxicity have been thoroughly reviewed by Atwell and Fitzgerald (1994). It has been confirmed by blood gas analyses that all dogs with tick paralysis have respiratory compromise (C Jensen, pers comm, 1998), however, only severely affected animals show obvious respiratory distress and these signs can be missed in stressed or nervous animals.
Based on these findings and on clinical experience (R Sillar, pers comm, 1998), a new classification system for staging tick poisoning has been proposed by the National Tick Paralysis Forum. Added to the existing stages of 1 to 5 (Ilkiw & Turner 1988), are four levels of respiratory compromise. The system, although simplistic, requires a respiratory assessment to be made and considered in the overall prognosis. The system is: (a) Normal, (b) Mild - increased respiratory and heart rates, (c) Moderate - restrictive breathing, coughing, gagging, retching, (d) Severe -expiratory grunt, dyspnoea, cyanosis. Thus a 2d dog would be given a poorer assessment than a 3b. This emphasises the importance of the extent of respiratory signs in establishing a prognosis.
TREATMENT OF TICK PARALYSIS
Reduction in Afterload
Reduction of respiratory compromise is a major goal in treating tick paralysis. Any drug that reduces afterload will have a beneficial effect on pulmonary oedema and will reduce respiratory distress. While no comparative therapeutic trials exist, everything from acetylpromazine to direct acting vasodilators to alpha blockers will have an effect. The original success of the use of phenoxybenzamine in experimental tick paralysis could have been due to its direct afterload effect. Additional therapies such as nasal oxygen and diuretics (care if PCV is high) may be needed to minimise lung compromise.
Tick Antiserum (TAS)
There is no standard dose for TAS. A range of 0.5 -1ml/kg intravenously is recommended, however this is adjusted according to the severity of clinical signs. There is no doubt that higher doses of TAS given sooner result in more toxin being neutralised more quickly. Considering the lag phase in toxin delivery and the potential for some dogs to deteriorate quickly, "more, sooner" should be the aim of treatment. With standardisation of commercial TAS, there should be little variation in antibody levels, thus, regardless of the product choice, the dose should depend on the staging and severity of respiratory compromise. For example, in a case assessed as 3d, the maximum amount of TAS should be given.
OTHER CONSIDERATIONS IN PATIENT MANAGEMENT
A recent survey (M Fitzgerald, pers comm, 1998) showed an enormous variation in treatment regimes for tick poisoning. Only one set of documented experiments based on therapy exists (Ilkiw et al 1988), thus it is difficult to give a definitive therapeutic regime. Thorough assessment and classification of each animal is advised. A routine PCV can help define the severity of a case. A high PCV suggests a fluid shift to the lung and the need for more intensive case management by relieving pulmonary oedema and maximising oxygenation.
CONCLUSION
This bulletin has attempted to update and summarise the research data and clinical experience of tick poisoning in Australia. A new classification system for grading cases of tick poisoning has been introduced to emphasise the need for an evaluation of the degree of respiratory compromise of these patients. Management of cases is important and will influence outcome.
The best results are thought to occur when organ compromise is fully assessed, minimal stress is placed on the patient, maximum amounts of TAS are used, some form of afterload reduction and sedation is used, and the animal is placed as early as possible in a cool environment.
REFERENCES
ATWELL RB (1998) Unusual identification of Nodes holocyclus. Aust Vet Pract 28(3) 1998
ATWELL RB & FITZGERALD M (1994) Unsolved issues in tick paralysis, Aust Vet Pract 24 (3), 156-161
CLELAND JB (1912) Injuries and diseases of man in Australia attributable to animals (except insects). The Australasian Medical Gazette XXXII, 295-299
COOPER JB (1976) Studies on the pathogenesis of tick paralysis. PhD thesis, University of Sydney.
DODD S (1921) Tick Paralysis. Journal of Comparative Pathology 34, 309323
HOWELL WH (1921) Journal kept on the journey from Lake George to Port Phillip, 1824-1825. The Royal Australian Historical Society Journal and Proceedings VII, 307-378
ILKIW JE & TURNER DM (1988) Infestation in the dog by the paralysis tick, Ixodes Holocyclus, 5. Treatment. Aust Vet J 65 (8), 236-238
ILKIW JE, TURNER DM & HOWLETT CR (1987) Infestation in the dog by the paralysis tick Ixodes holocyclus, 1. Clinical and histological findings Aust Vet 164 (5), 137-139
KOCH JH (1967) Some aspects of tick paralysis in dogs. NSW Veterinary Proceedings, 3,34-35
MASINA S, LOPRESTI C & BROADY KW (1999) Sequence determination, expression and purification of an Australian paralysis tick neurotoxin. 24th LORNE Protein Conference, USA
ROSS IC (1935) Tick paralysis: A fatal disease of dogs and other animals in eastern Australia. Journal of the Council of Scientific and Industrial Research 8:8.
STONE BF, BOURKE BW & BINNINGTON KC (1979) Toxins of Australian paralysis tick (Ixodes holocyclus). Rec. Adv. In Acarology, Vol 1, p34, Academic Press, New York
STONE BF & WRIGHT IG (1980) Toxins of Ixodes holocyclus and immunity to paralysis, in Johnston, LAY and Cooper MG (Eds): Ticks and Tick-borne diseases, Australian Veterinary Association, Sydney, 7578
STUART TPA (1894) Anniversary address. Journal and proceedings of the Royal Society of New South Wales XXVIII, 1-38
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*Attendees to the first meeting of the National Tick Paralysis Forum (NTPF) were:
Chairman, Dr Rick Atwell, University of Queensland; Dr Bernard Stone, CSIRO; Dr David Jones, Lismore; Dr Ross Sillar, Casino; Dr Paul Matthews, Cairns; Dr Helen Burns, Dayboro; Dr Chris Jensen, Brisbane; Dr David Johnson, Coffs Harbour; Dr Mike Fitzgerald, Alstonville; Dr Bryn Lynar, Pittwater; Dr Wayne Mizon, Bega; Dr Elizabeth Court, Merial; Dr Jim Cornish, Merial; Dr Maurice Webster, Merial.
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