Staggers Syndromes (Grass Staggers)

Robert J. MacKay

Forage-associated staggers syndromes are common and have been associated with protective fungal secondary metabolites, bacterial antibiotic corynetoxins, or neurotoxic chemicals produced by the forage itself.

Tremorgenic Mycotoxicoses

At least 20 tremorgenic mycotoxins are known; they are produced by several different fungi, have the same biologically active moiety, and give rise to similar clinical manifestations.^1,2 Indole-diterpenoid tremorgens are secondary fungal metabolites that act by blocking potassium outflow from cells via inhibition of cell membrane large-conductance calcium-activated potas­sium channels.^3,4 The most important classes of tremorgens are the Iolitrems (perennial ryegrass staggers) and paspalitrems (Paspalum staggers, Bermudagrass staggers). Other indole- diterpene tremorgens that may be elaborated on moldy feeds by saprophytic fungi and occasionally cause staggers in livestock include penitrems, janthitrems, aflatrem, and verruculogen. The major tremorgenic mycotoxicoses are similar or identical clinically; therefore clinical signs are discussed in detail only in the Perennial Ryegrass Staggers section.

PERENNIAL RYEGRASS STAGGERS. Perennial ryegrass staggers (PRS) is a syndrome of tremors and ataxia that result from ingestion of endophyte-infected perennial ryegrass (Lolium perenne) by horses, cattle, sheep, deer, goats, and alpacas.⁵ PRS is a common condition of livestock in New Zealand and Australia and occasional outbreaks occur in Northern Europe, the northwestern United States, South America, and Europe.^6-9 The case attack rate may reach 100%, but the mortality rate is generally low and attributable only to accidents.

PRS typically appears acutely 5 to 10 days after introduction of livestock onto endophyte-rich pastures; onsets as early as 48 hours and as late as 2 weeks after exposure have been recorded. The source of tremorgenic toxins is the symbiotic endophytic fungus Neotyphodium lolii( The fungal infection confers resistance to predation of grass by insects, including the Argentine stem weevil, and so there is selective pressure for expansion of toxigenic cultivars. N. Iolii produces three classes of alkaloids with approximately parallel profiles of production: tremorgens, ergopeptides, and peramine. The most abundant and active indole-diterpene tremorgen produced by endophyte-infected plants is lolitrem B.¹⁰ Lolitrem B concentra­tions of more than approximately 2 mg/kg (ppm) of dry matter in forage reliably cause staggers in sheep, cattle, and horses.¹¹ The concentration of lolitrem B in pasture increases from spring through fall. Plant infection rates below 25% (typical in northern hemisphere pastures) are associated with sporadic cases, whereas plots with 90% infection rates are common in Australasian pastures and are associated with outbreaks of PRS.

Ergovaline and other ergopeptide alkaloids (also see Chapter 54) produced by endophytes cause signs comparable with those of heat stress syndrome, a condition in cattle in the southwest­ern United States that graze on tall fescue infected with the endophyte Neotyphodium Coenophialum.⁹ The resulting clinical signs are diarrhea, hyperthermia, high heart and respiratory rates, poor weight gain, and reduced milk production. The high mortality rates (up to 30% of affected sheep) reported during PRS outbreaks in Australia in 1986, 1993, and 2002

have been attributed to heightened susceptibility to heat stress caused by ergopeptides in endophyte-infected perennial ryegrass.⁹ Horses experimentally fed endophyte-infected L. perenne seeds during cool conditions in New Zealand developed limb edema and exudative heel lesions, signs that reflected the vasoconstrictive “fescue foot^,,-like effects of ingested ergopeptides.¹¹ Peramine, a pyrrolopyrazine alkaloid, is a potent insect-feeding deterrent with substantial protective effects against the destructive Argentine stem weevil. Strains of endophyte-free perennial ryegrass have been propagated but are difficult to maintain without extensive insecticide use. Cultivars of L. perenne that are infected with strains of N. Iolii have been produced that contain peramine but not tremorgen or ergopeptide. These cultivars (e.g., AR1, AR37) therefore have multiple advantages over traditional endophyte-infected strains, in that they do not cause staggers or ergopeptide-associated production loss and substantially protect against stem weevil predation.¹² AR1 is not as broadly insect resistant as is wild­type N. lolii, however, and root aphid infestation is notably unaffected.

Clinical signs first occur approximately 5 to 10 days after livestock are introduced to infected pasture (or after they eat infected ryegrass seeds or straw^7,11) and become progressively more severe until the animals are removed from the endophyte source.

In all cases, signs are exacerbated by handling. Attempts to force affected animals through gates or onto trailers may precipitate recumbency. While down, the animals exhibit rigid extension of the legs with occasional flailing, opisthotonos, and tonic-clonic convulsions. Frothy exudate from the mouth has also been described. After approximately 10 to 20 minutes, the animal recovers if left undisturbed, stands, and walks back to the herd or flock.

Recovery occurs over days to weeks; longer recoveries are typical of severely affected animals. Most animals are normal within a week of removal from toxic pasture. Treatment is not usually necessary, but it is important not to disturb or frighten animals with tremors and to handle them as infrequently and carefully as possible. If practicable, they should be kept on level ground in an area free of potential hazards, especially water hazards. If handling is necessary, hyperresponsiveness can be controlled by sedation. Tremors can be suppressed temporarily by diazepam (0.02 to 0.1 mg/kg IV for horses or 0.1 to 0.2 mg/kg IV for small ruminants).

PASPALUM STAGGERS. Clavicepspaspali ergots parasitize Pas- palum spp. grasses and produce paspalitrems, indole-diterpene tremorgens that cause staggers syndromes in livestock similar or identical to perennial ryegrass staggers described earlier. Suscep­tible grasses include dallisgrass (Paspalum dilitatum), bahiagrass (Paspalum notatum), water couchgrass (Paspalum distichum), and knotgrass (Paspalum paspaloides).^14-16 Paspalum staggers has been recognized in the United States, South Africa, Great Britain, Australia, and New Zealand.^14,17-19 Natural outbreaks occur most commonly in cattle, but Paspalum staggers has been reported in three foals and two adult horses grazing on dallisgrass in Australia,²⁰ and sporadic cases are observed regularly by the author in horses on bahiagrass pastures in Florida.

C. paspali first attacks the pistil of the grass flower and replaces the ovary with a sclerotium (ergot).

Clinical diagnosis is made by observation of clinical signs, visible detection of the toxic agent in the feed, or detection of indole-diterpenes by thin-layer chromatography. Animals recover spontaneously within days to several weeks after being removed from the pasture.

BermudAGRASS STAGGERS. Bermudagrass (Cynodon dactylon) occasionally becomes toxic for livestock.¹⁹ Cattle are considered most susceptible, followed by sheep, goats, and horses. As is the case for Paspalum staggers, bermudagrass stag­gers results from ingestion of paspalitrems in grass parasitized by fungal ergots, in this case Claviceps cynodontis. C. cynodontis is closely related to C. paspali, and the chemical profiles of indole-diterpenoid and ergot alkaloids produced by the sclerotia of these two fungi are similar. The clinical and epidemiologic aspects of bermudagrass staggers and Paspalum staggers are likewise similar.²²

Animals may develop clinical signs as early as 36 hours after consuming toxic forage. Experimentally poisoned goats have developed clinical signs 8 days after being fed 772 g/head/ day of toxic hay.²³ The toxin survives drying, and hay that is cut from offending pastures may remain toxic for as long as 9 years.²⁴ Pastures that are toxic remain so for successive seasons unless the vegetation is burned off and the ground is tilled and reseeded. The clinical signs occur suddenly, usually simultaneously, in several animals in the herd. In some cases, most of the animals on a single pasture may be affected, whereas animals on an adjacent pasture remain normal. The mortality rate is low, and deaths usually result from self-inflicted trauma. Affected animals recover 2 days to 2 months after removal from the affected pasture or hay. Management is as for PRS.

Tremorgenic Mycotoxicoses Associated

With Saprophytic Fungi

Most tremorgenic mycotoxins are synthesized by common saprophytic fungi of the genera Penicillium and Aspergillus that elaborate mycotoxins onto improperly harvested or stored livestock feeds. Some Penicillium spp. can also act as opportunistic plant pathogens, most notably as a cause of ear rot in corn. Ingestion of moldy cornstalks is probably the most common source of fungus-related tremors in livestock. The fungi proliferate in the corn but do not produce tremorgens until the stalks touch the ground. After production at or near the soil surface, the toxins translocate in plants through root absorption.²⁵ Cases associated with Aspergillus molds (usually Aspergillus clavatus) have occurred worldwide, linked to feeding on sprouted grains and the by-products of beer production, both of which provide an environment for growth of the mold.^26,27 Clinical signs are indistinguishable from those of Paspalum, perennial ryegrass, and bermudagrass staggers.^16,25,28,29 Indole-diterpenoid tremorgens produced by Penicillium and Aspergillus spp. can be classified into four major groups: the aflatrem-paxilline group, the verruculogen-fumitremorgen group, the territrem group, and the tryptoquivaline group. Of these, the most important fungal tremorgens are aflatrem, penitrem A, fumitremorgen B, and verruculogen. In some cases, additional non-indole-diterpenoid mycotoxins elaborated by these fungi cause a wider spectrum of clinical signs. For example, A. clavatus caused a highly fatal mycotoxicosis of cattle in South Africa that was associated with widespread degeneration and necrosis of skeletal muscle and CNS motor neurons.¹⁵

Diagnosis is by demonstration of indole-diterpenoid tremorgens by thin-layer chromatography (sometimes in combination with a mouse tremorgen assay). Mycelial elements of Penicillium and Aspergillus molds may survive degradative conditions in the GI tract and can be identified and cultured from the feces of affected animals.

Corynetoxicoses (Annual Ryegrass Toxicity, Flood-Plain Staggers, Blown Grass Staggers)

Corynetoxicoses are severe, often fatal neurologic disorders of livestock in Australia and South Africa.³⁰ A related syndrome occurred in Oregon from the 1940s through the 1960s but apparently has not recurred since.^31,32 Corynetoxins are pro­duced by plants of several genera—including Lolium rigidum (annual ryegrass), Polypogon monspeliensis (annual beard grass), and Lachnagrostis filiformis (blown grass)—that are colonized by a nematode (Anguina sp.) and a bacterium (Rathayibacter toxicus).^33-35 Affected sheep and cattle with the same clinical syndrome in Oregon had been fed a fescue (Festuca nigrescens) infected with a grass seed nematode and a Rathayibacter-like 3132

organism.³¹,³² Corynetoxin-producing R. toxιcus is transported into host plants by nematode L2 larvae and ingested by sheep, cattle, and occasionally horses.³⁰ The colonized plant forms a hollow gall in response to larval invasion of the seed. Bacteria are thus carried into the galls, where they proliferate into a distinctive yellow to orange mass.³⁰ R. toxicus organisms produce a series of closely related corynetoxins that are glycolipids in the tunicaminyluracil class of antibiotics. Corynetoxins potently inhibit lipid-linked N-glycosylation of glycoprotein, and their toxicity in animals probably results from the depletion of essential N-glycosylated proteins. It takes up to 15 years after introduction of the nematode-bacterial complex to a pasture before clinically significant amounts of toxin are produced.³⁶ A method of evaluating toxic pastures has been developed; it is based both on enumeration of contaminated seedheads and on ELISA to quantify R. toxicus.³

Although the serum half-life of corynetoxins in livestock is only approximately 4 hours, repeated exposure leads to an accumulation of the toxin, and up to 12 weeks of continued ingestion may be necessary for the onset of clinical disease.³⁰ Also, the concentration of the toxin increases in the seedheads during the summer and is greatest as the plant dries and the seeds ripen. Outbreaks associated with the feeding of hay made from toxic pasture may occur at any time. Stock losses are highest in sheep, although cattle deaths can be substantial. Outbreaks in horses occur occasionally and generally involve only a few horses.^38,39 Clinical signs appear to reflect the cerebel­lar and thalamic lesions that are evident histologically.³⁹ All ages are affected, and morbidity and mortality rates are usually high. When an affected flock is driven, or when cattle are rounded up or otherwise stressed, some animals collapse in sternal or lateral recumbency. They often have muscle tremors, opisthotonos, head nodding, tetanic and clonic convulsions, limb extension, hypermetria, odontoprisis, nystagmus, and ptyalism. Animals may regain their footing after several minutes and stagger away with a stiff-legged, jumping, or swaying gait. These animals often wander aimlessly, exhibiting stupor and ataxia. In mildly and moderately affected animals, clinical signs usually resolve within a week of removal from affected pasture; however, relapses may occur in animals that appear to have recovered, and it may take several months for severely affected animals to recover. Treatment with magnesium sulfate solution (50 to 100 mg/kg, IV in horses, SC in ruminants, repeated as needed) is reportedly effective in some cases.^38,40 The most practical strategy for controlling annual ryegrass toxicity is to break the nematode’s life cycle by killing the ryegrass for two or three growing seasons. Otherwise, pastures remain perpetu­ally toxic. Integrated control measures that have been recom­mended for prevention of annual ryegrass toxicity include applying herbicides in the spring, seeding the pastures with legumes, burning the infected pasture grasses during early autumn, and applying ryegrass-selective herbicides in the summer months, combined with heavy winter grazing.

Pathologic changes associated with corynetoxin poisoning include widespread petechial hemorrhages and jaundice and friability of the liver. Histologically, CNS changes are surpris­ingly mild and nonspecific. Most lesions are cerebellar with proteinaceous fluid around vessels, especially in the meninges. There is diffuse vacuolation of hepatocytes and bile duct proliferation.

Kikuyu Grass Poisoning

A multiorgan disease characterized by peracute onset obtunda­tion, ataxia, drooling of saliva, sham drinking, ruminal disten­tion, and colic occurs in cattle and, to a much lesser extent, sheep and goats of New Zealand and Australia that are grazing on kikuyu grass (Pennisetum clandestinum).⁴ According to a review of nine reports involving 2719 cattle at risk, the morbidity rate was 23% and the case fatality rate was 70%.⁴¹ The cause and pathogenesis are poorly understood.

Canarygrass Staggers (Phalaris Staggers)

Phalaris poisoning has been reported in Australia, New Zealand, South Africa, Norway, Argentina, and the United States, in association with the ingestion of Phalaris spp. grasses by sheep and cattle, most notably Phalaris aquatica (bulbous canarygrass or hardinggrass) and Phalaris arundinacea (reed canarygrass).⁴² These outbreaks have been characterized by either sudden death due to peracute brain dysfunction (termed polioencephalomalacia- like sudden death) or myocardial dysfunction (termed cardiac sudden death)⁴⁴ Sheep are considered to be the most susceptible species, but cattle are also affected.⁴⁵ Only the cardiac sudden death syndrome has been reported in horses.^46,47 In the United States, outbreaks of canarygrass staggers have been reported in sheep and feedlot lambs in California (P. aquatica)(^9,49 as well as sheep and cows in Louisiana (Phalaris caroliniana)⁵ and cows in West Virginia (P. arundinacea).4

It has been suggested that phenylethylamines or derivatives of tyramine are involved in sudden death syndromes.^42,51 Staggers occurs in either an acute and reversible form or a chronic, irreversible, and typically lethal form. The latter, more common presentation usually occurs as outbreaks. Delayed or chronic Phalaris staggers is associated with tryptamine alkaloids produced by the plant.^42,51 These alkaloids structurally resemble serotonin and act as serotonergic receptor agonists, and accumulation within serotonergic tracts of the CNS eventually results in staggers signs. Rapid growth of canarygrass favors the formation and accumulation of toxin. Other factors that enhance the toxicity of canarygrass pasture include fog, humidity, or rain, followed by sunny, warm weather or sunshine on nitrogen- fertilized pastures.⁵² Grazing animals are not usually affected until Phalaris spp. grasses constitute more than 50% of the diet.⁵³ The concentration of tryptamine alkaloids may be reduced by curing the forage as hay. In contrast, ensiling canarygrass does not reduce the amount of toxin.⁵⁴

Staggers occurs after exposures lasting from 5 days to 33 weeks. Signs may be delayed for as long as 4 months after removal from the toxic grass.⁵⁰ Characteristic early clinical signs in sheep are constant anxious observation of handlers and continuous twitching ear movements. Signs progress to include hyperexcitability, exaggerated responses to auditory or tactile stimuli, fine muscular fasciculations (particularly of masseter muscles), licking of the lips, wrinkling of the facial muscles, repetitive chewing, inability to swallow, flaring of the nostrils, ptyalism, nystagmus, intention tremor of the head, ear and tail twitching, basewide stance, reduced menace response, and deficient pupillary reflexes.⁵⁵ The gait of affected sheep is described as stiff-legged, with both hindlimbs moving in unison at gaits above the trot (“bunny-hopping”). Affected sheep and cattle may buckle at the knees and assume sternal recumbency with the hindquarters elevated.^45,53 They then fall into lateral recumbency and flail wildly while attempting to stand. Poisoned cattle also become uncoordinated and may have distinctive stabbing movements of the tongue and inability to prehend forage.⁵⁶ They salivate profusely and drop feed from the mouth. Affected animals eventually die from starvation. There may be increased protein concentration (40 to 100 mg/ dL) and nucleated cell count (up to 50 mononuclear cells/pL) in CSF of affected animals.⁴⁸ Animals may survive the initial signs but have neurologic signs that wax and wane for up to 10 months. For confirmation of a diagnosis, tryptamine alkaloids in suspect grasses can be quantified by ELISA.⁵⁷ Concentrations greater than 30 to 50 mg/100 g dry weight of forage are 5255

considered toxic for sheep.,

The pathologic lesions in the CNS of affected animals are characteristic and include focal, demarcated, blue-green or slate-gray discoloration in the brainstem and corticomedullary junction of the kidney; intracytoplasmic accumulations of yellow-brown pigment in the dorsal root ganglia, brainstem nuclei, and ventral horns of the gray matter of the spinal cord; neuronal loss; focal gliosis; and swelling of axonal sheaths in the ventromedial aspect of the spinal cord.^45,48,53 The pigment is thought to originate from deamination of the toxic alkyl­amines, but their presence is not strongly correlated with the development of neurologic deficits.⁵⁵

Administration of cobalt to animals on toxic grass pastures is protective. In the presence of cobalt, rumen microflora inactivate toxic alkaloids. Weekly administration of 28 mg of cobalt to each animal was required experimentally to prevent clinical signs in exposed sheep.^58,59 Additional recommendations include removal of affected animals from the offending pasture, sedation with a phenothiazine tranquilizer, and administration of sodium pentobarbital or diazepam to convulsive animals. Phalaris plants may also contain potentially toxic concentrations of nitrate or cyanide. In any outbreak of suspected Phalaris toxicosis with sudden death, cyanide and nitrate poisonings should also be considered.⁴³

Differential Diagnoses for Staggers Syndromes

Grass staggers is easily recognized by clinical signs. The specific plant involved must be identified through examination of the pasture forage. Tremorgenic diseases of adult cattle are common throughout most of the world. In addition to the syndromes discussed earlier, plants that may cause staggers syndromes include toxic storage syndromes, such as locoism induced by the swainsonine-containing plants Swainsona luteola, Swainsona galegifolia, Astragalus spp., and Sida spp. and the tremor syn­drome induced by Solanum dimidiatum, Solanum fastigiatum, and Solanum viarum. Hypomagnesemia causes grass staggers and has been reported to cause cerebellar degeneration under some circumstances. The genetic storage diseases α- and β-mannosidosis, generalized glycogenosis, globoid cell leuko­dystrophy, and neuronal lipodystrophy may also be important in the differential diagnoses for ataxic animals with tremor and cerebellar signs.

Multiple Congenital Central Nervous System Defects

Multiple congenital defects that are suspected or documented to have a heritable (genetic) basis have been described in large animals. Many, but not all, of these disorders involve signs referable to cerebellar dysfunction; others may have signs referable to spinal cord dysfunction. These defects along with others are listed in Table 35.6.