CLOSTRIDIAL NEUROTOXINS

Transcription

1 THE See end of artile for authors affiliations Correspondene to: Dr A Goonetilleke, Department of Neurology, Newastle General Hospital, Regional Neurosienes Centre, Newastle upon Tyne, NE4 6BE; ajith.goonetilleke@ nuth.nhs.uk T CLOSTRIDIAL NEUROTOXINS A Goonetilleke, J B Harris J Neurol Neurosurg Psyhiatry 2004; 75(Suppl III):iii35 iii39. doi: /jnnp he genus Clostridium omprises a number of spore forming Gram positive, rod shaped bailli. They are found in the intestines of numerous mammalian speies inluding domesti animals, horses, hikens, and humans. They are also widely distributed in the soil and in marine and freshwater sediments. Many lostridial speies produe medially important toxins but the speies of neurologial interest (Clostridium tetani and Clostridium botulinum) produe neurotoxins. The toxins responsible for these neurotoxi syndromes are tetanus toxin (sometimes known as tetanospasmin) and the botulinum toxins. TOXINS Tetanus and botulinum toxins share several important features: they are produed as a single polypeptide of 75 kb whih undergoes post-translational leavage to form a heavy (H) hain and a lighter (L) hain of 100 kda and 50 kda, respetively, linked by a single disulfide bond. The H hain failitates binding to gangliosides on the plasma membrane of peripheral nerve terminals before internalisation via reeptor mediated endoytosis. Protonation of the endosome results in the redution of the disulfide bond. The H hain forms a transmembrane pore aross the endosome and the L hain then enters the nerve terminal ytosol. The L hains of both tetanus and botulinum toxins are zin ativated proteases. Their targets are a number of speifi proteins involved in synapti vesile doking synaptobrevin (also know as VAMP), SNAP-25, and syntaxin. 1 The toxins seletively target individual proteins (table 1), but the result is always the same the hydrolysis of the target protein, blokade of transmitter release, and a resultant flaid paralysis. While the botulinum toxins remain in the nerve terminal the tetanus toxin is transported by retrograde axonal transport into the ell body and then by transynapti exhange into the terminals of inhibitory neurones in the spinal ord and brain stem. The resultant inhibition of inhibitory transmission by the tetanus toxin results in the dominant linial features of hyperexitability ombined with linial weakness between spasms and the paralysis of ranial nerves (as seen in ephali tetanus). Both tetanus and botulinum toxins affet both somati and autonomi nervous systems, but autonomi features (for example, labile hypertension and tahyardia) are more ommon in tetanus. TETANUS C tetani form resilient spores apable of surviving household disinfetants and boiling in water for several minutes. In onditions of low oxygen tension (for example, wounds) the spores germinate and the resultant bateria multiply and produe a neurotoxin responsible for the linial features of tetanus. Generalised tetanus is the most ommon presentation in whih musles throughout the body are affeted, with the head and nek being usually affeted first followed by a audal spread of spasms. Tetanus following intramusular injetions of quinine has a partiularly poor prognosis; the low ph of quinine may failitate the entry of tetanus toxin into nerves. Quinine is often mixed with heroin as it has a bitter taste that resembles heroin. The effets of quinine may therefore also explain the poorer prognosis of tetanus in drug abusers. Loalised tetanus ours if the rigidity and pain remain loalised to the site of injury, and is usually assoiated with a better prognosis. An exeption is ephali tetanus following a head or nek injury, and whih is assoiated with a high mortality. A unilateral lower motor neurone faial weakness is the most ommon involvement in ephali tetanus, though other lower ranial nerves and the oulomotor nerve may also be affeted. Tetanus neonatorum is rare in the developed world. The ondition arises from poor umbilial hygiene, and is prevalent in ommunities that employ traditional midwifery praties suh as utting the ord with grass or dirty sissors, or rubbing manure on the umbilial stump. The affeted neonate presents within a week of birth with a failure to feed, vomiting, and iii35 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 August Downloaded from on 25 September 2018 by guest. Proteted by opyright.

2 iii36 Table 1 Toxin Clostridial neurotoxins and their target proteins Target Tetanus toxin VAMP (synaptobrevin) Botulinum toxin A SNAP-25 B VAMP (synaptobrevin) C SNAP-25, syntaxin D VAMP (synaptobrevin) E SNAP-25 F VAMP (synaptobrevin) G VAMP (synaptobrevin) onvulsions. The disease may be prevented by improved hygiene and by maternal vaination, even if the latter is administered during the pregnany. Despite the World Health Organization s intention of eradiating tetanus by 1995 there are still to 1 million deaths worldwide eah year from tetanus, with half these deaths aused by neonatal tetanus. Most fatal ases our in Afria and South East Asia, where the problem remains endemi. In these regions mortality is related to limited aess to artifiial ventilation for neonatal tetanus mortality is 65 90% without ventilation and drops to 10% with ventilation. There are ases in Britain and ases of tetanus in the USA eah year. In suh ountries with aess to assisted ventilation the mortality is negligible in young adults, but inreases to over 50% in patients over 60 years of age. The age related differenes in mortality may be aused by waning immunoprotetion. 2 Death may our due to autonomi dysfuntion or the ompliations (for example, sepsis, thromboemboli) of prolonged ritial illness. Although tetanus is easily preventable by immunisation (the first effetive vaine was produed over 100 years ago), it is tragi that many people still remain unproteted. Clinial features Tetanus usually ours following a deep penetrating wound where anaerobi baterial growth may our, partiularly if the wound is ontaminated by soil, manure or rusty metal. It may also our by other mehanisms suh as in burns, ulers, septi abortions, irumisions, intramusular injetions, aupunture, ear piering, tattooing, poor dentition, hroni otitis media, and following snakebites. In up to 30% of ases the portal of entry annot be identified. The inubation period (time of inoulation to the first symptom) is usually 7 10 days (range 1 60 days), and the period of onset (time from first symptoms to the start of spasms) is 1 7 days. The severer forms of the disease have shorter inubation periods and periods of onset. The linial piture is dominated by musle spasms, rigidity, and autonomi disturbanes. 3 4 Nek stiffness, sore throat, and diffiulty opening the mouth are the earliest features. Masseter spasm auses trismus ( lokjaw ), with the spasms extending to the faial musles to ause a harateristi faial expression ( risus sardonius ). Musle spasms may lead to laryngeal obstrution as well as dereased hest wall ompliane, resulting in respiratory ompromise. Involvement of axial musles leads to nek extension, and trunal rigidity may lead to opisthotonus. Bak pain, trismus, musle stiffness, and dysphagia are ommon. The episodi spasms tend to be extremely painful and affet agonist and antagonist musle groups together, and may be spontaneous or stimulus sensitive (triggered by touh, visual, auditory, or emotional stimuli). These spasms may appear onvulsive in nature and be violent enough to ause fratures or tendon avulsions. Rigidity is most prominent in musles adjaent to the portal of entry. The autonomi disturbanes an lead to labile hypertension, tahyardia, pyrexia, profuse sweating, exessive bronhial seretions, gastri stasis, and diarrhoea. The hypertension is predominantly aused by inreases in systemi vasular resistane seondary to raised onentrations of irulating ateholamines similar to those seen in phaeohromoytoma. Inreasing musle spasms and rigidity haraterise the first week of illness. Autonomi disturbanes usually start a few days after the spasms and reah a peak during the seond week, and persist for 1 2 weeks. Spasms start to subside after 2 3 weeks, but the musle rigidity may ontinue long after the spasms and autonomi involvement have subsided. Musle rigidity may last up to 6 8 weeks in severe ases. Various grading systems of severity of tetanus have been desribed, one of the most ommonly used being the Ablett system (table 2). Other soring systems (for example, Dakar and Phillips sores) have also been devised to assess overall prognosis. 3 Diagnosis The diagnosis is made linially as there is no speifi onfirmatory investigation. A positive ulture of C tetani from a wound would be supportive evidene for the diagnosis. The differential diagnosis for tetanus may be diverse. Intense musle rigidity may be mistaken for aute dystoni reations. Rigidity of abdominal musles may mimi an aute abdomen. Poisoning by stryhnine (a ompetitive antagonist of glyine) may mimi tetanus. Cephali tetanus may be diffiult to differentiate from other auses of ranial nerve palsies helpful linial pointers inlude impaired mouth opening and omplaints of dysphagia whih are ommonly seen in tetanus. The spatula test (stimulation of the pharynx with a spatula provokes an intense spasm of the masseters resulting in the patient biting the spatula) may aid in diagnosis, though this should be performed with great are as intense pharyngeal and laryngeal musle spasm may our leading to respiratory arrest. Neonatal tetanus may need to be differentiated from hypoalaemia, hypoglyaemia, neonatal seizures, and meningitis. Management Wounds from whih the infetion originated should be surgially debrided and an antibioti administered. Peniillin has been the worldwide antibioti of hoie. However, the struture of peniillin is similar to aminobutyri aid Table 2 Grade I II III IV The Ablett lassifiation of tetanus severity Clinial features Mild-moderate trismus; general spastiity; no spasms; no respiratory embarrassment; little or no dysphagia Moderate trismus; well marked rigidity; mild-moderate but short spasms; moderate respiratory embarrassment with RR.30/min; mild dysphagia Severe trismus; generalised spastiity; reflex prolonged spasms; RR.40/min; severe dysphagia; HR.120/min Grade III and severe autonomi disturbanes affeting ardiovasular system (for example, severe hypertension and tahyardia alternating with relative hypotension and bradyardia, either of whih may be persistent) HR, heart rate RR; respiratory rate. J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 August Downloaded from on 25 September 2018 by guest. Proteted by opyright.

3 (GABA); it therefore ats as a ompetitive GABA antagonist, and in high doses may ause entral nervous system (CNS) hyperexitability and onvulsions. In tetanus this potential side effet of peniillin may at synergistially with the toxin to blok GABA neuronal ativity. Metronidazole is therefore onsidered to be the antibioti of hoie in the treatment of tetanus. Comparative studies in human tetanus have demonstrated the superiority of metronidazole over peniillin. Antibiotis should be administered for 7 10 days. Alternative agents that may be used inlude erythromyin, tetrayline, vanomyin, lindamyin, doxyyline, and hlorampheniol. Passive vaination with anti-tetanus immunoglobulin shortens the ourse and may redue the severity of the illness. Anaphylati reations our in approximately 20% of ases reeiving the equine antitoxin, and in 1% may be severe enough to require the use of adrenaline (epinephrine), steroids, and intravenous fluids; suh reations our muh less frequently with the human antitoxin. For prophylaxis against tetanus passive immunisation should be given as soon as possible after an injury. Ative immunisation (that is, tetanus toxoid) also needs to be given to add to the short term immunity provided by antitetanus immunoglobulin, as well as providing longer term humoral and ellular immunity. The toxoid and the antitetanus immunoglobulin need to be given at different sites of the body to prevent interation at the injetion site. Also, if they are to be administered at the same time the dose of antitetanus immunoglobulin needs to be modified, as higher doses may neutralise the immunogeniity of the toxoid. Reations to the toxoid our in approximately one in of injetions. Reations inlude loal tenderness, oedema, flulike illness, and a low grade fever. Severe reations to the toxoid are rare, and inlude a Guillain-Barré type syndrome. External stimuli provoke musle spasms and may worsen the autonomi disturbanes in tetanus. Unneessary stimuli should therefore be minimised, and all patients should therefore reeive adequate sedation and be nursed in a darkened and quiet room. The benzodiazepines (whih augment GABA ativity) are the sedatives most ommonly used. Diazepam is given initially as intravenous boluses (total daily doses of up to 200 mg are ommon) followed by oral administration in the reovery phase. Midazolam is a suitable alternative with a shorter half life. Parenteral boluses of morphine an also prove benefiial for sedation. Morphine also indues peripheral venous and arteriolar dilatation, probably by reduing sympatheti disharge entrally, an effet whih an offset some of the autonomi disturbanes seen in tetanus. If musle spasms persist despite adequate sedation, musle relaxants may be required. Traditionally the long ating agent panuronium has been used to ahieve musular paralysis. However, this agent inhibits ateholamine reuptake and may therefore worsen autonomi instability and ause hypertension and tahyardia in the more severe ases. Piperuronium and rouronium are newer longer ating agents with fewer ardiovasular effets, but are relatively expensive. Veuronium similarly has fewer ardiovasular effets but is shorter ating. Balofen and dantrolene tend to be less effetive agents in relieving musle spasms in this ontext. If musle spasms are severe enough to require suh agents the patients also usually require assisted ventilation. Exessive bronhial seretions and hypersalivation resulting from autonomi overativity, in onjuntion with laryngeal spasms and dysphagia, make aspiration a partiular ompliation that needs to be guarded against in tetanus. Protetion of the airway may require perutaneous traheostomy. Assisted ventilation may be required if there is any respiratory impairment. Autonomi disturbanes (for example, labile hypertension, tahyardia, vasoonstrition, exess sweating) may need to be orreted. The routine use of agents that blok autonomi transmitters and reeptor blokers (for example, magnesium, a blokers, b blokers, atropine) have not shown onsistent benefits in tetanus; therefore, autonomi funtions should be monitored and any speifi ompliations treated as they arise. Most adults start to reover one the musle spasms have subsided. In most ases reovery is omplete. Some of the long term sequelae of tetanus inlude limb ontratures, bed sores, seizures, myolonus, and sleep disturbanes. The prognosis is generally worse in neonates, espeially if prolonged hypoxi periods had ourred during the illness. Overall the prognosis is dependent on disease severity and the medial failities available, with partiular regard to aess to ventilation. BOTULISM Human botulism ours in a variety of forms. Food-borne botulism ours after the ingestion of food ontaminated with C botulinum ontaining the pre-formed toxin. This form typially ours when suseptible foods are exposed to room temperatures for prolonged periods. Wound botulism ours in wounds ontaminated with C botulinum spores. Inreasing numbers of ases of wound botulism have been reported in drug addits in the USA following the subutaneous injetion of blak tar heroin ( skin popping ). 5 6 Infant/adult intestinal botulism ours when spores are ingested and then germinate in the intestinal trat. Infants less than 1 year of age (95% of infants being younger than 6 months) and adults with a history of gastrointestinal abnormalities or antibioti use may ontrat this form. Infant botulism is the most reported form of botulism. In the USA approximately 110 ases of botulism are reported annually, with infant botulism aounting for 72% of ases ompared to 25% aused by food borne botulism. The aeum is thought to be the initial site of ativity, and paralysis of the ileoaeal valve may allow the olonising bateria to extend into the terminal ileum. Soil and the ingestion of honey are the two well reognised soures of spores in infant botulism. 7 C botulinum may be present in 10% of honey supplies in the USA where it has been linked with 20 35% of known ases of infant botulism. As a preventative measure honey should not be fed to infants younger than 12 months of age. The infant s intestinal trat laks the protetive baterial flora of the adult, allowing olonisation by C botulinum. One olonisation ours the toxin produed is absorbed through the intestinal trat. The role of breastfeeding in infant botulism is unlear. Breastfeeding ours in 70 90% of infants with botulism, and in a prospetive ase ontrol study was found to be a risk fator for the development of the disease in infants younger than 2 months of age. 7 However, breast feeding may delay the disease suh that infants reah medial attention in time for supportive are, and may therefore be a protetive feature. 8 Inhalational botulism ours from the absorption of a man made aerosolised version of the toxin from the lung muosa, and may our in the ontext of a bioterrorist attak. 9 iii37 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 August Downloaded from on 25 September 2018 by guest. Proteted by opyright.

4 iii38 Inadvertent/iatrogeni botulism ours in patients being treated with botulinum toxin. Of the seven distint serotypes of botulinum toxin (types A G), most forms of human poisoning are aused by types A, B, E, and F. Food borne botulism results from the absorption of toxins A, B, E, and F, whereas intestinal and wound botulism results from toxin type C originating from dead tissue. Infant botulism is aused by types A and B. Type A toxin is typially found in home preserved and anned foods that have not been heated to the orret temperature. Home preserved vegetables, fish, and meat are reognised soures of infetion. Type A toxin is usually assoiated with more severe disease and a higher mortality rate than type B or E toxin. Type E toxin is often assoiated with the ingestion of ontaminated seafood, but an our with other foods. Clinial features All forms of botulism produe similar effets, and should always be onsidered in afebrile and alert patients presenting with a desending flaid paralysis with intat sensation. The inubation period and time to onset of symptoms is determined by the amount of toxin absorbed. In food borne botulism the time to onset of neurologial symptoms varies from 2 36 hours, but an be up to eight days. An initial involvement of ranial nerves (resulting in blurred vision, diplopia, dysarthria, dysphonia, or dysphagia) is usually followed by an aute, symmetri, desending flaid paralysis that may lead to respiratory failure. Enlarged or sluggishly reative pupils are ommon. There are no sensory or autonomi features, and the entral nervous system is rarely involved. In food borne botulism gastrointestinal effets (for example, nausea, vomiting, abdominal ramps, diarrhoea, and onstipation) may our in up to half the ases, and may preede the neurologial features. Infant botulism typially presents with lethargy, poor feeding, and loss of head ontrol. Constipation is a lassial presentation, and may preede weakness by several weeks. Hypotension, neurogeni bladder, and other autonomi features may our early. Weakness typially starts with ranial nerve involvement and loss of head ontrol. The infant may also have a weak ry, poor suking ability, impaired gag responses, pooling of seretions, and dereased oral intake. Diagnosis The diagnosis is predominantly a linial one, and is onfirmed by testing for the toxin or organism. Toxin isolation from serum ours in 35% of ases, but this figure drops if the sample is olleted more than two days after ingestion. Only 35% of stool ultures are positive after three days. 10 The most reliable test for the C botulinum toxin is the mouse inoulation test, whereby mie exposed and nonexposed to type speifi botulinum anti-toxin are injeted with the patient s serum. A test is deemed positive if the nonexposed mie die within hours. Neurophysiologial investigations may aid in the diagnosis and show features of a pre-synapti neuromusular juntion defiit, with redued amplitude ompound musle ation potentials (CMAPs) but with normal motor ondution veloities and ompletely normal sensory studies. A diagnosti triad of (1) dereased amplitude of CMAPs in at least two musle groups, (2) tetani or post-tetani failitation (defined by a CMAP amplitude of more than 120% of baseline) after at least Clostridial neurotoxins: key points Tetanus is easily preventable by ative immunisation with the tetanus toxoid The linial piture in tetanus is dominated by musle spasms, rigidity, and autonomi disturbanes The diagnosis in tetanus is made linially as there is no speifi onfirmatory investigation. A positive ulture of Clostridium tetani from a wound would be supportive evidene for the diagnosis Wounds from whih the infetion ausing tetanus originated should be surgially debrided. Metronidazole is onsidered to be the antibioti of hoie in the treatment of tetanus, but peniillin is a suitable alternative. Passive vaination with anti-tetanus immunoglobulin shortens the ourse and may redue the severity of the illness. Ative immunisation (that is, tetanus toxoid) also needs to be given to add to the short term immunity provided by antitetanus immunoglobulin, as well as providing longer term humoral and ellular immunity All forms of botulism produe a flaid paralysis with intat sensation In food borne and infant botulism gastrointestinal effets often preede the neurologial features The diagnosis in botulism is predominantly a linial one, and is onfirmed by testing for the toxin or organism. Neurophysiologial investigations may aid in the diagnosis and show features of a pre-synapti neuromusular juntion defet Speifi treatment in botulism historially onsists of the early use of a trivalent antitoxin that neutralises toxin serotypes A, B, and E The early use of antibiotis and surgial debridement should be onsidered in wound botulism 10 seonds of tetani stimulation at 50 Hz, and (3) prolonged post-tetani failitation of more than 120 seonds and absene of post-tetani exhaustion has been desribed for diagnosis. 11 As studies may be normal in the early stages repeat testing after an interval of 7 10 days may be required. The differential diagnosis for botulism inludes aute inflammatory demyelinating polyneuropathy (that is, Guillain-Barré syndrome), porphyria, poliomyelitis, diphtheria, tik paralysis, myasthenia gravis, and magnesium toxiity. Onset with a bulbar weakness followed by a desending paralysis in a patient with sluggish pupillary reations and intat sensation is suggestive of botulism. Diagnosis of infant botulism may be delayed beause of the relatively non-speifi symptoms that may our in this ondition at onset. Tik paralysis tends to our in older and more mobile hildren than in botulism. Management Treatment is mainly supportive. As respiratory musles may be involved rapidly, patients suspeted of botulism should be initially managed in an intensive therapy unit. In patients at risk of respiratory failure eletive intubation and ventilation should be undertaken. Gastri lavage or indued emesis should be onsidered if ontaminated food was ingested reently. The early use of antibiotis and surgial debridement should be onsidered in wound botulism. Neuromusular juntion bloking agents (for example, aminoglyosides, magnesium ontaining ompounds) should be avoided. J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 August Downloaded from on 25 September 2018 by guest. Proteted by opyright.

5 Speifi treatment historially onsists of the early use of a trivalent antitoxin that neutralises toxin types A, B, and E. Signifiant side effets to the antitoxin may our in more than 20% of ases. The equine derived antitoxin has now been superseded by a human derived antitoxin. A repeat dose of antitoxin may be given 2 4 hours later, with doses repeated at hour intervals if required. The antitoxin is traditionally thought to be relatively ineffetive against infant botulism as the type A toxin impliated in this form of botulism is rarely found in the blood of the infant affeted. However, a reent five year study of human derived antitoxin in infant botulism showed a redution in the time spent in hospital and the need for assisted ventilation and tube feeding. 12 Benefits from anti-toxin are most likely with type E botulism. A heptavalent antitoxin is available to the US Army in the event of a bioterrorist attak. With improved supportive are the overall mortality rates in botulism have dropped to less than 10%, with rates of less than 2% in infant botulism and higher rates in patients above 60 years of age. Reovery typially takes plae over a period of weeks to months, and is dependent on re-innervation following the growth of new motor neuronal sprouts. Respiratory support may therefore be required for months, and weakness and autonomi dysfuntion may persist for more than one year.... Authors affiliations A Goonetilleke, Department of Neurology, Newastle General Hospital, Regional Neurosienes Centre, Newastle upon Tyne, UK J B Harris, Shool of Neurology, Neurobiology & Psyhiatry, University of Newastle upon Tyne, Newastle upon Tyne, UK REFERENCES 1 Meunier FA, Herreros J, Shiavo G, et al. Moleular mehanisms of ation of botulinal neurotoxins and the synapti remodelling they indue in vivo at the skeletal neuromusular juntion. In: Massaro EJ, ed. Handbook of neurotoxiology, vol I. Totowa, New Jersey: Humana Press, 2002: An exellent review on the mehanisms of ation of the neurotoxins disussed. 2 Gergen PJ, MQuillan GM, Kiely M, et al. A population-based serologi survey of immunity to tetanus in the United States. N Engl J Med 1995;332: Farrer JJ, Yen LM, Cook T, et al. Tetanus. J Neurol Neurosurg Psyhiatry 2000;69: Exellent review artile ontaining information on the struture and ation of the tetanus toxin, the linial features of tetanus, and useful details on the management of the ondition. 4 Thwaites CL. Tetanus. Pratial Neurology 2002;2(3): Reent artile ontaining useful information on the linial features and management of tetanus. 5 Passaro DJ, Werner SB, MGee J, et al. Wound botulism assoiated with blak tar heroin among injeting drug users. JAMA 1998;279: Werner SB, Passaro D, MGee J, et al. Wound botulism in California, : reent epidemi in heroin injetors. Clin Infet Dis 2000;31: Spika JS, Shaffer N, Hargrett-Bean N, et al. Risk fators for infant botulism in the United States. Am J Dis Child 1989;143: Shmidt RD, Shmidt TW. Infant botulism: a ase series and review of the literature. J Emerg Med 1992;10: Coleman EA, Yergler ME. Botulism. Am J Nursing 2002;102(9):44 7. A good introdutory artile for the reader interested in the bioterrorist aspets of botulinum toxin. 10 Cherington M. Clinial spetrum of botulism. Musle Nerve 1998;21: Guiterrez AR, Bodensteiner J, Gutmann L. Eletrodiagnosis of infant botulism. J Child Neurol 1994;9: Amerian Aademy of Pediatris. Clostridial infetions. In: Pikering LK, ed Red book: report of the Committee on Infetious Diseases, 25th ed. Elk Grove Village, Illinois: Aademy of Pediatris, 2000: iii39 J Neurol Neurosurg Psyhiatry: first published as /jnnp on 16 August Downloaded from opyright. on 25 September 2018 by guest. Proteted by