Severe tetanus in immunized patients with high anti-tetanustiters N a t h a n E. Crone, MD, a n d Anthony T. Reder, MD

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Article abstract-Severe (grade 111) tetanus occurred in three immunized patients who had high serum levels of antitetanus antibody. The disease was fatal in one patient. One patient had been hyperimmunized to produce commercial tetanus immune globulin. Two patients had received immunizations 1year before presentation. Anti-tetanus antibody titers on admission were 25 IU/ml to 0.15 IU/ml by hemagglutination and ELISA assays; greater than 0.01 IU/ml is considered protective. Even though one patient had seemingly adequate anti-tetanus titers by in vitro measurement (0.20 IU), in vivo mouse protection bioassays showed a titer less than 0.01 IU/ml, implying that there may have been a hole in her immune repertoire to tetanus neurotoxin but not to toxoid. This is the first report of grade I11 tetanus with protective levels of antibody in the United States. The diagnosis of tetanus, nevertheless, should not be discarded solely on the basis of seemingly protective anti-tetanus titers. NEUROLOGY 1992;42:761-764

Tetanus is a rare disease i n the United States as a result of n e a r l y u n i v e r s a l active i m m u n i z a t i o n .

Although tetanus remains a significant threat in developing countries, the incidence in the United S t a t e s is o n e - t w e n t i e t h of the incidence before widespread immunization.’ During 1987 and 1988, only 1 0 1 c a s e s of tetanus w e r e r e p o r t e d t o the Centers for Disease Control (CDC).’ However, the p o t e n t i a l exists for a n i n c r e a s i n g i n c i d e n c e of t e t a n u s d u e to inadequate booster immunization in the elderly, the growing population of immunocompromised hosts, a n d the u r b a n epidemic of IV d r u g abuse. In spite of modern medical care, tetanus is fatal i n roughly 20%) of cases in the United States. Since tetanus is so rare i n the U n i t e d S t a t e s , m a n y physicians h a v e little experience w i t h i t s diagnosis and management. A history of immunization and a protective level of anti-tetanus antibody should not lead physicians away from t h e diagnosis of t e t a n u s i n a p a t i e n t with an otherwise classic clinical p r e s e n t a t i o n . Misdiagnosis and d e l a y in t h e r a p y c a n h a v e catastrophic consequences. We report three cases of severe, generalized t e t a n u s i n previously immunized p a t i e n t s who had “protective” levels of antibody to t e t a n u s toxin upon presentation. Case reports. Patient 1. A previously healthy 29-yearold man was first seen in the emergency room for left

antecubital swelling and ecchymosis that developed 1 week after donating plasma. The ecchymosis resolved after treatment with hot packs. Over the next several weeks, he helped demolish an old house and worked on a garbage pickup route. One month later, he was again seen following a week of flu-like symptoms. On the morning of admission he was found on his bedroom floor, appearing “bewildered” and “combative.” He had a lowgrade fever, was m u t e , and responded sluggishly. Otherwise, he had a normal physical and neurologic examination and had normal CSF. An EEG showed highamplitude, rhythmic, left-sided delta slowing and lower a m p l i t u d e i r r e g u l a r d e l t a activity on t h e r i g h t . Phenytoin was administered without any improvement in clinical condition. Two days later, he was transferred to the university hospital because of progressively increasing muscle spasms. He exhibited intermittent risus sardonicus, trismus, and generalized painful muscle spasms triggered by noise or attempts to speak or move. Despite this, he was mentally alert and oriented. Aside from moderately increased tone and very brisk deep tendon reflexes, his neurologic examination was normal. He was treated with 4,000 units IM human tetanus immune globulin. A tracheostomy was performed because of continuous severe generalized spasms, and the patient required hourly paralyzing doses of pancuronium for the next 5% weeks. The patient’s course was further complicated by rhabdomyolysis from the intense spasms and by pneumonia. Two lumbar punctures 4 days and 12 days after admission revealed an opening pressure of 280 mm CSF, as well as 5 and 1 WBCs, respectively, but were other-

From the Department of Neurology and the Brain Research Institute, University of Chicago, Chicago, IL. Presented in part a t the 43rd annual meeting of the American Academy of Neurology, Boston, MA, April 1991. Received July 2 , 1991. Accepted for publication in final form September 16, 1991. Address correspondence and reprint requests to Dr. Anthony T. Reder, Department of Neurology, Box 425, University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637.

April 1992 NEUROLOGY 42 761

wise normal. An EEG a t 3 weeks showed diffuse theta activity with occasional posterior temporal spikes, but he had no clinical evidence of seizure activity when the pancuronium was tapered. A CT of the brain with contrast a t 6 weeks was normal. Extensive serum and CSF cultures and stains were negative for infectious agents. Serum titers, corneal impressions, and hair follicle biopsies were negative for rabies. Urine heavy metal and toxicology screens were negative. At discharge, h e had amnesia for the period of paralysis and for the preceding y e a r of his life, a n d he was hypervigilant a n d had marked piloerection in response to light touch and breezes. His neurologic and mental status examinations were otherwise normal. The EEG had improved but was moderately abnormal with diffuse theta and a slow, disorganized, posterior rhythm. Ten years before, the patient had received a complete series of tetanus immunizations in the Army. Fifty-one days before he developed signs of tetanus, he had been hyperimmunized a t a plasma donor center with 1 cc tetanus toxoid intradermally plus 1 cc adsorbed tetanus toxoid IM i n order to produce commercial t e t a n u s immune globulin from his serum. Serum anti-tetanus antibody levels in the range of 14 to 33 IU/ml (hemagglutination assay performed by the plasma donor center) were measured weekly on four occasions after hyperimmunization. Upon admission to the university hospital, the patient’s anti-tetanus antibody titer was 1:1,280 (Minnesota Board of Public Health hemagglutination assay).

Patient 2. A 42-year-old HIV-negative woman with a 15year history of IV heroin abuse was admitted for a second bout of tetanus. One year before presentation she had been hospitalized for severe generalized tetanus associated with needle track abscesses. At that time, her spasms did not respond to IV diphenhydramine, and her urine toxicology screen did not show any evidence of neuroleptics. She was given 1,500 units IV human tetanus immune globulin soon after admission, and shortly thereafter she was intubated. CT of the brain and lumbar puncture were normal. She was immunized with 0.5 cc tetanus toxoid (Wyeth, AlPO, adsorbed) on the 20th hospital day. She required prolonged intubation and pharmacologic paralysis, and her course was complicated by rhabdomyolysis, autonomic instability, pneumonia, and pansinusitis. Clostridium tetani was never cultured from her abscesses. On the 58th hospital day, she was extubated, and within 3 weeks she was fully ambulatory, had “found Jesus,” and vowed to never again abuse drugs. However, soon after discharge the patient had resumed her daily drug abuse and was lost to follow-up. One year later, she arrived in the emergency room with a 24-hour history of acute jaw stiffness similar to her previous presenting symptoms. She had trismus and opisthotonic posturing, as well as diffusely increased tone and brisk reflexes. Urine toxicology screen was positive for opiates, methadone, cocaine, a n d benzodiazepines. Her CSF was normal. She was given 5,000 units IM human immune globulin, a s well a s 0.5 cc tetanus toxoid and IV penicillin. Because of progressively worsening muscle spasms, she was intubated and managed with pancuronium and lorazepam. On the sixth hospital day, the patient became hypotensive, and the next day she was found to be unresponsive and without brainstem reflexes. She died on the eighth hospital day. At autopsy, she had a massive intraparenchymal hemorrhage originating in the head of the 762 NEUROLOGY 42 April 1992

left caudate and extending into all four ventricles. Serum anti-tetanus antibody titer a t presentation to the emergency room, before treatment with antitoxin or toxoid, was 0.15 IU (CDC microhemagglutination assay).

Patient 3. A 57-year-old woman with a history of hypertension and insulin-dependent diabetes mellitus w a s a d m i t t e d for progressive muscle s p a s m s . S h e had received a tetanus booster after she stepped on a sewing needle 1 year before this admission. The evening before hospitalization she had difficulty swallowing and opening her mouth, and overnight she developed painful neck and back spasms. Although she admitted to a remote history of IV drug abuse, she denied any recent drug use or neuroleptic ingestion. She denied any recent penetrating injuries or other trauma but did admit to reusing an insulin syringe 1week before admission. On presentation she had a continuous risus sardonicus and rock-hard rigidity of her paraspinous muscles, a s well a s f r e q u e n t waves of painful t r i s m u s a n d opisthotonos initiated by attempts to speak or move. The remainder of her neurologic examination was normal. Urine toxicologic testing was unremarkable. HIV antibody was negative. Her CSF was normal. In the emergency room, the patient was given human tetanus immune globulin, 3,500 units IM, and was started on IV penicillin. She was electively intubated. Within 48 hours, she required continuous infusion of pentobarbital to control frequent tetanic spasms and paroxysms of hypertension and tachycardia. A tracheostomy was performed on the 13th hospital day, and she remained intubated for the next 2 months. Her hospital course was furt h e r complicated by p u r u l e n t p a n s i n u s i t i s which required surgical drainage. All cultures were negative for C tetani. Twelve weeks after admission, the patient was discharged with a mild downward deviation of the left soft palate and tongue deviation to the left which has persisted on subsequent examinations. Otherwise her examination was normal. Serum antibody to tetanus toxoid at the time of presentation (prior to antitoxin) was 0.2 IU/ml (by ELISA). Because of seemingly protective levels of anti-tetanus antibody by in vitro measurement, in vivo mouse protection assay (kindly performed by Jane Halpern, Bethesda, MD) was done and showed titers of less than 0.01 IU/ml.

Discussion. T h e diagnosis of t e t a n u s often m u s t be m a d e clinically, for n o laboratory test is diagnost i c in every case. C tetani can be isolated in only 30% of p a t i e n t s , 2 a n d n o b l a m e w o r t h y w o u n d is found i n 7 t o 30%.’JO n e m o n t h before admission, p a t i e n t 1 had sought help for antecubital swelling a n d ecchymosis. Patient 2 had injected heroin o n t h e d a y of admission and o n m a n y occasions preceding hospitalization. O n e week before admission, p a t i e n t 3 had reused o n e of h e r i n s u l i n syringes, and 10 d a y s after developing t e t a n u s s h e required s u r g i c a l drainage f o r p u r u l e n t p a n s i n u s i t i s . Nevertheless, in e a c h patient n u m e r o u s a t t e m p t s t o c u l t u r e C tetani were unsuccessful. I n all three patients, the clinical signs fulfilled c r i t e r i a f o r grade 111, o r s e v e r e , g e n e r a l i z e d tetanus., I n e a c h p a t i e n t , o t h e r d i s o r d e r s that could mimic generalized t e t a n u s (dystonic reaction t o phenothiazines, lead, phenytoin, organophosp h a t e or s t r y c h n i n e poisoning, h y s t e r i a , hypocal-

nificantly since one died and the other two survived cemia, black widow spider bite, “stiff-man” synonly after prolonged and complicated hospitalizadrome, myotonia, McArdle’s disease, seizures, tions. rabies, or viral encephalitis) were reasonably ruled Is the accepted definition of protective titers out either by clinical and laboratory evaluation or valid? The level of neutralizing antibody that is by the clinical course of the illness. Patient 2 had accepted a s protective is 0.01 IU/ml. Th’is was recently internalized cocaine, benzodiazepines, and derived from animal studies that correlated serum methadone, but none of these causes prolonged proanti-tetanus levels with symptoms of tetanus.17 In gressive muscular rigidity, spasms, and opistho1937, Sneath et alls estimated that the protective tonus. Although patient 1’s initial presentation was level of anti-tetanus antibody in human after active suspicious for seizures followed by a postictal state, immunization is 0.01 IU/ml because no guinea pigs his clinical course rapidly evolved into the classic with levels higher than this died of experimentally signs of tetanus. His generalized, painful spasms induced tetanus. However, 6/45 animals with titers were exquisitely sensitive to various forms of stim>0.01 IU/ml (two with levels between 0.1 and 0.5 ulation. They were not temporally linked to his IU/ml) developed nonfatal tetanus. Although sevEEG abnormalities and he did not respond to antieral other investigators have also found exceptions convulsants. Tetanus is generally not considered to to the 0.01 IU/ml threshold,Ig Sneath’s estimation cause an abnormal EEG.5 Illis and Taylor,6 howevof protective levels h a s been widely accepted. er, found t h a t 14 of 24 patients who survived Wolters and Dehrnel2Ohad such confidence in the tetanus had excess theta, delta, or sharp wave 0.01 IU/ml standard that they challenged themactivity on EEGs performed 1 month to 10 years selves with fatal doses of tetanus toxin knowing after clinical recovery. In patient 1, EEG changes they had antitoxin levels of only 0.007 to 0.01 may have been caused by hypoxia o r ischemia that IU/ml. However, in Goulon’s study of 64 consecuresulted from cardiac arrhythmias or interference tive tetanus patients, 10 had anti-tetanus titers with respiration, which a r e common i n severe greater than 0.01 IU/ml.12 tetanus. A concurrent viral infection is possible, How could high titers of antitoxin still be ineffecbut there was no rise in serum antiviral titers durtive in our patients and in the animal studies cited ing the illness. above? One possibility is that the burden of toxin Each of our patients had high titers of antisimply overwhelmed t h e patients’ seemingly tetanus antibody at the onset of clinical tetanus, impregnable defenses. In mice, guinea pigs, and before any toxoid or immune globulin were adminrabbits, survival times drop as increasing amounts istered. Levels greater than or equal to 0.01 IU are of tetanus toxin are injected. This dose-survival considered protective. Our patients’ titers were 20 relationship differs for each of the three animal to 2,000 times greater. Tetanus has been reported species and also varies among individuals.21 in immunized patients1a7-lo;however, protective Another cause of immunization failure could be titers of toxin-neutralizing antibody were not antigenic variability between toxin and toxoid. A demonstrated. polyclonal response to toxoid should recognize the Tetanus has rarely been reported in patients aluminum toxoid and the unmodified parts of the with protective titers. In all instances, the symptoxoid immunogen, as well as the toxin itself. Lack toms and signs were relatively mild.”-I4 Our of a n immune response to toxin is especially patients required tracheostomy, mechanical ventiunlikely in patient 1,who was immunized with two lation, and pharmacologic paralysis, and their hosforms of toxoid. pital course was much longer than the 15-day averP e r h a p s our p a t i e n t s h a d a “hole” i n t h e i r age length of stay for t e t a n u s patients in the immune repertoires. Suppression of the antibody United States.] response by mechanisms such as decreased antigen The relatively mild clinical course of tetanus in processing, decreased production of IgG,, anti-idiopatients with protective anti-tetanus titers and in typic antibodies, a less reactive HLA type (HLAnearly all immunized patients has fostered the controversial concept of “modified t e t a n ~ s . ” l l - ~ ~ JB5), ~ J ~high-dose tolerance, or senility are all mootour patients had protective antibody titers by Partially protected hosts are thought to have less ELISA or hemagglutination, and none had any hissevere infection t h a n unprotected hosts.g The tory of immunodeficiency. However, in patient 3, a . severity of tetanus can be classified as grade I: mouse protection bioassay was performed, and the moderate trismus and localized stiffness; grade 11: patient’s serum did not protect mice a g a i n s t marked trismus, dysphagia often present and gentetanus toxin even though the in vitro titer was eralized rigidity; o r grade 111: severe trismus, 0.20 IU/ml. severe dysphagia, respiratory difficulty, and freThe ultimate criterion for efficacy of immunizaquent generalized spasms (modified from Cole and tion is the ability to prevent human disease. The Youngman4). I n a series of 64 t e t a n u s cases, cases reported herein are too few and anecdotal to Goulon et all2 found t h a t none with grade I11 cast doubt on our current immunization practices. t e t a n u s h a d t i t e r s 20.01 IU/ml, whereas all The average annual incidence of tetanus in the patients with titers 20.01 had either grade I or United States in 1987-1988 was roughly one-twengrade I1 disease. The clinical courses of our t i e t h of the incidence in 1947, when national patients did not appear to have been “modified sigApril 1992 NEUROLOGY 42 763

reporting began.’ However, given the rather arbitrary basis for the “protective level” of antitoxin antibody, our cases suggest that a universally protective level may be much higher than assumed. Other host factors that are not adequately reflected by simple titers of antibody may play a role in the susceptibility of humans t o tetanus. In the early stages of muscular rigidity and at t h e onset of tetanic convulsions, tetanus can be confused with many other neurologic diseases. Since tetanus is likely to be fatal if not recognized and treated properly, clinicians should be willing t o entertain the diagnosis of tetanus regardless of the level of anti-tetanus antibody titers.

Acknowledgments We are grateful to Dr. Jane Halpern and Dr. Carolyn Hardegree of the Bureau of Biologicals, Bethesda, MD, for the mouse protection assays of serum anti-tetanus antibodies; Dr. Arthur Itkin and Dr. Onassis Caneris for their help in patient care; and Dr. L.D. Sabbath and Dr. Arthur C. Klassen for their helpful comments.

References 1. T e t a n u s - U n i t e d S t a t e s , 1 9 8 7 a n d 1 9 8 8 . MMWR 1990;39:37-41. 2. LaForce FM, Young LS, Bennett JV. Tetanus in the United States (1965-1966).N Engl J Med 1969;280:569-574. 3. Furste W. The Fifth International Conference on Tetanus, Ronneby, Sweden, 1978. J Trauma 1980;20:101-105. 4. Cole L, Y o u n g m a n H. T r e a t m e n t of t e t a n u s . L a n c e t 1969;1:1017-1020. 5 . Schmidt RP, Levy LL, Turrell RC, Hopkins WE, Bloor BM, Roseman E. Diagnostic and therapeutic clues in the study of

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tetanus. Arch Neurol Psychiat 1953;69:55-63. 6. Illis LS, Taylor FM. Neurological and electroencephalographic sequelae of tetanus. Lancet 1971:1:826-830. 7. Boyd JSK. Tetanus in the African and European theatres of war, 1939-1945. Lancet 1946;1:113-119. 8. Long AP, Sartwell PE. Tetanus in the United States Army in World War 11. Bull US Army Med Dept 1947;7:371-385. 9. Owa JA, Makinde 00. Neonatal tetanus in babies of immunized mothers. J Trap Pediatr 1990;36:143-144. 10. Vieira BI, Dunne JW, Summers Q . Cephalic tetanus in a n immunized patient. Med J Aust 1986;145:156-157. 11. Berger SA, Cherubin CE, Nelson S,Levine L. T e t a n u s d e s p i t e p r e e x i s t i n g a n t i - t e t a n u s a n t i b o d y . JAMA 1978;240:769-770. 12. Goulon M, Girard 0, Grosbuis S, Desormeau J-P, Capponi MF. Les anticorps antitetaniques: titrage avant sero-anatoxi n o t h e r a p i e chez 6 4 t e t a n i q u e s . Nouv P r e s s e Med 1972;1:3049-3050. 13. Passen EL, Andersen BR. Clinical tetanus despite a ‘protective’ level of t o x i n - n e u t r a l i z i n g a n t i b o d y . JAMA 1986;255:1171-1173. 14. Peterson H. A case of tetanus in spite of active toxoid prophylaxis. Acta Chir Scand 1965;129:235-237. 15. Can modified t e t a n u s occur? 1Editorial.l N Engl J bled 1962;266:1117-1118. 16. Edsall G. Modified tetanus. N Engl J Med 1962;267:520. 17. McComb JA. The prophylactic dose of homologous tetanus antitoxin. N Engl J Med 1964;270:175-178. 18. Sneath PAT, Kerslake EG, Scruby F. Tetanus immunity: the resistance of guinea pigs to lethal spore doses induced by a c t i v e a n d p a s s i v e i m m u n i z a t i o n . Am J H y g i e n e 1937;25:464-476. 19. Looney JM, Edsall G, Ipsen J , Chasen WH. Persistence of antitoxin levels after tetanus-toxoid inoculation in adults, and effect of a booster dose after various intervals. N Engl J Med 1956;254:6-12. 20. Wolters KL, Dehmel H. Abschliessende Untersuchunge uber die Tetanusprophylaxe durch aktive Immunisierung. Ztsch fr Hyg u Infektionskr 1942;124:326-332. 21. Ipsen J. Changes in immunity and antitoxin level immediately after secondary stimulus with tetanus toxoid in rabbits. J Immunol 1961;86:50-55.

Severe tetanus in immunized patients with high anti−tetanus titers Nathan E. Crone and Anthony T. Reder Neurology 1992;42;761 DOI 10.1212/WNL.42.4.761 This information is current as of April 1, 1992 Updated Information & Services

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Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1992 by AAN Enterprises, Inc.. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.

Severe tetanus in immunized patients with high anti-tetanus titers.

Severe (grade III) tetanus occurred in three immunized patients who had high serum levels of anti-tetanus antibody. The disease was fatal in one patie...
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