Atypical Tetanus in a Completely Immunized 14-Year-Old Boy

May 26, 2011

http://pediatrics.aappublications.org/content/120/5/e1355.full

(better formatting at webpage)

Kai König,

MD

a,

Hannelore Ringe,

MD

a,

Brigitte G. Dorner,

PhD

b,

Diers,

MD

a,

Birgit Uhlenberg,

MD

a,

Dominik Müller,

MD

a,

Verena Varnholt,

MD

a,

Gerhard Gaedicke,

MD

a

+ Author Affiliations

aChildren's Hospital, Charité

Universitätsmedizin Berlin, Campus Virchow-Klinikum,

Berlin, Germany b Koch

Institute, Microbial Toxins, Center for Biological Safety, Berlin,

Germany

Next Section

AbstractWe report the uncommon clinical course of tetanus

in a completely immunized 14-year-old boy. His initial symptoms, which

included a flaccid paralysis, supported a diagnosis of botulism.

Preliminary mouse-test results with combined botulinum antitoxins A, B,

and E, obtained from tetanus-immunized horses, backed this diagnosis. The

change in his clinical course from paralysis to rigor and the negative,

more specific, botulinum mouse test with isolated botulinum antitoxins A,

B, and E, obtained from nonvaccinated rabbits, disproved the diagnosis of

botulism. Tetanus was suspected despite complete vaccination. The final

results of a positive mouse test performed with isolated tetanus

antitoxin confirmed the diagnosis. Adequate treatment was begun, and the

boy recovered completely.

Key Words:

tetanus

botulism

infection

immunization

paralysis

mouse toxicity test

Today, tetanus is a rare disease in countries with primary immunization

programs. The reported incidence for adults and children is low, with an

average of 43 cases per year in the United

States,

1 12 to 15 per year in the United

Kingdom,

2 and <15 per year in

Germany.

3 However, tetanus occurs occasionally despite complete

vaccination status. In these cases, the clinical picture can be altered,

which hampers accurate and timely diagnosis. Here we report the unusual

clinical presentation of tetanus in a completely immunized 14-year-old

German boy.

Next Section

CASE REPORTThe patient was admitted to our hospital with

a 1-day history of headache, left-sided ptosis, generalized paresthesia,

and impaired vision. His oral mucous membranes were extremely dry. Three

days before he had suffered from mild diarrhea, and the day before

admission he had eaten grilled chicken with barbeque sauce. The parents

recalled a tick bite 1 year ago and an accidental abrasion at the

patient's left knee 1 week before, when the boy scratched himself on the

rough surface of wooden floorboards. He did not clean the wound, and at

admission it was small (2–3 mm in diameter), dry, and in the process of

healing. In his spare time, the patient, who is right-handed, used to

work with lacquers and glue. His medical history was uneventful. He had

had chicken pox at the age of 3 years and common upper respiratory tract

infections in his infancy. His immunization schedule was up-to-date with

initially 3 vaccinations in the first year of life and a tetanus booster

1 year before presentation. Communication with the patient's doctor and

with the manufacturer of the vaccine revealed that the booster was within

the vaccine's expiration date and that there were no reports of reduced

quality of that production lot.

After admission, an antibiotic and antiviral treatment with ceftriaxone

(200 mg/kg per day), clarithromycin (15 mg/kg per day), and acyclovir (30

mg/kg per day) was initiated for suspected early meningoencephalitis

despite normal cerebrospinal fluid test results. The results of

microbiologic and virological examinations (cultures and polymerase chain

reaction for bacteria and fungi, ameba, toxoplasmosis, Mycoplasma,

Borrelia, Chlamydia, rabies, herpes simplex 1–2, HIV 1/2,

cytomegalovirus, Epstein-Barr virus, enterovirus, early-summer

meningoencephalitis, measles, varicella, influenza and parainfluenza 1–3,

and parvovirus B19) in blood and cerebrospinal fluid were negative.

Results of drug screening, an edrophonium-provocation test, and testing

of autoimmune antibodies (antineutrophil cytoplasmic antibody,

antinuclear antibody, antimitochondrial antibody, and antibodies against

neurons, myelin, glycoprotein, and ganglioside) were negative.

On day 2, the patient's condition deteriorated severely, with alternating

hypopnea and tachypnea, anxiety, hyporeflexia, bilateral ptosis,

oculomotor nerve palsy, photophobia, dysarthria, dysphagia, and flaccid

paralysis of the trunk and lower limbs. The patient was transferred to

the PICU. Repeated electroencephalography, neurophysiologic examinations,

and cerebral MRI and magnetic resonance angiography were normal.

Treatment with intravenous immunoglobulin (Gamunex 10% [bayer Healthcare

AG, Leverkusen, Germany], 2 g/kg = 100 g over 5 days intravenously) was

started for suspected Guillain-Barré syndrome. Because an atypical

botulism infection could not be completely excluded, equine botulinum

antitoxin (Botulismus-Antitoxin [Chiron-Behring GmbH & Co KG,

Marburg, Germany], 1 mL = 750 IU of botulinum antitoxin A, 500 IU of

antitoxin B, and 50 IU of antitoxin E) was added on day 3. The antidote

treatment was ceased at 350 of 500 mL because of an anaphylactic

reaction. On the same evening he developed urine bladder dysfunction,

carpopedal spasms, intermittent rigors of the upper limbs, and increasing

rigors of the lower limbs and hypopnea. He received midazolam (0.04 mg/kg

per hour intravenously), tetrazepam (1 mg/kg per day orally), and

metamizole (80 mg/kg per day intravenously) to control spasms and pain.

Hypopnea and apnea were treated with theophylline (initially 5 mg/kg,

then 4 × 2.5 mg/kg per day intravenously) and oxygen supplementation.

The next morning our patient showed risus sardonicus and permanent rigor

of the upper and lower limbs. These symptoms supported a clinical

diagnosis of tetanus. Therefore, he was treated with 10000 IU of tetanus

antitoxin. Antibiotic treatment was changed to metronidazole (20 mg/kg

per day). The retrospective tetanus-immunoglobulin G (IgG) level at

admission was 2.11 IU/mL.

Twenty-four hours after initiation of the tetanus treatment, his

neurologic status remained stable. On day 5 he developed transient

bradycardia with prolonged QTc time interval (QT/QTc: 490/476

milliseconds). After 8 days his painful spasms became more infrequent.

One day later, he responded to questions by nodding. On day 15, the

dysarthria improved, and his speech became partially understandable; on

day 17, he showed normal or slightly decreased muscular reflexes and

increased muscular tone of all 4 limbs. He was able to sit upright

unsupported, and his muscular strength of the upper limbs was 3/5 to 4/5.

His right-sided ptosis resolved and improved on the left side. After 3

weeks the patient was transferred to a rehabilitation center.

Fourteen days after discharge he was able to walk independently with

normal power of the upper limbs and lower-limb power at 4/5. His muscular

reflexes and fine motor skills were slightly reduced. Minimal ptosis on

his left side persisted. At follow-up 6 months and 1 year later his

neurologic and psychological examinations were completely normal.

Next Section

DISCUSSIONTetanus occurs in different clinical patterns,

with generalized tetanus as the most common form. It is caused by the

Gram-positive, spore-forming Clostridium tetani, which produces

its toxins (tetanospasmin and tetanolysin) in a favorable environment,

preferentially in tissue wounds. Tetanospasmin is able to block

neurotransmitter release, which leads to the characteristic increased

muscle tone and spasms. In the typical course of tetanus, patients often

first notice trismus. Subsequently, dysphagia and stiffness or pain in

the upper trunk muscles appears, followed by descending muscular

rigidity. Other common clinical manifestations are risus sardonicus, the

continuing contractions of face muscles, and an opisthotonos. The

clinical course can be complicated by apnea, laryngospasm, aspiration

pneumonia, and autonomic dysfunction with need for intensive care

management.

4

In our patient, initial paralysis and dry mouth, after consumption

of grilled meat, misled to a diagnosis of botulism and seemed to be

confirmed by the positive mouse toxicity test for botulism: the mice died

after injection of the patient's blood serum but survived after

administration of the patient's serum mixed with botulinum antitoxins A,

B, and E (Fig

1). However, as the clinical signs changed from flaccid paralysis to

the tetanus-typical rigor, tetanus became clinically obvious despite the

patient's history of appropriate tetanus vaccination. At this stage, the

in vivo mouse test had to be doubted. Mice treated with blood serum and

botulinum antitoxin, containing antibodies specific for type A, B, or E

botulinum toxin separately, became severely paralyzed or died, as did the

control mice that received the patient's blood serum only. The assumed

explanation seemed unconventional but simple: single antitoxins originate

from rabbits, whereas the combination of A, B, and E botulinum antitoxins

is obtained from horses. In contrast to rabbits, horses are routinely

immunized against tetanus. Thus, the combined botulinum antitoxin mixture

also contained tetanus antitoxin. Conclusive results were obtained by the

tetanus mouse test (adapted from the work of Habermann and

Wiegand

5). Mice that received the patient's blood serum plus

tetanus antitoxin survived without symptoms. This result led to the

eventual diagnosis of atypical tetanus in a fully vaccinated child.

View larger version:

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Download as PowerPoint Slide FIGURE 1

All mice received an injection of the patient's blood serum. Mice

survived after treatment with combined antibotulinum neurotoxin A, B, and

E because of the tetanus antitoxin content, whereas mice that received

isolated antibotulinum neurotoxin A, B, or E died. The diagnosis of

tetanus was then confirmed by the survival of mice after administration

of the patient's blood serum and tetanus antitoxin. All mice were BALB/c:

a Chiron-Behring GmbH; b Statens Serum Institut

(Copenhagen, Denmark); c Aventis Behring (Marburg, Germany).

On the basis of its exquisite sensitivity, the gold standard of botulinum

and tetanus neurotoxin detection is still the mouse toxicity

test

6

,

7: the lethal amount for botulinum toxin is in the range of 0.5

to 1.2 ng per kg of body weight (depending on the botulinum toxin

subtype, intraperitoneal injection route), and for tetanus toxin it is 1

ng per kg of body weight (intraperitoneal injection route). Taking into

account the maximal injection volume of 1 mL and an average mouse weight

of 20 g, this results in a sensitivity of 10 to 20 pg/mL.

The procedures for the mouse toxicity test for botulinum and tetanus

toxin are

similar

8

,

9: the patient material is injected intraperitoneally into

mice, and symptoms are observed for several hours up to 4 days. In the

case of botulinum toxin intoxication, mice sequentially show ruffled fur,

labored but not rapid breathing, a characteristic wasp-like abdomen with

narrowed waist caused by increased respiratory effort, weakness of limbs

that progresses to total paralysis, and gasping for breath followed by

death as a result of respiratory failure. In the case of tetanus toxin

intoxication, similar symptoms may occur. However, the characteristic

wasp-like abdomen with its narrowed waist is only described in mice after

administration of botulinum toxin. This symptom is usually missing when

testing for tetanus toxin, and spastic paralysis indicates the presence

of tetanus

toxin.

8

–

10

Death of mice in the absence of neurologic symptoms is not an

acceptable indication of botulism or tetanus, because it may be

nonspecifically caused by other microorganisms, chemicals present in the

test fluids, or injection

trauma.

9

,

11 Confirmation and exact neurotoxin typing is performed by

mouse-protection tests using polyvalent or monovalent neutralizing

antibodies (which is better) as in our studies (refs

8 and

9 for botulinum toxin, refs

5 and

12 for tetanus toxin): on simultaneous application of toxin (or

patient material) and the respective neutralizing antibodies, the mice

are rescued and no symptoms occur.

Currently, the mouse-protection test is still the standard method of

choice for quantifying tetanus toxin–neutralizing antitoxin

titers.

13 Furthermore, the mouse assay for botulinum toxin is

used most frequently for detecting botulinum toxin in foods or patient

material or for assessing the potency of the toxin used as a drug in

medicine.

14

In our case, other differential diagnoses such as myasthenia

gravis, Guillain-Barré syndrome including variants, encephalitis, lupus

erythematosus or other autoimmune reactions, tumor, leukemia, botulism,

and intoxication seemed very unlikely, because the results of repeated

MRI and laboratory results were completely normal, and the patient's

clinical signs changed quickly from paralysis to rigor. A rare

differential diagnosis of tetanus is strychnine poisoning with some

similar symptoms such as restlessness, anxiety, muscle twitching, intense

pain, trismus, facial grimacing, opisthotonus, and extensor

spasm.

15 The rapid onset of symptoms in strychnine poisoning,

usually 10 to 20 minutes, made this diagnosis unlikely for our patient,

because his clinical picture first showed flaccid paralysis, and rigor of

the limbs and risus sardonicus occurred the next day. Hence, a screening

for strychnine and alkaloids of Strychnos species was not

performed. The intermittently observed bradycardia with prolonged QT-time

interval has been described in patients with

tetanus.

16

An increased incidence of tetanus in countries with immunization

programs has been reported in elderly adults with impaired immunity

despite preceding

vaccination.

17 In children with adequate immunization, there have been

only a few case reports of tetanus

infections.

18

–

20 Our patient's tetanus-IgG level at admission was 2.11 IU/mL,

which is considered to be long-lasting protection against infection

(range: >1.1 to 3 IU/mL). This level was rechecked at the same

laboratory. Unfortunately, no serum was left from the initial blood

sample for retesting in another institution; the patient had already been

treated with immunoglobulin and botulinum antitoxin before the eventual

diagnosis of tetanus was made. However, it should be noted that the

indicated antitetanus IgG level summarizes protecting and nonprotecting

antibodies. If the patient has either a low quantity of protecting

antibodies in the serum or, alternatively, the concentration of the toxin

is too high to be neutralized by the circulating protecting antibodies,

the patient develops tetanus and the mouse test for tetanus gives a

positive result. Crone and

Reder

21 speculated in their case series that burden of toxin

can overwhelm patients' defenses or that an antigenic variability between

toxin and toxoid could cause immunization failure.

Treatment of tetanus is based on 3 principles: neutralization of unbound

toxin, prevention of additional toxin release, and amelioration of

ongoing

symptoms.

22 Early, aggressive, intensive care treatment is

indicated to prevent or alleviate fatal complications such as respiratory

failure and autonomic dysfunction.

Although unintended, but presumably life saving, our patient was treated

early for tetanus: he received at least 750 IU of tetanus antitoxin with

the botulinum antitoxin (Chiron-Behring GmbH & Co KG, verbal

communication, 2005) and an additional 2000 IU with the immunoglobulin

infusion (Gamunex 10% has an average content of tetanus antitoxin of 2

IU/mL [bayer Healthcare AG, verbal communication, 2005]).

Next Section

CONCLUSIONSAtypical tetanus should be considered as a

rare differential diagnosis in patients with neurologic symptoms despite

complete tetanus vaccination. It can be proven unequivocally by the mouse

toxicity test.

Next Section

Footnotes

Accepted April 17, 2007.

Address correspondence to Kai König, MD, Mercy Hospital for Women,

Department of Paediatrics, 163 Studley Rd, Heidelberg/Melbourne,

3084, Australia. E-mail:

kkonig@... or

kai.koenig@...

The authors have indicated they have no financial relationships

relevant to this article to disclose.

IgG, immunoglobulin G

Previous Section

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