From the Department of Pediatrics (MDE, IU, CRK), Uniformed Services University, F. Edward Hebert School of Medicine, Bethesda, Maryland; and the Department of Pediatric Ophthalmology (RHB), Walter Reed Army Medical Center, Washington, DC.
The authors have no financial or proprietary interest in the materials presented herein.
The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Defense or U.S. Government.
Address correspondence to Matthew D. Eberly, MD, Department of Pediatrics, Uniformed Services University, F. Edward Hebert School of Medicine, 4301 Jones Bridge Road, Bethesda, MD 20814.
Infant botulism occurs when ingested spores of Clostridium botulinum germinate, colonize the infant colon, and produce botulinum neurotoxin. The absorbed toxin irreversibly binds to peripheral cholinergic synapses, resulting in a symmetric descending paralysis that typically affects cranial nerves first and often progresses to respiratory failure.1 We report a case of infant botulism in a patient who was diagnosed as having ocular hypertension versus infantile glaucoma due to the finding of significantly increased intraocular pressure (IOP). We propose that measuring IOP in infants with suspected botulism may provide additional data to support the diagnosis and help lead to prompt treatment.
An 8-week-old full-term previously healthy female infant presented to the local emergency department with 1 week of constipation and 3 days of progressive weakness, poor feeding, and weak cry. The parents denied any recent fever, vomiting, travel, or exposure to honey or corn syrup. The patient had an unremarkable birth history and normal metabolic screens. The physical examination was notable for an expressionless face, weak suck and cry, pooling of oral secretions, sluggish pupils, diminished gag reflex, absent Moro reflex and hand grasp, and bilateral 1+ deep tendon reflexes. Her serum electrolytes, liver function tests, and complete blood count were normal. Results of a lumbar puncture and a computed tomography scan of the head were also normal.
Despite inconclusive results on electromyography, the presumptive diagnosis of infant botulism was made and the patient received intravenous botulism immune globulin (BIG-IV). The diagnosis was later confirmed (C. botulinum type B) via a toxin neutralization bioassay performed at the local state health department. She remained clinically stable throughout her hospitalization and, following BIG-IV administration, her symptoms gradually improved until discharge on hospital day 10.
On review of the patient’s outpatient medical record, the infant had been seen 3 days prior to admission in the ophthalmology clinic for concern regarding an absent red light reflex and mild bilateral tearing with mucoid drainage. On examination, the retinae and optic discs were normal but the infant’s IOP, taken without an eyelid speculum by portable applanation tonometry while she was struggling, was significantly elevated at 38 mm Hg bilaterally (normal range, 10 to 21 mm Hg). No glaucoma treatment was initiated because there were no other signs of infantile glaucoma and follow-up IOP evaluation was arranged for 2 weeks later. Her admission for infant botulism interrupted this plan, but the IOP at her follow-up visit 2 months after hospitalization, also taken while struggling, had returned to normal (17 mm Hg in the right eye and 21 mm Hg in the left eye).
In 2003, the U.S. Food and Drug Administration approved human-derived botulinum antitoxin (BIG-IV) for use in infant botulism. BIG-IV has been shown to reduce the mean hospital stay for infected infants from 5.5 to 2.5 weeks and to reduce secondary complications including ventilator-associated pneumonia, tracheomalacia, and Clostridium difficile colitis.2 To achieve the greatest benefit, BIG-IV needs to be given as early as possible in the illness to neutralize botulinum toxemia and thereby maximally shorten the hospital stay.3 Although ultimately considered cost saving, BIG-IV is an expensive intervention at $45,300. Because confirmation of infant botulism through toxin bioassay requires several days and early electromyography results may be inconclusive, physicians often need to make the decision to administer BIG-IV on clinical grounds alone.
The finding of transiently elevated IOP and its potential association with infant botulism was further investigated. In the eye, acetylcholine is involved in stimulating ciliary muscle contraction for near vision and in the constriction of the pupillary sphincter muscle, causing miosis. Botulinum toxin blocks release of acetylcholine, thereby leading to ciliary muscle and pupillary sphincter muscle paralysis.4,5 We speculate that the cycloplegic effect of botulinum toxin can lead to anterior shift of the lens–iris diaphragm and closing of the trabecular meshwork and prevent the proper drainage of aqueous humor, resulting in increased IOP. To our knowledge, there are no published cases of infant botulism associated with ocular hypertension. However, dilated and sluggishly reactive pupils are commonly seen in patients associated with foodborne botulism outbreaks6–8 and have also been documented in newborns with infant botulism.9,10
Temporary increases in IOP associated with mydriasis after intraocular injection of botulinum toxin have been noted in animal studies.11 Additionally, we discovered three case reports of acute-onset ocular hypertension (IOP = 47, 50, and 60 mm Hg by tonometry, respectively) following therapeutic botulinum toxin A injections for conditions including paralytic strabismus, dysthyroid orbitopathy, and blepharospasm.12–14 The IOP rise in two of these cases was immediate and was most likely due to the hydromechanical effects of the inadvertent intraocular injection of botulinum toxin.12,13 One case reported onset of eye pain 3 hours after periocular botulinum toxin injection that worsened over an additional 3 hours, at which point the patient was found to have mydriasis, pupillary blockage, and acute angle-closure glaucoma.14 Paralysis of the ciliary body (accommodative paralysis) is a common and early sign of systemic botulism, and may be the presenting sign of neurologic involvement in the form of complaints of blurred vision in older children and adults.15,16
Increased IOP may be an early sign of infant botulism. Measuring IOP through simple bedside applanation tonometry may aid clinicians in making the timely diagnosis of infant botulism and subsequent administration of BIG-IV. Because this is the first report of an association between infant botulism and elevated IOP, the sensitivity and specificity of this test will need to be further validated. However, it is unlikely that diagnoses that can mimic infant botulism, such as metabolic disorders, spinal muscular atrophy, cerebral infarction, encephalitis, or viral-associated polio-like paralysis, would have an effect on the parasympathetic ciliary ganglion, ciliary body, or the iris sphincter muscle and thus lead to transient increases in IOP. Although we cannot rule out the possibility that the IOP may have risen in our infant due to struggling, we also cannot exclude the additional effects that botulinum toxin may have had on the iris until more reports confirm or refute this finding.
- Arnon SS, Midura TF, Clay SA, Wood RM, Chin J. Infant botulism: epidemiological, clinical, and laboratory aspects. JAMA. 1977;237:1946–1951. doi:10.1001/jama.237.18.1946 [CrossRef]
- Arnon SS, Schechter R, Maslanka SE, Jewell NP, Hatheway CL. Human botulism immune globulin for the treatment of infant botulism. N Engl J Med. 2006;354:462–471. doi:10.1056/NEJMoa051926 [CrossRef]
- Francisco AM, Arnon SS. Clinical mimics of infant botulism. Pediatrics. 2007;119:826–828. doi:10.1542/peds.2006-0645 [CrossRef]
- Kupfer C. Selective block of synaptic transmission in ciliary ganglion by type A botulinus toxin in rabbits. Proc Soc Exp Biol Med. 1958;99:474–476.
- Kao I, Drachman DB, Price DL. Botulinum toxin: mechanism of presynaptic blockade. Science. 1976;193:1256–1258. doi:10.1126/science.785600 [CrossRef]
- Konig H, Gassman HB, Jenzer G. Ocular involvement in benign botulism B. Am J Ophthalmol. 1975;80:430–432.
- Terranova W, Palumbo JN, Breman JG. Ocular findings in botulism type B. JAMA. 1979;241:475–477. doi:10.1001/jama.241.5.475 [CrossRef]
- Monaco S, Freddi N, Francavilla E, et al. Transient tonic pupils in botulism type B. J Neurol Sci. 1998;156:96–98. doi:10.1016/S0022-510X(98)00010-0 [CrossRef]
- McCurdy DM, Krishnan C, Hauschild AH. Infant botulism in Canada. Can Med Assoc J. 1981;125:741–743.
- Paricio C, Bey KJ, Teyssier G, et al. Botulism in a neonate [article in French]. Arch Pediatr. 2006;13:146–148. doi:10.1016/j.arcped.2005.11.006 [CrossRef]
- Wienkers K, Helveston EM, Ellis FD, Cadera W. Botulinum toxin injection into rabbit vitreous. Ophthalmic Surg. 1984;15:310–314.
- Liu M, Lee HC, Hertle RW, Ho AC. Retinal detachment from inadvertent intraocular injection of botulinum toxin A. Am J Ophthalmol. 2004;137:201–202. doi:10.1016/S0002-9394(03)00837-7 [CrossRef]
- Leung AK, Keyhani K, Ashenhurst M. Retinal tear and raised intraocular pressure following unintentional intraocular botulinum toxin type A injection. Can J Ophthalmol. 2007;42:746–747. doi:10.3129/i07-123 [CrossRef]
- Corridan P, Nightingale S, Mashoudi N, Williams AC. Acute angle-closure glaucoma following botulinum toxin injection for blepharospasm. Br J Ophthalmol. 1990;74:309–310. doi:10.1136/bjo.74.5.309 [CrossRef]
- Kawasaki A. Disorders of pupillary function, accommodation, and lacrimation. In: Miller NR, Newman NJ, eds. Walsh & Hoyt’s Clinical Neuro-Ophthalmology, 6th ed. Philadelphia: Lippincott, Williams & Wilkins; 2005:769,783.
- Calvert P. Disorders of neuromuscular transmission. In: Miller NR, Newman NJ, eds. Walsh & Hoyt’s Clinical Neuro-Ophthalmology, 6th ed. Philadelphia: Lippincott, Williams & Wilkins; 2005:1072–1074.