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Show Ophthalmic Manifestations in 18 Patients with Botulism Diagnosed in Porto, Portugal Between 1998 and 2003 Susana C. Penas, MD, Olinda M. Faria, MD, Rosdrio Serrdo, MD, Jodo A. Capdo- Filipe, MD, PhD, Antonio Mota- Miranda, MD, PhD, and Fernando Falcdo- Reis, MD, PhD Background: Botulism is a rare but potentially lethal different forms: 1) vegetative, responsible for the pro-disease in which ophthalmic signs and symptoms are among duction of toxin types A through G, and 2) spore- forming, the very earliest manifestations. The aim of this study was Clostridial spores have worldwide distribution in soil, fresh to investigate the epidemiological and clinical features of water, and salt water. They are able to survive for several botulism- infected patients admitted to a general hospital in hours at 100° C ( 1- 4). Porto, Portugal. C. botulinum produces the most potent known Methods: We performed a retrospective chart review of all neurotoxin. A single gram of crystalline toxin, whether botulism patients admitted to Sao Joao Hospital between dispersed or inhaled would kill more than one million January 1998 and January 2003. We excerpted data on people. The lethal toxin dose for humans is not known, epidemiology, ophthalmic and non- ophthalmic manifesta- but it is presumed that 0.09- 0.15 | Jig of toxin A, absorbed tions, and treatment. intravenously or intramuscularly, 0.70- 0.90 | JLg, absorbed Results: We identified 18 patients in nine registered by inhalation, and 70 | Jig, absorbed orally are lethal for a outbreaks. In two patients ( 11%), ophthalmic manifes- 70- kg human ( 2). However, this neurotoxin is a fragile pro-tations preceded systemic manifestations; in six patients tein that easily denatures. It is heat- labile and inactivated in ( 33%), ophthalmic and systemic manifestations occurred less than five minutes at temperatures above 85° C ( 1,3,5). simultaneously; in ten patients ( 56%), systemic manifes- Botulinum toxin is highly neurotrophic. It is in-tations occurred first. Ophthalmologists had examined only troduced in the human body from a mucosal surface seven patients and made the correct diagnosis in five. The ( gastrointestinal tract or lung) or a wound and rapidly most common ocular symptoms were blurred near vision reaches the bloodstream. It binds to nerve- ending receptors, ( 100%), blurred distant vision ( 94%), and diplopia ( 44%). causing irreversible blockage of cholinergic transmission Accommodation impairment was documented in all seven in all ganglionic synapses, post- ganglionic parasympa-patients examined by ophthalmologists. thetic synapses, and neuromuscular junctions. This binding Conclusions: Ophthalmic manifestations were among the ultimately results in an acute, afebrile, symmetric, and earliest and most prominent manifestations of botulism descending flaccid paralysis and autonomic nervous system in this series, as in earlier reports. The diagnosis should dysfunction ( 1,3). be suspected when impaired accommodation and gastro- Ophthalmic signs and symptoms are among the very intestinal symptoms occur together. earliest and most persistent manifestations. They include . , » r _ , , , , „„„^ „ „,„ -,_. disturbances of the intrinsic and extrinsic ocular muscu- { JNeuro- Ophthalmol 2005; 25: 262- 267) , . ., . j j , . j . , lature that produce dilated non- reactive pupils, accommo- Botulism is a disorder caused by neurotoxins produced dative paralysis, ptosis, diplopia, decreased lacrimation, by Clostridia species, which are strictly anaerobic gram- nystagmus, and extraocular muscle palsies ( 1- 3,6). positive bacilli. The most common offender is Clostridium Although the medical literature on botulism is vast botulinum. This microorganism can present itself in two ( 3)> m o s t r ePo r t s t h a t document ophthalmic manifestations are based on single cases. The purpose of this study was to analyze the epidemiology and clinical features of botulism Departments of Ophthalmology ( SCP, OMF, JACF, FFR) and • , • ., , • ,., , • , r *• T> , T. C > T., T.^ TT u. * T. ^ o , , * » » j m a single community with an emphasis on ophthalmic Infectious Diseases ( RS, AMM), University 01 Porto School 01 Medicine, . Sao Joao Hospital, Porto, Portugal. findings. Presented in part at the American Academy of Ophthalmology Annual Meeting, November 2003, Anaheim, California. Address correspondence to Susana C. Penas, MD, Department of lvnTTTTfYTlC Ophthalmology, University of Porto School of Medicine, Hospital Sao Joao, Alameda Prof. Hernani Monteiro, 4200- 319 Porto, Portugal; E- mail: Patients Were accrued from the database of the Statis-spenas75@ yahoo. com tics Department of Sao Joao Hospital, a general hospital in the city of Porto in northern Portugal. We drew from a list of patients admitted to the infectious diseases department of this hospital with a diagnosis of botulism from January 1998 to January 2003. During this five- year period, 18 patients were admitted with botulism. We recorded data regarding age, sex, region, mode of referral, source of infection, number of outbreaks, number of persons affected by outbreak, type of botulism, neurotoxin involved, incubation period, ophthalmic and non-ophthalmic manifestations, electromyography, and pulmonary function test results, treatment, and follow- up. Ophthalmological examinations occurred in seven patients and included determination of distant and near visual acuity, measurement of accommodation by a push- up method using a R. A. F. Near Point Rule ( Clement Clarke Ltd, Harlow, United Kingdom), slit- lamp examination, tonometry, ophthalmoscopy, Schirmer test, binocular visual fields, Hess test, and computerized infrared pupillometry. The diagnosis depended on clinical, epidemiological, and electrophysiological findings and was confirmed in most cases by the detection of C. botulinum neurotoxin in serum or stool or in the suspected food. Toxin determination was performed using a mouse bioassay, inoculating extracts of serum, stool, or suspect food intraperitoneally into mice previously protected with monospecific antitoxin. RESULTS Epidemiologic and Demographic Features Nine outbreaks occurred during this five- year period, and all 18 patients were hospitalized with food- borne botulism. There were no cases of wound or infantile botulism. All patients were admitted to the emergency room of this hospital. During this period, 1,040,682 patients were evaluated and treated in the emergency room of this hospital, 2717 of which were hospitalized in the Infectious Diseases Department. Therefore, botulism infection represented 0.7% of all the hospitalizations in that department during this five- year period. Two patients admitted themselves to the emergency room, ten were transferred from other hospitals, three were referred by a primary care physician, and three were referred by ophthalmologists. Ten were men, and eight were women, with a mean age of 28.8 ± 9.9 years ( range, 10- 47 years). The median number of cases per outbreak was 4.7 (± 2.9). Seven ( 78%) of the nine outbreaks occurred in rural areas. Clinical Features The latency between ingestion of the suspect food and the first symptoms ( incubation period) ranged from 1 to 12 days with a mean of 3.1 ± 2.9 days. Two patients ( 11%) had ophthalmic manifestations as the initial complaints, and ten patients ( 56%) had non- ophthalmic manifestations as the initial complaints. In the remaining six patients ( 33%), ophthalmic and non- ophthalmic manifestations occurred simultaneously. Blurred near vision was described by all patients ( Table 1). Among the seven patients examined by ophthalmologists, impaired accommodation was found in all. Seventeen patients ( 94%) complained of blurred distant vision, eight ( 44%) experienced diplopia, two ( 11%) had dry eye symptoms, and one ( 6%) mentioned photophobia. Apart from the confirmed accommodative loss, the ophthalmic signs included mydriatic pupils sluggishly reacting to light in 15 patients ( 83%) and bilateral ptosis in seven ( 39%) patients. Ocular movements were described in four of the eight patients complaining of diplopia. In three of those four patients, ocular alignment was evaluated by an ophthalmologist, and abnormal alignment and bilateral mild abduction weakness were found in one patient ( Case 2 below). Nystagmus was not reported in any patients. Among non- ophthalmological symptoms ( Table 2), dry mouth was the most common ( 100%), followed by constipation ( 83%) and dysphagia ( 72%). Nausea, vomiting, diarrhea, and abdominal cramps were also present. In this cohort, 50% experienced fatigue; only 12% reported urinary retention. No patient had dyspnea. Clinical Diagnosis Twelve patients ( 67%) were initially misdiagnosed as suffering from acute gastroenteritis or food poisoning. In five of the seven patients evaluated by an ophthalmologist, the ophthalmologist made the initial diagnosis of botulism. In the remaining two patients, the clinical diagnosis had already been made by an infectious disease specialist. Laboratory Tests In 15 ( 83%) cases, the neurotoxin was detected in the patients' serum and was classified as type B in all of them. Neither C. botulinum nor its neurotoxin was found in the patients' stool. The detection of the toxin in the suspect foodstuff was achieved in 11 cases ( 61%). Home- preserved foods were involved in all of the outbreaks, especially smoked ham ( 94%). Only one outbreak was attributed to the ingestion of homemade sausage. In none of the cases was the taste or smell of the food altered. In three ( 30%) of ten patients who underwent electromyography ( EMG), a pattern suggestive of pre- synaptic dysfunction was seen. The remaining seven ( 70%) patients had normal EMG results. A ventilatory restrictive pattern was found in only one ( 6%) patient. Treatment Fluid and nutritional support were given in all cases. Some patients required nasogastric tube feeding or parenteral nutrition. High enemas were given to patients with severe constipation. Oxygen saturation was monitored and the oropharyngeal secretions were controlled in all patients. No patient required tracheal intubation, respiratory support, or antitoxin administration. Induced emesis or gastric lavage was not performed in any of the patients because the exposure to the toxin had occurred several days before diagnosis. Clinical Course Patients were discharged after a mean of 5.7 ± 3.9 days ( range, 1- 19) and followed in the outpatient infectious diseases clinic. All showed ocular manifestations at the time of discharge. The last symptoms to disappear were constipation and blurred near vision. All patients had fully recovered after eight weeks. CASE REPORTS Case 1 A 42- year- old woman presented with nausea, fatigue, general weakness, and dizziness starting four days before admission. One day later, these symptoms were followed by dry mouth, dysphagia, abdominal cramps, and diarrhea. Two days later, she experienced blurred near vision, as well as problems in urinating. Her medical history was otherwise unremarkable. The patient was diagnosed has having acute gastroenteritis, but because of her visual complaints, an examination by an ophthalmologist was requested. On ophthalmologic examination, she had a corrected distance visual acuity of 20/ 20 OU, bilateral ptosis of 1 mm, bilaterally defective accommodation for her age ( three diopters), and 6 mm pupils with sluggish reaction to direct light. Ocular motility and alignment were normal. The rest of the ophthalmologic examination was normal. When asked by the ophthalmologist, this patient confirmed having ingested homemade smoked ham 24 hours before the onset of her first symptoms. She was hospitalized in the infectious diseases department with the diagnosis of food- borne botulism. Two days after admission, she displayed dilated non- reactive pupils and intermittent diplopia. Schirmer I and II tests were positive in both eyes. Although inconsistent diplopia was reported on binocular campimetry the Hess screen test was normal. Chest x- ray and electrocardiographic, electromyographic, and spirometric measurements were unrevealing. Treatment consisted of supportive care, including parenteral nutrition, fluid supplementation, and artificial tears. Her condition slowly improved during the following few days. Neurotoxin type B was detected by mouse bioassay in the patient's serum and in the suspected source ( the ham). Two months later, she had no ocular findings, and recovery of the pupillary light response was confirmed by pupil-lometry ( Fig. 1). Case 2 A 47- year- old man presented to an ophthalmologist complaining of blurred vision, sudden difficulty in focusing near objects, and intermittent diplopia, followed by dizziness, nausea, dysphagia, dry mouth, and constipation starting two days after the ingestion of a home- prepared smoked ham. Ophthalmologic examination showed bilateral ptosis of 2 mm, 6- mm pupils poorly reactive to light, and bilaterally defective accommodation for his age ( two diopters). Ocular movements were normal, but he complained of horizontal diplopia while performing horizontal versions. A Hess screen test revealed slight weakness of both lateral rectus muscles. Slit- lamp examination and ophthalmoscopy were unrevealing. Schirmer I and II tests were borderline abnormal. The ophthalmologist suspected botulism and sent the patient for an infectious diseases specialist evaluation. EMG was normal. A mild restrictive pattern was detected were identified in Portugal between 1996 and 2000, and on spirometry. The electrocardiogram and the chest x- ray 52% of them occurred in the northern part of the country, were within normal values. Type B neurotoxin was detected Fortunately, the outbreaks of botulism in Portugal in both the patient's blood and the suspect smoked ham. are usually mild treatable with supportive care measures, The patient received supportive care, including paren- and rarely requiring the use of antitoxin therapy. In a teral fluids, soft diet, and artificial tears. At the time of 30- year review from 1970 to 2000, 44 outbreaks with a discharge seven days later, he had recovered substantially. mean of three patients per outbreak, were registered Ophthalmic manifestations were absent six weeks later, and by the Infectious Diseases Department of this hospital ( 9). pupillometry was normal ( Fig. 1). A total of 137 patients were affected 85 of them needing hospitalization. In only one patient was antitoxin administered. Type B toxin was by far the most frequent toxin DISCUSSION detected ( 70%); only two outbreaks were caused by type In Portugal, especially in northern rural populations, E toxin. All patients recovered completely. As in other small family- centered outbreaks of botulism occur because European countries, where type A toxin is rare, the severity of the tradition of home- preserving some foods, particu- of the disease is usually low, probably because of implica-larly smoked ham, and because of unfamiliarity with the tion of a relatively less potent toxin. In countries where requisites of sterilization ( 7). In all European countries, the more aggressive type A toxin prevails, such as the food- borne botulism is much more associated with meats, United States, the case- fatality ratio is higher, although it especially ham and sausages, than in the United States has decreased from 60% to 15% over the last 50 years ( 8). ( 3- 5), where the most common cause is the consumption of The incubation period of food- borne botulism varies preserved vegetables, which accounts for 60% of the cases with the amount of toxin ingested and absorbed generally ( 5,8). ranging from 18 to 36 hours ( 4). Many patients first have An increase in the occurrence of botulism has been gastrointestinal symptoms, probably because of locally observed in Portugal in recent years. Approximately 0.6 acting toxin ( 5), before the onset of neurological manifes-outbreaks per year were reported in the Infectious Diseases rations. The upper cranial nerves seem to be affected first, Department of this hospital from 1970 to 1979, increasing resulting in early intraocular and extraocular ophthalmo-to 2.0 outbreaks per year from 1980 to 1989 and to 2.1 plegias. Later manifestations are associated with damage outbreaks per year from 1990 to 2000 ( 9). A median of 3.0 to the lower cranial nerves and the motor neurons to the cases per outbreak was registered in this 30- year period. somatic muscles. In comparison, approximately 9.5 outbreaks, with a median Ophthalmic manifestations are an almost universal of 2.5 cases per outbreak, of food- borne botulism occur finding in botulism, but most of the published literature is annually in the United States ( 8), a country with 29- fold not authored by ophthalmologists or found in ophthalmol-greater population than Portugal. According to the data ogy journals ( 3). Clinical examination and diagnosis are published by the Portuguese Governmental Center for generally made by non- ophthalmologists, so the reported Disease Control ( Direccao Geral de Saiide) ( 10), 33 cases incidence of ophthalmic findings maybe unreliable and not FIG. 1. Pupillometry performed eight weeks ( Patient 1) and six weeks ( Patient 2) after onset of botulism. Although there are some differences in initial, medium, and final pupil diameters, both patients show a normal pupillary light reflex, implying intact parasympathetic innervation of the constrictor muscle. quantified. As an example, impaired accommodation is not a previous viral illness, the presence of sensory symptoms, measured and is generally described as difficulty focusing and an increased cerebrospinal fluid protein value would on a near point. Ocular motility and decreased lacrimation support a diagnosis of GBS. Myasthenia gravis can be are also not documented frequently. In this study, only differentiated by the finding of muscular fatigability during seven ( 39%) of the 18 patients were examined by ophthal- exercise and by a positive response to edrophonium mologists, so that full documentation of the ophthalmic chloride testing. Stroke usually causes lateralizing signs, findings may be lacking. Allergic reactions to medications, organophosphate in- As in previous reports, we found that blurred near secticide poisoning, and psychiatric disease can also simu-vision was the most frequent symptom, occurring in all late botulism. patients. We presume that this complaint is consequent to Clinical diagnosis should be supported by a pertinent impaired accommodation because it was confirmed in all epidemiologic investigation, but it can be challenging when seven patients examined by ophthalmologists. A greater isolated cases occur. In these cases, involvement of the frequency of mydriasis was found than in earlier reports ophthalmologist may be decisive for a timely diagnosis, as ( 83% versus 44% ( 2) and 47% ( 11)), whereas a smaller has been shown in this study. Dynamic pupillometry is percentage of ptosis was found ( 44% versus 49% ( 11) and a useful adjunctive tool to analyze the parasympathetic 73% ( 2)). A previous study ( 11) found a greater frequency pupillary light, of lateral rectus weakness ( 98%) than we did. As the most poisonous substance currently known, A previous report ( 11) found that certain ocular signs borulinum toxin poses a major bio- weapon threat. In fact, predict disease severity. Thus, 8 ( 73%) of 11 patients its extreme potency and lethality, ease of production, trans-displaying medial rectus paresis, ptosis, and dilated pupils port, and elicitation of prolonged intensive care of affected later experienced respiratory insufficiency, whereas only persons encourage its use in bioterrorism, as has already 1 ( 3%) of 34 with fewer than three of these findings did been attempted ( 2). An aerosolized or food- borne boru-so ( P = 0.000006; Fisher exact test; two- tailed) ( 11). This linum toxin weapon could cause mass destruction of human study also found that when ventilatory failure did develop, life, but there are still some constraints for concentrating it did so 12 hours after the ophthalmic abnormalities and stabilizing the toxin for aerosol dissemination ( 2). The were recorded. traditional concept of food- borne botulism, usually asso- There are reported cases of tonic pupils in botulism ciated with home- preserved foods, has expanded now in- ( 12,13), which could be produced by the action of the toxin eluding commercially processed foods served in public at the ciliary ganglion, the neuromuscular junction to the eating places ( 8) and enlarging the target population in a ciliary muscles or pupillary sphincter, or a combination bioterrorist attack. thereof. Rapid quivering eye motions, observed during There are several features of an outbreak that suggest attempts at refixation of laterally placed objects, are also an intentional release of toxin: 1) large number of affected reported in some patients ( 6,14,15). patients; 2) multiple simultaneous outbreaks without Gastrointestinal symptoms, such as nausea, vomiting, a common source; 3) outbreaks with a common geographic abdominal cramps, and diarrhea, occur before neurological factor ( airport, hotel, or workplace); and 4) outbreaks with signs and resolve rapidly. Autonomic dysfunction mani- unusual toxin types C, D, F, G, or E unassociated with fested by dry mouth and dilated pupils, followed by diplopia, aquatic food ( 2). A detailed dietary, travel, and activity ptosis, dysarthria, dysphagia, and descending, symmetrical history should be taken, including questions about other flaccid muscle paralysis are the most prominent features of persons with similar symptoms. the disease. Apyrexia and a normal consciousness are If unintentional or intentional outbreak is suspected features to be remembered in the differential diagnosis. the clinician should immediately refer the patient to a hos- Diseases most often confused with botulism include pital with an intensive care unit and contact an infection acute gastroenteritis, the Guillain- Barre syndrome ( GBS), control practitioner and local and state health departments myasthenia gravis, and stroke involving the basilar artery. for prompt epidemiological investigation. Initial vomiting and diarrhea can mimic acute gastroenteritis Our study shows that the diagnosis of botulism is or other forms of food poisoning, but their latency is shorter likely to be made by a health care professional familiar in gastroenteritis and food poisoning than in botulism. Ex- with its clinical manifestations. Because ophthalmic mani-treme dry mouth, redness of oral mucosa, and sore throat festations are usually prominent, the contribution of an oph-frequently lead to a misdiagnosis of acute pharyngitis. The thalmologist can significantly hasten the correct diagnosis presence of visual complaints and other cranial nerve of this potentially lethal disease. In Portugal, botulism impairment may lead to a misdiagnosis of diphtheria. GBS usually presents itself in mild form, but in countries with is usually an ascending motor paralysis, although occasionally more aggressive forms, like the United States, early detection signs may be confined to the cranial nerves. The history of is critical to reduce morbidity and mortality. REFERENCES Prevention; 1998. Available at: http:// www. cdc. gov/ ncidod/ dbmd/ diseaseinfo/ botulism. pdf. Accessed: March 28, 2004. 1. Bleck TP. Clostridium botulinum ( Botulism). 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