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The Eyes Have It

Miten Vasa, M.D., Thomas E. Baudendistel, M.D., Christine E. Ohikhuare, M.D., Elizabeth M. Grace, M.D., Wilson Yan, M.D., S. Andrew Josephson, M.D., and Lawrence M. Tierney, Jr., M.D.
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors commentary follows.
From the Department of Medicine, University of California, Irvine (M.V., W.Y.); the Department of Medicine, Kaiser Permanente, Oakland (T.E.B.); the Department of Medicine, Kaiser Permanente, Anaheim (C.E.O.); and the Departments of Neurology (S.A.J.) and Medicine (L.M.T.), University of California, San Francisco all in California; and the Department of Ophthalmology, University of Illinois Eye and Ear Infirmary, Chicago (E.M.G.). Address reprint requests to Dr. Vasa at the University of California Irvine, 333 City Blvd. W, City Tower Suite 800, Orange, CA 92868, or at miten.vasa@ gmail.com.
N Engl J Med 2012;367:938-43. DOI: 10.1056/NEJMcps1105394

A 69-year-old man presented to the emergency department 2 hours after he awakened with slurred speech. In a patient with a focal neurologic deficit and risk factors for cerebrovascular disease, acute stroke is a possibility, and the patients candidacy for thrombolytic therapy must be considered. Determining the time of the onset of symptoms is difficult when a patient reports waking up with features that may represent a stroke. It must be assumed that the onset occurred when the patient was last known to be at baseline neurologically. Also, one must begin to localize the deficit neuroanatomically and to consider causes other than acute ischemic stroke to explain the symptoms. Slurred speech can result from lesions of the cortex, subcortex, brain stem, cerebellum, cranial nerves, or muscles that control speech. Basilar-artery thrombosis leading to brainstem stroke must be considered, owing to the high associated mortality and endovascular treatment options. Cerebral hemorrhage must be ruled out. Other mimickers of stroke to consider include hypoglycemia, severe hypertriglyceridemia, and mass lesions. The patient reported a single episode of sharp, self-limited, periumbilical pain after dinner the previous night, and he had awoken that morning with slurred speech, difficulty chewing, blurry vision in both eyes, generalized weakness, and unsteady gait. He had received a diagnosis of hypertension and hyperlipidemia 3 years earlier but had declined pharmacologic treatment. The patient reported no recent trauma or immunizations and no history of similar symptoms. He did not have fevers, night sweats, headaches, nausea, constipation, diarrhea, weight loss, diplopia, leg or arm weakness, or difficulty swallowing. Ischemic stroke appears to be unlikely, because it would be unusual for a single lesion to cause the bilateral cranial-nerve deficits without affecting the long motor and sensory tracts that course through the brain stem. The abnormalities appear to be confined to the brain stem, cranial nerves, neuromuscular junction, or bulbar muscles. The absence of headache or symptoms consistent with polymyalgia rheumatica argues against giant-cell arteritis. The absence of diplopia suggests that the patient does not have extraocular muscle palsies, with the caveats that patients with diplopia may initially report only blurry vision if the images are overlapping and patients who cannot move their eyes at all will not have diplopia.

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The patient lived at home with four healthy family members. He reported drinking one pint of vodka daily, smoking one pack of cigarettes daily for the past 30 years, and smoking crack cocaine three times a week, most recently about 24 hours before presentation. He said that he had never used intravenous drugs and had not been sexually active since his wife died the previous year. He was born in the United States and had not traveled beyond the San Francisco Bay area during the past year. Cocaine may cause focal neurologic deficits through a variety of mechanisms, including ischemic stroke from accelerated atherosclerosis, vasospasm, arterial dissection, and hemorrhagic stroke. As an illegal-drug user, the patient may have used black-tar heroin, which is associated with botulism. Botulism can cause cranial-nerve abnormalities that are often bilateral and symmetric and that may result in complete ophthalmoplegia. Patients with the Miller Fisher syndrome, an acute demyelinating polyneuropathy, may present with descending paralysis that affects the extraocular muscles early in the course of the syndrome. On physical examination, the patient appeared well nourished and in no acute distress. The temperature was 36.2C (97.2F), the blood pressure 203/93 mm Hg, the pulse 82 beats per minute, and the respiratory rate 16 breaths per minute. The oxygen saturation was 98% while he was breathing ambient air. There was no meningism or lymphadenopathy. Lung, heart, abdominal, extremity, and skin examinations were unremarkable. The patient was alert. Speech was decreased in volume, dysarthric, and almost unintelligible. The dysarthria was most pronounced when he was asked to repeat guttural sounds. He could name objects and follow commands. Results of motor, sensory, finger-to-nose, and rapid alternating hand-movement tests were normal. There was bilateral rotary nystagmus. Deep-tendon reflexes were normal. Plantar reflexes were flexor. On cranial-nerve testing, there was weakness on abduction of the right eye. Pupillary responses to light were intact. Gait was not assessed.

reflex). His preserved level of consciousness argues against the latter cause, and the absence of other signs of sympathetic hyperactivity (e.g., tachycardia, tremor, agitation, and diaphoresis) suggests causes other than acute cocaine intoxication. Untreated underlying hypertension and long-term cocaine use may explain his elevated blood pressure, which places him at risk for hemorrhagic stroke. Ophthalmoplegia and nystagmus suggest the possibility of Wernickes encephalopathy. The cerebellar hemispheres, which control rapid alternating movements, are often preserved in patients with Wernickes encephalopathy, so they may have intact finger-to-nose or heel-to-shin abilities but poor truncal balance, owing to involvement of the cerebellar vermis. Palsy of cranial nerve III, IV, or VI can cause nystagmus. The guttural dysarthria suggests that other cranial neuropathies may be developing (e.g., neuropathy of cranial nerve IX or X). I would empirically administer thiamine with glucose and obtain urgent imaging of the brain, though I cannot identify a single vascular territory to explain this patients symptoms. The results of a complete blood count, chemistry panel, coagulation studies, measurements of creatine kinase and troponin I levels, and liver-function tests were unremarkable. A urine toxicology screen was positive for cocaine. An electrocardiogram showed sinus rhythm at 82 beats per minute and nonspecific T-wave inversions in leads V3 through V6; there were no prior electrocardiographic results for comparison. Chest radiography and computed tomography (CT) of the head performed without the administration of contrast material showed no abnormalities. The patient was given 81 mg of aspirin, 40 mg of simvastatin, and intravenous saline with thiamine followed by dextrose, as well as topical nitroglycerin and intravenous labetalol to maintain systolic blood pressure at a level below 220 mm Hg. Because he reported difficulty chewing, a swallow evaluation was performed later that evening, during which he was unable to transfer soft food from his oropharynx. The results of neurologic examination were otherwise unchanged.

Markedly elevated systolic blood pressure could result from recent cocaine use or from a response CT of the head without the administration of to elevated intracranial pressure (e.g., Cushings contrast material is most useful in ruling out in-

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tracranial bleeding. Ischemic stroke remains a remote possibility, and treatment with simvastatin and permissive management of hypertension are therefore reasonable. The new swallowing problem must be recognized as a serious change in neurologic status. This problem could represent progressive disease in the lower part of the brain stem or impairment of cranial nerve IX or X. The dysarthric speech is compatible with cranial nerve VII, IX, X, or XII disease. I remain concerned about the possibility of the Miller Fisher syndrome or botulism and would also consider myasthenia gravis. Status with respect to progressive pupillary changes differs among these disorders; most patients with botulism, and some patients with the Miller Fisher syndrome, lose pupillary reactivity, whereas patients with myasthenia gravis do not. Because CT scans obtained without the administration of contrast material are insensitive for detecting lesions within the posterior fossa, magnetic resonance imaging (MRI) is indicated. On the morning of the second hospital day, dyspnea developed, and the patient reported diplopia with lateral gaze in either direction. The blood pressure was 183/115 mm Hg, the pulse 100 beats per minute, and the respiratory rate 20 breaths per minute. The oxygen saturation was 99% while he was breathing 2 liters of oxygen. The lungs remained clear, and the jugular venous pressure was normal. Examination by a neurology consultant identified intact comprehension, dysarthria without aphasia, limited lateral gaze in both eyes, ptosis of the right eye, and weakness when the patient attempted to puff out his cheeks, protrude his tongue, or open his mouth to show palate elevation. His pupils reacted sluggishly to light, from 3 to 2 mm bilaterally; visual fields were intact. There was no papilledema, and nystagmus was no longer present. Facial features were symmetrical, and facial sensation was normal. A motor examination showed decreased tone in the right upper arm and weakness in the right deltoid and trapezius muscles. Pronator drift was present in the right arm. Sensation of pinprick, light touch, and vibration was intact. Reflexes remained normal, and plantar reflexes were flexor.

would prevent horizontal eye movements. Trapezius weakness suggests that cranial nerve XI is now affected, either as a result of lower brain-stem disease or from a peripheral lesion. Vertebralartery dissection should be ruled out. However, additional findings argue against brain-stem disease. Deltoid weakness (and other proximal weakness) is typically associated with disorders of the neuromuscular junction or muscles. The preserved sensation and reflexes in this patient are consistent with these two possibilities but are not expected with the Miller Fisher syndrome. Areflexia is an early finding in the Miller Fisher syndrome, whereas it occurs late in the course of botulism, when muscle paralysis is severe. Dyspnea could represent diaphragmatic weakness. The posterior circulation and posterior fossa should be evaluated with MRI and magnetic resonance angiography (MRA), but my strongest suspicion at this point is botulism. The patients pupils are still reacting, albeit minimally. In the early afternoon, before a scheduled MRI and MRA evaluation of the head and neck, the patient was unresponsive, with his eyes closed. He was no longer breathing spontaneously and was intubated. An urgent CT scan of the head showed no acute hemorrhage or infarct. A CT angiogram of the head and neck revealed no evidence of arterial dissection. Results of a lumbar puncture showed a white-cell count of 2 per cubic millimeter with a normal differential count, a glucose level of 53 mg per deciliter (2.9 mmol per liter), and a protein level of 18.2 mg per deciliter, with a negative Grams stain. By the next day, the patient was becoming more alert and awake, but he was unable to tolerate spontaneous breathing trials. As the day progressed, he was able to open his eyes, albeit weakly, and his pupils were midposition and minimally reactive to light. He had bilateral ophthalmoplegia and bilateral ptosis of the upper eyelid, and deep-tendon reflexes were absent. The results of the remainder of his examination were unchanged.

Two possibilities come to the forefront now: myasthenia gravis and botulism. I would order tests for antibodies against the acetylcholine receptor and GQ1b, which are detected in the majority of The resolution of the nystagmus may be explained patients with myasthenia gravis and in those by the bilateral palsies of cranial nerve VI, which with the Miller Fisher syndrome, respectively. I
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would also obtain more information about the patients illicit-drug use (e.g., checking for signs of subcutaneous or intramuscular injection [skin popping] and asking about use of black-tar heroin) and his diet (e.g., asking about improperly canned foods) to identify potential sources of botulism. Nerve-conduction tests and electromyography might help differentiate among these disorders; the Miller Fisher syndrome is a demyelinating disease of the peripheral nerves, whereas botulism and myasthenia gravis target the neuromuscular junction. A test for antibodies against the human immunodeficiency virus was negative. Cerebrospinal fluid cultures showed no bacterial growth, and a polymerase-chain-reaction assay for herpes simplex virus was negative. Tests for acetylcholine-receptor blocking and binding antibodies and anti-GQ1b antibodies were negative. A nerve-conduction study revealed normal sensory but decreased compound motor action potentials as well as F-waves, but the patient was unable to tolerate repetitive stimulation (to assess for disorders of the neuromuscular junction) or electromyography. The results of the antibody tests, each of which is 80 to 90% sensitive and highly specific, indicate that diagnoses of myasthenia gravis and the Miller Fisher syndrome are less likely. Normal results of sensory-nerveconduction studies would make a demyelinating neuropathy such as the Miller Fisher syndrome unlikely. Botulism is the most likely diagnosis. The patients son stated that the patient had been eating home-preserved green beans and tomatoes in the 4 days before admission. The case was reported to the California Department of Public Health, and botulism antitoxin A was administered on the third hospital day. The patients canned vegetables were sent to the states public health laboratory, and the green beans tested positive for botulinum toxin A. There was no immediate apparent clinical response to the antitoxin. A tracheostomy was performed on hospital day 14, and the patient was weaned from the ventilator 3 months later. At that time, he was transferred to a skilled nursing facility. Five months after his initial presentation, the patient had made a full recovery, and his gastrostomy tube and tracheostomy were removed.

C om men ta r y
Clostridium botulinum is a neurotoxigenic, anaerobic, gram-positive, spore-forming bacillus named after an outbreak of sausage poisoning in the late 1700s (botulus is Latin for sausage). Of the variants of botulism, foodborne and wound botulism are the most common in adults.1-6 The manifestations of illness are due to botulisms potent neurotoxin, with the majority of cases in the United States caused by botulinum toxins A, B, and E.1,6-8 Foodborne botulism classically occurs after ingestion of spores contained in improperly prepared home-canned foods, particularly vegetables, meat, and seafood. The conditions that enable spore formation are rarely achieved within food or the human intestinal tract, which explains why there are fewer than 35 cases of foodborne botulism reported annually in the United States. Despite a marked increase in commercial food production and consumption, the number of botulism cases has remained relatively stable, an observation that has been attributed to the dissemination of guidelines for home and commercial canning by the Department of Agriculture and the Food and Drug Administration.1-3,6,7,9,10 For foodborne botulism to develop, neurotoxins must be absorbed from the gastrointestinal tract and disseminate hematogenously to produce an irreversible blockade of peripheral cholinergic nerve terminals, including all neuromuscular junctions, sympathetic and parasympathetic ganglia, and parasympathetic postganglionic sites. The central nervous system is spared, because the toxins are too large to cross the blood brain barrier.1,3,4,6,10 The initial gastrointestinal symptoms of foodborne botulism typically occur within 12 to 72 hours after ingestion of the spores. Although not prominent in this case, these symptoms include constipation, vomiting, abdominal cramps, and less commonly, diarrhea.6,11 Neurologic manifestations follow, initially with ophthalmologic and other bulbar signs; the characteristic features are listed in Table 1.10,11 It may be challenging to distinguish botulism from other disorders with predominantly early ophthalmologic manifestations, such as myasthenia gravis, the Miller Fisher syndrome, posterior circulation stroke, or carcinomatous meninseptember 6, 2012

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Table 1. Signs and Symptoms of Foodborne Botulism Types A and B (Dozen Ds), in the Typical Order of Their Appearance. Signs and Symptoms Dry mouth Diplopia (indicating involvement of cranial nerve III, IV, or VI) Dilated pupils, which may be unresponsive to light Droopy eyelids (ptosis) Droopy face Diminished gag reflex Dysphagia Dysarthria Dysphonia Difficulty lifting head Descending paralysis, usually symmetric and flaccid Dyspnea from diaphragmatic paralysis Percent of Cases* 93 91 44 73 63 65 96 84 NA NA NA 60

* Botulism should be considered when three or more of the Dozen Ds are present.10 The data are from outbreaks of botulism occurring in the United States from 1973 through 1974.11 The number of patients for whom data were available ranged from 35 to 55. Data on dysphonia, difficulty lifting the head, and descending paralysis were not available (NA) from this case series.

gitis. The key distinguishing features of botulism are a history of ingesting home-canned foods or injecting black-tar heroin; dilated, poorly reactive pupils; ptosis; a descending, flaccid, symmetric pattern of paralysis of the motor and autonomic nerves, with more proximal than distal muscle involvement and acute respiratory failure; preserved reflexes; normal findings in the cerebrospinal fluid; absence of fever and tremor; and normal cognition, sensation, and cerebellar studies.3,12,13 The results of routine laboratory tests are generally normal in patients with botulism. Electromyography usually reveals fibrillation potentials that are consistent with acute denervation. Nerve-conduction studies often show decreased motor-nerve but normal sensory-nerve action potentials, the latter distinguishing botulism from various forms of the GuillainBarr syndrome, including the Miller Fisher syndrome. Repetitive stimulation during nerve-conduction studies demonstrates facilitation (i.e., increasing amplitude of compound motor action potentials), indicating a presynaptic neuromuscular-junction problem; in contrast, postsynaptic neuromuscular-junction disorders, such as myasthenia gra-

vis, are associated with decreasing amplitude on repetitive nerve stimulation.1-5,10 Ventilatory support and antitoxin are the cornerstones of treatment for botulism. Ventilatory support is required for 2 to 8 weeks for most patients, and up to 7 months for some, which is the time needed to sprout new presynaptic terminals and form new synapses.1,2,5,6,10 Intravenous equine trivalent antitoxin (for types A, B, and E) or bivalent antitoxin (for types A and B), which can be obtained from state health departments or the Centers for Disease Control and Prevention, is most effective if given within the first 24 hours after the onset of symptoms or within 72 hours after ingestion of contaminated food.1,6,10 Mortality from foodborne botulism in the United States has decreased from 25%, during the period from 1950 through 1959, to 6%, during the period from 1990 through 1996.12 This improvement is attributed to advances in supportive care and earlier administration of antitoxin. A diagnosis of definite foodborne botulism requires demonstration of C. botulinum toxin in the patients serum or gastrointestinal tract or isolation of the toxin from food ingested by the patient, with clinical features of botulism. A mouse bioassay, which takes up to 4 days to produce results, is the most widely used test for identifying the toxin. The sensitivity of the assay, which ranges from 33 to 44%, is lower than that of a clinically based diagnosis by an expert; the lower sensitivity is due to low toxin concentrations and delays in obtaining specimens. The low sensitivity and the delay in obtaining results, and the fact that therapy is most effective when given early, underscore the need to initiate treatment on the basis of clinical suspicion.1,5,6,10,14 Botulism should be suspected in patients who present with three or more of the Dozen Ds listed in Table 1, and antitoxin treatment should be initiated as soon as the diagnosis is suspected. As in this case, an abnormal finding on pupillary examination, with preserved cognition, sensation, and reflexes, can help differentiate botulism from other disorders that cause descending paralysis.
No potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank Dr. Safa Magid for her contributions to the case presentation and an earlier version of the manuscript.

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References
1. Caya JG. Clostridium botulinum and the

ophthalmologist: a review of botulism, including biological warfare ramifications of botulinum toxin. Surv Ophthalmol 2001;46:25-34. 2. Shapiro RL, Hatheway C, Swerdlow DL. Botulism in the United States: a clinical and epidemiologic review. Ann Intern Med 1998;129:221-8. 3. Cherington M. Clinical spectrum of botulism. Muscle Nerve 1998;21:701-10. 4. Idem. Botulism: update and review. Semin Neurol 2004;24:155-63. 5. Sobel J. Botulism. Clin Infect Dis 2005;41:1167-73. 6. Villar RG, Elliot SP, Davenport KM. Botulism: the many faces of botulinum toxin and its potential for bioterrorism. Infect Dis Clin North Am 2006;20:313-27.

Sobel J, Tucker N, McLaughlin J, Maslanka S. Foodborne botulism in the United States, 1990-2000. Emerg Infect Dis 2004;10:1606-11. 8. Hatheway CL. Botulism: the present status of the disease. Curr Top Microbiol Immunol 1995;195:55-75. 9. National Center for Home Food Preservation. USDA complete guide to home canning, 2009 revision (http://www.uga .edu/nchfp/publications/publications _usda.html). 10. Horowitz BZ. Botulinum toxin. Crit Care Clin 2005;21:825-39. 11. Hughes JM, Blumenthal JR, Merson MH, Lombard GL, Dowell VR Jr, Gangarosa EJ. Clinical features of type A and B food-borne botulism. Ann Intern Med 1981;95:442-5.
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12. Arnon SS, Schechter R, Inglesby TV, et

al. Botulinum toxin as a biological weapon: medical and public health management. JAMA 2001;285:1059-70. [Erratum, JAMA 2001;285:2081.] 13. Friedman DI. Disorders of the neuromuscular junction. In: Yanoff M, Duker JS, eds. Ophthalmology. 3rd ed. New York: Mosby-Elsevier, 2009:1026-31. 14. Ferreira JL, Eliasberg SJ, Edmonds P, Harrison MA. Comparison of the mouse bioassay and enzyme-linked immunosorbent assay procedures for the detection of type A botulinal toxin in food. J Food Prot 2004;67:203-6.
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