PATIENTS WITH RAPID onset of bulbar and facial weakness

Transcription

1 122 CLINICAL NOTE Serum Positive Botulism With Neuropathic Features Victor H. Chang, MD, Lawrence R. Robinson, MD ABSTRACT. Chang VH, Robinson LR. Serum positive botulism with neuropathic features. Arch Phys Med Rehabil 2000;81: A 32-year-old man presented with multiple cranial neuropathies and his serum was positive for botulism type B. However, serial electrodiagnostic studies were consistent with a primarily neuropathic process, such as Fisher syndrome, rather than a neuromuscular junction disorder. Electrodiagnostic study findings in patients with presumed neuromuscular junction disorders may mimic findings suggestive of a neuropathic process, or the bioassay for botulism may be falsely positive in patients with Fisher Syndrome. Key Words: Botulism; Cranial nerve diseases; Rehabilitation by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation PATIENTS WITH RAPID onset of bulbar and facial weakness can be a diagnostic challenge. Early diagnosis is critical, because treatment must be implemented quickly to halt or reverse the progression of symptoms. The differential diagnosis is broad, but includes meningitis, brain stem encephalitis, vasculitis, botulism, Fisher syndrome, diphtheria, Lyme disease, and myasthenia gravis. Often, electrodiagnostic studies can be instrumental in determining the etiology of the patient s symptoms. They may be particularly helpful when laboratory results are not available for several days or when laboratory data are inconclusive. Early electrodiagnostic studies may identify or even refute neuropathic, myopathic, or neuromuscular junction disorders, allowing earlier initiation of treatment options pending further laboratory or radiologic studies. Botulism, a neuromuscular disorder, and Fisher syndrome, a neuropathic disorder once thought to be a variant of Guillain- Barré syndrome, are two entities that are frequently suspected when a patient presents with acute cranial neuropathies. However, the clinical history, physical examination, and initial laboratory studies may be nondiagnostic. Although specific laboratory studies are available to aid in arriving at the correct diagnosis, results may not be available for several days. In these situations, electrodiagnostic assessment may help to determine if the causative factor is botulism or Fisher syndrome. We present a patient with acute cranial neuropathies who had serial electrodiagnostic studies consistent with a neuropathic process such as Fisher syndrome, but who also had laboratory studies consistent with botulism. We briefly review the typical From the Department of Rehabilitation Medicine, University of Washington Medical Center (Drs. Chang, Robinson), and Rehabilitation Medicine, Harborview Medical Center (Dr. Robinson), Seattle, WA. Submitted for publication December 23, Accepted in revised from April 13, No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Reprint requests to Lawrence R. Robinson, MD, Physiatrist-in-Chief, Rehabilitation Medicine, Box , Harborview Medical Center, 325 Ninth Avenue, Seattle, WA by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation /00/ $3.00/0 electrodiagnostic features of botulism and Fisher syndrome and note exceptions to these typical findings. CASE REPORT A 32-year-old man presented to the hospital emergency department with a 2-day history of diplopia, dysarthria, dysphagia, vertigo, and oral and bilateral distal upper extremity paresthesias. Earlier that week his primary physician had started him on cephalexin to treat a tender, cutaneous mass on the back of his neck. His medical history was noncontributory and he was taking no medications other than cephalexin. Review of systems was significant for a viral respiratory illness 2 weeks before he came to the emergency department, and mild abdominal cramping with intermittent diarrhea several days before admission. He denited recent travel, outdoor activity, immunizations, or insect, spider, or animal bites. The patient denited fever, chills, stiff neck, visual changes, or cough. He had consumed canned chili several days before the onset of symptoms, but denied ingestion of other canned or jarred foods. There were no other reports of patients with similar complaints in his local area during this time period. Physical examination revealed a fatigued man who was communicative but dyspneic. His temperature was 37.5 C, pulse 106 beats/min, and blood pressure 150/104mmHg. A 5cm 5cm, mildly erythematous, tender, fluctuant mass was palpable along the superior, posterior cervical region. There was no nuchal rigidity. Pulmonary, cardiac, abdominal, and skin exams were otherwise unremarkable. Neurologic exam showed the patient to be cognitively intact and communicative, although his speech was dysarthric and breathy, and he was unable to complete a full sentence. His left pupil was minimally responsive to light and the right pupil was dilated and unresponsive. All extraocular movements were absent bilaterally. Facial sensation was intact. There was right-sided facial weakness (peripheral pattern). Auditory testing was unremarkable. Labored swallowing, minimal palatal elevation, and a weak gag reflex were noted. Sternocleidomastoid and trapezius strength were normal. Tongue movement lacked full protrusion but was midline. Strength was 5/5 throughout the upper and lower limbs and the patient denied subjective weakness. Deep tendon reflexes were diminished (1 ) throughout but symmetrical. Results of a sensory exam were unremarkable. Cerebellar testing was unremarkable in his upper and lower extremities. Gait was significant for ataxia with a widened base of support. Romberg s sign was negative. Differential diagnoses included meningitis, Fisher syndrome, brain stem encephalitis, botulism, diphtheria, Lyme disease, myasthenia gravis, and vasculitis. Initial limited electrodiagnostic studies performed the day after admission were significant for normal repetitive stimulation testing at both low (3Hz) and high (30Hz) frequency. Needle electromyographic (EMG) studies demonstrated a rapidfiring recruitment pattern. Findings were suggestive of an acute neuropathic process rather than a neuromuscular junction or myopathic disorder. A lumbar puncture was performed and cerebrospinal fluid (CSF) was significant for a high-normal protein level of 42mg/dL (normal range, 14 to 45mg/dL), but was negative for oligoclonal bands and malignant cells. CSF cultures (bacterial,

2 BOTULISM WITH NEUROPATHIC FEATURES, Chang 123 fungal and mycobacterial) and workup for Cryptococcus and syphilis were negative. A wound culture obtained from the cutaneous neck mass was significant for coagulase-positive Staphylococcus, but no other organisms were identified. Stool cultures were positive for Candida, but negative for white blood cells or infectious bacteria. Wound and stool specimens were not tested for botulinum toxin. Serum chemistries and liver function tests were unremarkable except for a blood glucose level of 242mg/dL, and a complete blood count was significant for an elevated white blood cell count of 11,400/µL. Serum tested for acetylcholine receptor binding antibody, Lyme antibody, hepatitis B and C, and complement studies was unremarkable. Serum was sent for botulinum toxin testing, and 2 days later botulinum toxin type B was detected by in vivo studies (mouse bioassay). Serum was not tested for antibodies to GQ1b ganglioside. Computed tomography of the head and neck was unremarkable other than for fat stranding in the posterior neck region, suggestive of superficial cellulitis. Magnetic resonance imaging of the head and brain stem was unremarkable. The patient was electively intubated for airway protection shortly after admission. In the next several days he developed proximal upper limb weakness. After botulinum toxin type B was detected from serum 2 days after admission, the patient was given trivalent botulinum antitoxin. Clinically, his condition continued to deteriorate, with worsening bulbar weakness as well as progression into his bilateral proximal upper extremities. Within a 7-day period deltoid strength deteriorated from 5/5 to 1/5 bilaterally. Biceps, wrist extensors, and triceps strength also deteriorated from 5/5 to 3/5. Deep tendon reflexes were absent several days after admission. Repeat electrodiagnostic testing was performed 10 days after admission (table 1). conduction studies were significant for (1) normal compound muscle action potential (CMAP) amplitudes, (2) diffusely decreased or absent sensory nerve action potential (SNAP) amplitudes, (3) absent blink and H-reflexes, (4) normal F-wave latencies and penetrance, and (5) normal responses to repetitive stimulation of the right accessory nerve (both at 3Hz and 30Hz frequency). Needle EMG studies were significant for (1) discrete and reduced recruitment patterns (ie, reduced numbers of rapidly firing motor unit action potentials [MUAPs]) in the biceps and trapezius, respectively, and (2) long duration motor units on quantitative electromyography of the biceps with rapid firing rates up to 35Hz. There was no evidence of membrane instability. These nerve conduction study and EMG results again supported a neuropathic process rather than a neuromuscular junction disorder. Intravenous immunoglobulin for presumed Fisher syndrome was started on the tenth day after admission and continued for 5 days, during which time the progression of weakness halted. Eleven days after admission, the patient also had an elective tracheostomy placement to manage secretions. He was weaned from assisted ventilation 14 days after admission. In the next 8 weeks the patient s condition stabilized, but he had only minimal recovery from bulbar and facial weakness, as well as continued bilateral, total ophthalmoplegia. Proximal upper extremity strength remained nonfunctional with slight improvement of distal upper extremity muscles. Bilateral fingertip paresthesias improved. Gait ataxia also resolved. The patient had a nearly full recovery by 4 months after onset of symptoms. Repeat electrodiagnostic testing (table 1) demonstrated significant recovery of SNAP amplitudes as well as development of membrane instability, polyphasic MUAPs, and a reduced (rapid-firing) recruitment pattern with maximal exertion. These findings were consistent with a resolving neuropathic process. DISCUSSION Diagnosis of patients presenting with rapidly progressive multiple cranial neuropathies can be difficult because the clinical examination may be nonspecific. This patient presented with acute development of bilateral bulbar and facial weakness, which rapidly progressed to involve upper extremity and respiratory weakness. His history, physical examination, and initial laboratory studies were inconclusive. The differential diagnosis included botulism and Fisher syndrome, so electrodiagnostic testing was performed the day after admission pending further laboratory studies. This initial electrodiagnostic study was consistent with Fisher syndrome rather than botulism, as were the follow-up studies 10 days and 4 months postonset. However, botulism was diagnosed 2 days postonset by in vivo mouse studies. Considering the patient s history, both botulism and Fisher syndrome were possibilities, particularly with the acute development of multiple cranial neuropathies. Botulism is a paralytic disease caused by a toxin synthesized by Clostridium botulinum, a gram-positive rod. This toxin blocks the formation or release of acetylcholine vesicles in the presynaptic terminal, thereby reducing acetylcholine release when a motor neuron is depolarized. 1 The classic presentation of botulism involves development of acute, bilateral cranial neuropathies associated with symmetric descending weakness. Patients may note dysphagia, dysarthria, diplopia, and dizziness, as well as fatigue, shortness of breath, abdominal cramping, diarrhea, and weakness affecting the upper extremities before the lower extremities. 2 Sensory complaints, although rare, are occasionally reported. 2-4 Review of systems may involve ingestion of home-canned vegetables. In Fisher syndrome, peripheral nerve demyelination with varying degrees of axonal loss is common. 5 It was originally described in 1956 as the acute development of ophthalmoplegia, ataxia, and loss of deep tendon reflexes. 6 Patients usually note diplopia, bulbar weakness, facial and distal extremity paresthesias, and difficulty with ambulation; limb weakness is generally not reported. 5,7 Review of systems may be significant for a viral illness in the recent past. This patient s history was consistent with either of these two processes, given his bulbar and facial weakness, visual symptoms, paresthesias, and recent history of diarrhea and viral illness. The patient s physical examination was also nonspecific. His facial and bulbar weakness was consistent with either diagnosis, as was his respiratory distress. Although fingertip paresthesias are more commonly associated with Fisher syndrome, sensory disturbances have been reported in botulism as well. 2-4 Areflexia is one of the common findings in Fisher syndrome, but can also occur in neuromuscular disorders such as botulism, although usually later than in neuropathic disorders. The patient s gait ataxia may have been superimposed on visual disturbance, peripheral sensory deficits, and fatigue as well. The patient s laboratory and electrodiagnostic studies provide the most interesting findings, individually being suggestive of two different pathophysiologic processes (botulism by laboratory method, and Fisher syndrome by electrodiagnosis). Detection of botulinum toxin type B in the patient s serum by in vivo studies (mouse bioassay) was highly suggestive of botulism. These results were confirmed by immediate, repeat testing, to ensure validity. In vivo testing for botulism involves injecting patient serum intraperitoneally into 8 mice divided into four groups: (1) no antitoxin, (2) type A antitoxin, (3) type

3 124 BOTULISM WITH NEUROPATHIC FEATURES, Chang Table 1: Electrodiagnostic Testing Results at 10 Days and 4 Months After Onset of Symptoms 10 Days Postonset Sensory Conduction Latency (msec) Amplitude (µv) R Median (14cm) L Median (14cm) R Ulnar (14cm) No response No response R Radial (14cm) R Sural (14cm) No response No response Motor Conduction Latency (msec) Amplitude (mv) Conduction Velocity (m/sec) R Ulnar Wrist Below elbow Above elbow Axilla R Spinal Accessory Repetitive Stimulation Rate (Hz) Amplitude Decrement (%) Area Decrement (%) /Muscle R Spinal Accessory Trapezius Preexercise Immediate postexercise Min postexercise Min postexercise Preexercise Late Responses F-Wave Min Latency (msec) Persistence (%) /Muscle R Ulnar ADM R Tibial Soleus H-Reflex No response Involuntary Activity Needle Electromyography Voluntary Activity Ins Act PSW Fib Amp (µv) Dur (ms) Phasicity Recruitment Muscle R Biceps* Normal % poly Discrete R Trapezius Normal Normal Reduced 4 Months Postonset Sensory Conduction Latency (msec) Amplitude (µv) R Median (14cm) R Ulnar (14cm) R Radial (14cm) R Sural (14cm) Involuntary Activity Needle Electromyography Voluntary Activity Ins Act PSW Fib Amp (µv) Dur (msec) Phasicity Recruitment Muscle R Biceps Increased 3 2 2,000 Increased Reduced R Trapezius Increased 2 2 1,500 Increased Reduced * Biceps EMG findings based on quantitative analysis of 21 MUAPs.

4 BOTULISM WITH NEUROPATHIC FEATURES, Chang 125 B antitoxin, and (4) polyvalent antitoxin. If type B botulinum toxin is present in sufficient concentration, all mice in groups 1 and 2 will die within 96 hours, while the mice receiving the type B and polyvalent antitoxins will be spared. Death occurs in a typical fashion, including ruffling of fur, labored breathing, limb weakness, and total paralysis. 8,9 Electrodiagnostic assessment of patients with suspected botulism or Fisher syndrome can be critical, as results can often be obtained before laboratory results are available. Botulinum toxin blocks the formation or release of acetylcholine vesicles in the presynaptic terminal, thereby reducing acetylcholine release when a motor neuron is depolarized. 1 Fisher syndrome is believed to involve peripheral nerve demyelination with varying degrees of axonal loss. 5 These different pathophysiologies usually have different electrodiagnostic features, because botulism is presumed to be a primarily neuromuscular junction disorder and Fisher syndrome a neuropathic disorder. Typical nerve conduction study findings in botulism include decreased CMAP amplitudes 10,11 and normal SNAP amplitudes. 2,11 F-waves typically have normal latencies and penetrance, and H-waves may have mildly prolonged latencies and small amplitudes. Repetitive stimulation can be extremely useful in determining the presence and type of a neuromuscular junction disorder. In botulism, at low rates of stimulation (2 to 5Hz), calcium concentration at the presynaptic terminal is not altered, and repetitive firing further depletes the low stores of available acetylcholine, resulting in decrementing CMAP amplitudes. High rates of stimulation (20 to 50Hz) or prolonged maximal voluntary contraction increases the calcium concentration in the presynaptic terminal, enhancing the release of acetylcholine and resulting in increased CMAP amplitudes. 10,12,13 In contrast to botulism, typical nerve conductron study findings in Fisher syndrome include normal CMAP amplitudes, decreased SNAP amplitudes, and no changes in CMAP amplitudes with repetitive stimulation. 5,14 F-waves usually have prolonged latencies 15 and decreased penetrance, and H-waves are frequently absent. 5 Our patient had several electrodiagnostic assessments over a 4-month period, all of which showed abnormalities consistent with a neuropathic process such as Fisher syndrome. Significant nerve conductron study findings 10 days after admission included (1) normal CMAP amplitudes, (2) decreased or absent SNAP amplitudes, and (3) normal responses to repetitive stimulation at both low and high frequencies. As the patient clinically improved, a follow-up study was performed at 4 months and was significant for recovery of SNAP amplitudes. Needle EMG studies can also be useful in differentiating neuromuscular junction disorders from neuropathic disorders. Typical needle EMG findings in botulism include short duration, small amplitude MUAPs with an early recruitment pattern, similar to a myopathic process. 2 Membrane instability may be absent early in the course of disease. Needle EMG findings in Fisher syndrome may be nondiagnostic early in the disease process other than a reduced, rapid-firing, recruitment pattern. 5 After recovery, however, MUAPs may have prolonged durations, increased polyphasicity, and large amplitudes with a reduced, rapid-firing, recruitment pattern, consistent with reinnervation. Early on in the disease process, membrane instability may be absent, but follow-up testing typically reveals increased insertional activity with positive sharp waves and fibrillation potentials. This patient s needle EMG studies at day 10 were significant for discrete and reduced recruitment patterns on needle EMG testing, and long duration motor units on quantitative electromyogram. At 4 months, his follow-up testing was significant for development of membrane instability, polyphasic MUAPs, and continued, reduced (rapid-firing) recruitment pattern with maximal exertion. These findings were more suggestive of a neuropathic process rather than a neuromuscular junction disorder. In this patient, in vivo studies detected botulinum toxin type B, but serial electrodiagnostic studies failed to reveal evidence of a neuromuscular junction disorder and, instead, were consistent with a neuropathic process. These seemingly contradictory findings raise legitimate concern about the current understanding of the pathophysiology and laboratory and electrodiagnostic diagnosis of both of these processes. Given the patient s available clinical and laboratory data, it is impossible to confirm either botulism or Fisher syndrome as the definitive diagnosis. However, we suspect that the patient probably had botulism with neuropathic features, without evidence of neuromuscular junction deficits on electrodiagnostic testing. Botulism may sometimes present with primarily neuropathic features, and sensory abnormalities should not exclude the diagnosis of botulism. There are several reports in the literature noting sensory disturbances as a major symptom in patients with botulism. 3,4,10 Vertigo and difficulty in hearing, two common findings in botulism, might also be representative of sensory nerve dysfunction. 3 In dogs with botulism type C, neuropathic findings including slowing of sensory and motor nerve conductions have been reported, with improvement of conduction velocity after clinical improvement. 16 These findings suggest that the toxins involved in botulism might have more of an action than just blocking acetylcholine release at the presynaptic terminal. Respiratory depression and hind-limb weakness has been noted in mice injected with serum from patients with Guillain- Barré syndrome, which are typical findings in mice injected with botulinum toxin prior to death. 15 These findings might suggest that in Fisher syndrome circulating toxins might also have a role. 17 It is possible that these toxins might bind to either botulism type B antibodies or contaminants in the antiserum during the mouse bioassay. Thus, serum from patients with Fisher syndrome may be toxic to mice and could theoretically cause a positive mouse bioassay on testing for botulism. If this hypothesis is true, then antitoxin to botulism B may offer some protection against Fisher syndrome. Regardless of the absolute etiology of this patient s symptoms, the importance of correlative electrodiagnostic and laboratory studies (especially microbiological and immunologic tests) is emphasized, particularly in determining the frequency of atypical findings in both botulism and Fisher syndrome. When serum is positive for botulinum toxin, correlation with wound or stool samples is also desirable, but a definitive source often cannot be demonstrated. 18 This patient did not have wound samples tested for botulism, and appropriate stool specimens were not obtainable for testing. In Fisher syndrome, CSF studies may show a slightly elevated protein level, but may be normal early in the course of the disease. 7,14 Other routine laboratory studies may be unremarkable. However, recent literature reports a correlation of patients with Fisher syndrome with high titers of antibodies to GQ1b ganglioside. 19 This patient did not have testing for antibodies to GQ1b ganglioside. In summary, patients with acute cranial neuropathies can be a diagnostic challenge. Results of laboratory studies may not be available for several days, and early electrodiagnostic assessment can be extremely useful in differentiating neuropathic from neuromuscular junction disorders. However, patients may

5 126 BOTULISM WITH NEUROPATHIC FEATURES, Chang demonstrate atypical findings that contradict the current understanding of certain disease processes. This report illustrates a case of a patient with probable botulism who had features suggesting a neuropathic process and no evidence of neuromuscular junction deficits on electrodiagnostic testing. Clinicians must be aware of the potential confusion between these two different disease processes, especially since their clinical presentations may be very similar and their electrodiagnostic features may occasionally be atypical. References 1. Hayes MT, Soto O, Ruoff KL. A 58-year-old woman with multiple cranial neuropathies. N Engl J Med 1997;337: Dumitru D. Neuromuscular junction disorders. In: Dumitru D, editor. Electrodiagnostic medicine. Philadelphia: Hanley & Belfus, Inc; p Goode GB, Shearn DL. Botulism: a case with associated sensory abnormalities. Arch Neurol 1982;39: Martinez-Castrillo JC, Del Real MA, Hernandez Gonzalez A, De Blas G, Alvarez-Cermeno JC. Botulism with sensory symptoms: a second case. J Neurol Neurosurg Psychiatry 1991;54: Dumitru D. Generalized peripheral neuropathies. In: Dumitru D, editor. Electrodiagnostic medicine. Philadelphia: Hanley & Belfus, Inc; p Fisher M. An unusual variant of acute idiopathic polyneuritis (syndrome of ophthalmoplegia, ataxia and areflexia). N Engl J Med 1956;255: Berlit P, Rakicky J. The Miller Fisher syndrome. Review of the literature. J Clin Neuroophthalmol 1992;12: Clostridium botulinum: toxin detection and identification. Olympia (WA): State of Washington Department of Health, Public Health Laboratories, Clinical and Environmental Microbiology, Reference and Testing Guidelines, Special Pathogens Unit; Clostridium botulinum. Polyvalent and monovalent antitoxins for neutralization. Atlanta: Centers for Disease Control; Oh SJ. Botulism: electrophysiological studies. Ann Neurol 1977;1: Valli G, Barbieri S, Scarlato G. Neurophysiological tests in human botulism. Electromyogr Clin Neurophysiol 1983;23: Keesey JC. AAEM Minimonograph #33: electrodiagnostic approach to defects of neuromuscular transmission. Muscle 1989;12: Cherington M. Electrophysiologic methods as an aid in diagnosis of botulism: a review. Muscle 1982;5:S Fross RD, Daube JR. Neuropathy in the Miller Fisher syndrome. Neurology 1987;37: van den Berg LH, Wokke JHJ, Veldman H, Wieneke GH, Notermans SHW. Features of the Guillain-Barré syndrome in mice following intraperitoneal injection of patient serum. J Neurol Sci 1994;127: van Nes JJ. Electrophysiological evidence of peripheral nerve dysfunction in six dogs with botulism type C. Res Vet Sci 1986;40: Notermans SHW, Wokke JHJ, van den Berg LH. Botulism and Guillain-Barré syndrome [letter]. Lancet 1992;340: Tacket CO, Rogawski MA. Botulism. In: Simpson LL, editor. Botulinum neurotoxin and tetanus toxin. San Diego: Academic Press; p Willison HJ, Veitch J, Paterson G, Kennedy PGE. Miller Fisher syndrome is associated with serum antibodies to GQ1B ganglioside. J Neurol Neurosurg Psychiatry 1993;56:204-6.