Journalof
J Neurol (1990) 237:62-63
Neurology
© Springer-Verlag 1990
Polyradiculoneuritis following botulinum toxin therapy B. A. Haug, D. Dressler, and H.W. Prange Neurologische Universitätsklinik. Robert-Koch-Strasse 40, D-3400 Göttingen, Federal Republic of Germany
Summary. The development of Guillain-Barré syndrome is reported in a patient, who had previously received botulinum toxin type A injections into both orbicularis oculi muscles to treat idiopathic blepharospasm. The possibility of a causal relationship is discussed with consideration of the literature on adverse effects of vaccinations and of Clostridium botulinum and its toxin.
Key words: Potyradiculoneuritis - Guillain-Barré syndrome Botulinum toxin type A - Idiopathic blepharospasm - Clostridium botulinum
lntroduction Botulinum toxin (BT) injections are being increasingly used in ophthalmology and neurology for the treatment of involuntary muscle contractions refractory to other therapeutic measures. Apart from three cases with skin rash [6] or short-lived influenza-like symptoms including fever, malaise and backache [3, 6] systemic side effects have not been recognized so far. We report the occurrence of Guillain-Barré syndrome (GBS) following a series of periorbital injections in a patient with blepharospasm.
Case report A 63-year-old man was admitted to our intensive care unit because of moderate paresis of the lower limbs, which ascended over 6 days to involve trunk, hands and forearms and rendered the patient unable to walk. Premonitory symptoms had heralded the acute illness for several months in the form of fatigue, non-specific weakness and diffuse arthralgia. Deep tendon reflexes and Babinski signs were absent. Disturbance of sensation was confined to diminished vibration and position sense and only mild paraesthesiae of glove and stocking distribution. Motor and sensory deficits gradually subsided during the 2 months of hospitalization. Mentation was only transiently impaired. Routine laboratory testing did not show significant abnormalities. Cerebrospinal fluid (CSF) examination revealed an elevated total white cell count of up to 17/mm3 with 88% lymphocytes, 12% monocytes, few plasma cells and eosinophils and 0.2% of IgG containing B lymphocytes. CSF protein reached 3.51 g/l, lactate 3.8 mmol/1. CSF/serum ratios of IgG, IgA and IgM were normal compared with CSF/serum ratio of
Offprint requests to." B. A. Haug
albumin, indicating a slight b]ood-brain-barrier disturbance without de novo IgG synthesis in the CNS. Corresponding oligoclonal bands were detected in CSF and serum. Repeated cuhures from sputum, tracheal swabs, urine and blood were essentially negative, including tests for mycobacteria and fungi (Klebsiella pneumophila was found in tracheal secretions 10 days after admission). Serum and CSF antibody studies were negative for cytomegalovirus, herpes simplex virus, adenovirus, Epstein-Barr virus, varicella, measles, early summer meningoencephalitis, human immunodeficiency virus I, treponema, borrelia, brucella, listeria, leptospirosis, ornithosis, Q-fever, mycoplasma, toxoplasma, Candida albicans, cryptococcus and various helminths and larvae, as well as autoantibodies, including acetylcholine receptor antibodies. Electromyography and electroneurography showed an overall decrease of motor nerve conduction velocity, loss of F waves, yet no signs of axonal degeneration. The diagnosis of idiopathic polyradiculoneuritis (PRN) was made. Subsequent more detailed history revealed that the patient had suffered a perforating wound to his right eyeball 13 years previously and that the injured eye later had to be excised to prevent further damage to its fellow by sympathetic ophthalmitis. Two years prior to this admission he had been started on a series of 4 courses of BT injections into both orbicularis oculi muscles to treat bilateral blepharospasm. A cumulative dose of 129 mouse units of Clostridiurn botulinum toxin type A (Smith Kettlewell Institute of Visual Sciences) had been applied. The last course of injections 11 months previously totalled 72.5 mouse units and was followed by a satisfying clinical resuh. Additional tests were carried out and excluded the presence of BT type A antibodies in serum (Behringwerke, Marburg, FRG) and an intestinal growth of C. botulinum (Sanitätsdienst der Bundeswehr, Kronshagen, FRG).
Discussion In PRN a cell-mediated immune response is considered to be the causative factor for peripheral demyelination. Facultative antinerve antibodies are supposed to reflect secondary reactions to nerve destruction [8]. Offen viral infections [1], sometimes vaccinations [7, 9, 11, 15], are the triggering offenders for the disease. In active tetanus immunization, too, GBS [14] and relapsing polyneuropathy on re-exposure [17] have been observed. In those cases pure tetanus toxoid had been applied, which may be closely related to BT, as both neurotoxins are proteins produced by the same genus of bacteria (Clostridiurn tetani versus C. botulinum).
63 M o r e o v e r , clinical data on infant botulism [2, 13, 16] and two case reports on adults [10, 18], as well as casual observations in foxhounds [4], indicate an association b e t w e e n persistent intestinal infection with C. botulinum and hence prolonged exposure to its toxin (toxicoinfection) and the incidental occurrence of clinical, laboratory and neurophysiological features of P R N . These reports could not clarify whether B T or some other factor emanating from the bacteria was the noxious agent leading to raised CSF protein and nerve demyelination. Our case favours the former possibility, since C. botulinum infection is unlikely and could not be detected in stool samples. A n t i b o d y production and natural immunity usually do not develop in cases of food-borne botulism, toxicoinfection and B T therapy [5], although humoral responses to botulinum toxoid can be elicited in humans [12] and animals. In our case a cellular immunization may still have occurred by means of the repeated injections of BT. We cannot provide evidence of this, because skin tests might be hazardous for the affected patient and in vitro tests such as antigen-induced lymphocyte activation have not b e e n available. To our knowledge this is the first case of P R N following B T therapy. A causal relationship cannot be proved and the temporal association is loose. Considering the great benefit of some 1000 patients treated with B T and not developing systemic side effects, we do not advise against this procedure. Careful checking, however, might be necessary in patients presenting with a history of cellular hypersensitivity.
References 1. Alvord EC Jr, Jahnke U, Fischer EH (1987) The causes of the syndromes of Landry (1859) and of Guillain, Barré and Strohl (1916). Rev Neurol (Paris) 143:571-579 2. Arnon SS, Midura TF, Clay SA, Wood RM, Chin J (1977) Infant botulism: epidemiological, clinical, and laboratory aspects. JAMA 237:1946-1951 3. Arthurs B, Flanders M, Codère F, Gauthier S, Dresner S, Stone L (1987) Treatment of blepharospasm with medication, surgery and type A botulinum toxin. Can J Ophthalmol 22: 24-28 4. Barsanti A, Walser M, Hatbeway CL, Bowen JM, Crowell W (1978) Type C botulism in American Foxhounds. JAVMA 172: 809-813
5. Biglan AW, Gonnering R, Lockhart LB, Rabin B, Fuerste FH (1986) Absence of antibody production in patients treated with botulinum toxin. Am J Ophthalmol 101 : 232-235 6. Fross RD, Calne S, Calne DB (1987) Local treatment of spasmodic torticollis with botulinum toxin. Can J Neurol Sci 14 : 533535 7. Hemachudha T, Griflin DE, Chen WW, Johnson RT (1988) Immunologic studies of rabies vaccination-induced Guillain-Barré syndrome. Neurology 38 : 375-378 8. Hoffman PM (1984) Acute idiopathic polyneuritis. In: Stites DP, Stobo JD, Fudenberg HH, Wells JV (eds) Basic and clinical immunology, vol 5. Lange, Los Altos, Calif, pp 665-667 9. Kaslow RA, Sullivan-Bolyai JZ, Holman RC, Hafkin B, Dicker RC, Schonberger LB (1987) Risk factors for Guillain-Barré syndrome. Neurology 37 : 685-688 10. Ketz E, Sonnabend WF, Sonnabend OA, Hungerbühler HJ (1984) Guillain-Barré-Syndrom bei Clostridium-botulinum-TypC-Toxikoinfektion. In: Gerstenbrand F, Mamoli B (eds) Metabolische und entzündliche Polyneuropathien. Springer, Berlin Heidelberg New York, pp 180-185 11. Langmuir AD, Bregman DJ, Kurland LT, Nathanson N, Victor M (1984) An epidemiologic and clinical evaluation of GuillainBarré syndrome reported in association with the administration of swine influenza vaccines. Am J Epidemiol 119 : 841-879 12. Metzger JF, Lewis GE Jr (1979) Human-derived immune globulins for the treatment of botulism. Rev Infeet Dis i : 689-690 13. Midura TF, Arnon SS (1976) Infant botulism: identification of clostridium botulinum and its toxins in faeces. Lancet I: 934-936 14. Newton N Jr, Janati A (1987) Guillain-Barré syndrome after vaccination with purified tetanus toxoid. South Med J 80:1053-1054 15. Norrby R (1984) Polyradiculitis following vaccination for measles, mumps and rubella. Läkartidningen 81:1636-1637 16. Pickett J, Berg B, Chaplin E, Brunstetter-Shafer MA (1976) Syndrome of botulism in infancy: clinical and electrophysiologic study. N Engl J Med 295 : 770-772 17. Pollard JD, Selby G (1978) Relapsing neuropathy due to tetanus toxoid. J Neurol Sci 37:113-125 18. Sonnabend WF, Sonnabend OA, Gründler P, Ketz E (1987) Intestinal toxicoinfection by clostridium botulinum type F in an adult. Lancet I : 357-360
Received August 7, 1989 / Received in revised form November 7, 1989 / Accepted November 20, 1989
J Neurol (1990) 237:62-63
Neurology
© Springer-Verlag 1990
Polyradiculoneuritis following botulinum toxin therapy B. A. Haug, D. Dressler, and H.W. Prange Neurologische Universitätsklinik. Robert-Koch-Strasse 40, D-3400 Göttingen, Federal Republic of Germany
Summary. The development of Guillain-Barré syndrome is reported in a patient, who had previously received botulinum toxin type A injections into both orbicularis oculi muscles to treat idiopathic blepharospasm. The possibility of a causal relationship is discussed with consideration of the literature on adverse effects of vaccinations and of Clostridium botulinum and its toxin.
Key words: Potyradiculoneuritis - Guillain-Barré syndrome Botulinum toxin type A - Idiopathic blepharospasm - Clostridium botulinum
lntroduction Botulinum toxin (BT) injections are being increasingly used in ophthalmology and neurology for the treatment of involuntary muscle contractions refractory to other therapeutic measures. Apart from three cases with skin rash [6] or short-lived influenza-like symptoms including fever, malaise and backache [3, 6] systemic side effects have not been recognized so far. We report the occurrence of Guillain-Barré syndrome (GBS) following a series of periorbital injections in a patient with blepharospasm.
Case report A 63-year-old man was admitted to our intensive care unit because of moderate paresis of the lower limbs, which ascended over 6 days to involve trunk, hands and forearms and rendered the patient unable to walk. Premonitory symptoms had heralded the acute illness for several months in the form of fatigue, non-specific weakness and diffuse arthralgia. Deep tendon reflexes and Babinski signs were absent. Disturbance of sensation was confined to diminished vibration and position sense and only mild paraesthesiae of glove and stocking distribution. Motor and sensory deficits gradually subsided during the 2 months of hospitalization. Mentation was only transiently impaired. Routine laboratory testing did not show significant abnormalities. Cerebrospinal fluid (CSF) examination revealed an elevated total white cell count of up to 17/mm3 with 88% lymphocytes, 12% monocytes, few plasma cells and eosinophils and 0.2% of IgG containing B lymphocytes. CSF protein reached 3.51 g/l, lactate 3.8 mmol/1. CSF/serum ratios of IgG, IgA and IgM were normal compared with CSF/serum ratio of
Offprint requests to." B. A. Haug
albumin, indicating a slight b]ood-brain-barrier disturbance without de novo IgG synthesis in the CNS. Corresponding oligoclonal bands were detected in CSF and serum. Repeated cuhures from sputum, tracheal swabs, urine and blood were essentially negative, including tests for mycobacteria and fungi (Klebsiella pneumophila was found in tracheal secretions 10 days after admission). Serum and CSF antibody studies were negative for cytomegalovirus, herpes simplex virus, adenovirus, Epstein-Barr virus, varicella, measles, early summer meningoencephalitis, human immunodeficiency virus I, treponema, borrelia, brucella, listeria, leptospirosis, ornithosis, Q-fever, mycoplasma, toxoplasma, Candida albicans, cryptococcus and various helminths and larvae, as well as autoantibodies, including acetylcholine receptor antibodies. Electromyography and electroneurography showed an overall decrease of motor nerve conduction velocity, loss of F waves, yet no signs of axonal degeneration. The diagnosis of idiopathic polyradiculoneuritis (PRN) was made. Subsequent more detailed history revealed that the patient had suffered a perforating wound to his right eyeball 13 years previously and that the injured eye later had to be excised to prevent further damage to its fellow by sympathetic ophthalmitis. Two years prior to this admission he had been started on a series of 4 courses of BT injections into both orbicularis oculi muscles to treat bilateral blepharospasm. A cumulative dose of 129 mouse units of Clostridiurn botulinum toxin type A (Smith Kettlewell Institute of Visual Sciences) had been applied. The last course of injections 11 months previously totalled 72.5 mouse units and was followed by a satisfying clinical resuh. Additional tests were carried out and excluded the presence of BT type A antibodies in serum (Behringwerke, Marburg, FRG) and an intestinal growth of C. botulinum (Sanitätsdienst der Bundeswehr, Kronshagen, FRG).
Discussion In PRN a cell-mediated immune response is considered to be the causative factor for peripheral demyelination. Facultative antinerve antibodies are supposed to reflect secondary reactions to nerve destruction [8]. Offen viral infections [1], sometimes vaccinations [7, 9, 11, 15], are the triggering offenders for the disease. In active tetanus immunization, too, GBS [14] and relapsing polyneuropathy on re-exposure [17] have been observed. In those cases pure tetanus toxoid had been applied, which may be closely related to BT, as both neurotoxins are proteins produced by the same genus of bacteria (Clostridiurn tetani versus C. botulinum).
63 M o r e o v e r , clinical data on infant botulism [2, 13, 16] and two case reports on adults [10, 18], as well as casual observations in foxhounds [4], indicate an association b e t w e e n persistent intestinal infection with C. botulinum and hence prolonged exposure to its toxin (toxicoinfection) and the incidental occurrence of clinical, laboratory and neurophysiological features of P R N . These reports could not clarify whether B T or some other factor emanating from the bacteria was the noxious agent leading to raised CSF protein and nerve demyelination. Our case favours the former possibility, since C. botulinum infection is unlikely and could not be detected in stool samples. A n t i b o d y production and natural immunity usually do not develop in cases of food-borne botulism, toxicoinfection and B T therapy [5], although humoral responses to botulinum toxoid can be elicited in humans [12] and animals. In our case a cellular immunization may still have occurred by means of the repeated injections of BT. We cannot provide evidence of this, because skin tests might be hazardous for the affected patient and in vitro tests such as antigen-induced lymphocyte activation have not b e e n available. To our knowledge this is the first case of P R N following B T therapy. A causal relationship cannot be proved and the temporal association is loose. Considering the great benefit of some 1000 patients treated with B T and not developing systemic side effects, we do not advise against this procedure. Careful checking, however, might be necessary in patients presenting with a history of cellular hypersensitivity.
References 1. Alvord EC Jr, Jahnke U, Fischer EH (1987) The causes of the syndromes of Landry (1859) and of Guillain, Barré and Strohl (1916). Rev Neurol (Paris) 143:571-579 2. Arnon SS, Midura TF, Clay SA, Wood RM, Chin J (1977) Infant botulism: epidemiological, clinical, and laboratory aspects. JAMA 237:1946-1951 3. Arthurs B, Flanders M, Codère F, Gauthier S, Dresner S, Stone L (1987) Treatment of blepharospasm with medication, surgery and type A botulinum toxin. Can J Ophthalmol 22: 24-28 4. Barsanti A, Walser M, Hatbeway CL, Bowen JM, Crowell W (1978) Type C botulism in American Foxhounds. JAVMA 172: 809-813
5. Biglan AW, Gonnering R, Lockhart LB, Rabin B, Fuerste FH (1986) Absence of antibody production in patients treated with botulinum toxin. Am J Ophthalmol 101 : 232-235 6. Fross RD, Calne S, Calne DB (1987) Local treatment of spasmodic torticollis with botulinum toxin. Can J Neurol Sci 14 : 533535 7. Hemachudha T, Griflin DE, Chen WW, Johnson RT (1988) Immunologic studies of rabies vaccination-induced Guillain-Barré syndrome. Neurology 38 : 375-378 8. Hoffman PM (1984) Acute idiopathic polyneuritis. In: Stites DP, Stobo JD, Fudenberg HH, Wells JV (eds) Basic and clinical immunology, vol 5. Lange, Los Altos, Calif, pp 665-667 9. Kaslow RA, Sullivan-Bolyai JZ, Holman RC, Hafkin B, Dicker RC, Schonberger LB (1987) Risk factors for Guillain-Barré syndrome. Neurology 37 : 685-688 10. Ketz E, Sonnabend WF, Sonnabend OA, Hungerbühler HJ (1984) Guillain-Barré-Syndrom bei Clostridium-botulinum-TypC-Toxikoinfektion. In: Gerstenbrand F, Mamoli B (eds) Metabolische und entzündliche Polyneuropathien. Springer, Berlin Heidelberg New York, pp 180-185 11. Langmuir AD, Bregman DJ, Kurland LT, Nathanson N, Victor M (1984) An epidemiologic and clinical evaluation of GuillainBarré syndrome reported in association with the administration of swine influenza vaccines. Am J Epidemiol 119 : 841-879 12. Metzger JF, Lewis GE Jr (1979) Human-derived immune globulins for the treatment of botulism. Rev Infeet Dis i : 689-690 13. Midura TF, Arnon SS (1976) Infant botulism: identification of clostridium botulinum and its toxins in faeces. Lancet I: 934-936 14. Newton N Jr, Janati A (1987) Guillain-Barré syndrome after vaccination with purified tetanus toxoid. South Med J 80:1053-1054 15. Norrby R (1984) Polyradiculitis following vaccination for measles, mumps and rubella. Läkartidningen 81:1636-1637 16. Pickett J, Berg B, Chaplin E, Brunstetter-Shafer MA (1976) Syndrome of botulism in infancy: clinical and electrophysiologic study. N Engl J Med 295 : 770-772 17. Pollard JD, Selby G (1978) Relapsing neuropathy due to tetanus toxoid. J Neurol Sci 37:113-125 18. Sonnabend WF, Sonnabend OA, Gründler P, Ketz E (1987) Intestinal toxicoinfection by clostridium botulinum type F in an adult. Lancet I : 357-360
Received August 7, 1989 / Received in revised form November 7, 1989 / Accepted November 20, 1989
