New formulation of Botox: complete antibody‐induced treatment failure in cervical dystonia

Botulinum toxin is used with remarkable success to treat various muscle and exocrine gland hyperactivity syndromes. Rarely, treatment failure due to formation of botulinum toxin antibodies (ABF) occurs.¹,² To reduce the risk of ABF, a new formulation of Botox (in the following referred to as “current Botox”; Allergan, Irvine, California, USA) with increased specific biological potency was introduced. Although ABF could not be detected with current Botox in a large prospective study, it has been reported recently in a patient with special immunoreactive predisposition.³,⁴ We are now reporting ABF after current Botox in an immunologically unremarkable patient.

A 50‐year‐old woman had substantial idiopathic tonic–clonic cervical dystonia for the past 7 months. Her score on the Toronto Western Torticollis Rating Scale (TWSTRS) was 25 (Torticollis Severity Scale), 22 (Disability Scale) and 17.5 (Pain Scale).⁵ Treatment was initiated with current Botox (100 MU/1.0 ml, 0.9% NaCl/H₂O) (table 1). Two weeks after injection series number 1, her TWSTRS score had decreased to 17 (Torticollis Severity Scale) and her overall subjective improvement, including motor symptoms and pain, was 30% of the original symptomatology. After the injection scheme was modified, her TWSTRS score on injection series 2 and 3 decreased to 5 (Torticollis Severity Scale), 7 (Disability Scale) and 0 (Pain Scale), and her overall subjective improvement rose to 90%. The target muscles then used were the left sternocleidomastoideus (60 MU), the right splenius capitis (60 MU), the right trapezius (30 MU), the left trapezius (20 MU), the right semispinalis (30 MU), the left levator scapuli (30 MU) and the left scalenii (70 MU). Side effects were not reported. On injection series 4 and 5, the therapeutic effect was stable. On injection series 6 and 7, her overall improvement declined to 40% and 20%, respectively, and partial treatment failure was concluded. On injection series 8, there was no therapeutic effect; her TWSTRS score had increased again to its pretreatment value and there was no target muscle paresis. Injection series 9 carried out with identical treatment parameters as before produced the same negative therapeutic effect. After other potential explanations were excluded, all criteria for complete antibody‐induced treatment failure were fulfilled as on injection series 8.⁶ Electromyography of the sternocleidomastoid muscles did not show amplitude reduction in the target muscles or denervation activity. On the mouse diaphragm assay, botulinum toxin antibody titres were negative after injection series 6, but showed a titre of >7.3 mU/ml after injection series 9.⁷ As shown in table 1, during the period from injection series 1 to 8, before complete treatment failure occurred, the treatment time was 644 days; the interinjection interval was 92 (standard deviation (SD) 9) days (minimum 84 days, maximum 105 days); the single botulinum toxin dose given at each injection series was 334 (SD 47) MU (minimum 200 MU, maximum 400 MU) and the cumulative botulinum toxin dose was 2540 MU. Throughout the botulinum toxin treatment, there was no rash, eyelid oedema, dyspnoea, flu‐like symptoms, muscle pain or general weakness. History of allergy was not reported.

Table 1 Treatment protocol.

Injection series	Time (days)	Interinjection interval (days)	Single dose (mouse units Botox)	Subjective improvement (% of original symptomatology)	Remarks
1	0		200	30	NR
2	98	98	300	50	NR
3	182	84	400	90	NR
4	287	105	300	90	NR
5	378	91	300	90	NR
6	478	100	300	40	PTF MDA: negative
7	562	84	340	20	PTF
8	644	82	400	0	CTF
9	728	84	400	0	CTF MDA: >7.3 mU/ml

CTF, complete treatment failure; MDA, mouse diaphragm assay; NR, normal response; PTF, partial treatment failure.

ABF can be partial or complete, as in our patient, depending on the balance between botulinum toxin and botulinum toxin antibodies. The risk of ABF is increased with short interinjection intervals and high botulinum toxin single doses.⁸ It is also increased by the low specific biological potency of the botulinum toxin preparation used—that is, by a low biological potency in relation to a high load of botulinum neurotoxin as caused by partial inactivation of the neurotoxin during manufacturing. With current Botox, the specific biological potency could be increased from 4 MU/ng neurotoxin‐non‐toxic protein complex of previous Botox to 20 MU/ng neurotoxin‐non‐toxic protein complex.³ As a consequence, the risk of ABF in patients with cervical dystonia could be reduced from about 5% to <1%.³ However, a case recently reported indicates that current Botox does not eliminate the risk of ABF entirely.⁴ With single doses of 48 MU botulinum toxin, only interinjection intervals as long as 98.3 (SD 36.1) days, only three injection series applied and administration of a cumulative botulinum toxin dose of only 96 MU. Suspicion of a special immunoreactive predisposition of this patient arose, especially since a similar case of ABF after Dysport has been reported previously.⁹ In the current patient, the treatment time was 644 days, the interinjection interval 92 (SD 9) days, the single botulinum toxin dose 334 (SD 47) MU and the cumulative botulinum toxin dose 2540 MU. With these unremarkable treatment parameters and no apparent special immunoreactive predisposition, this case indicates that current Botox can produce ABF not only in immunologically exceptional patients but also in unremarkable ones.