Impaired Neuronal Communication Syndrome (INCS) as Novel Neurological Side Effect to Botulinum Toxin Type A Therapy with 16 Case Reports

Review Article

J Bacteriol Mycol. 2016; 3(4): 1035.

Impaired Neuronal Communication Syndrome (INCS) as Novel Neurological Side Effect to Botulinum Toxin Type A Therapy with 16 Case Reports

Hristova AH

Institute for Future Sciences and Medicine, Virginia, USA

*Corresponding author: Hristova AH, Institute for Future Sciences and Medicine, Virginia, USA

Received: August 15, 2016; Accepted: September 16, 2016; Published: September 19, 2016


Based on the data of the 16 cases we report here, prior experience with side effects to botulinum, and the published literature, we define a novel syndrome as an adverse reaction to the toxin therapy which we named: Impaired Neuronal Communication Syndrome (INCS). We define INCS as a disease of toxininduced impairment of neuronal connection and impaired mediators balance in the central, peripheral and/or autonomic nervous system with, most of the time, no identifiable anatomical cell damage. This syndrome differs from the reported in the literature autoimmune adverse reactions to the toxin, affecting the central (encephalitis) or the peripheral nervous system (inflammatory polyneuropathies, brachial plexitis etc). The major difference is that, in toxin-induced autoimmune syndromes, it is more likely to have positive findings in laboratory tests and imaging or on examination while, in INCS the majority of the patients have normal laboratory and imaging tests and neurological examination. This suggests that, in such cases, the clinical features and the proximity of the symptoms’ occurrence to the toxin therapy are the main and often the only tools to achieve a correct diagnosis. We identify that the side effects from botulinum toxin therapy can be severe, persistent, and disabling. We suggest an algorithm for safer toxin use.

Keywords: Botulinum toxin; Side effects; Adverse events; Central nervous system; Autonomic nervous system; Impaired Neuronal Communication Syndrome (INCS)


3-4 DAP: 3-4 Diaminopyridine; Ach: Acetylcholine; BoNT/A: Botulinum Neurotoxin Type A; CNS: Central Nervous System; EEG: Electroencephalogram; ELISA: Enzyme Linked Immunosorbent Assay; INCS: Impaired Neuronal Communication Syndrome; LD50: Lethal Dose of the toxin that kills 50% of the mice population; SNAP- 25: Synaptosomal Associated Protein - 25.


Botulinum Neurotoxin Type A (BoNT/A) was purified in 1928. Three forms of BoNT/A were approved for use in USA: onabotulinumtoxinA: for therapeutic in 1989 and for cosmetic in 2002; abobotulinumtoxinA: for therapeutic and cosmetic in 2009 and incobotulinumtoxinA: for therapeutic in 2010 and for cosmetic in 2011. Since then thousands of patients have been injected worldwide, while the toxin sales have been increasing trough the decades. Numerous double-blind trials have been conducted. The toxin therapy was regarded as generally safe. In September 2009, after 20 years of use, a black-box warning for the toxin was issued indicating that BoNT/A could cause death and disability. This is not unusual in type B adverse events to drugs as defined in pharmacovigilance research [1], indicating that, double blind studies often cannot establish the long term safety of a drug even after decades of use. Type B adverse events are events displaying phenomenology other than the well known and expected reactions to a drug, known as type A events. Typically, type B events require a significant amount of adverse events reports before a drug to side effect connection is established [1]. Historically, in such cases, there are abnormal findings in the laboratory, imaging or other tests or in the clinical examination, facilitating the establishment of a relationship. A good example of the above is the chloramphenicolinduced aplastic anemia [2]. Unfortunately, in the case of BoNT/A, we do not have readily available laboratory, imaging or other study abnormalities to establish a relationship between an adverse event and the toxin. Autopsies of people and animals who died from botulism did not display specific changes to identify the toxin as cause of death [3, 4]. Herrero et al. [5] sacrificed monkeys to intra-venous injection with the toxin and found no specific morphological changes. In this article we demonstrate that, at present, the main and often the only tools to establish diagnosis are the symptoms proximity to the toxin injection and the clinical picture which bares great similarity across the patient’s population. We established the phenomenology of a novel syndrome, as an adverse event syndrome to BoNT/A and named it an “Impaired Neuronal Communication Syndrome” (INCS). We suggest an algorithm for safer BoNT/A use.

Clinical Cases

All patients were consulted for their condition by the author over a period of 4 years. Available data from other providers, imaging, laboratory and test results have been included in the data summaries (Tables 1a, 1b, 2a, 2b). The symptoms are graded in each case with one to three pluses in order of their severity and prevalence. All patients experienced multiple symptoms from each group with 12-25 range of total number of symptoms per patient. All patients had clinical effects from their injections. The demographics show significant female predominance due to the cosmetic use of the toxin in the majority of the presented cases. In addition, most of the patients were injected with onabotulinumtoxinA, likely because the drug has the longest market presence. The relevant data from past and family history and the abnormal findings from the general and the neurological examinations, done at time of presence of significant complains, are presented in Table 3a and 3b. The examination is often normal or minimally affected. The subtle positive signs can often be missed if fast or only a gross neurological examination is performed. We found that clock drawing, pictures and animals naming and at times muscle fatigability testing were useful tools in assessing patients’ status.