Journal of Alzheimer’s Disease & Parkinsonism Efficacy of Incobotulinumtoxin Type A (Xeomin ® ) in the Management of Sialorrhea in Neurodegenerative Diseases

Introduction: One of the symptoms of two very common and serious neurodegenerative diseases such as Amyotrophic Lateral Sclerosis and Parkinson’s disease is sialorrhea. It can cause macerations and fissures in perioral region, halitosis, dysarthria, aspiration penumonia, asphyxiation and patient’s awkwardness. Management can be conservative (medical therapy using anticholinergic drugs) or more invasive (surgery with excision of salivary glands, duct’s ligation and transposition). Botulinum toxin A is a non invasive and poor side effects alternative. Aim of this study is to examine therapeutic resources for sialorrhea in Amyotrophic Lateral Sclerosis and Parkinson’s disease, by objective and subjective evaluation. Materials and methods: 20 patients with sialorrhea caused by Parkinson’s disease (10 patients) and ALS (10 patients). Incobotulinum toxin A (XEOMIN ® , Merz Pharma), was injected under ultrasound guide in the submandibular and parotid glands. At t0 (pre-injection), t1 (30 days later), t2 (90 days later), t3 (120 days later), t4 (150 days later) and t5 (180 days later, only in PD group) we submitted Visual Analogue Scale (VAS) to estimated the level of salivation (1 was the best state and 10 the worst state), Gauze’s test to perform the weighed of the gauze after 1 minute and Sugar lump’s test to evaluate time necessary for melting. Results: In Parkinson’s and ALS group gauze’s test, sugar lump’s test and VAS improved until 6 months (PD group) and 5 months (ALS group), with p<0,05. Conclusion: This study concludes that therapeutic resource with Botulinum toxin A is an efficient treatment option for sialorrhea in patients with ALS and PD.


Introduction
Sialorrhea, a clinical state characterized by an abnormal and an over sediment of saliva in the oral cavity, is caused by a deglutition difficulty or an increased production of saliva, that flows out of the mouth [1]. There are three greater salivary glands (parotid, submandibular and sublingual) and a lot of lesser glands. In the unstimulated state, 70% of saliva is secreted by submandibular and sublingual glands [2]. Conversely, in the stimulated state the parotids glands provide most of the saliva [3].
ALS is characterized by a progressive degeneration of motor neurons in the spinal cord, brain stem and motor cerebral cortex, evolved to a muscular paralysis in bulbar, cervical, thoracic and lumbosacral regions [7]. Parkinson's disease has a progressive course and a shorter lifespan; there are three most important clinical signs: shaking, slow movement and muscle stiffness [8,9]. In these patients, the central process of drooling is the abnormal saliva's clearance. The abnormal coordination of buccal, facial and lingual musculature results in the over sediment of saliva in the oral cavity and in the inhibition of swallowing reflex; saliva get through the margin of the lips and the throat. Therefore the dysphagia caused by neuromuscolar disorder and normal saliva's flow cause sialorrhea in neurodegenerative diseases [10]. Clinically it can cause macerations and fissures in perioral region (so infections), halitosis, dysarthria, aspiration penumonia, asphyxiation [11]. Psychologically, patients feel uneasy, awkwardness and they tend to cut themself off, worsening mood.
Sialorrhea is known to be difficult to treat. Management can be conservative or more invasive. Medical therapy makes use of anticholinergic drugs [12]. Glycopyrrolate and transdermal scopolamine are very available in the treatment of sialorrhea but have also a lot of side effects (tachycardia, urinary retention, confused view, instability, daze).
Surgically it can be made the excision of salivary glands, duct's ligation and transposition; this solution is final but dangerous [13]. Radiation is not used because the side effects and the carcinogenic potential [14].
A non invasive and efficacy treatment is botulinum toxin A (BTX-A) injection in salivary glands. Botulinum toxin A temporarily blocks the release of acetylcholine and a number of other neurotransmitters from synaptic vesicles. The glands flow is controlled by autonomic nervous system: both parasympathetic and sympathetic have a role, but the latter is less important. The parasympathetic system uses acetylcholine to stimulate saliva's production, through glands receptor. BTX-A goes through cholinergic telodendrion and blocks neurotransmitter, so the gland's activity. Different study demonstrated efficacy (until 4-6 months) and safety of BTX-A injection in sialorrhea caused by Parkinson's disease and Amyotrophic Lateral Sclerosis with ultrasound guide [15][16][17].
Aim of this study is to examine, by objective and subjective evaluation, safety and efficacy of IncobotulinumtoxinA (Xeomin ® , Merz Pharma) in 20 patients with sialorrhea due to Amyotrophic Lateral Sclerosis (ALS) and Parkinson 's disease.

Materials and Methods
The study was performed in a term of six months (November 2016-April 2017); we have recruited 20 patients with sialorrhea, of which 10 suffering from Parkinson 's disease and 10 diagnosed with ALS.

Inclusion criteria
-Confirmed diagnosis of ALS and PD diagnosis.

Exclusion criteria
-No confirmed diagnosis of ALS and PD diagnosis; -No or severe (with PEG) dysphagia by FLS (nobody had PEG); -Efficacy of medical therapy with Amitriptyline (LAROXYL ® 7 drops/die).
Incobotulinum toxin A (XEOMIN ® ), reconstituted with saline water, was injected under ultrasound guide, so we had a great vision of submandibular and parotid glands, and of all surrounding structures including the facial nerve, that is very close to the parotid gland. We injected using two points for the parotid gland and one point for the submandibular gland. For the group of patients with Parkinson's disease the average drug's dosage given bilaterally in the parotid gland was 12,5 +/-3,9 U, in the submandibular gland was 12,2 +/-4,5 U. Patients with ALS were treated with 14,25 +/-4,3 U in the parotid gland and 13,3 +/-4,1 U in the submandibular gland.

Evaluation
The evaluation criteria were three, one subjective and two objectives: • Visual Analogue Scale (VAS): patients had to estimate the level of salivation (1 was the best state and 10 the worst state); • Gauze's test: patient shallows sitting; then we have put a piece of gauze, previously weighed, under the tongue, asking them to keep head tilted forward without swallowing. One minute later we have pulled off and weighed the gauze. Generally the gauze absorbs 0,12 g/min of saliva.
• Sugar lump's test: Patient shallows and then we put a sugar lump under the tongue, evaluating the necessity time for melting.
Data were noticed in these times: • t0=pre-injection We used TWO WAY ANOVA statistical analysis.
All patients were submitted to accurate anamnesis and medical exam, with attention to the swallowing; all patients signed informed consent in written form.

Parkinson's group
The two diagrams of gauze's test and sugar lump's test (Tables 1 and  2) show the clear reduction of the flow of saliva and the variations of the effect during the time.

ALS group
In the group of patients with ALS, data obtained by two objective tests are similar for the effect and the evolution of treatment (Tables 4-6).
In this case the effect lasts 5 months.

Discussion
Botulinumtoxin A treatment reduces saliva's flow to 50% both in patients with Parkinson's disease and with diagnosis of ALS [20]. This significant efficacy was obtained by a non-invasive treatment and a method of administration that thanks to ultra-sound guidance minimizes the risk of iatrogenic injuries, as the loss of the facial nerve [21].
Patients perceived and reported clinical benefit until 6 months in Parkinson's group and 5 months in ALS one. Efficacy was limited in time, for the event of sprouting. In this study, the transient effect makes necessary to repeat the treatment on average every six months in    patients with Parkinson's disease and every five months in patients with ALS. Maybe in this last group the effect lasts less for faster evolution of the disease and decline of deglutition [22].
Recruited patients did not showed collateral effects. In fact, no patients referred an important worsening of dysphagia caused by treatment. Some minimal worsening in Parkinson's group (1/10 patient) and in ALS group (2/10 patients) might be attributable to evolution of core disease; this did not caused PEG's use [23,24]. No patients referred paralysis of facial nerve due to sonographic guide that reduce incidence of nerve's lesion or others side effects, such as xerostomia.
In both groups, around 30% of patients reported a different pattern of saliva; after treatment they reported presence of most slimy saliva. Mainly this events due to transient interruption of parotids activity (watery secretion) and predominance of submandibular and sublingual (slimy secretion) [25,26]. The change of pattern did not cause any clinical problem to these patients; in some of them the different pattern was useful because reduced a lot the events of choking sensation (especially night-time) [27,28].
Advantages for patient subjected to these therapeutic treatment are important for lower incidence of aspiration pneumonia, macerations, rhagades and fissures in perioral region (so infections) and because decrease emargination and awkwardness in these patients that minimize relationship for embarrassment of drooling [29].
The objective of the treatment is to provide always a minimum flow of saliva in patients; indeed the dryness of oral cavity may cause the onset of other complications (fissures, dental decay, etc.) that are not easy to improve in these patients [30].
Also the caregivers benefit from treatment because the sialorrhea may require a continuous health care, so a distress for patient and for those who takes care of him [31,32]. 17