**3. Discussion**

Our study revealed that Botox injection to either the detrusor or the urethral sphincter achieved moderate or marked improvement in AD in 61% of SCI patients. There were more patients with marked improvement in the detrusor group, indicating a better control of AD. The baseline VUDS profile suggested that patients with poorer bladder compliance and higher detrusor pressure showed better responses to detrusor injection, and this response was best reflected by an increase in post-treatment compliance and a decrease in DO. The benefits that these patients might report could be related to their inferior pretreatment conditions, as these treatments did not help patients with borderline bladder dysfunction. In the urethral sphincter group, there were general improvements in VUDS parameters, including Qmax, VE, and BOOI, regardless of the subjective improvements in

AD after Botox injection. To our knowledge, this is the first study that has correlated VUDS findings and AD symptom improvements in SCI patients who received Botox injection at different sites.

The leading cause of death in SCI patients has shifted from urinary complications to cardiovascular events [15], marking the importance of the managemen<sup>t</sup> of AD. Since AD is highlighted by episodic hypertension, treatments for AD has been focused on blood pressure control with nitrites [16], calcium channel blockers [17], and alpha-adrenergic blockers [18]. However, the pathophysiology of AD includes a serial remodeling of the autonomic system: loss of supraspinal control over the sympathetic preganglionic neurons [19], synaptic reorganization of the sympathetic preganglionic neurons [20], primary afferent sprouting [21], and propriospinal plasticity [22]. This sensitized bladder proprioception, as well as other stimuli below the level of injury, are amplified to form an unregulated sympathetic reflex, resulting in an episode of AD. Considering the pathophysiology of AD, blood pressure control alone does not provide to-the-target management.

Botox paralyzes smooth or striated muscles through its inhibition of acetylcholine release in neuromuscular junctions. Through this mechanism of action, Botox has demonstrated effectiveness in reducing DO and urethral sphincter spasticity [23]. In addition to motor inhibition, Botox also has effects on the sensory neurons. The application of a sensory blockade has been proven effective in patients with bladder pain syndrome treated with intravesical injections [24]. These mechanisms include a decrease in both the release of neurotransmitters and the expression of nociceptors, as well as the suppression of afferent nerve sprouting and reorganization [25]. The diverse mechanisms of action make Botox an ideal therapy for SCI patients, as it targets both lower urinary tract symptoms and AD.

In our cohort of SCI patients who had AD that required anti-hypertensive management, LUTS-directed Botox injection yielded a 61% moderate or marked improvement in AD symptoms. There were two prior series addressing the role of Botox on AD. In the study by Schurch et al. evaluating the effect of Botox on LUTS, AD associated with bladder emptying that manifested as a hypertensive crisis during voiding disappeared after treatment in the three patients with tetraplegia [13]. Although this was a prospective study, AD was not an end point, but an incidental finding. Another study by Fougere et al. prospectively measured blood pressure during UDS and daily activity. The authors found that the amplitude of UDS-induced hypertension was attenuated in 17 patients after Botox injection; however, there were no significant differences found in 24-h ambulatory blood pressure monitoring [14].

Our results sugges<sup>t</sup> that improvement in AD can be more significant in those who have poorer bladder compliance and higher Pdet at baseline, which are typical UDS indications for Botox injection. This finding implies that additional detrusor injection can be considered in patients symptomatically indicated for urethral injection, in order to further eliminate their AD symptoms. Nonetheless, there were still 14% of patients who reported no improvement in AD, indicating insufficient managemen<sup>t</sup> for either LUTS or other stimulatory conditions such as constipation or pressure sores.

The strengths of our study are the large number of cases and complete VUDS evaluations. There are some limitations to our study. First, the baseline AD severity was unclear, and was not objectively measured. As there are currently no symptom scores or other objective evaluation tools for AD, we relied on patient-reported general assessments of the outcome to evaluate the treatment responses. Some studies used ambulatory blood pressure monitoring, but this method may not always record the blood pressure during AD episodes. Furthermore, there is no consensus on the criteria for blood pressure elevation. Second, this was not a randomized trial, and the decision for detrusor or urethral sphincter injection was based on the patients' main lower urinary tract symptoms and requirements. Although there has been no data suggesting predisposing factors for AD, significant bias might result from any unbalanced factors, such as age, sex, or the injury level between the two arms.
