Urinary dysfunction in acute brain injury: A narrative review

Journal Pre-proof Urinary Dysfunction in Acute Brain Injury: A Narrative Review Brandon Lucke-Wold, Sasha Vaziri, Kyle Scott, Katharina Busl

PII:

S0303-8467(19)30410-X

DOI:

https://doi.org/10.1016/j.clineuro.2019.105614

Reference:

CLINEU 105614

To appear in:

Clinical Neurology and Neurosurgery

Received Date:

23 September 2019

Revised Date:

11 November 2019

Accepted Date:

15 November 2019

Please cite this article as: Lucke-Wold B, Vaziri S, Scott K, Busl K, Urinary Dysfunction in Acute Brain Injury: A Narrative Review, Clinical Neurology and Neurosurgery (2019), doi: https://doi.org/10.1016/j.clineuro.2019.105614

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.

Urinary Dysfunction in Acute Brain Injury: A Narrative Review Brandon Lucke-Wold MD, PhD, MCTS1, Sasha Vaziri MD1, Kyle Scott BS1, Katharina Busl MD, MS1,2 1

University of Florida, Department of Neurosurgery, Gainesville, FL

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University of Florida, Department of Neurology, Gainesville, FL

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Neurosurgery University of Florida 1149 S. Newell Dr.

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Brandon Lucke-Wold MD, PhD, MCTS Department of

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Emails: [email protected], [email protected], [email protected], [email protected]

Building 59, RM L2-100 POB 100265 Gainesville, FL

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Little is known regarding the best management strategy for urinary dysfunction in neurologic injury patients We present key points regarding the most common neurologic injury paradigms The user-friendly figure offers a springboard for an effective management strategy This review will serve as a catalyst for future investigation regarding urinary dysfunction in the neurologic population

Abstract

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Highlights

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The frontal lobe urinary control center is an important regulator of urinary function. Neurologic injury often causes damage or temporary dysfunction of this center and other related urinary control pathways. Little has been reported about this topic in the literature although a majority of neurologic injury patients suffer from some type of urinary dysfunction. In this review, we highlight what is known about urinary dysfunction based on injury type (traumatic brain injury, hemorrhagic stroke, ischemic stroke, subarachnoid hemorrhage, subdural hematoma, and epilepsy). We discuss both clinical and pre-clinical data and pinpoint areas warranting further investigation. In the final section, we provide proposed practice suggestions for managing these patients clinically with the intended goal for refinement in these approaches following further clinical trials.

Key words: brain injury, urologic dysfunction, treatment approaches, frontal control center

Introduction:

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Urologic control has long been postulate to be controlled by the connections between the brain micturition centers and bladder. These pathways can be disrupted during injury. It has been well reported in the literature that patients with neurologic injury patients are more susceptible to urinary retention and a dysfunctional urinary tract compared to the general medical population 1. Rodent studies have correlated injury severity to increased likelihood of urinary dysfunction 2. Furthermore, human case reports have shown that location of injury may also contribute to different types of problems such as neurogenic bladder and sphincter dyssynergy 3. Other groups have even investigated the topic that post-injury urinary retention may be contributed to common medications given to neurologic injury patients 4. Due to this multi-pronged dysfunction, neurologically injured patients often require bladder catheterization and long-term medical management for urinary problems. The risk of catheter-associated urinary tract infections (CAUTIs) is higher in the neuro-ICU population due to the need for catheter-placement and maintenance in many brain-injured patients 5. In fact, brain injury increases the risk of developing urinary dysfunction 5 fold 6. Despite the high incidence and the relevant clinical challenge, little is known about how the injuries affect underlying pathophysiology. The current accepted management approaches for these patients have focused on urinary catheter bundles, but few studies have looked at neurologic populations specifically. Due to the importance of this topic in terms of managing long-term outcomes for patients, we have summarized the current findings in this review and present topics warranting further investigation.

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Methods: We systematically examined the literature using the search terms urinary dysfunction and neurologic injury in PubMed, EMBASE, and Science Direct. PRISMA criteria were considered for this review in order to meet standards for systematic review. Due to the paucity of literature involving any intervention, cohorts, or comparisons, the PRISMA criteria could not be sufficiently analyzed or met. The majority of studies were case studies, case series, or preclinical analysis in animal models that had little to no description of methods. The following criteria were therefore utilized: relevant literature was critically evaluated by two separate reviewers for relevance to the proposed review and divided into clinical and pre-clinical categories. A paper was deemed relevant if it met the following criteria 1) focused on urinary dysfunction pathophysiology or management, 2) was related to a neurologic injury, 3) was published in a well-respected journal (having several citations, deemed clinically relevant, and having relevant discussion regarding the pathophysiology), and 4) was agreed upon by both reviewers. We grouped the relevant literature by the following neurologic injury subtypes as a methodologically approach to help with ease of reference: traumatic brain injury, hemorrhagic stroke, ischemic stroke, subarachnoid hemorrhage, subdural hematoma, and epilepsy. Our search yielded 19 papers for traumatic brain injury and urinary dysfunction, with 8 deemed relevant (7 clinical, 1 pre-clinical). 17 papers were found for hemorrhagic stroke and urinary

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dysfunction, with 8 deemed relevant (7 clinical, 1 pre-clinical). 31 papers were found for ischemic stroke and urinary dysfunction, with 10 deemed relevant (9 clinical, 1 pre-clinical). 23 papers were found for subarachnoid hemorrhage and urinary dysfunction, with 6 deemed relevant (6 clinical). 22 papers were found for subdural hematoma and urinary dysfunction, with 6 deemed relevant (6 clinical). 11 papers were found for epilepsy and urinary dysfunction, with 4 deemed relevant (4 clinical). The relevant data is presented based on injury type starting with the clinical discussion (Figure 1) and progressing into pre-clinical based evidence. In the clinical synopsis, we present recommendations for management of urinary dysfunction in neurologic injury patients. Although individual contributing patient factors may alter the recommended approach, we have sought to provide general guidance for a topic sparsely covered in the literature. Anatomy Overview

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The process of urine storage and conversely micturition involves the coordinated effort of smooth and striated muscles throughout the bladder and bladder neck. The reflexes that coordinate this process originate in the brain. For bladder storage, the pontine storage center stimulates the pudendal nerve, which increases striated uretheral sphincter activity. This activity normally occurs in conjunction with sympathetic drive from the spinal cord that stimulates what is known as the guarding reflex 7. On the flip side, ascending input from the spine to the periaqueductal grey stimulates the pontine micturition center once the bladder becomes full. The pontine micturition center then stimulates the pelvic nerve and parasympathetic nerves to initiate micturition. The pontine micturition center also sends inhibitory input to the sympathetic system 8 .

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Signaling from the periaqueductal grey to the pontinue micturition center can be modulated from the prefrontal cortex. The prefontal cortex initiates modulation through three distinct pathways. The first pathway involves stimulating the insula, which directly targets the periaqueductal grey. The second pathway involves an indirect system. The prefrontal cortex stimulates anterior cingulate cortex that then targets hypothalamus and finally periaqueductal grey. The final pathway is less important but involves prefrontal cortex stimulation to basal ganglia that then sends efferents to the periaqueductal grey. It is therefore no surprise the diseases that alter the frontal lobe such as fronto-temporal dementia contribute to urologic dysfunction 9. The thalamus and cerebellum also play a role in controlling the pontine micturition center, but these pathways are not fully known 10.

Findings: Injury Types and Urinary Dysfunction Traumatic Brain Injury Traumatic brain injury (TBI) affects millions of people across the globe every year, resulting in close to 300,000 hospitalizations annually in the U.S. 11. The injury spectrum ranges from mild to severe, with severe TBI patients often requiring care in trauma or neurologic intensive care units. Severe TBI patients have augmented renal clearance and increased urine output 12. The

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proposed mechanism for this is believed to have two reasons: increase of cardiovascular output in reaction to the trauma with resultant increased renal perfusion, and secondly release of atrial natriuretic protein with facilitation of further renal clearance 13. The result is that several TBI patients experience increased urinary frequency during and after hospital admission 14. In a subset of patients with affected frontal lobe, frontal lobe damage can contribute to dysfunction due to involvement of the bladder control center. Often this manifests as acute incontinence that slowly recovers with time 15. Jiang and colleagues, using a rodent model, have linked the progression from incontinence to return of function. They found that increased collagen deposition in the bladder after TBI increases bladder tone to compensate for initial de-enervation 16 . Interestingly, patients with the most severe brain injuries don’t develop this compensatory response and this has been correlated to worse overall outcomes 17. One potential reason is that these patients require more long-term bladder catheters increasing the overall likelihood of infection 18.

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Hemorrhagic stroke

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Hemorrhagic stroke patients are more likely to present with urologic dysfunction compared to ischemic stroke patients 19. One of the proposed reasons is that hemorrhagic stroke is often caused by hypertension. The elevated blood pressure also damages kidney vasculature making the kidneys further susceptible after neurologic insult 20. Some groups have even proposed that albuminuria might even be a predictor of hemorrhagic stroke 21. This is likely true due to the fact that patients with chronic kidney disease (CKD) are known to have larger intracerebral hemorrhage than those without CKD 22. Another interesting hypothesis is that hemorrhagic stroke disrupts the brain micturition centers. Cho and colleagues, using a rodent model, showed that intracerebral hemorrhage originating near the hippocampus damaged the medial preoptic area, ventrolateral gray, and pontine micturition center thereby leading to increased bladder contractions but decreased bladder pressure and voiding time. Therefore patients may exhibit urinary frequency similar to that seen following TBI, but also have high residual volumes due to decreased bladder-emptying times 23. This has been clinically verified by poor creatinine clearance following hemorrhagic stroke 24. The proposed mechanism is disruption of the pathway connecting the brain to the detrusor external sphincter 25. If the stroke occurs below the tentorium however, instead of urinary retention the patient is likely to experience urinary incontinence 26. These patients with cerebellar hemorrhages therefore are more likely to require increased rehabilitation and longer admission stays, which is correlated with increased morbidity 27 . Ischemic Stroke

The degree of renal dysfunction measured by glomerular filtration rate is an independent predictor of outcomes following ischemic stroke 28. Patients that have glomerular filtration rates <60ml/min per 1.73 m2 have worse 28 day mortality, worse modified rankin scale scores, and worse stroke disability scores than those with a glomerular filtration rate >60ml/min per 1.73 m2 29 . A proposed mechanism is that urinary dysfunction in ischemic stroke leads to higher risk of thromboembolism and increased risk of bleeding initiated by a positive feedback loop that increases overall time spent in atrial fibrillation 30. Not surprisingly therefore those with urinary

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dysfunction post-stroke had worse diagnostic findings on follow-up brain scans compared to those without urinary dysfunction post-stroke 31. Another hypothesis is that stroke increases the sympathetic response and renin-angiotensin pathway, which initially improves kidney perfusion but ultimately overtaxes an already stressed organ 32. Rodent studies have shown that urinary dysfunction in stroke is likely due to damage to the frontal micturition center 33. Some researchers have therefore argued for urodynamic studies whenever a stroke involves any portion of the frontal lobes regardless of side 34. Urodynamic studies have shown that of patients with urinary retention post-stroke, 90% had overactive detrusor activity. Furthermore, 62.5% of patients with overactive detrusor also had sphincter dysynergy 35. Interestingly, patients with diabetes were more likely to have urinary retention post-stroke 36. Based on this association, Lee and colleagues have urged clinicians to check for albuminuria prior to urodynamic studies to stratify the groups since patients with albuminuria are prone to do worse 37.

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Subarachnoid Hemorrhage

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Often times, subarachnoid hemorrhage patients due to aneurysm rupture do not initially present with urinary retention. On the contrary, they often have increased urination due to cerebral salt wasting 38. Urinary retention however becomes much more common in the time period of vasospasm (4-21 days) 39. Similarly, patients with reversible cerebral vasoconstriction syndrome (RCVS) with vasospasm at presentation often have a degree of urinary retention early during their hospital stay 40. Patients with traumatic subarachnoid hemorrhage may also develop urinary retention early, perhaps due to the wider and less predictable vasospasm window 41, and possibly also due to dysfunction of the frontal micturition center. Unfortunately, regardless of subarachnoid hemorrhage type (aneurysm, trauma, RCVS) the degree of urinary retention has been associated with deleterious outcomes. For aneurysmal patients, 26% develop some form and degree of renal failure 42. For trauma patients, catecholamine detection in the urine early in the course of the hospital stay may predict future urinary dysfunction 43. Further work is needed to elucidate treatment options for these patients. Subdural Hematoma

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It has been reported in the literature that acute on chronic subdural hematoma can lead to increased urinary retention due to mass effect of the subdural hematoma onto parenchyma, with resulting brain compression 44. When the subdural hematoma involves the frontal lobe, the voiding reflex loop and urinary control center are often disrupted 45. Headache often precedes the onset of the urinary retention and both can persist for some time even after the subdural has been evacuated 46. Amnestic voiding has also been reported likely due to overflow incontinence 47. If the subdural hematoma is not evacuated quickly, the patient can develop overactive detrusor contractions and urgency incontinence 48. Even after surgical evacuation, these patients are at increased risk for urinary dysfunction frequently manifesting as urinary tract infections 49. In fact, Abulhasan found that for every 1000 ICU days in this patient population, 11 urinary tract infections could be expected 50. Epilepsy

Clinical Synopsis

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Urinary dysfunction, and most commonly, urinary incontinence can be hallmarks of epilepsy, with studies showing that as much as 39% of all epilepsy patients have some form of urinary symptoms. Studies have established that during the peri-ictal period, urinary urge and urinary incontinence seem to be most prevalent, whereas during post-ictal period, urinary retention seems to be the most common symptom 51. Urinary incontinence has been associated with the end of the clonic phase of a tonic-clonic seizure, due to relaxation of the sphincter muscles during the muscular recovery phase, or with absence and partial seizures, hypothesized to be due to increased intra-vesicular pressure and a loss of cortical inhibition of the micturition reflex 52. Electroencephalogram studies have shown that seizure onset from the cortical regions, specifically the supracallosal part of the medial frontal cortex, can explain an interaction between seizures, the supra-pontine micturition centers and urinary incontinence 51. As a topic of much debate, the diagnostic value of urinary incontinence in seizures presents with conflicting evidence. While it has been reported to help in differentiation from non-epileptic seizures, most studies seem to indicate that it has no reliable value in the differential diagnosis 53. Furthermore, it has been shown that the presence of urinary incontinence offers little to no lateralizing value 54. Urinary urgency has most commonly been reported during the aura or at the beginning of seizures in adults with non-dominant temporal lobe epilepsy 52. Other studies have also associated ictal urinary urgency with non-dominant hemisphere lateralization and with hyper perfusion of the insula 51. Urinary retention is thought to be associated with Todd’s paresis, due to the absence of an excitatory signaling from the periaqueductal gray matter and of a safe signal from the hypothalamus. EEG monitoring has further elucidated that alteration of cortical activity on supra-pontine micturition potentially contributes to postictal urinary retention 51. Of note, micturition has been reported to actually trigger reflex epilepsy; the neuromechanism of which is thought to be an over activation of the midline or frontotemporal lobe 51.

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Despite clear preclinical evidence that pathologic pathways are present in the common forms of acute brain injury that directly affect urinary function, clinical data and management trials are surprisingly sparse. Urinary catheters or intermittent catheterization is required in a large proportion of patients with acute neurologic injury, and presence of catheters is well known to enhance the risk for CAUTIs 55. Several institutions have extrapolated urinary protocols from other patient populations with variable success. We present below a management algorithm for urinary dysfunction in the neurologic population. Although we fully acknowledge that the protocol is not all-inclusive, the goal is to provide an initial basis that can be refined for neurologic patients once additional data becomes available. Management of Urinary Dysfunction Early recognition is key in management of urinary dysfunction. Most patients will have a bladder scan early in the course of their hospital stay. This is a crude measurement of urinary function but can be used as an indicator for bladder volume and pressure that ultimately dictate the need for intermittent catheterization or catheter placement. If a foley catheter is placed, urodynamic studies can be performed with or without sphincter electromyography. The study consists of both a bladder filling component as well as a bladder-emptying component. A pressure catheter is

placed in the bladder and can detect pressure changes from both the abdomen and detrusor muscle 56. The studies can determine detrusor reflex status and help pinpoint where the dysfunction originates. In select patients, a voiding cystourethrogram may be necessary to determine if the pathology is cranial or urethral/bladder in origin. In our practical experience, urological dysfunction in acute brain injury is usually temporary, and additional urological testing is rarely needed or obtained.

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The primary goal is to prevent urinary tract infections, renal calculi, and ureteral reflux. Patients suffering from increased bladder pressure will benefit from catheters, and perhaps tamsulosin 57. Most of these patients will regain some function with time, but exact data on resolution and time course are not available. Oftentimes urinary recovery is hampered by coexistent use of opiates in this population, which independently contribute to urinary retention 58. New treatment modalities with implanted detrusor stimulators may be of value 59. These stimulators have primarily been used thus far in spinal cord injury patients but expanded implications have been suggested for TBI and ischemic stroke patients. Patients that have partial retained urinary function with increased voiding frequency and/or urgency are best treated by a combination of anticholinergics and behavioral therapy. 30% of patients have complete resolution of symptoms with mind body therapy only, which is comparable to medication alone 60. The type of therapy with the bestproven efficacy is mind-body awareness exercises 60. In select cases, intradetrusor botulinum A might be an option as well if other therapies have failed 61. A diagram for treatment approach is highlighted in figure 2. Conclusions

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In summary, most neurologic injuries seen in the intensive care unit frequently cause urinary dysfunction, but exact data on incidence and duration is still lacking. Broadly grouped, the injury subtypes can be divided into damage to the frontal lobe bladder control center or the pontine micturition center. Depending on location of damage, the clinical outcomes vary from increased bladder function and urinary frequency to completely halted function with urinary retention. Little research has also been done for most effective management for acute neurological injury patients. Ongoing research is necessary to improve understanding and management of urinary dysfunction in patients with acute neurologic injury.

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Figure Legends

Figure 1: urinary dysfunction categorized by injury subtype and underlying pathophysiology

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Figure 2: management algorithm for urinary dysfunction in the neurologic injury patient

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