Muscle & Nerve

MUSCLE & NERVE

Invited Review

Bladder Dysfunction in Peripheral Neuropathies

Ahmet Z. Burakgazi, MD, Bander Alsowaity, MD, Zeynep Aydin Burakgazi, BS, Dogan Unal, MD, And John J. Kelly, MD

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Ahmet Z. Burakgazi, MD, Bander Alsowaity, MD, Zeynep Aydin Burakgazi, BS, Dogan Unal, MD, and John J. Kelly, MD

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BLADDER DYSFUNCTION IN PERIPHERAL NEUROPATHIES

AHMET Z. BURAKGAZI, MD, BANDER ALSOWAITY, MD, ZEYNEP AYDIN BURAKGAZI, BS, DOGAN UNAL, MD, AND JOHN J. KELLY, MD

EDUCATIONAL OBJECTIVES Upon completion of this monograph, the reader will acquire skills to: (1) describe the normal neuroanatomy and neurophysiology of the bladder and micturition, (2) describe the causes of bladder dysfunction caused by various neuropathies, (3) seek and recognize the symptoms of bladder dysfunction in neuropathy patients, (4) describe the tests necessary to diagnose the nature of bladder dysfunction, and (5) describe the proper pharmacologic and non-pharmacologic treatment of bladder dysfunction.

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INVITED REVIEW BLADDER DYSFUNCTION IN PERIPHERAL NEUROPATHIES AHMET Z. BURAKGAZI, MD,1 BANDER ALSOWAITY, MD,1 ZEYNEP AYDIN BURAKGAZI, BS,2 DOGAN UNAL, MD,3 and JOHN J. KELLY, MD1,4 1 Department of Neurology, George Washington University, 2150 Pennsylvania Avenue NW, Suite 7-404, Washington, DC 20037, USA 2 Pharmacist, Washington, DC, USA 3 Department of Urology, School of Medicine, Fatih University, Ankara, Turkey 4 Department of Neurology, George Washington University, Washington, DC, USA Accepted 20 May 2011

ABSTRACT: Normal bladder function depends on the complex Guillain–Barre´ syndrome (GBS), chronic inflam- interaction of sensory and motor pathways. Bladder dysfunction matory neuropathies, human immunodeficiency vi- can develop as a result of several neurological conditions. It can happen in a number of ways, including diabetic cystopathy, rus (HIV)-associated neuropathy, amyloid neuropa- detrusor overactivity, bladder outlet obstruction, and urge and thy, and hereditary neuropathies. stress urinary incontinence. Diabetic neuropathy is the most common cause of peripheral neuropathy–associated bladder dysfunction. Guillain–Barre´ syndrome (GBS), human immunodeficiency virus (HIV)-associated neuropathy, chronic inflamma- NEUROANATOMY AND NEUROPHYSIOLOGY OF THE tory demyelinating polyneuropathy (CIDP), and amyloid URINARY SYSTEM neuropathy are other major causes. The diagnosis of bladder dysfunction should be established by the history of neurological Understanding the neuroanatomy of the urinary symptoms, neurological examination, and urological evaluation. system provides better insight into the pathogene- Functional evaluation of the lower urinary tract includes cystom- sis of BD. The bladder wall is formed by three etry, sphincter electromyography, uroflowmetry, and urethral pressure profilometry. Management of urinary symptoms in layers of interdigitating smooth muscle (the detru- patients with bladder dysfunction is usually supportive. In some sor muscle) and works as a vesicle for the storage cases, alpha-blocker and/or anti-muscarinic agents are needed and evacuation of urine. The internal sphincter is to help improve urinary dysfunction. Intermittent self-catheterization is needed occasionally for patients with slow and/or poor the part of the detrusor muscle that is localized at recovery. the junction of the bladder neck and urethra. This Muscle Nerve 45: 2–8, 2012 sphincter is not anatomically isolated but functions as a physiological sphincter. Normal bladder function in humans depends on Reflex bladder contractions are activated by sympathetic, parasympathetic, and somatic nerves the complex interaction of sensory and motor 2 pathways at numerous levels in the central and pe- from the spinal cord. The preganglionic parasympathetic efferent nerves arise from the S2–S4 spi- ripheral nervous systems. Bladder dysfunction 3 (BD) can develop as a result of several neurologi- nal nerves. The axons run a long distance within the pelvic nerves to the ganglia (pelvic plexus), cal conditions, including cortical lesions such as 3 stroke, multiple sclerosis, and dementia; subcorti- which are located close to the bladder. Acetylcho- line (ACh) is the main neurotransmitter for both cal lesions such as Parkinson disease and multiple 4–6 system atrophy; brainstem lesions; spinal cord pre- and postganglionic parasympathetic fibers. lesions; conus medullaris syndrome; cauda equina The preganglionic sympathetic efferent fibers arise 1 from the thoracolumbar segment of the spinal syndrome; and peripheral neuropathy. 3,7 In this study we focus on the prevalence, clini- cord at T10–L2. Those fibers intermingle with cal characteristics, electrodiagnostic findings, and somatic efferents from spinal nerves and synapse management of BD associated with certain periph- in one of the nearby paravertabral ganglia of the eral neuropathies, including diabetic neuropathy, sympathetic chain, which continue peripherally with associated somatic segmental fibers.5,6 Alterna- Abbreviations: ACh, acetylcholine; AIDS, acquired immune deficiency tively, some fibers pass through the paravertabral syndrome; AL, amyloid light chain; BD, bladder dysfunction; CIDP, chronic inflammatory demyelinating polyneuropathy; CMT, Charcot–Marie–Tooth; ganglia and synapse with one of the prevertebral DM, diabetes mellitus; EMG, electromyography; FAP, familial amyloid poly- or collateral ganglia on the aorta or internal iliac neuropathy; GBS, Guillain–Barre´ syndrome; HIV, human immunodeficiency virus; MCV, motor conduction velocity; nAChR, nicotinic acetylcholine re- vessels, such as the inferior mesenteric ganglia, ceptor; SCV, sensory conduction velocity; TTR, transthyretin; UTI, urinary then continue inferiorly as the hypogastric nerves. tract infection; Vds, vesical denervation supersensitivity Key words: amyloid neuropathy; bladder dysfunction; chronic inflammatory Some fibers pass through both pre- and paraverte- demyelinating polyneuropathy; diabetic cystopathy; Guillain–Barre´ bral ganglia and synapse with the end organ.5,6 syndrome; HIV-associated neuropathy; peripheral neuropathy A.Z.B. is currently affiliated with Neuroscience Section, Virginia Tech The main neurotransmitter for postganglionic sym- Carilion School of Medicine, Roanoke, VA. pathetic fibers is norepinephrine, and for pregan- Correspondence to: A. Z. Burakgazi; e-mail: [email protected] glionic sympathetic fibers it is ACh.5,6 VC 2011 Wiley Periodicals, Inc. Published online in Wiley Online Library (wileyonlinelibrary.com). The preganglionic somatic efferent nerves orig- DOI 10.1002/mus.22178 inate from the nucleus of Onuf (at S2–S4) in the

2 January 2012 MUSCLE & NERVE Bladder Dysfunction in Peripheral Neuropathies

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sacral spinal cord. The nerve fibers travel within around 25% after 10 years of diabetes, and >50% the pudendal nerve to the external urethral after 45 years of diabetes.18 It has been reported sphincter.3,5,6 In addition, afferent nerves are that 75–100% of patients with diabetic peripheral located in the detrusor muscle and the suburothe- neuropathy develop diabetic cystopathy.19–22 lium.8 The afferent nerve fibers form plexiform The cause of BD in DM is primarily peripheral structures beneath the urothelial lining (more and autonomic neuropathy. Animal and human prominent in the trigone and bladder neck and studies have revealed that diabetic cystopathy relatively sparse in the bladder dome), with some develops as a result of polyneuropathy, which pre- nerve ends extending into the urothelium.5,6 The dominantly affects sensory and autonomic nerve afferent fibers travel within pelvic, hypogastric, and fibers.15,19,23,24 The pathogenesis of diabetic neu- pudendal nerves.6 Two types of afferent nerves ropathy is not fully clarified. Some of the proposed have been described: (1) myelinated Ad fibers, pathogeneses include altered metabolism of glu- which respond to normal bladder distention and cose, ischemia, superoxide-induced free-radical for- 18,25 the main afferent nerve during normal micturi- mation, and impaired axonal transport. tion; and (2) unmyelinated C fibers, which The exact prevalence of voiding dysfunction 19,21,26 respond to chemical irritation or cold, and are caused by diabetes is, however, uncertain. BD usually silent normally, but appear to be more in DM can occur in a number of ways, including di- active during pathological conditions.6,9,10 abetic cystopathy, detrusor overactivity, and urge During the storage phase, the bladder and the in- urinary incontinence. Each form of BD in DM has ternal urethral sphincter are predominantly acti- been reported with variable prevalence in the litera- vated by the sympathetic nervous system. Activation ture. In earlier studies, the frequency of diabetic of the sympathetic nervous system leads to contrac- cystopathy varied from 25% to 80%, and the rate of tion of smooth muscles in the bladder base and detrusor overactivity ranged from 39% to 61%. The proximal urethra via activation of a-adrenergic differences depend on the diagnostic methods, study criteria, and patient characteristics.27 receptors (the a1A subtype is the main subtype in the urethra and prostate) and relaxation of the detrusor Onset of diabetic BD in most patients is insidi- ous and often not recognized until it has reached via activation of b-adrenergic receptors (b2 and b3 are the main receptors located in the lower urinary an advanced stage. Patients often remain asymp- tract) in the bladder body. Overall, sympathetic nerv- tomatic in early stages despite demonstrable bladder abnormality. Impaired bladder sensation is ous system activation provides urinary accommoda- usually the first manifestation of lower urinary tract tion and inhibition of the micturition reflex.3,5,6,11 involvement. Micturition reflexes are delayed due During the voiding phase, which is initiated vol- to diminished bladder sensation with increases in untarily from the cerebral cortex, the voiding pro- bladder capacity and urinary retention that usually cess begins with relaxation of the external sphinc- occur asymptomatically.16,28–31 Patients are fre- ter, followed by activation of parasympathetic quently unaware of bladder dysfunction until they efferent activity that leads to contraction of the have a urinary tract infection (UTI) secondary to detrusor muscle (mediated via muscarinic recep- 14 increased residual urine volume. The common tors, M and M , as predominant subtypes, in the 2 3 symptoms are straining, hesitation, and weakness bladder) and relaxation of the smooth muscles in of stream.32 Diabetic cystopathy is characterized by the bladder base and proximal urethra (mediated 3,5–7 impaired sensation of bladder fullness, which leads by the release of nitric oxide). to overstretched bladder, reduced bladder contrac- In BD caused by peripheral neuropathy, the tility, increased residual urine, and impaired affected individual usually demonstrates urinary uroflow.15,23,31,33 retention. In these diseases, the nerves to the bladder are destroyed, resulting in silent, painless dis- ELECTRODIAGNOSTIC FINDINGS tension of the bladder.10,12,13 Similar to injury of Diabetic neuropathy is characterized by axonal the sacral spinal cord, the detrusor is unable to degeneration, demyelination, and fiber loss. Elec- contract to empty the bladder, a condition known tromyography (EMG) is usually normal but some- as detrusor areflexia.14,15 Affected individuals have times shows sphincter denervation and uninhibited difficulty eliminating urine and develop overflow sphincter relaxation. EMG of perineal muscles can incontinence.12 be used to show denervation and detrusor-sphincter dyssynergia.32 Bradley et al. reported that a pro- DIABETIC NEUROPATHY longed latency of evoked potentials in response to Diabetes mellitus (DM)1,16,17 is the most common detrusor stimulation would be evidence of visceral cause of peripheral neuropathy in North America. neuropathy.34 A prolonged latency of the bulboca- The prevalence rate of BD increases with the dura- vernosus reflex is another abnormal finding in vis- tion of diabetes mellitus. For instance, the rate is ceral neuropathy.35

Bladder Dysfunction in Peripheral Neuropathies MUSCLE & NERVE January 2012 3

Mitsui et al. studied the relationship between psychotics. Further work-up should be done abnormal nerve conduction velocity and vesicou- including evaluation of a patient’s voiding record, rethral dysfunction in 29 asymptomatic diabetic post-void residual testing, and urinalysis. Cystomet- subjects. Nerve conduction velocities were meas- ric and urodynamic studies should be done to con- ured in the sural sensory nerve (sensory conduc- firm the diagnosis. Vinik et al. recommended tion velocity, SCV) and the fibular nerve (motor screening that includes renal function, urine resid- conduction velocity, MCV). In 12 patients with nor- ual, and voiding cystometrogram for diabetic blad- mal SCV and MCV, voiding dysfunction was not der dysfunction for any diabetic patient with recur- noted. Thirteen patients with voiding dysfunction rent UTI, pyelonephritis, incontinence, or had abnormal SCV and MCV. Thus, diabetic vesi- palpable bladder.30 courethral dysfunction is highly correlated with Functional evaluation of the lower urinary tract abnormal nerve conduction.33 includes cystometry, sphincter electromyography, In an historical context, different diagnostic uroflowmetry, and urethral pressure profile. In tests, such as the denervation cholinergic supersen- most typical cases of diabetic cystopathy, cystome- sitivity test of the bladder and urethra, have been try shows a long curve with lack of sensation, often used for evaluation of bladder function in diabetic until bladder capacity is reached, with a low detru- patients. The denervation test consists of a contin- sor pressure.19,23 Uroflowmetry shows low peak ual reading of the intravesical pressure response to flow and prolonged duration of flow associated subcutaneous administration of 0.25 mg carbachol with increased residual urine.14,23 Kebapci et al. (equivalent to 2.5 mg bethanechol) after the blad- recommended urodynamic study for all type 2 DM der has previously been filled with 100 ml saline patients at least 8–9 years after the diagnosis.27 and allowed to accommodate. The positive test results were postulated to be related to axonop- MANAGEMENT athy, which is evidence of denervation, in the neu- Patients with diabetic bladder dysfunction usually ral pathway innervating the bladder.24,36 However, have a combination of urinary retention, overflow recent data show that urothelium afferent nerve incontinence, and UTI. The management of lower endings and interstitial cells all express muscarinic urinary tract symptoms in DM depends on the receptors, so theoretically conditions other than degree of complaints and their impact on quality ‘‘denervation’’ can lead to an abnormal test.8,37,38 of life. Little research has been published to guide Morita et al. reported in diabetic patients that practice for the treatment of lower urinary tract there was a greater chance of detecting denerva- symptoms in DM, but the important goal is to tion supersensitivity of the urethra to an a-sympa- eliminate or modify risk factors that can cause wor- thetic agonist than of the bladder.33,39 This implies sening of DM-related nephropathy and that the isolated neurogenic dysfunction of the neuropathy.40 urethra, as evidenced by denervation supersensitiv- Poor glycemic control and diabetic nephropa- ity in the absence of vesical denervation supersensi- thy can cause increased urine output, which leads tivity (Vds), can cause voiding dysfunction in dia- to increased mean voided volume and inconti- betic patients.33,39 nence. Optimal glycemic control should be A correlation between diabetic cystopathy and achieved. Diet, exercise, and weight loss are abnormal sympathetic skin response has been encouraged in diabetic patients, but individuals reported.23 Sympathetic skin responses are medi- who are unable to achieve or maintain optimum ated by unmyelinated postganglionic sympathetic glucose control by diet and exercise alone should fibers. Abnormal sympathetic skin responses initiate oral glucose-lowering agents, insulin, or among diabetic patients would suggest that dia- both.40 betic bladder dysfunction is caused by axonopathy Different strategies can be applied in bladder in autonomic nerves innervating the bladder. dysfunction in DM to prevent complications and improve quality of life. Diabetic patients with DIAGNOSIS reduced bladder sensation and infrequent voiding The diagnosis of diabetic cystopathy should be should practice timed voiding on a consistent and established by a history of neurological symptoms, regular schedule (every 2–4 hours). Intermittent neurological examination, and bladder evaluation. catheterization is often needed to achieve bladder The evaluation of BD in DM should start with a emptying and reduce the risk of UTI with poten- detailed history including medication review for tial deterioration of renal function. drugs that might impair detrusor contractility and Long-term antimicrobial prophylaxis may be increase urethal tone. These include calcium chan- required for recurrent UTI. The optimal catheteri- nel blockers, anticholinergics, a- and b-adrenergic zation frequency is not clear and may vary from agonists, narcotics, antidepressants, and anti- one to four times daily depending on the

4 Bladder Dysfunction in Peripheral Neuropathies MUSCLE & NERVE January 2012

individual’s needs.41 In addition, elderly diabetic paraneoplastic autonomic neuropathy. In that patients usually have concomitant disorders, such model, once rabbits were immunized with the as benign prostatic enlargement, stress inconti- recombinant a3 subunit, they developed profound nence, and bladder or prostate cancer or infection, gastrointestinal hypomotility, dilated pupils with which should be taken into consideration in differ- impaired light response, and grossly distended ential diagnosis and management.40 There is no bladders. As in patients with idiopathic and para- effective medication currently available to assist neoplastic autoimmune autonomic neuropathy, with bladder emptying in diabetic cystopathy, but the severity parallels the serum levels of ganglionic a-blockers may be helpful in outlet obstruction nAChR autoantibody.51 from prostatic enlargement.40 Besides cystometric and urodynamic studies for the evaluation of bladder function, specific auto- AUTONOMIC NEUROPATHY nomic tests should be performed to assess the au- Autonomic neuropathies comprise a wide spec- tonomic nervous system. Such tests include the trum of syndromes and diseases that affect the au- thermoregulatory sweat test (TST), quantitative tonomic nervous system. Autonomic neuropathies sudomotor axon reflex test (QSART), sympathetic can be caused by hereditary or acquired diseases. skin response (SSR) test, and quantitative sensory The autonomic nervous system subserves numer- testing (QST).26,52,53 A skin biopsy for a quantifica- ous body functions; thus, autonomic dysfunction tion of pilomotor nerves may be performed to eval- may manifest with various clinical presentations, uate autonomic involvement.54 including bladder dysfunction and numerous labo- ratory and neurophysiological abnormalities.1,42–44 GUILLAIN–BARRE´ SYNDROME Inherited autonomic neuropathies occur rarely. Guillain–Barre´ syndrome (GBS) is comprised of a The most common genetic disorders presenting group of acute demyelinating and axonal autoim- with autonomic dysfunction include familial amy- mune polyneuropathies. It is characterized by a loid polyneuropathy, hereditary sensory autonomic largely symmetrical, ascending motor paralysis with neuropathies, Fabry disease, and porphyrias.26,42–44 or without sensory and autonomic disturbances. The acquired autonomic neuropathies that can Although complete recovery is possible, GBS may be subclassified into primary and secondary disor- leave patients severely disabled.48 ders are much more prevalent than the inherited A range of incidence rates for autonomic dys- ones. Primary autonomic neuropathies are idio- function in GBS has been reported in different pathic and have autonomic dysfunction as a part studies. Sakakibara et al. found BD, including uri- of the disease process itself. In the secondary auto- nary retention, voiding difficulties, and urinary ur- nomic neuropathies, a certain cause may lead to gency, in 7 of 28 (25%) cases in one GBS series autonomic neuropathy, but autonomic neuropathy and in 18 of 65 (27.7%) cases in another se- is not a defining feature of the disease process.43,44 ries.55,56 In other reports, micturition dysfunction There are several identifiable causes of secondary was present in 11–30% of patients studied.56,57 acquired autonomic neuropathies, including meta- Peripheral nerve malfunction of lumbosacral bolic derangements, such as DM, hepatic disease, autonomic fibers, from either inflammation or and uremia; vitamin deficiencies, such as vitamin immune attack on autonomic fibers, might cause B12 deficiency; toxins and prescription medica- either an underactive bladder (weak detrusor or tions, such as alcohol and chemotherapeutic medi- detrusor hypocontractility) or bladder overactivity cations; infectious diseases, such as Lyme disease, in GBS without central nervous system involve- HIV, botulism, diphtheria, tabes dorsalis, and poli- ment. The possible mechanism for overactive blad- omyelitis; and autoimmune conditions, such as der might be generation of abnormal (spontane- paraneoplastic autonomic neuropathy, Lambert– ous) depolarizations in demyelinated nerve fibers Eaton myasthenic syndrome, and GBS.1,26,30,42,45–48 and immune attack on inhibitory spinal cord inter- Some of the causes, such as DM, GBS, and neurons, both of which cause lumbosacral auto- HIV, are discussed separately in this review. Herein nomic hyperactivity.13,55 we emphasize the relationship between the autoim- de Jager et al. reported a close relationship mune response of the body and the severity of au- between severity of GBS and bladder dysfunction. tonomic neuropathy. Nicotinic acetylcholine recep- They reviewed 63 cases of GBS patients who were tors (nAChRs), particularly the a3 and the b4 intubated during the disease course and showed subunits, are necessary for normal bladder func- that 75% of them developed micturition prob- tion.49 Bladder dysfunction may be associated with lems.58 In addition, Sakakibara et al. stated that neuronal nAChR antibodies.49,50 Lennon et al. micturition symptoms in GBS seemed to be more developed the model of an acquired neuronal common in patients with severe weakness than in nAChR disorder and assessed its pertinence to those with mild weakness.55 In their study of 65

Bladder Dysfunction in Peripheral Neuropathies MUSCLE & NERVE January 2012 5

cases of GBS, 27.7% had urinary dysfunction, HIV-ASSOCIATED NEUROPATHY including urinary retention in 9.2%. Underactive Voiding dysfunction in acquired immune defi- detrusor, overactive detrusor, and to a lesser ciency syndrome (AIDS) patients may be related to extent, hyperactive sphincter, were the major uro- several conditions, including encephalitis, cerebral dynamic abnormalities.13 Sakakibara et al. further toxoplasmosis, meningitis, myelitis, polyradiculo- reported that urinary dysfunction was clearly neuritis, tumors, peripheral neuropathy, and 45,61 related to the Hughes motor grade and defecation others. dysfunction, and it was negatively related to serum Around 9–16% patient with AIDS have periph- 62,63 immunoglobulin G class and antiganglioside anti- eral nervous system dysfunction. There is some body GalNAc-GD1a; there was no relationship to disagreement as to the overall prevalence of blad- 64 superficial or deep sensory defects. Therefore, they der dysfunction in HIV patients, but there are no recommended checking post-void residual by ultra- data available describing the frequency of bladder sound echography in GBS patients with a higher dysfunction in HIV-related peripheral neuropathy. Hughes motor grade, older age, and defecation Hermieu et al. studied 39 HIV-positive patients dysfunction.13 with voiding symptoms, such as straining, urinary Management of urinary symptoms in patients retention, frequency, and urgency. Their urody- with GBS is usually supportive. Urinary symptoms namic examination revealed that 56% had signs of usually resolve during the natural course of the dis- central neurological bladder disturbances (hyperac- ease. In some cases, a-blockers are needed to amel- tive bladder and/or bladder sphincter dysfunction), iorate urinary dysfunction. Intermittent self-cathe- 13% had a presumably peripheral deficit such as a terization is occasionally needed for those patients hypoactive bladder, 10% had isolated urethal hyper- with slow and/or poor recovery.13 tonia, and the remainder had minor (hypersensitive bladder) or no urodynamic abnormalities.65 A detailed history is necessary for precise diagno- CHRONIC INFLAMMATORY DEMYELINATING sis and choice of proper treatment. Appropriate POLYNEUROPATHY drugs improve the condition in more than half of Autonomic dysfunction in chronic inflammatory patients, but neurogenic voiding disturbances herald demyelinating polyneuropathy (CIDP) is not com- a poor prognosis. Urgency related to detrusor hyper- mon, in contrast to GBS. In CIDP, micturation dis- activity without UTI can be treated with anticholiner- turbance was reported in only 2% of patients in gic medications. Low flow and straining to void in the Dyck et al. series,46 and in 8% in the Prineas the absence of obstruction are due to impaired blad- et al. series.59 On the contrary, in another study, 8 der contraction and can be treated with a-blockers 64,65 of 32 (25%) CIDP patients had micturation and clean intermittent catheterization. disturbance.46,59,60 The frequency of micturition disturbance may AMYLOID NEUROPATHY depend on the method of history-taking.60 Micturi- Amyloid proteins are insoluble and accumulate in tion symptoms were seen more commonly in tissues. Primary systemic amyloidosis is character- severe CIDP cases presenting with severe ized by the deposition of monoclonal immuno- weakness.60 globulin light chains (AL). In the familial form, The major symptoms were voiding difficulty the deposits are produced from abnormally folded and urinary urgency, evidence of both evacuation transthyretin gene products (ATTR).66–68 Regard- and storage disorders in previous CIDP series.60 less of differences in the substance of the amyloid The only urodynamic data available on CIDP are deposit, small-fiber neuropathy is seen in AL and the report by Sakakibara et al. of urodynamic ATTR amyloidosis.66–68 Amyloid neuropathies are studies in 4 symptomatic patients in whom they rare, but well known.47,66,67 Autonomic dysfunction found disturbed bladder sensation in 2 patients in either type of amyloidosis may cause lower uri- and bladder areflexia in 1 patient. External sphinc- nary tract dysfunction in around 30% of cases. ter electromyography showed high-amplitude and Impairment of the lower urinary tract can manifest polyphasic motor unit potential changes in sphinc- as urinary retention and urinary incontinence. The ter muscles in 1 patient, suggesting pudendal first urinary symptom is usually voiding difficulty. nerve dysfunction. Cystometry showed detrusor Andrade et al. assessed lower urinary dysfunction overactivity in 2 patients without evidence of cen- in 54 familial amyloidotic polyneuropathy tral nervous system involvement that was probably patients.69 Initial urinary symptoms, including related to pelvic nerve irritation or ephaptic dysuria, incontinence, and sensitivity and contrac- transmission.60 tility disturbances of the detrusor, appeared during The management of urinary symptoms in CIDP the first 3 years of the disease in 50% of their would be the same as in GBS, as discussed earlier. patients. Vesicosphincter dysfunction in familial

6 Bladder Dysfunction in Peripheral Neuropathies MUSCLE & NERVE January 2012

amyloid polyneuropathy (FAP) occurs at an early Bladder involvement is very rarely seen in he- stage of the disease even in asymptomatic patients. reditary peripheral neuropathy. A few patients Retention is due to inadequate contraction of the have been reported with the coincidence of hered- detrusor, probably associated with non-relaxation itary neuropathy and bladder dysfunction. Auto- of the internal and external sphincters. The under- nomic disturbance, including bladder dysfunction, lying pathogenesis of these dysfunctions is thought was reported as one of the major clinical signs to be damage to small nerve endings and deposi- associated with CMT secondary to the MPZ gene tion of amyloid in the detrusor.69 mutation in codon 124.4 Miura et al. studied a Ito et al. performed uro-neurological assess- four-generation Japanese pedigree with hereditary ment in 4 patients with amyloid neuropathy. All of motor and sensory neuropathy (proximal domi- the patients described symptoms of lower urinary nant form), and all affected members showed uri- tract dysfunction and had voiding difficulties due nary dysfunction.76 to detrusor weakness and impaired bladder sensa- CONCLUSIONS tion. In 2 patients, cholinesterase inhibition caused Normal bladder function depends on the complex urge incontinence, indicating denervation super- interaction of sensory and motor pathways. Several sensitivity. The postulated underlying mechanism neurological conditions can cause BD. Diabetic may be degeneration of postganglionic cholinergic 66,69 neuropathy is the most common cause of periph- and afferent somatic nerves. eral neuropathy associated with BD. GBS, HIV-asso- The consensus for management of bladder dys- ciated neuropathy, CIDP, and amyloid neuropathy function due to amyloidosis is clean, intermittent, are other major reasons for BD. The diagnosis of periodic self-catheterization, particularly when 66,69 BD should be established by the history of neuro- post-void residual volume is large. Because of logical symptoms, neurological examination, and impaired bladder sensation, scheduled catheteriza- bladder evaluation. Management of urinary symp- tion should be performed in order to avoid possi- 45 toms in patients with BD is usually supportive. In ble injury from bladder overdistention. Care some cases, an a-blocker and/or cholinesterase in- must be taken, however, because a-adrenergic hibitor may be needed to improve urinary func- blocking agents can exacerbate the postural hypo- 66 tion. Intermittent self-catheterization may be tension which is common in these patients. Mil- needed for patients with slow and/or poor nacipran, a serotonin–noradrenaline reuptake in- recovery. hibitor, lacks a muscarinic receptor–blocking 70 property, and therefore it is useful in the treat- The first two authors (A.Z.B. and B.A.) contributed equally to this ment of incontinence due to sphincter deficiency study and both should be considered as first authors. A.Z.B.’s cur- with detrusor overactivity.66,70 In addition, duloxe- rent affiliation is Neuroscience Section, Virginia Tech Carilion tine, a dual serotonin (5-HT)/norepinephrine School of Medicine, Roanoke, VA. reuptake inhibitor, may be used in the treatment 71 of stress urinary incontinence. Duloxetine modu- REFERENCES lates lower urinary tract function centrally at the 1. Bradley WG DR, Fenichel GM, Jankovic J. Neurology in clinical practice, 4th ed. Onuf nucleus to increase activity of the pudendal 2. Blaivas JG. The neurophysiology of micturition: a clinical study of 72 nerve. 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