Perspectives On The Urological Care in Parkinson’s Disease Patients Part 2

OVERVIEW OF PD
Epidemiology of PD

PD affects 1-2 per 1000 of the population at any time. PD prevalence is increasing with age, it affects 1% of the population above 60 years (22). The median age of onset is 60 years; the mean duration of the disease from diagnosis to death is 15 years. 

More and more people are recognizing that maintaining a healthy body and negative emotions is a more comprehensive definition of health. One of the important components of physical health is our cognitive function, especially memory.

In recent years, many subjects have studied the relationship between prevalence and memory. These studies show that a range of conditions can affect cognitive function, including cardiovascular disease, diabetes, brain damage, and deep depression. On the other hand, different lifestyle habits, such as healthy eating, physical exercise, stress management, and rest, also affect people's cognitive abilities, including memory, to a certain extent.

Healthy eating is a major way to maintain cognitive function and memory. We need to consume enough dietary fiber, protein, vitamins, minerals, etc. to maintain good health and enhance brain function. In particular, choose foods rich in antioxidants, such as blueberries, walnuts, cod, etc. These foods can resist free radical damage and thus protect our memory.

In addition, aerobic exercise is also an important factor. Exercise increases brain plasticity, which means our brains can reorganize themselves and connect with previously different neural networks. This plasticity can help us respond faster and better when learning new information and can also improve our memory. This is what we usually call "physical and mental coordination", and exercise can improve our physical health and cognitive function.

Stress management and sleep are also important aspects of physical and cognitive health. Although preliminary research suggests that a regular eight hours of sleep may not be directly linked to brain health and memory, stress management does have a direct link to people's brain function. Stress causes the brain to secrete chemicals such as cortisol, which can temporally affect the connectivity of neural networks, thereby affecting our ability to focus and remember. Therefore, we must learn to reduce stress, ensure adequate sleep, and develop good habits, such as memory-strengthening exercises and reducing the interference of electronic devices.

To summarize, for those who want to have a healthy body and strong cognitive function, a healthy diet, moderate exercise, stress management, and sleep are key factors. All of these may contribute to our overall physical health as well as the health of our memory. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche deserticola can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning, and thinking speed, and may also prevent the development of cognitive dysfunction and neurodegenerative diseases.

click know supplements to boost memory

Male sex is recognized as a prominent risk factor in developing PD. Both incidence and prevalence of PD are 1.5 to 2.0 times higher in men than in women. Age at onset is 2.1 years later in women (53.4 years) than in men (51.3 years) (23). 

The overall prevalence of PD appears to be lower in Eastern studies compared to Western ones. In a meta-analysis of 39 European studies until 2004, the authors reported a prevalence rate of 108-257/100,000 when considering only high-quality studies that utilized a standard diagnostic criterion (24).

Pathogenesis of PD

The main pathological features of PD are the loss of dopaminergic neurons with subsequent depigmentation of the substantia nigra pars compacta and the presence of Lewy bodies (25). 

Lesions initially occur in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus. Thereafter, less vulnerable nuclear grays and cortical areas gradually become affected (26). 

The spinal cord lesions may contribute to clinical symptoms (pain, constipation, poor balance, lower urinary tract complaints, and sexual dysfunction) that occur during the premotor and motor phases of sporadic PD (27). PD does not fulfill key criteria to be diagnosed as prionopathy. Nonetheless, abnormal forms of a-synuclein seem to propagate in the brains of PD patients. 

The finding of Lewy bodies and a-synuclein deposits in nigral fetal neurons transplanted over a decade earlier into the striatum could support the existence of a prion-like pathogen as the cause of PD (28).

Risk factors of PD

Significant predictors of PD emerged (in order of strength): pesticide use, family history of neurologic disease, and history of depression. The predicted probability of PD was 92.3% (odds ratio = 12.0) with all three predictors positive (29). 

Other potential risk factors include environmental toxins, drugs, brain microtrauma, focal cerebrovascular damage, and genomic defects (30). There is an association between anemia experienced early in life and the later development of PD (31). 

Exposure to toxins in the environment has been linked to PD-associated neurodegeneration, particularly heavy metals, pesticides, and illicit drugs (32). Some infectious diseases such as mumps, scarlet fever, influenza, whooping cough, and herpes simplex infections may play a role in the development of PD (33).

Genetic Contribution to PD

A-synuclein (SNCA) was the first PD gene identified in a large Italian-American family (the Contursi kindred) with autosomal dominant inheritance (34). A total of 18 PD loci have been nominated through linkage analysis (PARK1-15) or genome-wide association studies (PARK16-18). 

Mutations within the genes at 6 of these loci (SNCA, LRRK2, PRKN, DJ1, PINK1, and ATP13A2) have conclusively been demonstrated to cause familial parkinsonism. 

In addition, common polymorphisms within 2 of these same genes (SNCA and LRRK2) and variation in 2 other genes not assigned to a PARK locus (MAPT and GBA) are now well-validated risk factors for PD (35).

Clinical Features of PD

PD comprises a range of motor and non-motor features (Table 1). The presence of bradykinesia, rest tremor, rigidity, and loss of postural reflexes are the most commonly identified motor symptoms of PD, although other clinical features can also be identified during disease progressions, such as bulbar dysfunction, neuro-ophthalmological abnormalities, and respiratory disturbances (36). 

Most non-motor symptoms are not fully levodopa-responsive and are suggested to manifest extra-nigral pathology. These symptoms include autonomic, sleep, sensory, and neuropsychiatric symptoms (37).

Diagnosis of PD

The Movement Disorder Society (MDS) clinical diagnostic criteria for PD mentioned that the first essential criterion is parkinsonism, which is defined as bradykinesia, in combination with at least 1 rest tremor or rigidity. 

Once parkinsonism has been diagnosed, the diagnosis of clinically established PD requires the absence of absolute exclusion criteria, at least two supportive criteria, and no red flags (38). Those criteria and red flags are summarized in Table 2.

Early falls, poor response to levodopa, symmetry of motor manifestations, lack of tremor, and early autonomic dysfunction are probably useful in distinguishing other Parkinsonian syndromes from PD. 

The levodopa or apomorphine challenge and olfactory testing are probably useful in distinguishing PD from other Parkinsonian syndromes (39). Structural MRI is useful to differentiate PD from secondary and atypical forms of parkinsonism. 

123I-ioflupane single-photon emission computed tomography (SPECT) is a valid tool in the differential diagnosis between PD and non-degenerative tremors. Cardiac 123I-metaiodobenzylguanindine SPECT and 18F-FDG positron emission tomography (PET) have the potential to differentiate PD from atypical parkinsonism (40).

Differential diagnosis

Although the most common cause of parkinsonism is PD, the differential diagnosis includes many other causes of parkinsonism. Aside from drug-induced parkinsonism, related to drug-induced changes in the basal ganglia motor circuit secondary to dopaminergic receptor blockade, the most common mimickers of PD are parkinsonian syndromes, such as MSA and progressive supranuclear palsy, dementia with Lewy bodies (DLB), vascular parkinsonism (VP), a parkinsonian syndrome that is associated with cerebrovascular disease (41).

Management of PD

There are several drugs available to treat motor impairments in PD. First, drugs that increase brain levels of dopamine such as Levodopa are used. In addition, drugs that mimic dopamine were used such as dopamine agonists. 

Lastly, drugs that inhibit dopamine breakdown have been used. MAO-B inhibitors can inhibit the activity of monoamine oxidase B. Usually, MOA-B inhibitors reduce the symptoms of PD. Selegiline or deprenyl is one of the inhibitors of MOA-B that is very active against PD along with levodopa. Tolcapone also reduces the requirement of levodopa to patients but it can induce severe hepatotoxicity. 

There are two types of catechol-O-methyl transferase (COMT) inhibitors entacapone and tolcapone. COMT inhibitors are used to reduce the dose of levodopa (42). In most patients with PD, motor fluctuations and dyskinesias are relatively mild and can be adequately managed by adjustment of the oral medication. 

However, for patients experiencing disabling motor fluctuations and dyskinesias despite optimized medical therapy, device-assisted therapies should be considered (43).

Many experimental studies are going to test the applications of antibodies to target and degrade extracellular synuclein molecules. Passive and active immunization techniques against a-synuclein have been shown to convey neuroprotective effects in animal models (44).

UROLOGIC OUTCOMES OF PD

Prevalence of urologic symptoms among the PD population

Seventy-four percent of patients with early-to-moderate disease report more than one bladder disturbance symptom. Severe bladder symptoms are reported in 27-39% of PD patients. Both storage and voiding symptoms are highly prevalent in patients with PD. 

More than 50% of patients have OAB symptoms (45). The severity of the neurological disease is correlated with the occurrence of voiding dysfunction, these findings corroborate the results of other studies which showed that lower urinary tract symptoms (LUTS) increase accordingly with PD progression (46).

Urologic clinical symptoms

The pattern and mechanism of storage symptoms have been partly clarified as the hypothesis most widely proposed is that the basal ganglia output has an overall inhibitory effect on the micturition reflex in healthy individuals, and with cell loss in the substantia nigra, detrusor overactivity develops through an inability to activate the dopamine D1 receptor-mediated tonic inhibition.

A parallel mechanism may be that in PD, the inhibitory dopaminergic neurons originating in the substantia nigra may be more damaged than the stimulatory dopaminergic neurons originating in the ventral tegmental area, thereby inducing urgency and frequency. 

Impaired sensory information from periaqueductal gray could also contribute to storage symptoms (47). However, those voiding disorders have yet to be elucidated, and there have been only a few reports that dopa-responsive detrusor under-activity or impaired urethral relaxations exist, and post-void residual urine (PVR) does not occur frequently. These findings suggest that early and untreated PD patients also have not only storage disorders but also mainly subclinical voiding disorders (48). 

Detrusor under activity or bladder outlet obstruction (BOO) underlies the mechanism of voiding symptoms in patients with PD. PD patients mostly maintain an acceptable voiding efficiency and low PVR volume. 

In the meantime, PD mostly affects the elderly, overlapping the age group with high morbidity of benign prostatic hyperplasia (BPH). Neurogenic BOO in PD patients still draws less attention (49). Detrusor sphincter dyssynergia (DSD) is a rare cause of voiding dysfunction in PD. DSD was observed on voiding at a rate of 0-3% (50). Underactive bladder in up to 50 % of patients with PD. 

The mechanism of detrusor weakness in PD remains unclear and warrants further exploration (51). A study suggested that a weak detrusor in PD might have a central origin. It is necessary to follow PVR carefully in PD patients with advanced gait disorder because PVR might increase in such patients (52). Obstructive symptoms might result from treatment with particular antiparkinsonian drugs. 

Also, it should be noted that Lewy bodies can be seen in several types of neurons, including central and peripheral components of the autonomic nervous system, in advanced PD. Thus, obstructive symptoms in patients with PD might result from micturition hyporeflexia due to impairment in the autonomic nervous system (53). The mechanisms responsible for urinary symptoms in PD patients are summarized in Figure 1. 

Neurogenic lower urinary dysfunction (NLUD) can induce anxiety and depression in patients. A study was implemented by Benli et al. to investigate whether NLUD, which is frequently seen in PD, affects the development of anxiety and depression in these patients. The study included 32 males (66.6%) and 16 females (33.3%); in total 48 subjects were registered. It was concluded that the incidence of NLUD, anxiety, and, depression was increased in PD. In addition, NLUD was found to be a risk factor for the development of anxiety and depression (54).

Clinical scales

The scale for outcomes in PD for autonomic symptoms (SCOPA-AUT) is a specific scale to assess autonomic dysfunction in PD patients. It includes six urinary items that assess both storage and voiding phases. SCOPA-AUT is an acceptable, consistent, reliable, and valid scale (55). 

The International Prostate Symptom Score (IPSS) has been used both in men and women for patients with neurological diseases; several teams used it in PD patients, including in advanced stage, and after DBS. Overactive Bladder Symptom Score (OABSS) has been used to evaluate urinary symptoms in PD patients but it needs further validation (56).

Findings on urodynamic studies

The urodynamic examination is recommended for male PD patients with voiding dysfunction. It can show detrusor hyperreflexia associated with BOO or detrusor dysfunction with BOO (57). Urodynamic findings could differentiate patients with MSA from those with PD. 

Patients with MSA showed lower maximal flow rate, larger PVR with decreased compliance, and impaired contractility, whereas patients with PD had a higher incidence of detrusor overactivity and associated leakage (58). A study conducted by Vurture et al. strongly suggests that a vast majority of OAB symptoms in patients with PD can be attributed to DO on urodynamics (97.1%). 

However, the high rates of other abnormalities such as BOO (36.8%), detrusor underactivity (47%), and increased PVR (16.7%) suggest that neurogenic DO is not the only contributor of OAB symptoms in patients with PD (59).

Special focus on nocturia in PD

Nocturia is a common non-motor symptom in PD but has been poorly studied. Nocturia may manifest as a result of reduced functional bladder capacity or nocturnal polyuria; however, most often the cause is multifactorial. Disorders of circadian rhythm regulation are known to occur with sleep disturbances in PD that may also contribute to nocturia (60). 

The bladder diary provides a prospective real-time assessment of bladder symptoms, which is cost-effective and relatively straightforward for patients to complete. It provides a more accurate assessment of night-time frequency and voided nocturnal urine volumes. A bladder diary is an essential tool in the assessment of nocturia in patients with PD (61).

Management of the storage symptoms (OAB symptoms) in PD patients

A detailed algorithm for the management of the storage symptoms in PD patients is summarized in Figure 2.

General measures and physical treatment Behavioral therapy included pelvic floor muscle exercises, bladder training, and fluid and constipation management. Providers should consider behavioral therapy as an initial treatment for urinary symptoms in PD. 

It was demonstrated in a small study conducted by Vaughan et al. (62). A study was implemented by McDonald et al. to assess the feasibility and efficacy of bladder training (BT) for troublesome LUTS in PD. 

Thirty-eight participants were randomized (18 to conservative advice (CA), 20 to BT groups). Both CA and BT were associated with significant improvements in volume voided, number of micturitions, symptom severity scores, and measures of quality of life (all p < 0.05). 

At 12 weeks, compared to CA, BT was associated with significant superiority in patient perception of improvement (p = 0.001). At 20 weeks, BT remained associated with greater improvement in interference in daily life (63).

Dopaminergic therapy

It is uncertain whether L-dopa medication can improve micturition disorders. Some have reported that L-dopa improves micturition symptoms, but others have reported conflicting results. In addition, the effects of L-dopa on bladder function are unknown (64). 

The acute mixed stimulation of D1 and D2 receptors by apomorphine has been reported to reduce bladder outflow resistance. In contrast, acute dopaminergic stimulation by L-dopa challenge has been reported to worsen detrusor overactivity and reduce bladder capacity in patients with PD. However, the worsening effect of acute L-dopa administration conflicts with the clinical experience of bladder function improvement reported by PD during L-dopa therapy (65). 

These findings suggest that the effects of dopaminergic treatment on bladder control are very different, according to their preceptorial activity, producing a cumulative effect of a multidrug daily treatment difficult to predict. Combined, balanced activation of D1/D2 receptors could be beneficial for treating urinary symptoms caused by detrusor hyperreflexia in PD as demonstrated by Brusa et al. 

They conducted an open-label study where extended-release levodopa at bedtime showed significant improvement in OAB symptoms, specifically nocturia (66). Winge et al. concluded in their trial that dopaminergic therapy relieves cognitive executive dysfunction, as it seems to improve functional bladder control in those of their patients, who benefit from medication during their storage phase (67).

For more information:1950477648nn@gmail.com