Low-dose fenfluramine significantly reduces seizure frequency in Dravet syndrome: a prospective study of a new cohort of patients.

BACKGROUND AND PURPOSE: Dravet syndrome (DS) is a severe, drug-resistant epilepsy. Fenfluramine has been reported to have a long-term clinically meaningful anticonvulsive effect in patients with DS. METHODS: This prospective, open-label study assessed the safety and effectiveness of low-dose fenfluramine in a new cohort of patients with DS. Following a 3-month baseline period, fenfluramine was added to each patient's current antiepileptic drug regimen at a dose of 0.25-1.0 mg/kg/day (max. 20 mg/day). The incidence of major motor seizures (tonic, clonic, tonic-clonic, atonic and myoclonic seizures lasting >30 s) in both the baseline and treatment periods was assessed via a seizure diary. Periodic echocardiographic examinations during the treatment period were used to assess cardiovascular safety. RESULTS: Nine patients (aged 1.2-29.8 years) enrolled in the study and were treated with fenfluramine for a median duration of 1.5 (range, 0.3-5.1) years. Median frequency of major motor seizures was 15.0/month in the baseline period. All patients demonstrated a reduction in seizure frequency during the treatment period with a median reduction of 75% (range, 28-100%). Seven patients (78%) experienced a ≥50% reduction in major motor seizure frequency. The most common adverse events were somnolence (n = 5) and anorexia (n = 4). No evidence of cardiac valvulopathy or pulmonary hypertension was observed. CONCLUSIONS: The effectiveness and safety of low-dose fenfluramine as an add-on therapy for DS in this new prospective cohort supports previous findings.

A randomized, double-blind, placebo-controlled trial of a glycine antagonist in neuropathic pain.

BACKGROUND: Nerve injury results in increases in spinal glutamate, which opens the NMDA ionophore channel, causing an influx of calcium. A glycine-binding site must be occupied for the channel to open. GV196771 is a selective antagonist of the glycine-binding site of the NMDA ionophore. OBJECTIVE: To determine the efficacy of GV196771 in subjects with chronic neuropathic pain in a proof-of-concept study. METHODS: With informed consent, 63 subjects (31 placebo, 32 GV196771) with neuropathic pain (diabetic neuropathy, postherpetic neuralgia, complex regional pain syndrome, or peripheral nerve injury), a visual analogue score averaging > or =30 mm during the screening period, and a well-defined primary area of mechanical allodynia were recruited for the study. A multicenter, randomized, double-blind, placebo-controlled, parallel-group study design was utilized. Subjects came to the research center for a total of five visits over a 21-day period, which consisted of a 14-day treatment period followed by a 7-day washout period. Spontaneous and evoked pain scores, mechanical sensory testing, quantitative sensory testing, Short Form McGill Pain Questionnaire, patient global satisfaction, and safety assessments were made during the study. RESULTS: There was no significant effect of GV196771 on spontaneous or evoked pain, quantitative sensory testing, or patient global satisfaction. There was a significant effect of GV196771 on the area of dynamic and static allodynia on days 7 and 14. The overall incidence of adverse events during treatment was similar for GV196771 (56%) and placebo (71%). The incidence of drug-related adverse events during treatment was higher for placebo (42%) than GV196771 (28%). CONCLUSIONS: Although the glycine antagonists show anti-hyperalgesic action in animal models of neuropathic pain, GV196771 does not appear to be an effective treatment in subjects with chronic neuropathic pain. This may be due to insufficient penetration of GV196771 to central sites of action, differences between the human and animal glycine receptors, or differences between neuropathic pain in animal models and humans.

Advances in the management of neuropathic pain.

Much progress has been made in the assessment and management of neuropathic pain over the past 5 years. Assessment has improved with the Neuropathic Pain Scale, a new, easily administered, diagnostic tool. Mechanistically, recent studies indicate that peripheral neuropathic pain is generated through a focal inflammatory process rather than axonal destruction. This process also appears to involve mRNA regulation of fast sodium channels, which produce ectopic discharges and are presumably responsible for pain generation. In addition the entire neuraxis undergoes neuroplastic changes as a result of peripheral nerve injury. The available clinical trial data indicate that newer antiepileptic drugs (AEDs), most notably gabapentin, are better alternatives to older medications such as carbamazepine or phenytoin in the treatment of neuropathic pain. Gabapentin is at least as good with respect to actual pain relief as the antidepressants, including amitriptyline, but has a much better safety profile with minimal drug-drug interactions and side effects. Mexiletine is a reasonable alternative agent in patients who have not had a satisfactory response to, or cannot tolerate, the AEDs or antidepressants. Long-acting opioids should be considered in patients refractory to these adjunctive agents. With the advent of the topical lidocaine patch, the first drug with an FDA-approved indication for postherpetic neuralgia, a revolutionary new agent is now available for the treatment of neuropathic pain that does not have any systemic side effects.

Lack of efficacy of riluzole in the treatment of peripheral neuropathic pain conditions.

OBJECTIVE: To assess the efficacy, tolerability, and safety of riluzole in the treatment of peripheral neuropathic pain conditions. BACKGROUND: Both basic and clinical research has demonstrated that drugs with sodium channel and NMDA antagonism can be effective in alleviating neuropathic pain. Riluzole, a drug currently used for treatment of ALS, possesses these properties. It was hypothesized that riluzole would be effective in reducing the pain in subjects with peripheral neuropathic pain. METHODS: Two randomized, placebo-controlled, crossover studies were performed at two sites. Study 1 compared 100 mg/day of riluzole (the currently recommended dosage for treatment of ALS) versus placebo, and Study 2 compared 200 mg/day of riluzole versus placebo. Each treatment phase (both studies) was 2 weeks long, separated by 2-week wash-out periods. Outcome measures included change in the score on a 100-mm pain intensity visual analog scale, the Neuropathic Pain Scale, allodynia, hyperalgesia, and preference for study treatment phase. RESULTS: Twenty-two subjects completed Study 1, and 21 subjects completed Study 2. Four subjects (two from each study) discontinued the study because of intolerable side effects. No statistical difference was found for any study outcome measure between riluzole and placebo for either study. In Study 1, pain intensity was more likely to increase than decrease with riluzole (mean treatment difference 8.7 mm; 95% CI -19.5 to +2.1 mm). In Study 2, very slight pain reduction was observed with riluzole compared with placebo (mean treatment difference 1.4 mm; 95% CI -5.1 to +8.0 mm). In both studies, the majority of subjects chose "no change" in pain on the category relief scale after placebo and riluzole treatment phases. On study completion, no treatment preference was reported by 76% of the subjects in Study 1 and by 61% of the subjects in Study 2. CONCLUSIONS: Doses of riluzole at (100 mg) or above (200 mg) those used for the treatment of ALS were not effective in alleviating peripheral neuropathic pain.

Topical lidocaine patch relieves a variety of neuropathic pain conditions: an open-label study.

OBJECTIVE: Our goal was to perform a pilot study to assess the effectiveness and tolerability of a topical lidocaine patch (Lidoderm) for the treatment of peripheral neuropathic pain conditions other than postherpetic neuralgia. DESIGN: This was an open-label prospective study. PATIENTS: Sixteen patients with refractory peripheral neuropathic pain conditions who had reported intolerable side effects or inadequate pain relief with antidepressant, anticonvulsant, antiarrhythmic, and opioid medications participated in this study. Diagnoses included postthoracotomy pain, stump neuroma pain, intercostal neuralgia, diabetic polyneuropathy, meralgia paresthetica, complex regional pain syndrome, radiculopathy, and postmastectomy pain. OUTCOME MEASURES: A six-item Pain Relief Scale was used (0 = worse pain, 1 = no change, 2 = slight relief, 3 = moderate relief, 4 = a lot of relief, 5 = complete relief). RESULTS: Moderate or better pain relief was reported by 13 of the 16 participants (81%). One patient stopped treatment after 4 days due to lack of relief. The remaining 15 patients had a mean duration of patch use of 6.2 weeks with continued relief. Only 1 patient reported a side effect, a mild skin irritation. CONCLUSIONS: The Lidoderm patch provided clinically meaningful pain relief in most of these refractory neuropathic pain patients without side effects. Controlled trials need to be performed to confirm these preliminary findings.

Course of symptoms and quality of life measurement in Complex Regional Pain Syndrome: a pilot survey.

Few data have been published regarding the natural history, course of symptoms, and quality of life in Complex Regional Pain Syndrome (CRPS). To obtain preliminary data regarding these important issues in CRPS, a set of patient self-report questionnaires were mailed to patients with the diagnosis of CRPS who had been assessed and/or treated at a tertiary university-based pain center in the United States. Self-reports of demographic information, symptoms, the Neuropathic Pain Scale, and a modified Brief Pain Inventory (mBPI) were received from 31 CRPS patients. Approximately 75% of patients reported initial symptoms of pain, swelling, coldness, and color changes. An additional 71% had weakness and inability to move the extremity as initial symptoms. Weakness at some time during their course of CRPS was described by 97%. A majority reported no overall improvement or worsening of symptoms over time (mean 3.3 years). The pain descriptors with the highest mean values were "deep" (6.4/10), "unpleasant" (6.4), "sensitive" (5.7), "surface" (5.4), and "dull" (5.3) pains. Significant sleep disturbance was reported by 80%. CRPS had a severe impact on quality of life, with substantial interference reported in 9 of 10 mBPI activity items by a majority of these patients. These findings should be viewed with caution and should not be generalized to the entire CRPS population because the cohort was small and select. A large multicenter prospective study needs to be performed to validate these preliminary findings.

A drug use evaluation of selected opioid and nonopioid analgesics in the nursing facility setting.

OBJECTIVES: To determine the medical conditions for which selected analgesics are most frequently prescribed in nursing facilities (NFs), describe the use of pharmacologic and nonpharmacologic pain therapies, and determine the frequency and quality of pain assessment in NF residents. DESIGN: A multicenter, 3-month retrospective drug use evaluation conducted by consultant pharmacists. SETTING: Eighty-nine NFs having no more than 25% of their patient census representing special populations (e.g., head trauma). PARTICIPANTS: A total of 2065 adult NF residents who received at least one selected analgesic. MEASUREMENTS: Primary indication for analgesics, pain type, method of pain assessment, nonpharmacologic therapies for pain, prescribed analgesics and regimens, and comorbid conditions were recorded. RESULTS: A total of 54.3% of residents had one indication for analgesic therapy, 31.0% had two indications, and 14.7% had three or more indications. Arthritis was the most prevalent indication for analgesics (41.7% of residents), followed by bone fracture (12.4%) and other musculoskeletal conditions (9.7%). More residents (76.8%) were reported to have chronic pain than acute pain (19.9%), and 3.0% had both chronic and acute pain. Pain type was unknown for 0.2% of residents. Observational pain assessments were used more frequently (for 55.9% of residents) than objective methods (16.6%), and pain was not assessed in 40.6% of residents. Most residents (69.4%) received no nonpharmacologic treatment for pain. Of the 2542 opioid and nonsteroidal anti-inflammatory drug (NSAID) prescriptions, 67.6% were for opioids, 24.8% were for NSAIDs, and 7.6% were for tramadol. Propoxyphene-containing drugs were the most frequently prescribed opioid group, and propoxyphene with acetaminophen was the most frequently prescribed analgesic (35.6% of all analgesics). Most analgesics (63.2%) were prescribed on an as-needed (prn) basis. CONCLUSIONS: The findings show a lack of adequate pain assessments, little use of nonpharmacologic interventions, and inappropriate use of analgesic medication. The small percentage of residents with chronic pain assessed objectively suggests the difficulty of monitoring pain progression in NFs. The prescribing of analgesic for most residents (with propoxyphene used most often, long-acting opioids used infrequently, and frequent prn use) was inconsistent with recommended pain therapy in older people and attests to the urgent need to educate NF practitioners on the appropriate use of analgesics.

Topical diclofenac patch relieves minor sports injury pain: results of a multicenter controlled clinical trial.

Sports-related soft tissue injuries, such as sprains, strains, and contusions, are a common painful condition. Current treatment includes oral nonsteroidal anti-inflammatory drugs (NSAIDs), which have a high incidence of intolerable gastrointestinal side effects. Topically applied drugs have the potential to act locally in the soft tissues without systemic effects. This study assessed the efficacy and safety of topical diclofenac (NSAID) patch applied directly to the painful injury site for the treatment of acute minor sports injury pain. Adult subjects (N = 222) were recruited from two communities for a multicenter, randomized, placebo-controlled, parallel design study. All subjects had suffered a painful minor sports injury within the prior 72 hours of study entry. Either a diclofenac epolamine or placebo topical patch was applied directly to the skin overlying the painful injured site twice daily for 2 weeks. Measures of pain intensity were performed in a daily diary and at clinic visits on days 3, 7, and 14. Diclofenac patch was superior to placebo patch in relieving pain. Statistical significance was seen on clinic days 3 (P = 0.036) and 14 (P = 0. 048), as well as the daily diary pain ratings at days 3, 7, and 14 (P < or =0.044). No statistically significant differences were seen in any safety or side-effect measures with the diclofenac patch as compared to the placebo patch. Diclofenac epolamine patch is an effective and safe pain reliever for treatment of minor sports injury pain. The advantages of this novel therapy include its ease of use and lack of systemic side effects.

Painful diabetic polyneuropathy: epidemiology, pain description, and quality of life.

A prospective survey study was performed in patients with painful diabetic polyneuropathy (PDN) to assess the nature and scope of their pain. Pain associated with diabetic neuropathy is commonly encountered in clinical practice. Yet, little is known regarding the pain experience and impact on quality of life in persons with painful diabetic neuropathy. These 105 patients noted an average of 6/10 pain, most often described as 'burning', 'electric', 'sharp', and 'dull/ache', which, for most, is worse at night time and when tired or stressed. On average, patients reported that the pain caused substantial interference in sleep and enjoyment of life and moderate interference in recreational activities, normal work, mobility, general activity, social activities, and mood. Unexpectedly, a potential genetic predisposition to the development of painful neuropathy was suggested by the fact that a majority (56%) reported a family member with PDN. Thus, this study found that pain associated with diabetic neuropathy is a significant medical issue that has a substantial impact on the quality of life of many people with this condition.

Neglect-like symptoms in complex regional pain syndrome: results of a self-administered survey.

Reflex sympathetic dystrophy (RSD), recently reclassified as a complex regional pain syndrome, type I (CRPS-I), is best known for its disabling sensory symptoms, including pain, allodynia, and abnormal skin temperature. Yet, motor dysfunction is common in CRPS and can result in major disability. In addition to weakness of the involved limb, CRPS patients may develop symptoms akin to a neurological neglect-like syndrome, whereby the limb may feel foreign ("cognitive neglect") and directed mental and visual attention is needed to move the limb ("motor neglect"). Members of the patient support group, the Reflex Sympathetic Dystrophy Syndrome Association (RSDSA), were mailed a questionnaire inserted in their newsletter which inquired about the presence of these neglect-like symptoms; in addition, a separate medical history questionnaire was included to assess adequate documentation for the diagnosis of CRPS. A total of 242 patients returned the questionnaire but only 224 of the questionnaires were analyzed; 15 were excluded due to inadequate documentation of CRPS and 3 were excluded due to non-limb involvement. Eighty-four percent (84%) of these respondents endorsed the presence of at least one neglect symptom and 47% indicated they had both "cognitive" and "motor" neglect symptoms. Of interest, approximately 33% of respondents spontaneously wrote comments regarding the significant disability due to these neglect symptoms and the difficulty explaining these unusual symptoms to their health care providers and family. This patient survey confirms the presence of neglect-like symptoms in a subset of CRPS patients. Neglect-like symptoms need to be addressed and validated by health care providers.

Complex regional pain syndrome: are the IASP diagnostic criteria valid and sufficiently comprehensive?

This is a multisite study examining the internal validity and comprehensiveness of the International Association for the Study of Pain (IASP) diagnostic criteria for Complex Regional Pain Syndrome (CRPS). A standardized sign/symptom checklist was used in patient evaluations to obtain data on CRPS-related signs and symptoms in a series of 123 patients meeting IASP criteria for CRPS. Principal components factor analysis (PCA) was used to detect statistical groupings of signs/symptoms (factors). CRPS signs and symptoms grouped together statistically in a manner somewhat different than in current IASP/CRPS criteria. As in current criteria, a separate pain/sensation criterion was supported. However, unlike in current criteria, PCA indicated that vasomotor symptoms form a factor distinct from a sudomotor/edema factor. Changes in range of motion, motor dysfunction, and trophic changes, which are not included in the IASP criteria, formed a distinct fourth factor. Scores on the pain/sensation factor correlated positively with pain duration (P<0. 001), but there was a negative correlation between the sudomotor/edema factor scores and pain duration (P<0.05). The motor/trophic factor predicted positive responses to sympathetic block (P<0.05). These results suggest that the internal validity of the IASP/CRPS criteria could be improved by separating vasomotor signs/symptoms (e.g. temperature and skin color asymmetry) from those reflecting sudomotor dysfunction (e.g. sweating changes) and edema. Results also indicate motor and trophic changes may be an important and distinct component of CRPS which is not currently incorporated in the IASP criteria. An experimental revision of CRPS diagnostic criteria for research purposes is proposed. Implications for diagnostic sensitivity and specificity are discussed.

Headache medication-use among primary care headache patients in a health maintenance organization.

OBJECTIVE: Medication-use among headache patients 2 and 5 years after a primary care headache visit is assessed, and the pattern of medication-use compared before and after the introduction of subcutaneous sumatriptan among migraineurs. SETTING AND PATIENTS: The study was carried out among headache patients visiting a primary care physician at the Group Health Cooperative of Puget Sound in 1989-90. METHODS: We report medication-use patterns 2 and 5 years later for the 530 subjects completing both a 2-year (1991-92) and a 5-year (1994-95) follow-up interview. Medication-use was determined by self-report for the month prior to the interview. Medication-use to control or prevent headache is shown for all headache patients and for those meeting International Headache Society criteria for migraine at the 2-year and the 5-year follow-up. RESULTS: The overall pattern of medication-use was similar at the 2-year and the 5-year follow-up, before and after the introduction of subcutaneous sumatriptan (March, 1993). There was a modest but statistically significant decline in the use of opioid and sedative-hypnotic medications, and in the use of ergotamine. At 5 years, 11% of migraineurs reported use of sumatriptan in the prior month. The large majority of study patients used symptomatic medications, usually non-prescription analgesics, sedative-hypnotics, and opiates. Only one-fifth of the migraineurs reported use of a prophylactic medication for headache. CONCLUSIONS: Continuing use of symptomatic headache medications was characteristic of patients with migraine and other common forms of headache. The introduction of subcutaneous sumatriptan was not associated with notable change in this pattern, although a modest reduction in use of sedative-hypnotics and opiates was observed. Overall, the pattern of use of headache medications was similar before and after the introduction of subcutaneous sumatriptan.

Proximal myofascial dysfunction in complex regional pain syndrome: a retrospective prevalence study.

OBJECTIVE: To assess the prevalence of clinically evident myofascial dysfunction (MD) and its relationship to motor neglect (MN) in Complex Regional Pain Syndrome (CRPS). DESIGN: Retrospective chart review. PATIENTS: Forty-one consecutively evaluated CRPS patients. OUTCOME MEASURES: (a) Prevalence of trigger points in the proximal musculature of the CRPS limb. (b) Prevalence of MN in a subset (n = 34). RESULTS: MD was detected in 61 % of CRPS patients. It was more prevalent in the upper limb (70%) than in the lower limb (47%). MN was more common in those who also had MD. CONCLUSION: MD is common in CRPS patients, especially in the upper limb and in those patients with MN. Prospective trials are needed to confirm these intriguing findings, which may have important implications regarding CRPS pathophysiology and treatment.

External validation of IASP diagnostic criteria for Complex Regional Pain Syndrome and proposed research diagnostic criteria. International Association for the Study of Pain.

Recent work in our research consortium has raised internal validity concerns regarding the current IASP criteria for Complex Regional Pain Syndrome (CRPS), suggesting problems with inadequate sensitivity and specificity. The current study explored the external validity of these IASP criteria for CRPS. A standardized evaluation of signs and symptoms of CRPS was conducted by study physicians in 117 patients meeting IASP criteria for CRPS, and 43 patients experiencing neuropathic pain with established non-CRPS etiology (e.g. diabetic neuropathy, post-herpetic neuralgia). Multiple discriminant function analyses were used to test the ability of the IASP diagnostic criteria and decision rules, as well as proposed research modifications of these criteria, to discriminate between CRPS patients and those experiencing non-CRPS neuropathic pain. Current IASP criteria and decision rules (e.g. signs or symptoms of edema, or color changes or sweating changes satisfy criterion 3) discriminated significantly between groups (P < 0.001). However, although sensitivity was quite high (0.98), specificity was poor (0.36), and a positive diagnosis of CRPS was likely to be correct in as few as 40% of cases. Empirically-based research modifications to the criteria, which are more comprehensive and require presence of signs and symptoms, were also tested. These modified criteria were also able to discriminate significantly, between the CRPS and non-CRPS groups (P < 0.001). A decision rule, requiring at least two sign categories and four symptom categories to be positive optimized diagnostic efficiency, with a diagnosis of CRPS likely to be accurate in up to 84% of cases, and a diagnosis of non-CRPS neuropathic pain likely to be accurate in up to 88% of cases. These results indicate that the current IASP criteria for CRPS have inadequate specificity and are likely to lead to overdiagnosis. Proposed modifications to these criteria substantially improve their external validity and merit further evaluation.

Pain medicine education among American neurologists: a need for improvement.

To assess pain medicine education, surveys were mailed to practicing neurologists (PNs) and residency program directors (PDs). Thirty percent of PNs felt adequately trained to diagnose and 20% to treat pain disorders. PNs stated that more pain education is needed for resident training (89%) and for PNs (91%). PDs ranked the importance of a pain subspecialty seventh out of eight subspecialties; only 29% reported having a neurology pain specialist on the faculty. These data strongly suggest a need to improve the pain medicine education of neurologists.

A case of reflex sympathetic dystrophy (complex regional pain syndrome, type I) resolved by cerebral contusion.

We present a case of refractory reflex sympathetic dystrophy (RSD) (complex regional pain syndrome, type I) whose symptoms (ongoing pain, allodynia, hyperhydrosis and temperature abnormalities) were resolved after the patient suffered a traumatic cerebral contusion in the left temporal lobe, which caused no neurological deficit. This case suggests that symptoms of some RSD patients may largely sustained by a complex network involving the brain.

Neuropathic pain in Charcot-Marie-Tooth disease.

OBJECTIVES: To determine the frequency and extent to which subjects with Charcot-Marie-Tooth (CMT) disease report pain and to compare qualities of pain in CMT to other painful neuropathic conditions. STUDY DESIGN: Descriptive, nonexperimental survey, using a previously validated measurement tool, the Neuropathic Pain Scale (NPS). PARTICIPANTS: Participants were recruited from the membership roster of a worldwide CMT support organization. MAIN OUTCOME MEASURES: NPS pain descriptors reported in CMT were compared with those reported by subjects with postherpetic neuralgia (PHN), complex regional pain syndrome, type 1 (CRPS-1), also known as reflex sympathetic dystrophy, diabetic neuropathy (DN), and peripheral nerve injury (PNI). RESULTS: Of 617 CMT subjects (40% response rate), 440 (71%) reported pain. with the most severe pain sites noted as low back (70%), knees (53%), ankles (50%), toes (46%), and feet (44%). Of this group, 171 (39%) reported interruption of activities of daily living by pain; 168 (38%) used non-narcotic pain medication and 113 (23%) used narcotics and/or benzodiazepines for pain. The use of pain description was similar for CMT, PHN, CRPS-1, DN, and PNI in terms of intensity and the descriptors hot, dull, and deep. CONCLUSIONS: Neuropathic pain is a significant problem for many people with CMT. The frequency and intensity of pain reported in CMT is comparable in many ways to PHN, CRPS-1, DN. and PNI. Further studies are needed to examine possible pain generators and pharmacologic and rehabilitative modalities to treat pain in CMT.

Pain assessment and evaluation of patients who have neuropathic pain.

Pain assessment and physical examination are the first crucial steps in diagnosis of neuropathic pain disorders because these are still solely diagnosed on clinical grounds. The physical examination should be conducted in such a way that all of the positive sensory phenomena, such as allodynia, hyperalgesia, hyperpathia, summation, and after-sensation are elicited. Other physical examination findings should corroborate the diagnostic impression of neuropathic pain. Specific pain diagnosis should then lead to more specific therapy.

Painful polyneuropathy.

Painful polyneuropathy is one of the most common chronic pain syndromes neurologists are asked to assess for diagnostic and therapeutic purposes. This article reviews the most current clinical guidelines, including history, pain assessment, physical examination findings, treatment recommendations, and pathophysiologic pain mechanisms underlying this condition. As a result of recent advances, the understanding and therapy of pain associated with polyneuropathy has evolved over the past several years and will continue to do so in the years to come.