Although the progression of the disease may be slowed, it is not considered to be preventable in all patients due to the multifactorial nature of the process; however, glycemic control remains the most important goal in this aspect (American Diabetes Association, 2014,Park, Park & Baek, 2004). While all medication used in the management of neuropathy is implemented on the basis of altering pathophysiologic mechanisms of the disease, no protocols have been established regarding drug combinations in this context (Boucek, 2006). One of the most interesting aspects of this case was the remission of pain-related symptoms after starting on duloxetine and capsaicin, remaining still after suspension of both drugs, suggesting reversibility of neuronal damage even in cases as severe as ours.
In order to assess this progression, DSP should be evaluated annually utilizing methods such as (American Diabetes Association, 2014): a) Exploration of pain sensation to pinching (mechanic pain threshold) and touch sensation to cotton swabs, both transmitted through Type C and A-ï¤ fibers; b) Vibration perception threshold of Type A-ï¢ fibers, assessed with 128 Hz tuning forks; c) Semmes-Weinstein monofilament test for the evaluation of deep protective sensation by Pacinian corpuscules; and d) Calcaneal/Patellar reflex exploration, assessing proprioceptive sensation by Golgi tendon organs. The combination of these techniques offers over 87% sensitivity for detecting DSP (American Diabetes Association, 2014). The utilization of tuning forks renders higher sensitivity and positive predictive value when compared to neurothesiometers (Kästenbauer et al, 2004). Furthermore, vibratory methods offer 53% sensitivity and 99% specificity, while superficial pain assessment through the pinching method offers 59% sensitivity and 97% specificity (Perkins et al, 2001).
Nevertheless, the Semmes-Weinstein monofilament test appears to offer the smallest margin of error, as well as require minimal training (Lee et al, 2003). This technique encompasses evaluation of 10 distinct sites in feet, with sensitivity varying between 57-93%, specificity 75-100%, positive predictive value 84-100% and negative predictive value 36-94% for the diagnosis of DSP (Freng, Schlösser & Sumpio, 2009). Moreover, different kinds of filaments yield distinct predictive results depending on the sites they are used in; for example, application of the 4.3/2-g monofilament renders remarkable diagnostic values in the hallux and the 5th metatarsal, with 60% sensitivity and 73.8% specificity (Kamei et al, 2005) with positive results being linked to alterations in vibratory perception and syncope, reflecting small-fiber damage (Perkins et al, 2001). These data have led to the proposal of limiting the sites of evaluation in order to guarantee more homogeneous results (Boucek, 2006). Particularly, the use of the 10g monofilament in 3 areas offers several advantages, including a higher risk in ulceration depth (Tan, 2010) and a lack of perception of this filament is regarded as an independent risk factor for ulceration, due to the loss of protective sensitivity (Tan, 2010).
Finally, nerve conduction assessment techniques and electromyography (Brij et al, 1996) may be implemented in the diagnosis of DSP, regarded as the most objective tests to this end (Hsu et al, 2012; Said 2007), returning documentation on the type of neuronal injury and its localization (Boulton 2005; Said 2007). In symptomatic DN, findings include longer conduction speeds due to demyelination, and lower action potentials, owing to axonal loss (Boulton 2005; Tan, 2010; Said 2007). The application of needle electromyography is reserved for assessment of abnormal spontaneous potentials and exploration of motor unit configuration, as required in cases of generalized neuropathy, atrophy of proximal muscle groups, and radiculopathy (Boulton 2005; Said 2007).
Additionally, nerve conduction studies are valuable tools in the evaluation of nerve preservation, yet they may not be applicable in all cases, such as in polyneuropathy affecting small fibers, since these do not participate in sensorial action potentials (Said 2007). In DN, axonal loss with reduction or absence of action potentials may be observed, predominating in lower limbs, although according to the stage of progression, it may involve the hands; however, many DM patients may present nerve conduction abnormalities without any clinical signs. Weisman et al. (2013) reported the predictive profile of the conduction speed of individual nerves and combinations in the diagnosis of DSP, where the conduction speed in the peroneal and the sural nerve identified cases with sensitivities of 80% and 83% respectively, and 89% and 72% specificity, correspondingly. Furthermore, the sum of the F wave of tibial latency plus peroneal conduction speed, and the sum of 3 conduction speeds of the lower limb (sural peroneal and tibial) predicted a 4-year incidence with 79-81% sensitivity and 63-77% specificity.
There are other methods for pain and quality of life assessment, such as DN4 (Douleur Neuropathique 4 Questions) for pain, which boasts 95% sensitivity and 96.6% specificity (Unal-Cevik, Sarioglu-Ay & Evcik, 2010); the LANSS Pain Scale (Leeds Assessment of Neuropathic Symptoms and Signs) with 70.2% sensitivity and 96.6% specificity (Unal-Cevik, Sarioglu-Ay & Evcik, 2010; Bennet, 2001); and the McGill Pain Questionnaire (Burckhardt & Jones, 2003). Although these methods allow for a quick screening and personal assessment of pain in correlation to clinical findings, confirmation through tuning fork assessment, monofilament test or anatomic-specific pulse and reflex exploration should always be sought.
On the other hand, DAN assessment is recommended starting 5 years after diagnosis of DM1 (American Diabetes Association, 2014), surveying the following manifestations: Tachycardia at rest, exercise intolerance, orthostatic hypotension constipation, gastroparesis, erectile dysfunction, intolerance to hypoglycemia and sweating dysfunction (American Diabetes Association, 2014). The RINES-VALCARDI test (Chacín, Jatem & Rojas, 2009) is a diagnostic tool developed in Venezuela by Dr. Luis Chacín in 1981, wherein heart rate is registered with a conventional 12-lead electrocardiograph in 6 1-minute cycles: at rest, during deep inspiration, during expiration, while performing the Valsalva maneuver, and while softly massaging the left and right carotid sinuses (Figure 2). Results ≤15 points are compatible with cardiac DAN. Indeed, in comparison to non-diabetic subjects, diabetic individuals with RINES-VALCARDI scores ≤15 points presented greater frequency of postural hypotension (40%), loss of morning urinary urgency (53,3%), periodic nocturnal diarrhea (40%) and erectile dysfunction (44,4%) (Figuera et al, 1997). A new, less cumbersome version of the test has been recently proposed by the same research group (Chacín et al, 2009), which involves the utilization of a pulse oximeter for heart rate monitoring during each of the 6 cycles, registering this parameter at 0”, 15”, 30”, 45” and 60”. For each cycle, the difference between the highest and lowest values is calculated, and finally all 6 differences are added to obtain a final score. With this form of test, scores <27 points appear to detect cardiac DAN with 60.86% sensitivity, 86.61% specificity, 92.45% positive predictive value and 45.6% negative predictive value.
Regarding pharmacologic therapy of DN, a wide array of drugs with diverse mechanisms of action may be utilized, including (Attala et al, 2010): Inhibition of monoamine reuptake, calcium channel blockers N-Methyl-D-Aspartate receptor antagonists, Substance P-depleting agents, opioid agonists, GABA modulators, and NSAIDs. Indication of the drugs is issued in a progressive, stratified fashion including combinations, since monotherapy appears to offer relief to less than 50% of cases (Weisman et al, 2013). First-line medication includes (Vinik & Casellini, 2013): ï¡2-ï¤ agonists (pregabalin or gabapentin), serotonin-norepinephrine reuptake inhibitors (SNRI) (duloxetine) and tricyclic antidepressants (TCA). If pain management is inadequate or these are contraindicated, second-line treatment involves the following combinations (64): TCA with SNRI, TCA with ï¡2-ï¤ agonists or SNRI with ï¡2-ï¤ agonists. Finally, if control remains insufficient, an opioid is added into the combination. The corresponding efficacy rates and numbers needed to treat (NNT) are (Vinik, 2010): a) TCA OR 22.2 and NNT 1.5-3.5; b) Duloxetine OR 2.6 and NNT 5.7-5.8; c) Traditional Anticonvulsants OR 5.3 and NNT 2-9-4.3; and e) Opioids OR 4.3 and NNT 2.6-3.9.
According to the American Neurology Academy (Bril et al, 2011) and the Toronto Consensus Panel on Diabetic Neuropathy Management (Tesfaye et al, 2011), Level A of recommendation is Pregabalin (300-600 mg/day), whereas all other medication is considered Level B: Gabapentin 900-3600 mg/day, Duloxetine 60-120 mg/day, Amitriptyline 25-100 mg/day, Sodium Valproate 500-1200 mg/day, Tramadol 210 mg/day, and 0.075% Capsaicin cream. TCA are contraindicated in patients with glaucoma, orthostatic hypotension, overweight and cardiovascular disease. Duloxetine is contraindicated in subjects with hepatic disease, and ï¡2-ï¤ agonists contraindicated in subjects with edema and weight gain (Bril et al, 2011).
Achievement of metabolic goals accompanied by possible reversibility of neural damage was observed in these cases, where patient reeducation, psychological therapy, adequate weight gain, adherence to insulin therapy, improvement of lipid profile and inclusion of physical activity in daily routine served as key components for restitution of the functional anatomy of nerve tissue. Evidence of neuropathic damage reversibility exists in contexts such as cachectic DN (Tesfaye et al, 2011), characterized by intense neuropathic pain and wasting syndrome associated with the initiation of insulin therapy and the sudden lowering of HbA1c (Weintrob et al, 1997). This clinical picture is accompanied by finings of nervous potential ablation and slower conduction speeds in both motor and sensitive nerves (Weintrob et al, 1997; Kihara et al, 1994). Although its pathophysiology is yet to be elucidated, Grewal et al. (2006) have described the first report of objective confirmation of damage reversibility through nerve conduction studies during pain crises within the cachectic phase, suggesting this reversion to be dependent on replenishment of neuronal normoxia.
It is well-known that the application of intensive insulin therapy allows for the restoration of intraaxonal sodium ion transit patterns, in turn improving action potential capacity (Sima & Brismar, 1985). Furthermore, the reversion of hyperglycemia-triggered damage in DN may also be associated with the restoration of myoinositol metabolism defects and sodium permeability gradients (Brismar, Sima & Greene, 1987). Although several mechanisms are involved in axonal damage (Sytze Van Dam et al, 2013), these specific components share the polyol pathway as an etiopathogenic element. Williamson et al. (Williamson et al, 1993) have proposed hyperglycemia to generate the same effects as ischemia through the sorbitol pathway —termed hyperglycemic pseudohypoxia— such as an elevation of the NADH/NAD+ ratio, which induces electric, mechanic and vascular dysfunction with a consequent rise in lactate production. Moreover, it has been reported that the main mediator of oxidative neuronal damage is Aldose Reductase (AR), a key enzyme in the polyol pathway (Chung et al, 2003).
The increase of NADH due to AR and its consequent redox imbalance augment diacylglycerol synthesis and Protein Kinase C activity, leading to lowered Na+/K+ ATPase pump activity, myoinositol depletion, induction of prostaglandin synthesis, and production of reactive oxygen species and nitric oxide (Brismar, Sima & Greene, 1987). Moreover, this state of pseudohypoxia may trigger the expression of HIF-1 through nitric oxide acting on the genetic regulation of this protein (Marfella et al, 2002), enabling its participation in aberrant angiogenesis, a classic feature found in diabetic patients (Kota et al, 2012). Because AR is predominantly expressed in Schwann cells (Tomlinson & Gardiner, 2008), this aspect of neuropathic damage does not begin in neurons themselves, but rather in their myelination and support cellular system.
Considering this succession of cellular and clinical events, a possible interventional window may be outlined, wherein the main source of damage leading to conduction impairment first appears in Schwann cells (Zenker, Ziegler & Chrast, 2013); with this state of refractoriness and/or sodium gradient alteration being sufficient to modify axonal conduction patterns and “stunned” neurons, before the onset of overt clinical manifestation (Arnold et al, 2013). This phenomenon may also be observed in autonomic nerves, as reported by Kiyono et al. (2005) who found that a progressive potentiation of the polyol pathway induces sympathetic fiber dysfunction, associated with down-regulation of norepinephrine transporters, a loss of cardiac neuroautonomic control. The early detection of the neuropathic phenomenon and adequate, quick and precise control of hyperglycemia may allow for reversion of the events previously described, by rescuing neurons from stunning and impeding the development of the irreversible histopathologic changes seen in DN.
In conclusion, because DN is one of the most concerning complications — owing not only to its complex pathophysiology, but also to its booming incidence in the last decade (Mohsin et al, 2005) — early detection, strict glycemic control and management of amplifying factors are extremely valuable tools in order to delay progression and potentially favor reversibility of this disease.
Acknowledement
This work was supported by research grant Nº CC-0437-10-21-09-10 from the Technological, Humanistic, and Scientific Development Council, University of Zulia, and research grant Nº. FZ-0058-2007 from Fundacite-Zulia.
Disclosure
The authors have are no conflicts of interest to disclose.
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