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Neuropathy in young diabetic patients
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Review/Praca poglądowa
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Neuropathy in young diabetic patients
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Neuropatia młodych pacjentów z cukrzycą
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Ewa Otto-Buczkowska 1, Marek Dryżałowski 2,* 1 2
Medical Specialist Centre in Gliwice, Poland Independent Public Healthcare Centre of the Ministry of Internal Affairs in Katowice, Poland
article info
abstract
Article history:
Diabetic neuropathy is one of the most common and serious complications of both type
Received: 02.10.2015
1 and type 2 diabetes. In type 1 diabetes mellitus, neuropathy usually takes form of distal
Accepted: 19.11.2015
symmetric polyneuropathy (DPN) and/or diabetic autonomic neuropathy (DAN). Other
Available online: xxx
forms such as acute sensory neuropathy, cranial neuropathy, truncal radiculoneuropathy or proximal motor neuropathy are present sporadically in those patients. There are three
Keywords: Type 1 diabetes mellitus Diabetic neuropathy
hypotheses that explain the pathogenetic mechanism of polyneuropathy: metabolic, vas-
Peripheral neuropathy Autonomic neuropathy
nomic function and tests of conduction velocity in peripheral nerves are assumed to be
Diagnosis of neuropathy Management of neuropathy
cular and immunological. Many diabetic patients have demonstrable abnormalities of autonomic neurological function without any evidence of clinical disease. Tests of autoa measure of neurological state and may be important methods of assessing the therapy of diabetic complications. When it comes to therapeutic management, good metabolic control is essential for the prevention of diabetic neuropathy and remains the key element of treatment. Other methods (e.g. pharmacological) are used for the management
Słowa kluczowe: cukrzyca typu 1 neuropatia cukrzycowa
of symptoms and are rarely used in the juvenile population. © 2015 Published by Elsevier Sp. z o.o. on behalf of Polish Pediatric Society.
neuropatia obwodowa neuropatia autonomiczna diagnostyka neuropatii postępowanie w neuropatii
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Introduction
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The most common form of diabetes in young patients is type 1 diabetes [1]. As the association between diabetes mellitus and neuropathy has been recognized for well over 100 years, it is not surprising that damage to the peripheral nervous system has also been documented [2]. The first
reports of neuropathy in children with diabetes already appeared in the middle of the last century. Later studies were based on broader material and included, among others, the nervous conduction velocity tests [3]. Diabetes is the most common cause of neuropathy in United States and neuropathies are the most common complication of diabetes mellitus, affecting up to 50% of patients with type 1 and type 2 diabetes mellitus [4].
* Corresponding author at: Szpital MSWiA w Katowicach, ul. Głowackiego 10, 40-052 Katowice, Poland. Tel.: +48 605675310. E-mail address: [email protected] (M. Dryżałowski). http://dx.doi.org/10.1016/j.pepo.2015.11.008 0031-3939/© 2015 Published by Elsevier Sp. z o.o. on behalf of Polish Pediatric Society.
Please cite this article in press as: Otto-Buczkowska E, Dryżałowski M. Neuropathy in young diabetic patients. Pediatr Pol. (2015), http://dx. doi.org/10.1016/j.pepo.2015.11.008
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Great advances in the treatment of type 1 diabetes that have been made in the last 20 years mean that chronic complications of the disease appear later than they used to. However, even the most careful treatment cannot completely eliminate the risk of their occurrence. Although overt diabetic neuropathy is rarely present in children and adolescents with diabetes, subclinical diabetic neuropathy has been estimated to occur in approximately half of all children with type 1 diabetes with a disease duration of 5 years or longer. In addition, up to 25% of pediatric patients with newly diagnosed diabetes have abnormal findings on nerve conduction studies [5]. In diabetic patients, the risk of DPN (distal symmetric neuropathy) and autonomic neuropathy can be reduced with better glycemic control and the improvement of lipid and blood pressure indexes [6–9].
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Definition and classification
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Diabetic neuropathy (DN) is defined as “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes” [2, 10–13]. It is a common complication of diabetes mellitus which requires a multifactorial approach to clinical assessment since diabetes mellitus is associated with many different neuropathic syndromes [2, 14–16]. The spectrum of diabetes mellitus-associated neuropathies is large and our knowledge of these syndromes continues to evolve. Two main types are usually distinguished, named as sensorimotor and autonomic neuropathies. Sensorimotor neuropathy is characterized by pain, paresthesia and sensory loss while autonomic neuropathy causes a constellation of symptoms and signs affecting the cardiovascular, urogenital, gastrointestinal, pupillomotor, thermoregulatory and sudomotor systems [17–20]. It is important to bear in mind that autonomic neuropathy may also contribute to myocardial infarction, malignant arrhythmia and sudden death [7]. In currently proposed classification of diabetic neuropathy, the following can be distinguished [10]: 1. Generalized symmetric polyneuropathies a) acute sensory b) chronic sensorimotor c) autonomic 2. Focal and multifocal neuropathies. Focal and multifocal neuropathies are typical for diabetes in the elderly and occur extremely rarely in children and adolescents – therefore they will not be addressed in this article.
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Acute sensory neuropathy (acute painful neuropathy)
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This form, manifesting itself with pain and paresthesia, develops in the early stage of diabetes mellitus, sometimes directly after the implementation of insulin therapy. This syndrome may associate itself with considerable loss of
body weight and depression. The mechanisms underlying the development of this syndrome are still unclear [21]. Its occurrence in young patients is only occasional.
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Chronic sensorimotor polyneuropathy – distal symmetric polyneuropathy (DPN)
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Sensory diabetic neuropathy, determined by nerve conduction studies, is common in children with type 1 diabetes but is rarely diagnosed because of its lack of symptoms. Höliner et al. [22] found that DPN is highly prevalent in children and adolescents with type 1 diabetes mellitus but subclinical in the majority of patients. Additionally, Moser et al. [23] conducted a study which suggested that DPN can occur in young children, with short diabetes duration, and good diabetes control. The American Diabetes Association (ADA) recommends screening for DPN in children and adolescents at diagnosis (in type 2 diabetes) or 5 years after diagnosis (in type 1 diabetes), followed by annual evaluations thereafter, using simple clinical tests [6]. Screening is required in order to identify subclinical signs of DPN in its earliest stages. Recently, Hirschfeld et al. [24, 25] analyzed the usefulness of certain diagnostic tests to screen for diabetic peripheral neuropathies (DPN) in children and adolescents. They demonstrated that diagnostic accuracy was heterogeneous for the different screening methods. Acceptable performance was demonstrated for the biothesiometer and the monofilament in detecting DPN in children and adolescents compared with the gold standard nerve conduction studies. According to the authors, the problem of reliability needs to be more thoroughly addressed in order to improve the screening procedures in diabetes management. Nerve conduction studies (NCS) are the gold-standard for the detection of subclinical DPN – however, it is an invasive method. Thermal discrimination thresholds (TDTs) and vibration sensation thresholds (VSTs) are quicker, easier and, therefore, more suitable as screening tools [26]. Blankenburg et al. [27] think that quantitative sensory testing (QST) is a valuable tool for the assessment of neuropathy as well as a target of interventional studies in children with diabetes. On the other hand, the neuropathy disability score (NDS) has been evaluated as a possible alternative method for measuring DPN. For example, Weintrob et al. [28] compared it to QST and found it to have better correlation with glycemic control and microvascular complications. Such performance, in the scope of easy access and cost-effectiveness, would make NDS the preferred method of evaluating neuropathy in young patients. The most common of the diagnostic methods mentioned above and in the further parts of this article will be described in more detail in the “Examinations” section.
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Diabetic autonomic neuropathy (DAN)
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Diabetic autonomic neuropathy may develop as one of two categories:
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Please cite this article in press as: Otto-Buczkowska E, Dryżałowski M. Neuropathy in young diabetic patients. Pediatr Pol. (2015), http://dx. doi.org/10.1016/j.pepo.2015.11.008
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1) functional neuropathy in which no structural changes are found 2) neuropathy accompanied by structural changes of the peripheral autonomous neuron. Diabetic autonomic neuropathy occurs as a systemic disorder affecting all parts of the autonomic nervous system (ANS) and manifesting itself first of all in long nerves. Nervus vagus (the longest one) is a carrier of approximately 75% of the entire parasympathetic activity of the autonomous system, therefore early effects of DAN are widespread. Diabetic autonomic neuropathy is one of the chronic complications of diabetes mellitus which can involve one or more organ systems. DAN without apparent symptoms is more usual in childhood and adolescence. When it comes to patient evaluation, heart rate variability (HRV) and Ewing's battery of cardiovascular tests are regarded as a gold standard for the diagnosis of DAN. Another sensitive method is the examination of cough reflex sensitivity (CRS) – especially in the subclinical form of autonomic neuropathy [29]. Finally, laboratory testing of catecholamine concentrations in the blood and catecholamine metabolites in the urine are a valuable addition to the diagnostic process in DAN [30, 31].
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Cardiovascular autonomic neuropathy – CAN
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Cardiac autonomic neuropathy is a common complication in type 1 diabetes mellitus and it may also occur in young patients. Hypertension in children with type 1 diabetes mellitus is correlated with the presence of autonomous neuropathy [32]. In addition to this, a study by Karavanaki et al. [33] suggests that there is a close relationship between autonomic function and left ventricular remodeling in patients with type 1 diabetes. Patients with very early stages of diabetic nephropathy also appear to suffer from simultaneous BP elevation and subclinical DAN [34]. Boysen et al. [35] conducted a study of autonomic function in pediatric patients with type 1 diabetes and found that classical cardiorespiratory reflexes seemed to be less specific testing methods than heart rate variability (HRV) and baroreflex sensitivity (BRS). BRS in diabetic children was also studied by Dalla Pozza et al. [36] who concluded that the degree of BRS impairment was related to the degree of autonomic imbalance. Another study of cardiovascular autonomic neuropathy tests in young patients with type 1 diabetes mellitus was conducted by Lucini et al. [37] and showed a significant increase in arterial pressure, a reduced gain of the baroreflex regulation of the heart period and an increase of the low-frequency component of systolic arterial pressure variability. Such results were suggestive of simultaneous impairment of vagal cardiac control and increase of sympathetic vasomotor regulation. The authors concluded that new methods, such as spectral analysis of RR interval variability or BRS, can be obtained automatically from a computer analysis without the need for active patient participation and could be considered more sensitive than traditional tests. The presence of CAN in young and slim diabetic patients may lead to obstructive sleep apnea (OSA). During sleep,
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respiratory function is partially controlled by the autonomic nervous system (ANS). When this system is impaired, as in diabetic autonomic neuropathy, the airway may be less functional and breathing control more variable, resulting in OSA [38].
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Gastrointestinal (GI) neuropathy
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Gastrointestinal symptoms occur frequently among patients with diabetes. Diabetic gastrointestinal autonomic neuropathy represents a complex disorder with multifactorial pathogenesis. Clinical manifestations are often underestimated, and therefore autonomic neuropathy should be suspected in all diabetic patients with unexplained gastrointestinal symptoms [39, 40]. GI neuropathy manifests through disturbances of the peristaltic movements of various segments of the gastrointestinal system. In the esophagus, it may lead to reduced peristalsis during swallowing and reduction of inferior sphincter tonus which may result in delayed evacuation of food from the esophagus or the reflux of gastric contents. Gastroparesis is the most debilitating complication of GI autonomic neuropathy. In majority of patients, stomach emptying gets slowed down and gastric disturbances also manifest themselves with the impaired secretion of the gastric acid. Gastroparesis even at early stages may be a reason of very high blood glucose fluctuations with unexpected episodes of postprandial hypoglycemia. Thus, it may also cause symptoms of brittle diabetes. Diarrhea is another symptom of autonomic neuropathy of the gastrointestinal system. Diabetic diarrhea is usually plentiful, aqueous and nocturnal and may last for hours or days, frequently alternating with constipations. Lastly, disturbances of the gallbladder mobility may also be the result of GI autonomic neuropathy in diabetes.
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Neurogenic urinary bladder
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Urinary bladder dysfunction is a frequent complication of diabetes mellitus in adults. Szabo et al. [41] investigated the bladder urine flow parameters in children with type 1 diabetes and found them to be abnormal. The authors believe that the use of uroflowmetry could be useful in diagnosing autonomic neuropathy since the method is easy to perform, sensitive, gives reproducible results and requires minimal patient cooperation.
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Manifestations of autonomic neuropathy associated with the endocrine system
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Hypoglycemia-associated autonomic failure (HAAF) in diabetes is caused both by defective glucose counter regulation and hypoglycemia unawareness [42, 43]. Autonomic neuropathy is an important reason for its occurrence, although not exclusively. HAAF is mostly related to disturbances in epinephrine secretion. In patients with type 1 diabetes, autonomic neuropathy further reduces counterregulatory catecholamine responses – this in turn increases the risk for severe hypoglycemia.
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Please cite this article in press as: Otto-Buczkowska E, Dryżałowski M. Neuropathy in young diabetic patients. Pediatr Pol. (2015), http://dx. doi.org/10.1016/j.pepo.2015.11.008
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Pupillary dysfunction
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Many authors believe that the assessment of pupillary function is a very useful method in the diagnostics of early stages of autonomic neuropathy. Maguire et al. [44] suggest that pupillometry abnormalities may be early indicators of possible future microvascular disease. Therefore, pupillary testing can be utilized in the evaluation of autonomic neuropathy and can help manage the complications of diabetes [45, 46].
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Examinations
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Testing of nerve conduction velocity and electromyographic examination
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Electromyographic examinations and nerve conduction velocity tests are useful for the assessment of various forms of diabetic neuropathy [3]. They are a perfect tool for the assessment of peripheral nerves in type 1 diabetes mellitus – also when the progression of the disease is to be evaluated. Introduction of these examinations into the assessment of the peripheral nervous system in children with insulin dependent diabetes mellitus led to changes in opinion about the incidence of peripheral nerve damage in this group of patients. It has been discovered that decreased nerve conduction velocity is present in adolescents with diabetes mellitus significantly more frequently than the clinical symptoms of neuropathy [47]. The literature is not consistent as to the question which nervous fibers – motor or sensory – are more frequently affected in children with diabetes mellitus.
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2 points (normal – 0 points, reinforced – 1, absent – 2) and the other tests are scored from 0 to 1 points (0 – normal, 1 – reduced or absent). The testing is performed bilaterally on both feet which gives a maximum score of 10 points – results greater than 6 points are considered abnormal [51, 52].
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Biothesiometer (vibrometer) and monofilament testing
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A vibrometer is an electronic device used to provide vibration stimuli with preset amplitude and frequency and – as it was mentioned above – is a valid candidate for replacing the classic vibration testing with the use of a tuning fork. However, as of today, no standardized examination protocol nor universal reference values have been established, which limits a broad implementation of the method [53]. Monofilament testing is a widely used method for screening in neuropathy. It involves the use of a standardized monofilament fiber which bends when a specific force threshold is achieved (most commonly, a force of 10G). This provides a reproducible stimulus which can then be applied to various sites of sensory testing. Specific protocols have been established, e.g. for the assessment of sensation in the feet – however, this tool can be used for any region of the body [54].
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Tests of the autonomous system
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Screening tests for autonomic neuropathy are performed in adult patients with type 1 diabetes mellitus 5 years after the initial diagnosis. In children undergoing puberty, such tests should be performed earlier, since this period is a very serious risk factor for the occurrence of chronic complications of diabetes.
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Quantitative measurements of sensory disturbances
Tests of the cardiovascular system
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Quantitative measurements of sensory disturbances (or quantitative sensory testing – QST) are performed by means of appropriate automated devices that enable repeatable assessment of the threshold of a particular type of perception. American Academy of Neurology stated: “QST is designated as safe, effective and established with type B strength of recommendation” [48]. QST testing involves the assessment of 13 somatosensory parameters in pre-defined test conditions – following the protocol of the German research network on neuropathic pain (DFNS), with appropriate modifications for children and adolescents. The procedure requires adequate equipment and takes approximately 3–4 h to perform in juvenile patients [49, 50].
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Revised neuropathy disability score (NDS)
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The revised (simplified) NDS is a relatively easy-to-perform battery of neurological tests which has been proven to be comparable to QST in terms of diagnostic value and superior in terms of practical applicability [28]. The NDS protocol (in its most popular form) involves testing of: vibration, temperature and pin-prick sensation and the ankle reflex. The ankle reflex is scored from 0 to
In juvenile patients, neural autonomic function can be assessed by RR variation measurement during deep breathing, the Valsalva ratio test (VR), the heart rate response to standing (30/15 ratio), the blood pressure response to standing (Postural BP) and the sustained handgrip test – a series of examinations first proposed by Ewing et al. [57] in 1980 and therefore referred to as “the Ewing's battery of tests” [55–57]. In the clinical setting, not all of these tests are always performed – the most common one is the deep breathing test, which has been proven to be the most convenient, specific and reproducible [58]. Detailed instructions on the proper technique and interpretations of the mentioned tests can be found in the original article by Ewing et al. and other related sources. Skinner et al. [59] found that a new heart rate variability (HRV) complexity measure, the Point Correlation Dimension (PD2i), provided diagnostic information regarding early subclinical autonomic dysfunction in asymptomatic young diabetic patients without overt neuropathy [59]. According to the authors, the PD2i algorithm may prove to be an easy to perform and clinically useful tool for the early detection of autonomic neuropathy in type 1 diabetics. Regarding other methods, Boysen et al. [35] expressed the view that HRV and BRS as testing methods are specific
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and non-invasive. Dalla Pozza et al. [36] expressed the view that degree of BRS impairment was related to the degree of autonomic imbalance in diabetic children.
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Tests of the gastrointestinal system
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Various diagnostic techniques are used for the assessment of GI peristalsis, including fluoroscopy, X-ray imaging, scintigraphy, isotopic techniques, endoscopy, ultrasonography, computed tomography and magnetic resonance.
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Tests of the urinary bladder function
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Urinary bladder function is assessed through cystometrography and post voiding sonography. As it was mentioned above, in children the evaluation of urinary autonomic neuropathy may be easily performed using uroflowmetry.
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Therapeutic management
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In the majority of juvenile patients, diabetic neuropathy is subclinical. Prevention and treatment of neuropathy is mainly based on maximum metabolic control of diabetes. Pharmacotherapy is used only in extreme and rare cases.
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Conclusion
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The spectrum of diabetes mellitus-associated neuropathies is extremely broad. Nerve damage can arise from metabolic, compressive or ischemic injury and altered immune responses – these varied pathologies can present in many different ways. Identifying the pathogenesis of these syndromes is valuable as there are clear differences in assessment and disease prevention. Correct diagnosis is important before starting an appropriate therapy. Poor glycemic control is the most important risk factor for the development of diabetic neuropathy. Maintaining near-normoglycemia is the only way to prevent or reverse neural impairment, as the currently available treatments can only relieve the symptoms of DN.
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Authors’ contributions/Wkład autorów
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EO-B – study design, data collection and interpretation, acceptance of final manuscript version, literature search. MD – data collection and interpretation, acceptance of final manuscript version, literature search.
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Conflict of interest/Konflikt interesu
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None declared.
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Financial support/Finansowanie
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None declared.
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Ethics/Etyka
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The work described in this article has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans; EU Directive 2010/63/EU for animal experiments; Uniform Requirements for manuscripts submitted to Biomedical journals.
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references/pi smiennictwo
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[34] Darcan S, Goksen D, Mir S, Serdaroglu E, Buyukinan M, Coker M, et al. Alterations of blood pressure in type 1 diabetic children and adolescents. Pediatr Nephrol 2006;21:672–676. [35] Boysen A, Lewin MA, Hecker W, Leichter HE, Uhlemann F. Autonomic function testing in children and adolescents with diabetes mellitus. Pediatr Diabetes 2007;8:261–264. [36] Dalla Pozza R, Bechtold S, Bonfig W, Putzker S, KozlikFeldmann R, Schwarz HP, et al. Impaired short-term blood pressure regulation and autonomic dysbalance in children with type 1 diabetes mellitus. Diabetologia 2007;50:2417–2423. [37] Lucini D, Zuccotti G, Malacarne M, Scaramuzza A, Riboni S, Palombo C, et al. Early progression of the autonomic dysfunction observed in pediatric type 1 diabetes mellitus. Hypertension 2009;54:987–994. [38] Janovsky CC, Rolim LC, de Sá JR, Poyares D, Tufik S, Silva AB, et al. Cardiovascular autonomic neuropathy contributes to sleep apnea in young and lean type 1 diabetes mellitus patients. Front Endocrinol (Lausanne) 2014;5:119. [39] Gatopoulou A, Papanas N, Maltezos E. Diabetic gastrointestinal autonomic neuropathy: current status and new achievements for everyday clinical practice. Eur J Intern Med 2012;23:499–505. [40] Guerci B, Bourgeois C, Bresler L, Scherrer ML, Böhme P. Gastric electrical stimulation for the treatment of diabetic gastroparesis. Diabetes Metab 2012;38:393–402. [41] Szabo L, Barkai L, Lombay B. Urinary flow disturbance as an early sign of autonomic neuropathy in diabetic children and adolescents. Neurourol Urodyn 2007;26:218–221. [42] Cryer PE. Hypoglycemia-associated autonomic failure in diabetes. Handb Clin Neurol 2013;117:295–307. [43] Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 2013;369: 362–372. [44] Maguire AM, Craig ME, Craighead A, Chan AK, Cusumano JM, Hing SJ, et al. Autonomic nerve testing predicts the development of complications: a 12-year follow-up study. Diabetes Care 2007;30:77–82. [45] Kwon HJ, Kim HY. A pharmacologic pupillary test in the diagnosis of diabetic autonomic neuropathy. Korean J Ophthalmol 2009;23:291–295. [46] Várkonyi TT, Börcsök E, Tóth F, Fülöp Z, Takács R, Rovó L, et al. Severity of autonomic and sensory neuropathy and the impairment of visual- and auditory-evoked potentials in type 1 diabetes: is there a relationship? Diabetes Care 2006;29:2325–2326. [47] Hyllienmark L, Alstrand N, Jonsson B, Ludvigsson J, Cooray G, Wahlberg-Topp J. Early electrophysiological abnormalities and clinical neuropathy: a prospective study in patients with type 1 diabetes. Diabetes Care 2013;36:3187–3194. [48] Shy ME, Frohman E, So YT, Arezzo JC, Cornblath DC, Giuliani MJ. Subcomittee of the American Academy of Neurology Quantitative sensory testing. Neurology 2003;602:898–906. [49] Blankenburg M, Boekens H, Hechler T, Maier C, Krumova E, Scherens A, et al. Reference values for quantitative sensory testing in children and adolescents: developmental and gender differences of somatosensory perception. Pain 2010;149:76–88. [50] Rolke R, Baron R, Maier C, Tolle TR, Treede RD, Beyer A, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 2006;123:231–243. [51] In: Zochodne DW, Malik RA, editors. Diabetes and the nervous system: handbook of clinical neurology. Elsevier; 2014. p. 100–101.
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[52] Yang Z, Chen R, Zhang Y, Huang Y, Hong T, Sun F, et al. Scoring systems to screen for diabetic peripheral neuropathy. Cochrane Database Syst Rev 2014. http://dx. doi.org/10.1002/14651858.CD010974. [53] Maffei L, Premrou V, Roldan P, Copetti M, Pellegrini F, Rossi MC, et al. Vibration perception threshold in the screening of sensorimotor distal symmetric polyneuropathy: the need of more accurate age-specific reference values. J Diabetes Sci Technol 2014;8:621–622. [54] Boulton AJM, Armstrong DG, Albert SF, Frykberg RG, Hellman R, Kirkman MS, et al. Comprehensive Foot Examination and Risk Assessment: A report of the Task Force of the Foot Care Interest Group of the American Diabetes Association, with endorsement by the American Association of Clinical Endocrinologists. Diabetes Care 2008;31:1679–1685. [55] Vazeou A, Papadopoulou A, Miha M, Drakatos A, Georgacopoulos D. Cardiovascular impairment in children,
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Review/Praca poglądowa
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Neuropathy in young diabetic patients
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Neuropatia młodych pacjentów z cukrzycą
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Q1
Ewa Otto-Buczkowska 1, Marek Dryżałowski 2,* 1 2
Medical Specialist Centre in Gliwice, Poland Independent Public Healthcare Centre of the Ministry of Internal Affairs in Katowice, Poland
article info
abstract
Article history:
Diabetic neuropathy is one of the most common and serious complications of both type
Received: 02.10.2015
1 and type 2 diabetes. In type 1 diabetes mellitus, neuropathy usually takes form of distal
Accepted: 19.11.2015
symmetric polyneuropathy (DPN) and/or diabetic autonomic neuropathy (DAN). Other
Available online: xxx
forms such as acute sensory neuropathy, cranial neuropathy, truncal radiculoneuropathy or proximal motor neuropathy are present sporadically in those patients. There are three
Keywords: Type 1 diabetes mellitus Diabetic neuropathy
hypotheses that explain the pathogenetic mechanism of polyneuropathy: metabolic, vas-
Peripheral neuropathy Autonomic neuropathy
nomic function and tests of conduction velocity in peripheral nerves are assumed to be
Diagnosis of neuropathy Management of neuropathy
cular and immunological. Many diabetic patients have demonstrable abnormalities of autonomic neurological function without any evidence of clinical disease. Tests of autoa measure of neurological state and may be important methods of assessing the therapy of diabetic complications. When it comes to therapeutic management, good metabolic control is essential for the prevention of diabetic neuropathy and remains the key element of treatment. Other methods (e.g. pharmacological) are used for the management
Słowa kluczowe: cukrzyca typu 1 neuropatia cukrzycowa
of symptoms and are rarely used in the juvenile population. © 2015 Published by Elsevier Sp. z o.o. on behalf of Polish Pediatric Society.
neuropatia obwodowa neuropatia autonomiczna diagnostyka neuropatii postępowanie w neuropatii
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Introduction
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The most common form of diabetes in young patients is type 1 diabetes [1]. As the association between diabetes mellitus and neuropathy has been recognized for well over 100 years, it is not surprising that damage to the peripheral nervous system has also been documented [2]. The first
reports of neuropathy in children with diabetes already appeared in the middle of the last century. Later studies were based on broader material and included, among others, the nervous conduction velocity tests [3]. Diabetes is the most common cause of neuropathy in United States and neuropathies are the most common complication of diabetes mellitus, affecting up to 50% of patients with type 1 and type 2 diabetes mellitus [4].
* Corresponding author at: Szpital MSWiA w Katowicach, ul. Głowackiego 10, 40-052 Katowice, Poland. Tel.: +48 605675310. E-mail address: [email protected] (M. Dryżałowski). http://dx.doi.org/10.1016/j.pepo.2015.11.008 0031-3939/© 2015 Published by Elsevier Sp. z o.o. on behalf of Polish Pediatric Society.
Please cite this article in press as: Otto-Buczkowska E, Dryżałowski M. Neuropathy in young diabetic patients. Pediatr Pol. (2015), http://dx. doi.org/10.1016/j.pepo.2015.11.008
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Great advances in the treatment of type 1 diabetes that have been made in the last 20 years mean that chronic complications of the disease appear later than they used to. However, even the most careful treatment cannot completely eliminate the risk of their occurrence. Although overt diabetic neuropathy is rarely present in children and adolescents with diabetes, subclinical diabetic neuropathy has been estimated to occur in approximately half of all children with type 1 diabetes with a disease duration of 5 years or longer. In addition, up to 25% of pediatric patients with newly diagnosed diabetes have abnormal findings on nerve conduction studies [5]. In diabetic patients, the risk of DPN (distal symmetric neuropathy) and autonomic neuropathy can be reduced with better glycemic control and the improvement of lipid and blood pressure indexes [6–9].
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Definition and classification
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Diabetic neuropathy (DN) is defined as “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes” [2, 10–13]. It is a common complication of diabetes mellitus which requires a multifactorial approach to clinical assessment since diabetes mellitus is associated with many different neuropathic syndromes [2, 14–16]. The spectrum of diabetes mellitus-associated neuropathies is large and our knowledge of these syndromes continues to evolve. Two main types are usually distinguished, named as sensorimotor and autonomic neuropathies. Sensorimotor neuropathy is characterized by pain, paresthesia and sensory loss while autonomic neuropathy causes a constellation of symptoms and signs affecting the cardiovascular, urogenital, gastrointestinal, pupillomotor, thermoregulatory and sudomotor systems [17–20]. It is important to bear in mind that autonomic neuropathy may also contribute to myocardial infarction, malignant arrhythmia and sudden death [7]. In currently proposed classification of diabetic neuropathy, the following can be distinguished [10]: 1. Generalized symmetric polyneuropathies a) acute sensory b) chronic sensorimotor c) autonomic 2. Focal and multifocal neuropathies. Focal and multifocal neuropathies are typical for diabetes in the elderly and occur extremely rarely in children and adolescents – therefore they will not be addressed in this article.
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Acute sensory neuropathy (acute painful neuropathy)
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This form, manifesting itself with pain and paresthesia, develops in the early stage of diabetes mellitus, sometimes directly after the implementation of insulin therapy. This syndrome may associate itself with considerable loss of
body weight and depression. The mechanisms underlying the development of this syndrome are still unclear [21]. Its occurrence in young patients is only occasional.
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Chronic sensorimotor polyneuropathy – distal symmetric polyneuropathy (DPN)
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Sensory diabetic neuropathy, determined by nerve conduction studies, is common in children with type 1 diabetes but is rarely diagnosed because of its lack of symptoms. Höliner et al. [22] found that DPN is highly prevalent in children and adolescents with type 1 diabetes mellitus but subclinical in the majority of patients. Additionally, Moser et al. [23] conducted a study which suggested that DPN can occur in young children, with short diabetes duration, and good diabetes control. The American Diabetes Association (ADA) recommends screening for DPN in children and adolescents at diagnosis (in type 2 diabetes) or 5 years after diagnosis (in type 1 diabetes), followed by annual evaluations thereafter, using simple clinical tests [6]. Screening is required in order to identify subclinical signs of DPN in its earliest stages. Recently, Hirschfeld et al. [24, 25] analyzed the usefulness of certain diagnostic tests to screen for diabetic peripheral neuropathies (DPN) in children and adolescents. They demonstrated that diagnostic accuracy was heterogeneous for the different screening methods. Acceptable performance was demonstrated for the biothesiometer and the monofilament in detecting DPN in children and adolescents compared with the gold standard nerve conduction studies. According to the authors, the problem of reliability needs to be more thoroughly addressed in order to improve the screening procedures in diabetes management. Nerve conduction studies (NCS) are the gold-standard for the detection of subclinical DPN – however, it is an invasive method. Thermal discrimination thresholds (TDTs) and vibration sensation thresholds (VSTs) are quicker, easier and, therefore, more suitable as screening tools [26]. Blankenburg et al. [27] think that quantitative sensory testing (QST) is a valuable tool for the assessment of neuropathy as well as a target of interventional studies in children with diabetes. On the other hand, the neuropathy disability score (NDS) has been evaluated as a possible alternative method for measuring DPN. For example, Weintrob et al. [28] compared it to QST and found it to have better correlation with glycemic control and microvascular complications. Such performance, in the scope of easy access and cost-effectiveness, would make NDS the preferred method of evaluating neuropathy in young patients. The most common of the diagnostic methods mentioned above and in the further parts of this article will be described in more detail in the “Examinations” section.
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Diabetic autonomic neuropathy (DAN)
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Diabetic autonomic neuropathy may develop as one of two categories:
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1) functional neuropathy in which no structural changes are found 2) neuropathy accompanied by structural changes of the peripheral autonomous neuron. Diabetic autonomic neuropathy occurs as a systemic disorder affecting all parts of the autonomic nervous system (ANS) and manifesting itself first of all in long nerves. Nervus vagus (the longest one) is a carrier of approximately 75% of the entire parasympathetic activity of the autonomous system, therefore early effects of DAN are widespread. Diabetic autonomic neuropathy is one of the chronic complications of diabetes mellitus which can involve one or more organ systems. DAN without apparent symptoms is more usual in childhood and adolescence. When it comes to patient evaluation, heart rate variability (HRV) and Ewing's battery of cardiovascular tests are regarded as a gold standard for the diagnosis of DAN. Another sensitive method is the examination of cough reflex sensitivity (CRS) – especially in the subclinical form of autonomic neuropathy [29]. Finally, laboratory testing of catecholamine concentrations in the blood and catecholamine metabolites in the urine are a valuable addition to the diagnostic process in DAN [30, 31].
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Cardiovascular autonomic neuropathy – CAN
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Cardiac autonomic neuropathy is a common complication in type 1 diabetes mellitus and it may also occur in young patients. Hypertension in children with type 1 diabetes mellitus is correlated with the presence of autonomous neuropathy [32]. In addition to this, a study by Karavanaki et al. [33] suggests that there is a close relationship between autonomic function and left ventricular remodeling in patients with type 1 diabetes. Patients with very early stages of diabetic nephropathy also appear to suffer from simultaneous BP elevation and subclinical DAN [34]. Boysen et al. [35] conducted a study of autonomic function in pediatric patients with type 1 diabetes and found that classical cardiorespiratory reflexes seemed to be less specific testing methods than heart rate variability (HRV) and baroreflex sensitivity (BRS). BRS in diabetic children was also studied by Dalla Pozza et al. [36] who concluded that the degree of BRS impairment was related to the degree of autonomic imbalance. Another study of cardiovascular autonomic neuropathy tests in young patients with type 1 diabetes mellitus was conducted by Lucini et al. [37] and showed a significant increase in arterial pressure, a reduced gain of the baroreflex regulation of the heart period and an increase of the low-frequency component of systolic arterial pressure variability. Such results were suggestive of simultaneous impairment of vagal cardiac control and increase of sympathetic vasomotor regulation. The authors concluded that new methods, such as spectral analysis of RR interval variability or BRS, can be obtained automatically from a computer analysis without the need for active patient participation and could be considered more sensitive than traditional tests. The presence of CAN in young and slim diabetic patients may lead to obstructive sleep apnea (OSA). During sleep,
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respiratory function is partially controlled by the autonomic nervous system (ANS). When this system is impaired, as in diabetic autonomic neuropathy, the airway may be less functional and breathing control more variable, resulting in OSA [38].
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Gastrointestinal (GI) neuropathy
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Gastrointestinal symptoms occur frequently among patients with diabetes. Diabetic gastrointestinal autonomic neuropathy represents a complex disorder with multifactorial pathogenesis. Clinical manifestations are often underestimated, and therefore autonomic neuropathy should be suspected in all diabetic patients with unexplained gastrointestinal symptoms [39, 40]. GI neuropathy manifests through disturbances of the peristaltic movements of various segments of the gastrointestinal system. In the esophagus, it may lead to reduced peristalsis during swallowing and reduction of inferior sphincter tonus which may result in delayed evacuation of food from the esophagus or the reflux of gastric contents. Gastroparesis is the most debilitating complication of GI autonomic neuropathy. In majority of patients, stomach emptying gets slowed down and gastric disturbances also manifest themselves with the impaired secretion of the gastric acid. Gastroparesis even at early stages may be a reason of very high blood glucose fluctuations with unexpected episodes of postprandial hypoglycemia. Thus, it may also cause symptoms of brittle diabetes. Diarrhea is another symptom of autonomic neuropathy of the gastrointestinal system. Diabetic diarrhea is usually plentiful, aqueous and nocturnal and may last for hours or days, frequently alternating with constipations. Lastly, disturbances of the gallbladder mobility may also be the result of GI autonomic neuropathy in diabetes.
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Neurogenic urinary bladder
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Urinary bladder dysfunction is a frequent complication of diabetes mellitus in adults. Szabo et al. [41] investigated the bladder urine flow parameters in children with type 1 diabetes and found them to be abnormal. The authors believe that the use of uroflowmetry could be useful in diagnosing autonomic neuropathy since the method is easy to perform, sensitive, gives reproducible results and requires minimal patient cooperation.
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Manifestations of autonomic neuropathy associated with the endocrine system
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Hypoglycemia-associated autonomic failure (HAAF) in diabetes is caused both by defective glucose counter regulation and hypoglycemia unawareness [42, 43]. Autonomic neuropathy is an important reason for its occurrence, although not exclusively. HAAF is mostly related to disturbances in epinephrine secretion. In patients with type 1 diabetes, autonomic neuropathy further reduces counterregulatory catecholamine responses – this in turn increases the risk for severe hypoglycemia.
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Pupillary dysfunction
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Many authors believe that the assessment of pupillary function is a very useful method in the diagnostics of early stages of autonomic neuropathy. Maguire et al. [44] suggest that pupillometry abnormalities may be early indicators of possible future microvascular disease. Therefore, pupillary testing can be utilized in the evaluation of autonomic neuropathy and can help manage the complications of diabetes [45, 46].
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Examinations
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Testing of nerve conduction velocity and electromyographic examination
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Electromyographic examinations and nerve conduction velocity tests are useful for the assessment of various forms of diabetic neuropathy [3]. They are a perfect tool for the assessment of peripheral nerves in type 1 diabetes mellitus – also when the progression of the disease is to be evaluated. Introduction of these examinations into the assessment of the peripheral nervous system in children with insulin dependent diabetes mellitus led to changes in opinion about the incidence of peripheral nerve damage in this group of patients. It has been discovered that decreased nerve conduction velocity is present in adolescents with diabetes mellitus significantly more frequently than the clinical symptoms of neuropathy [47]. The literature is not consistent as to the question which nervous fibers – motor or sensory – are more frequently affected in children with diabetes mellitus.
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2 points (normal – 0 points, reinforced – 1, absent – 2) and the other tests are scored from 0 to 1 points (0 – normal, 1 – reduced or absent). The testing is performed bilaterally on both feet which gives a maximum score of 10 points – results greater than 6 points are considered abnormal [51, 52].
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Biothesiometer (vibrometer) and monofilament testing
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A vibrometer is an electronic device used to provide vibration stimuli with preset amplitude and frequency and – as it was mentioned above – is a valid candidate for replacing the classic vibration testing with the use of a tuning fork. However, as of today, no standardized examination protocol nor universal reference values have been established, which limits a broad implementation of the method [53]. Monofilament testing is a widely used method for screening in neuropathy. It involves the use of a standardized monofilament fiber which bends when a specific force threshold is achieved (most commonly, a force of 10G). This provides a reproducible stimulus which can then be applied to various sites of sensory testing. Specific protocols have been established, e.g. for the assessment of sensation in the feet – however, this tool can be used for any region of the body [54].
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Tests of the autonomous system
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Screening tests for autonomic neuropathy are performed in adult patients with type 1 diabetes mellitus 5 years after the initial diagnosis. In children undergoing puberty, such tests should be performed earlier, since this period is a very serious risk factor for the occurrence of chronic complications of diabetes.
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Quantitative measurements of sensory disturbances
Tests of the cardiovascular system
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Quantitative measurements of sensory disturbances (or quantitative sensory testing – QST) are performed by means of appropriate automated devices that enable repeatable assessment of the threshold of a particular type of perception. American Academy of Neurology stated: “QST is designated as safe, effective and established with type B strength of recommendation” [48]. QST testing involves the assessment of 13 somatosensory parameters in pre-defined test conditions – following the protocol of the German research network on neuropathic pain (DFNS), with appropriate modifications for children and adolescents. The procedure requires adequate equipment and takes approximately 3–4 h to perform in juvenile patients [49, 50].
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Revised neuropathy disability score (NDS)
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The revised (simplified) NDS is a relatively easy-to-perform battery of neurological tests which has been proven to be comparable to QST in terms of diagnostic value and superior in terms of practical applicability [28]. The NDS protocol (in its most popular form) involves testing of: vibration, temperature and pin-prick sensation and the ankle reflex. The ankle reflex is scored from 0 to
In juvenile patients, neural autonomic function can be assessed by RR variation measurement during deep breathing, the Valsalva ratio test (VR), the heart rate response to standing (30/15 ratio), the blood pressure response to standing (Postural BP) and the sustained handgrip test – a series of examinations first proposed by Ewing et al. [57] in 1980 and therefore referred to as “the Ewing's battery of tests” [55–57]. In the clinical setting, not all of these tests are always performed – the most common one is the deep breathing test, which has been proven to be the most convenient, specific and reproducible [58]. Detailed instructions on the proper technique and interpretations of the mentioned tests can be found in the original article by Ewing et al. and other related sources. Skinner et al. [59] found that a new heart rate variability (HRV) complexity measure, the Point Correlation Dimension (PD2i), provided diagnostic information regarding early subclinical autonomic dysfunction in asymptomatic young diabetic patients without overt neuropathy [59]. According to the authors, the PD2i algorithm may prove to be an easy to perform and clinically useful tool for the early detection of autonomic neuropathy in type 1 diabetics. Regarding other methods, Boysen et al. [35] expressed the view that HRV and BRS as testing methods are specific
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and non-invasive. Dalla Pozza et al. [36] expressed the view that degree of BRS impairment was related to the degree of autonomic imbalance in diabetic children.
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Tests of the gastrointestinal system
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Various diagnostic techniques are used for the assessment of GI peristalsis, including fluoroscopy, X-ray imaging, scintigraphy, isotopic techniques, endoscopy, ultrasonography, computed tomography and magnetic resonance.
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Tests of the urinary bladder function
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Urinary bladder function is assessed through cystometrography and post voiding sonography. As it was mentioned above, in children the evaluation of urinary autonomic neuropathy may be easily performed using uroflowmetry.
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Therapeutic management
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In the majority of juvenile patients, diabetic neuropathy is subclinical. Prevention and treatment of neuropathy is mainly based on maximum metabolic control of diabetes. Pharmacotherapy is used only in extreme and rare cases.
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Conclusion
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The spectrum of diabetes mellitus-associated neuropathies is extremely broad. Nerve damage can arise from metabolic, compressive or ischemic injury and altered immune responses – these varied pathologies can present in many different ways. Identifying the pathogenesis of these syndromes is valuable as there are clear differences in assessment and disease prevention. Correct diagnosis is important before starting an appropriate therapy. Poor glycemic control is the most important risk factor for the development of diabetic neuropathy. Maintaining near-normoglycemia is the only way to prevent or reverse neural impairment, as the currently available treatments can only relieve the symptoms of DN.
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Authors’ contributions/Wkład autorów
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EO-B – study design, data collection and interpretation, acceptance of final manuscript version, literature search. MD – data collection and interpretation, acceptance of final manuscript version, literature search.
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Conflict of interest/Konflikt interesu
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None declared.
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Financial support/Finansowanie
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None declared.
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Ethics/Etyka
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The work described in this article has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans; EU Directive 2010/63/EU for animal experiments; Uniform Requirements for manuscripts submitted to Biomedical journals.
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