Signs,+Symptoms,+Diagnosis,+and+Comorbidities

BY SHEENA NG  Neuropathic pain (NP) is generated by tissue lesions or disorders in the peripheral and central nervous system 1 where it is characterized by clinical symptoms that is associated with abnormalities in the sensations of pain. Patients with neuropathic pain usually experience aberrant sensations that are stimulus-independent, such as shooting pain, burning, and numbness, whereas other stimulus-evoking pain symptoms can be categorized as positive and negative sensory symptoms. 1 Positive sensory symptoms are caused by hyperactivity and increased sensitivity in nociceptors, while negative sensory symptoms are marked by the reduction in sensations upon stimulation. Generally, the diagnosis of NP is often challenging due to the dynamic pain pathways,  complexities in the distinction between nociceptive pain and NP, as well as its numerous pain mechanisms that make NP difficult to be determined.1 Hence, a combination of tests and examinations are required for optimal diagnosis of NP. In addition, patients with NP often have various comorbidities that affect their functionality and quality of life. The interdependent relationship of the triad of chronic pain, sleep interference and psychological disturbances complicate the diagnosis of NP. In addition, prolonged NP will lead to neuroplasticity in several regions of the brain which can be attributed to the emotional and chronicity processing of NP.2 Overall, the manifestation of symptoms and diagnosis of NP must be carefully characterized in order to apply treatments effectively for every individual with NP.

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4.1 Signs/ Symptoms
Neuropathic pain is associated with lesions or damages to the nervous system that cause nerve dysfunction, resulting in both abnormalities of input into the nervous system, as well as the corresponding sensory system.7 So, patients with neuropathic pain often have a range of sensory symptoms. There are no definite symptoms present in every case of neuropathic pain as the sensory system is very dynamic and symptoms may vary with the course of the disease.7 However, neuropathic pain symptoms can be categorized into two broad categories: spontaneous pain and stimulus-evoked pain.1

4.1a Spontaneous Pain
Spontaneous pain is described as aberrant, stimulus-independent pain that is experienced by most of the neuropathic pain patients.9 It is comprised of three main categories: paraesthesia, paroxysmal, and superficial.1
 * **//Paraesthesia//**: non-painful ongoing sensations that could persist throughout the course of disease. It is often described as sensations like ant crawling, numbness, and tingling.<span style="font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">1
 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">**//Paroxysmal//**: sensations such as shooting pain, lancination, pins and needles sensation, and electric shock-like pain that occur in episodic fashion.<span style="font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">1
 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">**//Superficial pain//**: painful sensations that are intermittent and are usually characterized by burning sensations.<span style="font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">1

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">Meanwhile, some of the individuals may also experience deep, aching pain and itching.<span style="font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">6

<span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 12px; text-align: justify;"> **4.1b Stimulus-evoked pain** <span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: justify;"><span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">Stimulus-evoke pain is a broad range of pain sensations that are stimulus-dependent. It can be divide <span style="font-family: Arial,Helvetica,sans-serif; font-size: 16px; line-height: 23px;">d into both positive symptoms and negative symptoms, based on the patient's response towards a given stimulus.<span style="font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">1

**<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">i) Negative symptoms **
<span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: justify;"><span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">Negative symptoms mark the reduction in sensations, either to non-painful stimuli, painful stimuli or to thermal stimuli. 1

**<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">ii) Positive symptoms **
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;"> Positive symptoms indicate hypexcitability and excessive neuronal activity in the sensory system, which are <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;"> characterized by two hallmark features, allodynia and hyperalgesia. 1


 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">**Allodynia** is described as pain caused by non-nociceptive stimuli, where the lightest stimulus is sufficient to yield painful sensations. 1 There are a few subclasses of allodynia, categorized according to the state or characteristic of the stimuli.
 * 1) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">//Mechanical dynamic/ static allodynia//- pain evoked by light static/ moving pressure on skin.<span style="font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">1
 * 2) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">//Mechanical deep somatic allodynia//- pain evoked by pressure on deep somatic tissue.<span style="font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">1
 * 3) <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">Thermal allodynia- pain evoked by thermal stimuli on skin.<span style="font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">1


 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">**Hyperalgesia** is involved in the increase in pain responses upon stimulation of nociceptive stimuli.<span style="font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">1 Similarly, it is further divided into subgroups such as mechanical dynamic/ static hyperalgesia, thermal hyperalgesia, and chemical hyperalgesia.<span style="font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">1

media type="youtube" key="-b8J6_hMC84" height="315" width="420" align="center"

This is a description of neuropathic pain clinical symptoms by a patient with neuropathy diabetic.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 140%;">**4.2 Diagnosis**
<span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: justify;"><span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">Diagnosis of neuropathic pain is often challenging due to the dynamic nature of the nociceptive pathways.<span style="font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">7 Often time, the symptoms will change over time and vary among individuals with the same disease.<span style="font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">7 In some cases, the most problematic issue arises when neuropathic pain coexists with idiopathic pain and nociceptive pain, where definite diagnosis is not possible.<span style="font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">8 As a result, these issues are contributing to the complexities in diagnosis, where a single diagnostic tool is not possible to identify the clinical characteristics of neuropathic pain. Therefore, multiple diagnostic tools should be performed in combinations in order to provide a precise and reliable diagnosis. <span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: justify;"><span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">By far, there are four main diagnostic tools that are being commonly used in diagnosing neuropathic pain. They are i) medical history; ii) clinical examinations; iii) laboratory testing; iv) functional imaging tools.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 19px;">4.2a Medical History
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">The first critical step in carrying out the diagnosis of neuropathic pain is to gather medical history of the patients in order to establish the recognition of neuropathic pain in each patient. 8 The medical history should include thorough details about the sites of pain, intensity, time course of the pain, underlying diseases, previously attempted treatments, possible exacerbating factors, and the associated symptoms. 10 <span style="font-family: Arial,Helvetica,sans-serif; font-size: 16px; line-height: 23px;">

**<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">i) Screening tools (Questionnaires) **
<span style="display: block; font-family: Arial,Helvetica,sans-serif; text-align: justify;"><span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">Questionnaires are widely used as a screening tool to obtain verbal descriptions and detail pain quality from patients in order to carefully examine and distinguish neuropathic pain from other chronic pain conditions.<span style="font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">8 <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">The questionnaires that are commonly used by clinicians are as the following:
 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">Leeds Assessment of Neuropathic Symptoms and Signs (LANSS)
 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">Neuropathic Pain Questionnaires (NPQ)
 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">Douleur Neuropathique en 4 questions (DN4)
 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%; line-height: 24px;">McGill Pain Questionnaires

**<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">ii) Assessment of Co-morbidities **
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">Neuropathic pain, unlike any other chronic pain diseases, exhibits variable responses to analgesics and is associated with numerous co-morbidities.<span style="font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">11 Therefore, assessments of co-morbidities have to be taken into account as part of the medical history of patients to allow appropriate treatments to be carried out.<span style="font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">11

<span style="display: block; font-family: Arial,Helvetica,sans-serif; font-size: 12px; text-align: justify;">

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 19px;">4.2b Clinical Examinations
<span style="color: #000000; display: block; font-family: Arial,Helvetica,sans-serif; text-align: justify;"><span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">The later step in the diagnosis involves neurological examination that aims to identify the underlying physiological mechanisms and to further distinguish neuropathic pain from nociceptor or idiopathic pain conditions.<span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">8 This is usually done by performing a series of sensory tests that involve mapping of sensory abnormalities, which are associated with lesions in order to reveal the neuroanatomical distribution underlying pain.<span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">3  <span style="color: #000000; display: block; font-family: Arial,Helvetica,sans-serif; text-align: justify;">

**<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">i) Bedside Testing **
<span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 120%;"> It is a form of diagnosis that is used to test sensory abnormalities by carry out various sensory testings. 11 Each form of sensory abnormality can be tested and examined separately by using different diagnostic tools. 3 The test usually starts off by testing tactile sensation, which is assessed by cotton wool; while pinprick sense is tested by using wooden cocktail-stick. 3 Also, thermal testing is accomplished by metal thermoroller; while vibration sense is tested by using tuning fork. 3 The sites of pain will be best documented through pain mapping and pain drawing, where the locations of pain, distributions of other abnormal sensations will be mapped in a precise and organized manner. 3

**<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">ii) Quantitative Sensory Testing **
<span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 120%;">QST is a psychophysical test used to assess damage of nerve endings by using stimuli with calibrated intensity. 3 It is an appropriate tool in detecting small-fibre neuropathies by measuring sensory responses towards thermal and mechanical stimuli, where mechanical allodynia/ hyperalgesia and thermal allodynia/ hyperalgesia would be determined. 16 Furthermore, QST is used to determine if the neuropathy is responding to the treatments. 3

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 19px;">4.2c Laboratory Testing
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;"> Neuropathic pain is associated with a wide range of symptoms that are simply not caused by a specific underlying mechanism. Hence, laboratory tests are required to be performed in some cases of neuropathic pain to determine the causative diseases.

**<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">i) Microneurography **
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">Microneurography is a minimal invasive laboratory technique that directly records the nerve fibre activities in the peripheral nervous system. 3 It provides information about the neurophysiology of nociceptors and their correlations with the positive sensory symptoms shown in neuropathic pain patients. 3,8

**<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">ii) Pharmacological testing **
<span style="color: black; display: block; font-family: Arial,Helvetica,sans-serif; text-align: justify;"><span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 120%;">Pharmacological drugs are being used in some laboratory settings to pinpoint the pain-generating sites and the associated underlying mechanisms based on the modes of administration, functions and the pharmacological targets of the drug agents.<span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">7

**<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">iii) Biopsy **
<span style="color: black; display: block; font-family: Arial,Helvetica,sans-serif; text-align: justify;"><span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 120%;">Nerve biopsy is a diagnostic tool that helps to assess small-fibre neuropathies.<span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">3 It is rarely performed in the early detection of the diseases due to the difficulties in locating small fibres.<span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">3 There are two variations of nerve biopsy as listed as the following:
 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;"> **//Skin biopsy//**- It provides diagnostic information on small nerve fibres, mechanoreceptors and the myelinated afferents. 3 It is more advantageous as compared to other conventional nerve biopsy as it has the ability to distinguish somatic nerves fibre from autonomic nerves fibres. 17
 * <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;"> **//Punch biopsy//**- It provides diagnostic assessment of small-caliber ( C and A delta ) nerve fibres. 3 It is minimal invasive and easy to follow- up. 3

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 19px;">4.2d Neuroimaging Tools
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%; line-height: 24px;">In some cases, structural imaging tools like CT scan and MRI will be used to examine the underlying causes of nerve compression and nerve infiltration. 11 Besides that, functional imaging tools like PET and fMRI will be used to facilitate diagnoses by the measurement of cerebral blood flow or metabolic changes that reflect local nociceptor synaptic functions in some define brain regions. 3

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 140%;">**5.1 Comorbidities**
<span style="color: black; display: block; font-family: Arial,Helvetica,sans-serif; text-align: justify;"><span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 120%;">Nueropathic pain is associated with comorbidities that increase the complications of disease and make it more difficult to treat.<span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">15 The comorbidities present in neuropathic pain patients include sleep interference, depression, anxiety, poor appetite, attention deficit, drowsiness, and fatigue. However, the most prevalence comorbidities found among neuropathic pain patients are the triad of chronic pain, sleep interference, and depression/anxiety.<span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">15

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 19px;">5.1a Triad of chronic pain, sleep interference, and psychological disturbances
<span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 120%;">It is found that 70% of patients that experience chronic pain also suffer from sleep interference. 12 These patients will have difficulties in initiating and maintaining good quality of sleep, increase sleep latency and wakefulness in sleep cycles. 12 Subsequently, sleep interference decreases pain threshold, causes muscle aches and stiffness that further exacerbate the intensity of pain among neuropathic pain patients. 12 Upon sleep interference and the exacerbated chronic pain, neuropathic pain patients are found to engage in the decrease of role and social functioning. 5,15 The reduced social interactions and physical impairments experienced by neuropathic pain patients will in turn impose negative effects on their psychological functioning. 5,15 Thus, patients with neuropathic pain are more prone to depression and anxiety than patients in other physical illness. 12 Consecutively, depression and anxiety will increase sleep disturbances and further exacerbate the onset and maintenance of pain. Overall, the interrelationship of the triad leads to the continuation of vicious cycle that increases the severity a <span style="font-family: Arial,Helvetica,sans-serif; font-size: 16px; line-height: 23px;">nd complications of neuropathic pain, eventually leads to severe impacts on the health-related quality of life. 5

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<span style="font-family: Arial,Helvetica,sans-serif; font-size: 19px;">5.1b Neuroplastic <span style="font-family: Arial,Helvetica,sans-serif; font-size: 19px; line-height: 28px;">**ity**
<span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 120%;">Apart from the triad of chronic pain, sleep interference, and psychological disturbances, long term neuropathic pain is found to cause neuroplasticity in brain regions that contribute to the maintenance of pain chronicity. 2,14 Based on a study on emotional processing and neuronal chang <span style="font-family: Arial,Helvetica,sans-serif; font-size: 16px; line-height: 23px;">es, it was found that neuropathic rat displays cell proliferation in the amygdala regions. 2 This suggests that prolonged neuropathic pain increases the flow of nociceptor information to amygdala, enhancing cell proliferation in both central and basolateral amygdala nuclei.<span style="font-family: Arial,Helvetica,sans-serif; font-size: 70%; line-height: 23px; vertical-align: super;">2 In addition, amygdala is also found to be involved in the modulation of brainstem pain centres that are associated with fine regulation of spinal nociceptive transmission.<span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 70%; vertical-align: super;">2 Thus, the neuroplasticity that occurs in the amygdala regions will affect both the emotional regulation and nociceptive transmission that act as driving forces for the maintenance of pain chronicity. 2,14



<span style="font-family: Arial,Helvetica,sans-serif; font-size: 16px; line-height: 23px;">In addition, there are numerous functional and structural imaging studies which demonstrate that pain-induced neuroplasticity causes alterations in the nociceptive system, cortical organization, neuronal network-connectivity, and several brain structural changes that will give rise to pain chronicity. 14

<span style="color: #000000; font-family: Arial,Helvetica,sans-serif; font-size: 120%;">Overall, it is apparent that neuropathic pain is associated with multiple comorbidities that aggravate the severity of disease, make it harder to treat. Therefore, clinicians have to be careful in addressing the associated co-morbidities in neuropathic pain patients in order to carry out treatments that can both effectively relieve pain and restore functionality in patients to improve their health conditions.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">**See Also:** <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;"> <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">@Mechanisms of Neuropathic Pain <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">Causes and Genetic Variability of Neuropathic Pain <span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">Treatment and Therapy of Neuropathic Pain

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 120%;">**References:**
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