Journal of Dermatology 2014; 41: 98–101
doi: 10.1111/1346-8138.12340
ORIGINAL ARTICLE
Pruritus: Do Ad fibers play a role? Aslan TEKATAS,1 Ozer ARICAN,2 Sibel GULER,1 Ozer AYNACI,1 Nejla DINCER2 1
Departments of Neurology, and 2Dermatology, Medical Faculty, Trakya University, Edirne, Turkey
ABSTRACT Neuropathological and molecular basis of pruritus has not been clarified and the presence of certain specific neural circuits have been proposed. Our aim in this study was to evaluate the role of Ad fibers in the neural circuits of pruritus by cutaneous silent period (CSP). Thirty-six patients with chronic idiopathic generalized pruritus and 32 healthy controls were enrolled in the study. CSP and nerve conduction studies of upper and lower extremities were performed in both groups. Latencies of CSP in the upper and lower extremities were observed to be prolonged in the patient group compared with the controls while durations were shortened (all P < 0.001). However, these values were not correlated with sex, age, duration or severity of the disease (all P > 0.05). Our data suggest that pruritus may be developed by a nerve conduction abnormality in the afferent fibers of Ad, or cortical hypersensitivity, abnormality of the cortical inhibitory mechanisms or lack of inhibition in the intermediate spinal inhibitory neurons generating CSP. This topic needs to be evaluated thoroughly in larger series with more detailed studies.
Key words:
Ad fibers, cutaneous silent period, nerve conductions study, neural circuits, pruritus.
INTRODUCTION Pruritus (or itching) is a well-defined unpleasant sensation and an unfavorable factor which affects quality of life of the patients negatively. The neurophysiological and molecular bases of pruritus have not been properly investigated because there is a lack of a specific and sensitive research methodology for humans and adaptive animal models.1,2 The knowledge regarding its neurophysiology is limited and the presence of itching-specific neural circuits is controversial.3,4 Itching sensation is accepted to be perceived in free nerve endings at the dermal–epidermal junction, transmitting impulses from peripheral nerves to the dorsal horn of the spinal cord, across the cord via the anterior commissure, and ascending along the spinothalamic tract to the laminar nuclei of the contralateral thalamus. These fibers crossing in the area in front of the central canal, reaches the thalamus via the spinothalamic tract and then ends in the somatosensorial cortex.5,6 Primary sensory neurons are categorized according to their physical features such as myelination, fiber size and axonal conduction velocity. Ad and C fibers conduct thermal, pain and itching sensations while A beta fibers are responsible for the conduction of tactile impulses.7 According to the data from human and animal electrophysiological studies, a subgroup of unmyelinated C fibers of the primary sensory neurons are responsible for the transmission of itching sensation.4,8–10 Besides the C fibers, it is suggested that thinly myelinated Ad contributes
to itching sensation as well11,12 and this evidence was supported with animal models.13 Conduction of the Ad fibers is evaluated by the cutaneous silent period (CSP).14–18 The physiological mechanisms causing the CSP remain uncertain. However, many researchers agree that it is a spinal inhibitory reflex.14,15,19 Cutaneous reflexes are useful to study the circuits for sensorimotor integration at spinal and supraspinal levels. Clinical interest in the CSP stems from its potential usefulness for evaluating segments and components of sensory nerves that are not well assessed by current electrodiagnostic methods.20 The suggested mechanism of CSP is stimuli reaching the medulla spinalis by Ad fibers via the dorsal root and a postsynaptic inhibition by spinal interneurons and motor neurons. This inhibition is controlled via supraspinal efferent pathways from the motor cortex.20 The CSP is an inhibitory spinal reflex that refers to the suppression in voluntary contraction that follows strong electrical stimulation of a cutaneous nerve.20,21 The CSP is supposed to assess the somatic afferent small fibers (Ad).16,22,23 While the prolongation of CSP latency value is associated with decrease in the conduction velocity of the afferent Ad fibers, shortening of CSP duration is associated with an abnormality in the spinal inhibitory mechanism or loss of inhibition in the supraspinal upper center.24 It is difficult to elucidate all the causes of pruritus with just one mechanism. Pruritus can appear due to dysfunction of the peripheral or central nervous system structures in addition to dermatological diseases. Therefore, in the treatment of pruritus
Correspondence: Aslan Tekatas, M.D., Medical Faculty, Department of Neurology, Trakya University, Edirne 22030, Turkey. Email: atekatas@hotmail. com Received 17 September 2013; accepted 7 October 2013.
98
© 2013 Japanese Dermatological Association
Pruritus and Ad fibers
several neuronal approaches have been adopted.25 In the present published work, we have not come across any studies with pruritus patients evaluated with CSP. In this study, our aim was to investigate the role of Ad fibers and its connection with upper brain centers in the neural circuits of pruritus with CSP.
METHODS Our study was conducted on 36 patients presenting to the Department of Dermatology of Trakya University between January and June 2013 and diagnosed with idiopathic generalized pruritus. Ethical consent was obtained from the local ethics committee. Informed consent was obtained from every subject before the study. Age, sex and disease duration were noted down. Detailed medical history was obtained and all patients were questioned on history of atopy, and dermatological or any other systemic disease. Dermatological and neurological examinations were performed by the same physicians. The scale used in evaluating the itching score consisted of three options: (i) slight (occasional, slight itching); (ii) moderate (persistent or intermittent itching not disturbing sleep); and (iii) severe (irritative itching disturbing sleep). Complete blood count, fasting blood glucose, serology for hepatitis viruses and HIV, and comprehensive renal, hormonal and hepatic function tests were performed. Patients with history of a systemic or dermatological disease, extremely dry skin, atopy, neurological disease including peripheral neuropathy, history of psychiatric disorder, eating disorders, alcohol and tobacco consumers, pediatric patients (aged 0.05). Disease duration was 15.27 15.36 months (2–60, mean: 9). Disease duration for female patients was 12.33 12.08 months, while for male patients it was 40 18.72 months. The disease duration was longer in male patients (P = 0.04). According to dermatological examination, pruritus was considered to be mild in 10 patients, intermediate in 20 patients and severe in six patients.
99
A. Tekatas et al.
Table 1. Cutaneous silent period data on patient (n = 36) and control (n = 32) groups Cutaneous silent period Latency (msec)
Upper extremity Lower extremity
Duration (msec)
Upper extremity Lower extremity
Groups
Mean SD
Patient Control Patient Control Patient Control Patient Control
82.97 71.27 116.08 92.02 38.14 50.99 28.58 49.62
12.55 8.70 20.28 13.21 12.87 6.02 9.87 7.48
Range
Median
P*
67.00–120.50 55.00–94.75 74.00–167.00 57.75–118.00 14.75–69.25 39.00–64.75 13.75–54.25 33.00–65.25
79.37 71.12 112.37 91.75 39.25 50.25 28.25 50.50
doi: 10.1111/1346-8138.12340
ORIGINAL ARTICLE
Pruritus: Do Ad fibers play a role? Aslan TEKATAS,1 Ozer ARICAN,2 Sibel GULER,1 Ozer AYNACI,1 Nejla DINCER2 1
Departments of Neurology, and 2Dermatology, Medical Faculty, Trakya University, Edirne, Turkey
ABSTRACT Neuropathological and molecular basis of pruritus has not been clarified and the presence of certain specific neural circuits have been proposed. Our aim in this study was to evaluate the role of Ad fibers in the neural circuits of pruritus by cutaneous silent period (CSP). Thirty-six patients with chronic idiopathic generalized pruritus and 32 healthy controls were enrolled in the study. CSP and nerve conduction studies of upper and lower extremities were performed in both groups. Latencies of CSP in the upper and lower extremities were observed to be prolonged in the patient group compared with the controls while durations were shortened (all P < 0.001). However, these values were not correlated with sex, age, duration or severity of the disease (all P > 0.05). Our data suggest that pruritus may be developed by a nerve conduction abnormality in the afferent fibers of Ad, or cortical hypersensitivity, abnormality of the cortical inhibitory mechanisms or lack of inhibition in the intermediate spinal inhibitory neurons generating CSP. This topic needs to be evaluated thoroughly in larger series with more detailed studies.
Key words:
Ad fibers, cutaneous silent period, nerve conductions study, neural circuits, pruritus.
INTRODUCTION Pruritus (or itching) is a well-defined unpleasant sensation and an unfavorable factor which affects quality of life of the patients negatively. The neurophysiological and molecular bases of pruritus have not been properly investigated because there is a lack of a specific and sensitive research methodology for humans and adaptive animal models.1,2 The knowledge regarding its neurophysiology is limited and the presence of itching-specific neural circuits is controversial.3,4 Itching sensation is accepted to be perceived in free nerve endings at the dermal–epidermal junction, transmitting impulses from peripheral nerves to the dorsal horn of the spinal cord, across the cord via the anterior commissure, and ascending along the spinothalamic tract to the laminar nuclei of the contralateral thalamus. These fibers crossing in the area in front of the central canal, reaches the thalamus via the spinothalamic tract and then ends in the somatosensorial cortex.5,6 Primary sensory neurons are categorized according to their physical features such as myelination, fiber size and axonal conduction velocity. Ad and C fibers conduct thermal, pain and itching sensations while A beta fibers are responsible for the conduction of tactile impulses.7 According to the data from human and animal electrophysiological studies, a subgroup of unmyelinated C fibers of the primary sensory neurons are responsible for the transmission of itching sensation.4,8–10 Besides the C fibers, it is suggested that thinly myelinated Ad contributes
to itching sensation as well11,12 and this evidence was supported with animal models.13 Conduction of the Ad fibers is evaluated by the cutaneous silent period (CSP).14–18 The physiological mechanisms causing the CSP remain uncertain. However, many researchers agree that it is a spinal inhibitory reflex.14,15,19 Cutaneous reflexes are useful to study the circuits for sensorimotor integration at spinal and supraspinal levels. Clinical interest in the CSP stems from its potential usefulness for evaluating segments and components of sensory nerves that are not well assessed by current electrodiagnostic methods.20 The suggested mechanism of CSP is stimuli reaching the medulla spinalis by Ad fibers via the dorsal root and a postsynaptic inhibition by spinal interneurons and motor neurons. This inhibition is controlled via supraspinal efferent pathways from the motor cortex.20 The CSP is an inhibitory spinal reflex that refers to the suppression in voluntary contraction that follows strong electrical stimulation of a cutaneous nerve.20,21 The CSP is supposed to assess the somatic afferent small fibers (Ad).16,22,23 While the prolongation of CSP latency value is associated with decrease in the conduction velocity of the afferent Ad fibers, shortening of CSP duration is associated with an abnormality in the spinal inhibitory mechanism or loss of inhibition in the supraspinal upper center.24 It is difficult to elucidate all the causes of pruritus with just one mechanism. Pruritus can appear due to dysfunction of the peripheral or central nervous system structures in addition to dermatological diseases. Therefore, in the treatment of pruritus
Correspondence: Aslan Tekatas, M.D., Medical Faculty, Department of Neurology, Trakya University, Edirne 22030, Turkey. Email: atekatas@hotmail. com Received 17 September 2013; accepted 7 October 2013.
98
© 2013 Japanese Dermatological Association
Pruritus and Ad fibers
several neuronal approaches have been adopted.25 In the present published work, we have not come across any studies with pruritus patients evaluated with CSP. In this study, our aim was to investigate the role of Ad fibers and its connection with upper brain centers in the neural circuits of pruritus with CSP.
METHODS Our study was conducted on 36 patients presenting to the Department of Dermatology of Trakya University between January and June 2013 and diagnosed with idiopathic generalized pruritus. Ethical consent was obtained from the local ethics committee. Informed consent was obtained from every subject before the study. Age, sex and disease duration were noted down. Detailed medical history was obtained and all patients were questioned on history of atopy, and dermatological or any other systemic disease. Dermatological and neurological examinations were performed by the same physicians. The scale used in evaluating the itching score consisted of three options: (i) slight (occasional, slight itching); (ii) moderate (persistent or intermittent itching not disturbing sleep); and (iii) severe (irritative itching disturbing sleep). Complete blood count, fasting blood glucose, serology for hepatitis viruses and HIV, and comprehensive renal, hormonal and hepatic function tests were performed. Patients with history of a systemic or dermatological disease, extremely dry skin, atopy, neurological disease including peripheral neuropathy, history of psychiatric disorder, eating disorders, alcohol and tobacco consumers, pediatric patients (aged 0.05). Disease duration was 15.27 15.36 months (2–60, mean: 9). Disease duration for female patients was 12.33 12.08 months, while for male patients it was 40 18.72 months. The disease duration was longer in male patients (P = 0.04). According to dermatological examination, pruritus was considered to be mild in 10 patients, intermediate in 20 patients and severe in six patients.
99
A. Tekatas et al.
Table 1. Cutaneous silent period data on patient (n = 36) and control (n = 32) groups Cutaneous silent period Latency (msec)
Upper extremity Lower extremity
Duration (msec)
Upper extremity Lower extremity
Groups
Mean SD
Patient Control Patient Control Patient Control Patient Control
82.97 71.27 116.08 92.02 38.14 50.99 28.58 49.62
12.55 8.70 20.28 13.21 12.87 6.02 9.87 7.48
Range
Median
P*
67.00–120.50 55.00–94.75 74.00–167.00 57.75–118.00 14.75–69.25 39.00–64.75 13.75–54.25 33.00–65.25
79.37 71.12 112.37 91.75 39.25 50.25 28.25 50.50
