Diagnostic of Chemotherapy Induced Neuropathy in Children
Condition: Chemotherapy-induced Peripheral Neuropathy
MeSH terms: Peripheral Nervous System Diseases
Study type: Observational

Summary: 
      The purpose of this study is to determine the diagnostic accuracy of a newly developed tool
      (Electrochemical Skin Conductances (ESC) measurement) easy-to-perform, non-invasive, highly
      reproductible and not requiring specific training, to identify pediatric
      chemotherapy-induced-peripheral-neuropathies (CIPN). CIPN are a frequent (20 to 75% depending
      on the drug), early and potentially severe long-lasting and dose limiting adverse effect of
      treatments in immuno-hematology and cancerology. The pathophysiology, the chronology of
      injury (ie small then large sensory nerve fiber or vice-versa) and the age-related
      short/long-term impact on peripheral nerves remain largely not understood. Clinical signs of
      CIPN are highly heterogenous, often under-recognized and include diverse sensory symptoms and
      pain. Persistent loss of sensation and strength as well as neuropathic pain may have a
      short/long-term impact in term of functional limitations and quality of life. There is a lack
      of specific and sensitive measurement tools for CIPN in the pediatric population.
      Neurophysiological tools (except electro-neuro-myography allowing only the assessment of
      large myelinated nerves) are not implemented in the pediatric oncology-hematology everyday
      practice: they are often invasive and/or poorly reproducible, not accessible for "bedside"
      follow-up, and lacking normative values, thus often dedicated only to research. ESC may
      provide an early and quantitative assessment of small fiber dysfunction in children, a
      prerequisite for the identification of additional preventive or curative approaches in CIPN.
    

Detailed description: 
      Epidemiology and suggested mechanisms involved in pediatric chemotherapy induced neuropathy:
      Pediatric chemotherapy induced peripheral neuropathy (CIPN) is an early (often occurring
      within the first three months), potentially severe long-lasting and dose limiting adverse
      effect of treatment in immuno-hematology and cancerology. It constitutes the second most
      common cause of dose limitation compromising therapy efficacy after hematological adverse
      effects. Expanding number of potentially toxic treatment for the peripheral nervous system
      are currently used. Peripheral nerve toxicity has been mainly described with the
      platinum-based antineoplastics (particularly oxaliplatin and cisplatin), vinca-alkaloids
      (particularly vincristine and vinblastine), taxanes (paclitaxel, docetaxel), proteasome
      inhibitors (bortezomib) and immunomodulatory drugs (thalidomide). Vinca-alkaloids are used
      for treatment of acute leukemia, lymphoma, various solid tumors and are responsible for
      neuropathy of any grade (National Cancer Institute Common Terminology Criteria for Adverse
      Effects, NCI-CTAE grade 1 to 4) in 75-100% of patients, including 10-52% grade 3/4 neuropathy
      with probable dose-toxicity relationship. Platinum compounds (Cisplatin, Carboplatin,
      Oxaliplatin) are used for the treatment of various solid tumors. Cisplatin and Carboplatin
      are often used in combination therapy with Vincristine making it difficult to appreciate its
      relative contribution to peripheral toxicity. Oxaliplatin peripheral neurotoxicity is
      observed in 37-50% and 3-8% of patients for Common Terminology Criteria for Adverse Effects
      (CTAE) grade 1/2 and grade 3/4 respectively. Bortezomib is used for preventing antibody
      mediated in transplantation and for others autoimmune diseases. Thalidomide is used for the
      treatment of diverse inflammatory conditions such as refractory inflammatory bowel disease,
      juvenile rheumatoid arthritis and vasculitis and is associated with peripheral neuropathy in
      20-40% (Grade > = 2). Clinical features of CIPN are heterogeneous but sensory nerves
      involvement is prominent. In a very recent study, 23,5% of patients presented with a decrease
      in sural sensory nerve amplitude several years after exposure of neurotoxic chemotherapy,
      suggesting a long-term impact with an irreversible reduction of functioning axons. Various
      molecular and cellular mechanisms have been suggested. Indeed, chemotherapy treatments result
      in changes to cellular structure and function including alteration in voltage gate ion
      channels, neurotransmission, organelle function and intracellular signalling. For example,
      putative mechanisms involved in the development of vincristine-induced peripheral neuropathy
      are highly multifactorial and depending on disease and patient factors (age, genetic
      alterations in pharmacokinetic/pharmacodynamic pathways, and susceptibility to hereditary
      neuropathy). Possible effects of vincristine on tubulin polymerization leading to microtubule
      destabilization and deficit in axonal transport may be the main mechanisms contributing to
      the development of vincristine-induced CIPN. Although the individual biological eﬀects of
      these drugs on cancer cells are relatively well known and studied extensively, the
      age-related short- and long-term impact on peripheral nerves, prerequisite for the
      identification of additional preventive or curative approaches, remains incompletely
      understood.

      -Diagnosis and management of pediatric chemotherapy induced neuropathy: Symptoms of
      neurotoxicity induced by chemotherapy in the peripheral nerve system are often
      under-recognized and undiagnosed. One major reason has been the lack of specific and
      sensitive measurement tools for CIPN in the pediatric population. Clinical signs of CIPN are
      highly heterogenous and include sensory symptoms, including paresthesia (tingling, numbness),
      dysesthesia, allodynia, hyperalgesia, hypoalgesia or pain (burning/shooting sensation,
      electric-shock-like). Clinical manifestations could be related to dysfunction of small
      sensory nerve fibers causing allodynia or hyperpathia. The younger the patient, the less
      specific the complaints may be. Patients may manifest behavior troubles or refuse to move or
      to be touched (4). Furthermore, little is known about the long-term impact of CIPN in
      survivors of childhood cancer in term of quality of life, sleep disorders, psychopathological
      disorders and learning skills. There is also currently no evidence-based preventive and
      treatment strategy for CIPN in children. Drugs used in routine clinical practice are those
      that are efficient in other neuropathic conditions including tricyclic antidepressant,
      GABAergic agents. However, systemic adverse effects of these treatments are frequent, and the
      control of the neuropathic pain remains to be optimized. The most commonly used assessment
      scale for CIPN is the CTCAE, rating 0 to 5 the severity of the sensory or motor neuropathy.
      CTCAE, although easy to use, displays a poor interobserver agreement and do not provide the
      specific clinical characteristics of CIPN. In recent years, the Total Neuropathy Scale (TNS)
      was developed as clinical assessment of peripheral neuropathy in adults and has demonstrated
      reliability and validity in measuring CIPN in adult cancer patient. The pediatric modified
      Total Neuropathy Scale (Ped-mTNS) has been developed and tested in population of children
      (for patient age above 5 years) with cancer with acceptable interrater reliability, test
      retest reliability and internal consistency. The Ped-mTNS has 5 clinical testing domains:
      light touch sensation, pin sensibility, vibration sensibility, strength, and deep tendon
      reflexes. The most widely agreed method for diagnosing small fiber neuropathy is skin biopsy.
      Intraepidermal nerve ﬁber density (IENFD) assessment via skin biopsies, which evaluates the
      epidermal loss of Aδ/C small ﬁber, cannot be used for follow-up in current practice due to
      its invasiveness, delay in obtaining results. Furthermore, normal values are lacking in
      children. Various neurophysiological methods are available in adult for detecting CIPN. Nerve
      conduction studies (NCS) allows only the assessment of large myelinated nerves and therefore
      are not suitable for non-myelinated small ﬁber assessment. In addition, specialized tool are
      used for the exploration of small non-myelinated fibers including, quantified exploration of
      the thermal sensitivity (Quantitative Sensory Testing assessing sensory C fibers), laser
      evoked potentials (PEL assessing sensory A-delta fibers), quantitative Sudomotor Axon Reﬂex
      Testing (QSART) assessing small ﬁber impairment via sudomotor function.

      All these tools are not implemented in the pediatric current clinical practice because they
      are either reserved for research, or technically challenging to perform. or invasive, or
      poorly reproducible, or lacking normal values. These methods are not accessible to pediatric
      oncologists and not suitable for follow up patients during chemotherapy.

      -Longitudinal assessment of CIPN by the measurement of electrochemical skin conductances
      (ESC) by SUDOSCAN® (Impeto Medical, Paris, France) Among the small fibers, those innervating
      the sweat glands degenerate after toxic injury, and are the first to regenerate if the toxic
      injury is removed. Thus, the fibers innervating the sweat glands could be considered a good
      marker of small fibers injuries. A new device has been recently developed to quantify the
      sudomotor function, quickly, non-invasively and quantitatively. The technique is based on the
      measurement of an electrical signal produced by an electrochemical reaction between the
      chloride ions present in the sweat and stainless-steel electrodes at which a low current (< 4
      V) is applied. The device automatically calculates ESC, expressed in microSiemens (µS), as
      the ratio between the current generated and the constant direct current stimulus applied to
      the electrodes. ESC is thought to reflect the innervation of cutaneous sweat glands
      (autonomic unmyelinated nerve fibres) containing functional chloride channels. In adult,
      several studies have validated the method and evaluated its diagnostic accuracy to detect
      small fiber dysfunction in diverse conditions, including diabetes, Familial Transthyretin
      Amyloid Polyneuropathy, Fabry disease, toxic neuropathy…etc. This method has been compared to
      reference methods assessing small fiber dysfunction and its diagnostic performance has been
      evaluated in comparison with the gold standard IENFD. Furthermore, the diagnostic sensitivity
      for detecting small-fiber neuropathies of ESC measurements was compared to four other
      neurophysiological tests in 87 adult patients with clinically defined (n = 33) or possible (n
      = 54) small-fiber neuropathy. The neurophysiological tests, performed at the four extremities
      (hands and feet), included a quantified study of the thermal sensitivity, with determination
      of the detection of warm and cold thresholds (WDT and CDT), the recording of evoked
      potentials by laser stimulation (ELP) and Sympathetic Skin Responses (SSR) and measurement of
      ESCs. ELPs were the most sensitive test (modified in 56/71 patients with at least one
      abnormal test (79%)), followed by ESCs (61%), WDT (55%), SSR (41%) and finally the CDT (29%).
      Thus, in adult, the combination of PEL, assessing sensory A-delta fibers of WDT assessing
      sensory C fibers, and ESCs, evaluating autonomous C fibers, seems to represent a relevant
      approach for the diagnosis of SFN. The ELP, although technically efficient, still has some
      disadvantages, such as the cost of the equipment, the duration of the examination and the
      technicity of the recordings, contrarily to ESCs that remains a quick test (3 minutes), easy
      to do and to interpret and can be used as bedside tool.

      To date, no research on using this method in children has been published. Very recently
      normative values have been established in children. Values observed for ESC measurements in
      healthy children are similar in all group of age and values observed in healthy adults
      suggesting that sudomotor nerve maturation occurs very early in life. Thus, ESC measurement
      may be a quick, reproductible, non-invasive and quantitative assessment of small fiber
      dysfunction in children.
    

Intervention name(s): electrochemical skin conductance measurement
Intervention type(s): Diagnostic Test
Intervention description(s): electrochemical skin conductance measurement
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Child receiving a Potentially Neurotoxic Chemotherapy
      
Keywords: Chemotherapy induced peripheral neuropathy (CIPN); child; outcome; electrochemical skin conductances (ESC)