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Chemotherapy-induced peripheral neuropathy: Current status and future directions
Shripad S Pujari1, Padmaj S Kulkarni2, Rahul V Kulkarni1
1 Department of Brain and Spine, Deenanath Mangeshkar Hospital and Research Center, Pune, Maharashtra, India
2 Department of Oncology, Deenanath Mangeshkar Hospital and Research Center, Pune, Maharashtra, India
|Date of Submission||15-Apr-2020|
|Date of Decision||27-Apr-2020|
|Date of Acceptance||03-Aug-2020|
|Date of Web Publication||12-Nov-2020|
Shripad S Pujari,
425/57, T. M. V. Colony, Gultekadi, Pune - 411 037, Maharashtra
Source of Support: None, Conflict of Interest: None
Chemotherapy-induced peripheral neuropathy (CIPN) and dorsal root ganglionopathy occur because of several categories of chemotherapeutic drugs, the important ones being taxanes, platins, vinca alkaloids, epothilones, proteasome inhibitors, immunomodulators and topoisomerase II inhibitors. There are many predisposing factors such as diabetes, nutritional deficiencies, hypothyroidism, renal failure and HIV disease. Leprosy and antimicrobial use such as anti-tubercular therapy and antibiotics are predisposing factors specific for India. Genetic susceptibility for toxicity toward most of the chemotherapy drugs has also been identified. Important mechanisms by which these agents injure nerves/dorsal root ganglia are causing microtubule disarray, impairing DNA repair, mitochondrial and ion channel dysfunction, increasing oxidative stress, increase pro-inflammatory cytokines and chemokines and glial cell activation. Damage can at times be irreversible, leaving behind not only significant sensorimotor disability but also increased suffering through neuropathic pain. Meticulous clinical evaluation and electrophysiology can anticipate this problem and prevent progression. The present treatment modalities such as oral selective serotonergic norepinephrine inhibitors and ion channel blockers and topical agents such as ketamine, baclofen, lidocaine and menthol predominantly offer symptomatic relief. Altering doses and dosing intervals prevents/minimizes the risk to some degree, but at the cost of delivering suboptimal chemotherapy for the cancer under treatment. Future lies in addressing basic mechanisms and genetic susceptibility to help prevent and improve therapeutic armamentarium for this disabling and painful disease.
Keywords: Basic mechanisms, chemotherapy-induced peripheral neuropathy, dorsal root ganglionopathy, genetic susceptibility, predisposing factors
|How to cite this URL:|
Pujari SS, Kulkarni PS, Kulkarni RV. Chemotherapy-induced peripheral neuropathy: Current status and future directions. Indian J Med Paediatr Oncol [Epub ahead of print] [cited 2020 Nov 25]. Available from: https://www.ijmpo.org/preprintarticle.asp?id=300609
| Introduction|| |
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common adverse effects encountered by oncologist and a frequent disease to look after for the neurologist in today's multi-disciplinary practice. Symptoms are similar to diabetic neuropathy but, treatments on the line of diabetic neuropathy are not helpful for preventing or treating CIPN. Chemotherapeutic agents causing CIPN are taxanes (paclitaxel, docetaxel), platins (cisplatin, carboplatin, oxaliplatin), vinca alkaloids (vincristine, vinblastine, vinorelbine, vinflunine), proteasome inhibitors (bortezomib), epothilones (ixabepilone), eribulin, immunomodulators (thalidomide, lenalidomide, pomalidomide), antimitotic alkylating agents (cyclophosphamide, ifosfamide, procarbazine, altretamine), antimetabolites (cytarabine, fluorouracil, fludarabine, methotrexate) and topoisomerase II inhibitor (etoposide). Platins and taxanes also produce toxic effect on dorsal root ganglia (DRG) [Table 1] shows the list of chemotherapy agents causing CIPN].,,,,,,,,,, There are several causes of peripheral neuropathy (PN) and many of them are very common such as diabetes mellitus (DM), nutritional deficiency, alcohol abuse and hypothyroidism. Hence, when a patient of cancer develops PN, it needs to be established that the PN is because of drug exposure. For that, the neuropathic symptoms have to begin concurrently within 1–3 months from the onset of chemotherapy, have to be proportionate to the duration and dose and clinical features should be consistent with pattern previously described. Stopping exposure should stop progression and be followed by a variable degree of improvement over a period of time., In certain neuropathies, symptoms may continue to worsen for up to 2 months even after exposure is stopped, before progression plateaus. This phenomenon is called “coasting.”,,
|Table 1: Mechanisms by which each drug/category damages nerves/dorsal root ganglia|
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In a systematic review which included data of 4179 patients, the prevalence of CIPN was 68.1% when assessed within the 1st month of the end of chemotherapy, 60% at 3 months and 30% at 6 months or more. Different chemotherapy drugs were associated with differences in CIPN prevalence. In a study by Shah et al., 52.7% of 509 patients who received chemotherapy suffered CIPN with a median time from the beginning of chemotherapy to appearance of symptoms was 71 days. In a study from South India, 26/122 (21%) were found to have CIPN, of which 48% received combinations of drugs and paclitaxel was the biggest culprit at 32%.
| Predisposing Factors|| |
Patients with cancer may have or are predisposed to neuropathy because of several background causes, even before they receive chemotherapy.,,,,,, Chemotherapy is one of the causes of PN in cancer patients. Paraneoplastic neuropathy, neuropathy due to monoclonal protein and amyloidosis are other causes of neuropathy in relevant case scenarios. Many patients have a background history of DM, hypothyroidism, alcohol abuse and Vitamin B12 and folic acid deficiency which are common causes of PN.,,,,,, Renal impairment in cancer patients leads to uremic neuropathy. Collagen vascular diseases and vasculitides can cause nerve involvement. If patients with these background illnesses receive chemotherapy for a malignancy, they get exposed to two independent damaging factors and so, are more vulnerable to develop neuropathy. Rarely, a preexisting hereditary neuropathy increases susceptibility to toxic neuropathy.
If patients with cancer receive antimicrobials such as anti-tubercular therapy (isoniazid and ethambutol), metronidazole, nitrofurantoin, linezolid or aminoglycosides, then such agents can occasionally cause PN. Leprosy prevails in India. This disease as well as the anti-leprosy drug dapsone can cause neuropathy. Patients with cerebral metastases suffer seizures and they end up receiving long term anti-epileptic drugs. Phenytoin is one of the most common anti-epileptic drugs used in clinical practice. Long-term use of phenytoin may cause neuropathy. We encounter an occasional patient with rheumatoid arthritis on long duration chloroquine or leflunomide. Both drugs can rarely cause neuropathy., Some of the patients who are diagnosed with cancer have cardiac disease and are on amiodarone, which can give PN. Patients who are on statin are more susceptible to develop PN. Patients with advance HIV disease may have neuropathy and nucleoside analog reverse transcriptase inhibitors category of antiretroviral therapy can cause neuropathy.,,,
Compression or direct infiltration of the nerves can occur predominantly by head and neck tumors as well as other organs, for example, lung apex or breast carcinoma engulfing the brachial plexus and cervix or rectal carcinoma infiltrating the lumbosacral plexus. Some cancer patients become bed-ridden and hence are susceptible to compression of ulnar and peroneal nerves. Cachexia can cause entrapment neuropathies. Hence, there is a host of not that uncommon background illnesses, which cause neuropathy in a patient of cancer who receives chemotherapy.
| Mechanisms of Nerve Damage|| |
Chemotherapy agents are able to penetrate the blood-nerve barrier which is not completely efficient in preventing their ingress into the nerve. Mechanisms by which each drug/category damages nerves/DRG is presented in [Table 1]. A summary as to how these agents destroy nerves are: impaired DNA synthesis, causing nucleolar damage, inhibition of microtubule polymerization, mitochondrial dysfunction, increasing oxidative stress (by causing increased production of reactive oxygen species and reactive nitrogen species), impairing axonal transport (by reducing the supply of trophic factors), breaking down endoplasmic reticulum, promoting apoptosis (through calpain and caspases), inhibition of angiogenesis, influx of monocyte macrophage lineage cells, upregulation of pro-inflammatory cytokines (interleukins, tumor necrosis factor [TNF] and chemokines) and activation of neuroimmune system (glial cells and astrocyte proliferation). Pain and allodynia occur because these agents increase activity of voltage gated sodium and calcium channels.,,,,,,,,,
Like drug response can vary between individuals, an individual's specific genetic makeup may influence the drug pharmacokinetics and DNA repair, thus deciding the individual susceptibility to develop CIPN. Several such aberrations in genes called single nucleotide polymorphisms have been identified which predict vulnerability of individuals to a particular chemotherapeutic agent. However, they have not yet been validated for use in daily clinical practice.,,,,
| Pathophysiology|| |
How damage to the nerve/DRG translates into clinical presentation is simplified in [Figure 1]. Whatever the mechanism of nerve destruction, the final end-point with majority of agents is loss of axoplasmic transport of nutrients across the axons. Hence, the distal most portion of the nerve terminal stops receiving nutrition first, breaks down and then, there is a “dying back phenomenon.” This is what is called “length dependent” neuropathy, so, the symptoms and signs start in the distal most portion of the lower limb first and gradually ascend-the “glove and stocking” distribution. Legs being longer are affected before the hands. In addition to the peripheral nerves, platins and taxanes can also damage DRG causing dorsal root ganglionopathy (DRGP) or sensory neuronopathy. DRGP does not present in length dependent pattern, i.e., hands and feet can get affected simultaneously and proximal and distal portion of a limb will be affected at the same time.,,,,,,,,
|Figure 1: Depiction as to how nerve and dorsal root ganglia damage leads to clinical presentations of peripheral neuropathy and dorsal root ganglionopathy|
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In PN, most of the agents cause what is pathologically classified as an axonal neuropathy, wherein the target organ of damage is the axon itself. Breakdown of myelin causes demyelinating variety, which is uncommon with chemotherapeutic agents.
| Symptoms and Signs|| |
Salient features of type of nerve/DRG involvement and related clinical features are listed in [Table 2]. Sensory involvement is more common than motor. In sensory type, large and small fiber can get affected. Large fibers are the heavily myelinated nerve fibers (A-beta) which carry joint position (proprioception), vibration and deep pressure sensation and small fibers are the unmyelinated (C) and lightly myelinated (A-delta) ones which carry pain, temperature, crude touch and autonomic sensations. Neuropathy causes two types of symptoms-positive and negative. Positive are sensory phenomenon which are an expression of an abnormally increased function of the sensory system, such as paraesthesia or neuropathic pain. Neuropathic pain may be spontaneous or stimulus induced. Positive symptoms are generated by impulses generated from diseased nerve fibers which have developed lowered threshold and increased sensitivity. Negative symptoms are loss of function. Symptoms and signs of large fiber involvement consist of tingling, shooting, or lancinating pain and imbalance which worsens in dark/closing eyes (wash basin phenomenon-patient feels unsteady as soon as closes eyes), impaired joint position, vibration, deep pressure and a positive Romberg's sign. Features of small fibers are burning, pricking, searing, dull aching pain, band-like sensation, loss of pain, temperature and crude touch. Autonomic symptoms are light-headedness and syncope (due to postural hypotension), abnormalities of sweating, bladder, bowel and erectile dysfunction. DRGP can also cause sensory symptoms and signs as said earlier, in a nonlength-dependent fashion. Motor fiber involvement causes distal weakness leading to slipping of footwear, inability to use fingers (e.g., buttoning and eating), foot drop, stamping gait, objective motor weakness and distal wasting.,,,,,
|Table 2: Salient features of type of nerve/dorsal root ganglia involvement and related clinical features|
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The common presentation is of gradually progressive neuropathic symptoms which are dose related and go on worsening after cumulative dosing. There are exceptions to this rule. Oxaliplatin causes an acute and usually transient, predominantly sensory disturbance in 85%–95% of patients, which may be aggravated or precipitated by cold exposure. This syndrome starts acutely within hours to days following infusion and symptoms may revert between treatment cycles, but frequently recur with further treatment., In addition to sensory disturbances in limbs, patients suffer paraesthesia and dysesthesia in perioral and pharyngo-laryngeal region. These symptoms are precipitated by cold and the mechanism is the effect of oxaliplatin on voltage-gated sodium channel kinetics. Paclitaxel is also associated with an acute pain syndrome (P-APS) which begins 1–3 days after the infusion, peaks on 4th day and generally, lasts for 7 days. The pain is in the form of myalgias and arthralgia affecting the lower limbs, shoulder and axial muscles and joints. It is seen in 56%–69% of patients. There is a higher incidence of chronic neuropathy in patients who suffer this P-APS.
| Comparisons between Agents in the Same Category|| |
There is not much difference in the progressive CIPN between the three platins, i.e., cisplatin, oxaliplatin and carboplatin. Among taxanes, the incidence and severity of neuropathy between paclitaxel and docetaxel are similar. Nanoparticle albumin-bound (nab)-paclitaxel is a paclitaxel bound to albumin nanoparticle to help improve its solubility. This nanotechnology form of delivery system has improved its pharmacokinetics. A randomized trial compared nab-paclitaxel at 300 mg/m2 every three weekly, 150 mg/m2 every weekly (3/4 weeks) and 100 mg/m2 every weekly (3/4 weeks) in metastatic breast cancer. CIPN was significantly more frequent in 300 mg/m2 every three weekly and 150 mg/m2 every weekly (3/4 weeks) group than the 100 mg/m2 every weekly (3/4 weeks). The mechanism of higher incidence and severity of CIPN with nab-paclitaxel is not clear. Uptake of nab-paclitaxel is aided by interaction of the albumin with certain cell surface receptor expressed on the surface of the endothelial cells. This could increase internalization of drug-albumin complex causing greater buildup of paclitaxel within the cells. Vinblastine and vinorelbine are all known to cause CIPN that is clinically similar to that of vincristine, but the incidence appears to be lower than for vincristine.
| Assessment and Diagnosis|| |
In addition to objective clinical assessment (always include quantified monofilament testing and vibration perception threshold), several clinical disability scales and patient reported outcomes to diagnose and quantify CIPN have been developed which report clinician and patients' perspectives. The American Society of Clinical Oncology Clinical Practice Guideline has reported that patient-related outcome measures of sensory CIPN should also supplement clinician determined assessments, as it is predominantly a sensory problem with subjective component and amplification of central sensitization.,,,, Electrophysiology (nerve conduction studies) shows abnormalities initially in the sural nerves, then progresses proximally in length dependent CIPN, but have equal involvement of legs and arms in DRPN.,,,,,,, Sural nerve biopsy, which shows the pathological changes in the nerve and skin biopsy, which measures reduction of intraepidermal nerve fiber density are diagnostic tools used in research and not recommended in clinical practice.
| Treatment and Prognosis|| |
Treatment is divided into medical and nonpharmacological therapies. Medicines used are categorized into two groups: those which provide symptom relief and those acting on the basic mechanism causing nerve damage. Symptom relief is provided by systemic and topical medicines. Route of administration, class and names of drugs, mechanisms of action, dosages, common side-effects to watch for and significant drug interactions are summarized in [Table 3].
|Table 3: Route of administration, class and names of drugs, mechanisms of action, dosages, common side-effects and significant drug interactions|
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There have been only a few trials showing benefit of serotonin norepinephrine uptake inhibitors (SNRIs), presynaptic calcium channel blockers (gabapentin and pregabalin), tricyclic anti-depressants (TCAs) and even of all the topical agents and so the evidence is limited. Important trials conducted on duloxetine and venlafaxine are discussed. These drugs are recommended in CIPN based on the outcomes of the trials described. A randomized Phase III double-blind placebo-controlled crossover trial assessed whether duloxetine 60 mg taken orally once daily decreases CIPN pain severity. Patients above 25 years of age who reported CIPN and ≥4/10 average CIPN-related pain following paclitaxel or oxaliplatin treatment were recruited. Two hundred and thirty-one patients were randomized to receive either duloxetine followed by placebo or placebo followed by duloxetine. Duloxetine was administered at a dose of 30 mg once a day for 1st week followed by 60 mg daily for the next 4 weeks followed by a crossover. 81% completed the initial treatment period. There was a statistically significant reduction in pain in patients receiving duloxetine. In another randomized double-blind study, venlafaxine was administered to patients with oxaliplatin-induced acute neurotoxicity. Forty-eight patients were included which mostly included patients having colorectal cancer (72.9% had this cancer). The median number of cycles administered at inclusion was 4.5. They received either venlafaxine 50 mg 1 h prior to oxaliplatin infusion and venlafaxine extended release 37.5 mg twice a day from day 2 to day 11 or placebo. Numeric rating scale was used to evaluate neurotoxicity. The Neuropathic Pain Symptom Inventory was administered to rate pain intensity and the oxaliplatin-specific neurotoxicity scale to assess the level of neurotoxicity. Full relief was more frequent in the venlafaxine arm. Venlafaxine side-effects were mild and included nausea and asthenia.,
Mechanisms of actions of all drugs are discussed briefly. The SNRIs and TCAs restore the levels of serotonin (5-hyroxytryptamine) and noradrenaline in the synaptic cleft by binding to their re-uptake transporters, thus, inhibiting nociception. Gabapentin and pregabalin block the calcium channel on the presynaptic neuron and prevent the release of excitatory neurotransmitters, thereby decreasing the irritability and firing of sensitized nociceptive neurons. Opioids bind to opioid receptors which cause release of intracellular guanosine triphosphate. This leads to closing of voltage gated calcium channels and opening of voltage gated potassium channels resulting in hyperpolarization.,,,,,, Opioids provide faster pain relief and tapentadol has shown better efficacy and tolerance than tramadol due to its additional effect on noradrenaline uptake. Drugs blocking sodium channels such as carbamazepine, oxcarbazepine and lamotrigine have shown inconsistent efficacy in all the trials in which they were assessed.,
Topical ketamine inhibits the excitatory N-methyl d-aspartate receptors, baclofen acts as agonist of the inhibitory gamma-amino butyric acid (GABA) receptor and lidocaine blocks sodium channels (the channels responsible for depolarization). Capsaicin, as a member of the vanilloid family, binds to a receptor called the transient receptor potential channel vanilloid receptor subtype 1 (TRPV1). Transient receptor potential channels play a crucial role in pain modulation. Menthol has vasodilatory and counter irritant effect, as well as acts centrally through GABA-A receptors. Menthol also acts peripherally on a specific channel called transient receptor potential channel 8 (TRPM8) which is critical in pain modulation and temperature transduction and through this channel, produces analgesic and cooling effect.,,,,,,, Topical agents combined with systemic agents cover more than one pathways inhibiting pain.
Therapeutic research is ongoing on several pathways addressing basic mechanisms.,,,, Nerve protection is being explored with erythropoietin, Ca/Mg infusions, glutamine, glutathione, acetyl L carnitine, N acetylcysteine, glutamate and many other biological neurotrophic factors.,,,,,,,, Anti-oxidants and chemoprotective agents such as Vitamin E, alpha-lipoic acid, omega 3 fatty acid, all-trans retinoic acid as well as novel molecules such as amifostine and mangafodipir have not found consistent benefit and further trials are recommended.,,,,,, Anti-inflammatory molecules acting on TNF, inter-leukins and chemokines are also being researched.,,, Metformin also is known to reduce pro-inflammatory cytokines and suppress macrophage response and protect mitochondria, so, systematic studies are recommended in CIPN. Xaliproden, a neurotrophic agent, nimodipine, a calcium channel antagonist, Org 276637, an adrenocorticotrophic hormone analog and recombinant human leukemia inhibitory factor failed to show any benefit., Pathways to prevent damage to mitochondria are also being explored.,
Other methods of reducing chance of developing CIPN are changing to agents having no toxic effects on nerves, avoiding co-administration of neurotoxic agents, reducing the dose and delaying the next dosing and the number of cycles of chemotherapy.,,,,,
Non-medical treatment modalities found useful in small trials are transcutaneous electric nerve stimulation, physical exercises (resistance, aerobic and stretching), cognitive behavior therapy and cryotherapy.,,, Goshajinkigan (Kampo medicine), a Japanese medicine composed of ten natural ingredients with neuroprotective potentials, has shown to reduce neurotoxicity, but only in small cohorts and mainly nonblinded studies. A pilot study on oncology massage therapy showed benefit on symptom control.
Cisplatin and carboplatin neuropathy may be irreversible depending on the cumulative dose whereas many patients with oxaliplatin exposure show reversal of symptoms. Neuropathy caused by paclitaxel, docetaxel, vinca alkaloids and bortezomib is related to cumulative dose and is reversible in majority of patients if exposure is ceased. Thalidomide neuropathy is dose limiting and can reverse, but at times can become permanent.
| Preventive Measures|| |
All predisposing factors such as DM, hypothyroidism, B12/folic acid deficiency, alcohol and tobacco abuse should be well controlled/addressed before initiating chemotherapy. Any other drugs which are toxic to the nerves not to be co-administered to avoid synergistic toxicity or used with caution and under very close observation (in case the drug plays very important role and it is absolutely necessary). Nerve conduction abnormalities, mainly in the sural nerve, precede appearance of symptoms and show worsening as duration and dose of exposure increases.,,, Hence, in our center, at times, we consider electrophysiology testing even before starting chemotherapy in patients who are high risk of developing PN. In addition to periodic focused neurological examinations, patients are monitored with nerve conduction studies to guide further therapy. If feasible, we choose to avoid nerve toxic chemotherapeutic agents or reduce doses and/or increase time intervals between chemotherapy cycles on a case by case basis.
How simple measures can control neuropathy and facilitate chemotherapy is described through a case vignette.
A 55-year-old female, with history of DM and hypothyroidism for the past 8 years, was diagnosed with ovarian cancer stage 2. After cytoreductive surgery, she was initiated on chemotherapy which constituted carboplatin and paclitaxel. At the beginning of chemotherapy, she had hemogram, blood sugars, renal and liver function tests as a part of standard protocol, which were normal. Few days after her second cycle, she developed severe distal paraesthesia in all four limbs and imbalance on walking which was worsening in dark. Examination revealed a normal motor power, glove and stocking hypoesthesia, impaired joint position till ankles and vibration till malleoli, absent ankles reflexes, a positive Romberg's sign and a stomping gait. Her nerve conduction study confirmed an axonal neuropathy. We found that she had been so depressed since the diagnosis of cancer, that she had neglected her DM and thyroid treatment. She had been very irregular with her previous medicines. Her food intake had gone down substantially. Her blood tests showed fasting and postprandial sugars at 300 and 390 mg%, respectively, hemoglobin A1c of 12.3%, thyroid stimulating Hormone of 32.4 mU/L and serum B12 at 124 ng/ml. She was receiving dexamethasone along with chemotherapy and her carboplatin infusions were prepared in 5% dextrose, which also may have contributed to the rise in sugars. She was admitted, her sugars were controlled with insulin for a short period, she was given injectable vitamin B12 and her dose of levothyroxine was optimized. She also received oral duloxetine at 60 mg/day (which also addressed her depression) and a topical gel containing a combination of lignocaine and capsaicin for symptomatic relief. There was a significant improvement in her neuropathy. Her chemotherapy dose for the next cycle was reduced by 10% and subsequent doses were administered as per standard schedule. She tolerated the rest of the chemotherapy very well.
| Practical Guidelines|| |
Practical guidelines for prevention and management of CIPN are summarized
- Before starting chemotherapy, address/treat preexisting predisposing factors causing neuropathy
- If possible, avoid combination of two or more nerve toxic chemotherapy agents
- Unless necessary, avoid other drugs having peripheral nerve toxicity
- Meticulous monitoring with focused neurological examination (quantified monofilament testing and vibration perception threshold) and nerve conduction studies
- May consider dose reduction/increasing interval between doses of chemotherapy on a case by case basis
- Use combination of oral and topical medicines as well as nonpharmacological therapies for symptom relief.
| Future Directions|| |
All of the above methods have limited success and research in prevention and treatment of CIPN has a long way to go. A pharmacogenomic approach using genetic susceptibility data may be applied in the future. This may help us to individualize chemotherapeutic agents as per the patient's genetic makeup. In addition to clinician assessments, patient-related outcome measures are recommended to improve the sensitivity of diagnosing CIPN.,,
Strategies to develop biomarkers for predicting the development of CIPN may guide us to administer preventive medicines. Initiating such medicines even before beginning chemotherapy may prevent its occurrence. The severity of symptoms may be reduced by prescribing drugs acting on basic pathogenesis of CIPN.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Authors would like to thank artist Parth Pujari for his contribution in the figure drawing.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]