INTRODUCTION
Multiple myeloma (MM) can be defined from a diagnostic view as an occupation of clonal plasma cells for 10% or more of bone marrow; and/or the biopsy proves there is plasmacytoma. Also, one or more of these events are accompanied: damage to end- organ as (renal impairment, hypercalcemia, destructive bone disease or anemia) provided that the cause is a problem with the plasma cells. There are 60% or more clonal plasma cells in the bone marrow; Positive or negative free light chain in the serum (100 mg\L); or magnetic resonance imaging (MRI) should prove there is focal damage (5mm).(Rajkumar et al, 2014) The incident cases of MM were 138,509 in 2016 with 2.1 per 100 000 people worldwide. This rose by 126% internationally from 1990 to 2016 (Cowan et al, 2018).
MM Disease course can lead to complications such as bony lesions, renal insufficiency, hematologic problems, infections and neurological deficit. These complications may be the beginning of a diagnosis with bone destruction predominance. (blade & Rosinol, 2007), (Rauniyar, 2015) and (Nau & lewis, 2008).
Neurological diseases are serious complications, including spinal cord compression, peripheral neuropathy, and numb chin syndrome, for example.
Although neurological complications are rare, their incidence cannot be ignored. A study found that, the number of MM patients who are exposed to neurological complications was 28/72, 39% (Tirumani et al, 2014). On the other hand, it has been shown that the life quality of the majority of cancer patients is affected by neurological complications (Driessen et al, 2012). This does not only impact the patient but also negatively affects his family, the society and his country’s economy.. Most neuropathologies lead to disability that has adverse psychological effects on the patient that may lead to depression. When depression is mentioned, it is worth considering suicide, which represents the way of salvation for a significant proportion of the people who suffer it, which is estimated at 9.5% of patients with major depressive disorder (Holma et al, 2014). What we did to reduce numbers above is more important Moreover, it is essential to have enough knowledge to conduct precautionary measures, and to design remedy and habilitative plans that match their needs. There are many reviews of neurological problems related to MM In terms of treatment methods, but few have addressed the mechanism of disease, though adequate understanding of the mechanism is the gateway to access effective treatment plans. In this review, our goal will be to discuss most of the mechanisms of neurological problems related to MM, and to combine them into common sections according to the causative process to simplify understanding and to infer the symptoms that can result.
This paper will be a scientific basis, and a logical enhancement of the knowledge that follows to target the methods of diagnosis and treatment.
COMPRESSIVE COMPLICATIONS
SPINAL CORD COMPRESSION &CAUDAEQUINA
The spinal cord compression occurrence resulting from MM is 11.1% (Mak et al, 2011). However, this problem is caused by the direct extension of the tumor from the bone marrow of vertebrae to the extradural space · Thoracic vertebrae are often affected as compression at that level resulting in paraplegia that affects the motor and sensory functions. Motor dysfunction results in the appearance of upper motor neuron lesion (UMNL) features from the beginning, without going through the stage of neuronal shock, including paraparesis below the level, hypertonia, hyperreflexia, and positive of Babinski sign. In terms of the sensation, the patient loses all sensations below the level. (Paleologos & Weathers, 2016).
Cauda equine occurs when the lumbosacral plexus is destroyed below L-1 , regardless of the type, number, or side of nerves. As a result of this problem, the autonomic , motor, or sensory functions are affected. The urinary bladder can be damaged if the S2 , S3 , and S4 are injured. Besides, caudaequina is damaged on both sides. For the motor action, the movement of the muscle innervated by the damaged root is affected, losing hip and knee flexion, if L2 and L3 are damaged, respectively, and so on. The sensation is applied to the same concept of motion, losing the sensation below the inguinal ligament and anterior aspect of the thigh, when L1, L2 and L3 are injured. and so on. (Blade & Rosinol, 2007) and(Dispenzieri & Kyle, 2005).
After we knew the pathophysiology of the disorder, we must figure out how to manage the disease in terms of detection and treatment.
Whole-body low dose CT (WBLDCT) appearance has led to a decline in whole-body X-ray (WBXR) use, because of its superior advantages over the latter in terms of high resolution, no need to use contrast, and a small dose of radiation sufficient for a clear vision of bone lysis. (Ippolito et al, 2013) and (Pianko et al, 2014).
FDG-PET/CT is one of the most effective diagnostic methods, since PET integration with CT produces the most sensitive and specific tool for extramedullary bone damage by 80% and 100%, respectively. (Lu et al, 2012).
MRI is the standard bone investigation, as it can detect bone marrow infiltration. Many studies have shown that the axial and whole-body MRI is more accurate than the whole-body X-ray in detecting bone damage in terms of sensitivity, and that 40%-50% of normal whole-body X-ray results have abnormal findings in MRI. (Dimopoulos et al, 2015), (Messiou & Kaiser, 2015) and (Hillengass et al, 2010).
The current treatment modalities used to prevent bone lysis related to MM are centered on inhibiting osteoclastic activity. (Raje & Roodman, 2011).
Biphosphonates is one targeted therapy that is subject to the mentioned mechanics, which prevents new lytic lesions of the bones, hypercalcemia, and pathological fractures. (Kyle et al, 2007).
In addition, Biphosphonates relieves bone pain by osteoclast-mediated proton release, spinal cord compression, and the need for surgical operations by 50%. (Hiasa et al, 2017).
Unfortunately, it was found that biphosphonates might cause kidney damage, and osteonecrosis of the jaw. Therefore, the function of the kidneys should be monitored when used, especially serum creatinine. Also, periodically teeth examination, correct prompt treatment for problems, and oral hygiene maintenance. (Van den Wyngaert, et al, 2007).
Denozomab is a monoclonal antibody that prevents RANKL from being linked to its receptor, RANK, on the surface of osteoclasts. This path is responsible for normal and abnormal bone remodeling. (Raje et al, 2018).
This treatment is highly capable of reducing calcium in the blood, and is safe to use compared to biphosphonate. However, denozomab is similar to biphosphonate in terms of jaw osteonecrosis, which means that the patient needs to do dental follow up periodically, and use vitamin-D supplements (Raje et al, 2018).
RADICULOPATHY
This disorder occurs due to a problem at the nerve root level, or slightly after it leaves the spinal cord. In this context, the problem is caused by tumor compression (Caridi et al, 2011). The clinical image resulting from this problem is symptoms that indicate lower motor neuron lesion (LMNL) as an example: Weakness, hypotonia, and hyporeflexia. Also, there are radicular signs, such as pain, paresthesia , or even loss of sensation. All the above symptoms and signs appear only at the level, in other words, on the body part innervated by the same damaged nerve root. For example, if radiculopathy occurs at the level of cervical vertebrae where there is the brachial plexus, clinical manifestations appear on the upper extremities (Eubanks, 2010). If it occurs at the level of thoracic vertebrae, clinical manifestations will appear on the trunk (O’Connor et al, 2002).
The nerve roots impingement can be confirmed by CT or MRI. The non-surgical treatment provides improvement for most patients including cervical collar to reduce mobilization, traction to relieve compression on the nerve, analgesics, physiotherapy, and selective nerve block to relieve pain and provide a sense of comfort. (Eubanks, 2010).
PERIPHERAL NEUROPATHY
Peripheral neuropathy is one of the most significant neurological complications related to MM. In a study of 170 patients, 20% of patients were proven to have MM. Their initial symptoms are unusual, mostly due to neurological diseases. Peripheral neuropathy is the third of these neuropathies (Talamo et al, 2010). On the other hand, there are many mechanisms for this problem, most of which relate to medications used in the treatment of MM as they have proved to have a toxic effect on neurons. Specifically, the neuronal cell bodies of the dorsal root ganglion (DRG) and the Axons extension to the peripheral nerves. The longer the axon is, the more likely the nerve is to be damaged by the drug, affecting the transmission and metabolism of energy (Isoardo et al, 2004).The Thalidomide-based treatment is one of the accused, where 83% of MM patients treated with it appeared to have a mild clinical and electrophysiological features of peripheral neuropathy related to the sensation at the end of their treatment period (Mohty et al, 2010). Thalidomide also prevents endothelial cells migration induced by nitric oxide in the formation of new blood vessels, resulting in ischemia of nerve fibers (Tamilarasan et al, 2006). Another mechanism that Thalidomide can follow to cause peripheral neuropathy is its ability to prevent activation of NF-KB upon which neural growth processes are based (Keifer et al, 2001).
Bortezomib is another drug involved in peripheral neuropathy in various ways. It has the potential to cause a disorder in calcium regulation within cells that leads to apoptosis (Landowski et al, 2005). The direct effect of bortezomib is observed on nerve endings (Delforge et al, 2010). In another study on rats, researchers found that bortezomib leads to pathological changes, and the destruction of sensory nerves in DRG and satellite cells (Meregalli et al, 2010). On the other hand, the drug has proved to hurt DRG. It changes in transports in axons of sensory nerves (Antoine & Camdessanché, 2007). For the chemotherapy-related to MM, it has been established that, Vincristine damages the microtubule-related transportations that occur in axons. Cisplatine also destroys DNA, disrupting the protein synthesis process that results in apoptosis of DRG (Broyl et al, 2010).
Peripheral neuropathy induced by treatment is relative to the patient’s age, dose, drug route of administration, and treatment period (Chakraborty & Majhail, 2020).
Moreover, precipitation of amyloid protein, or immunoglobulins, especially IgG and IgM around peripheral nerves or their blood vessels, Vasa Nervosa, can lead to the same problem (Silberman & Lonial, 2008).
However, no matter how diverse the mechanisms of the defect are, they are subject to clinical picture based on the type of nerve affected, sensory, motor, or autonomic. Sensory nerves are often damaged, as the patient complains of limb pain, anesthesia, or even total loss of sensation. When the motor nerves are damaged, LMNL symptoms such as weakness, atrophy, hypotonia and hyporeflexia appear. If autonomic nerves are affected, the patient suffers from postural hypotension, change of bowel habits, change in sweating, and urine retention (Argyriou et al, 2008).
This modification is based on peripheral neuropathy grade; grade 1, grade 2, grade 3 and grade 4, where dose modification begins to decrease, pausing until the pain is relieved or permanently stopping treatment (Qureshi et al, 2020). (Qureshi et al, 2020) Unfortunately, there is no specific drug for the treatment of peripheral neuropathy due to chemotherapy. All that can be done is to adjust the chemotherapy regimen after evaluating the patient’s general condition. However, Venlafaxine has been found to have the ability to mitigate and prevent neuropathic pain associated with Oxaliplatin. (Cavaletti & Marmiroli, 2010) (Durand et al, 2012).
Tricyclic anti-depressants, pregabalin, and gabapentin are often used off-label to relieve symptoms. (Delforge & Ludwig, 2017).
METABOLIC COMPLICATIONS
HYPERCALCEMIA
MM is characterized by high osteoclastic activity that results in increased calcium in the blood. It has recently been established that one of the effects of these catabolic functions is over- expression of Dickkopf-1 in MM, which is a powerful factor for configuring and activating osteoclast, in addition to the receptor activation of nuclear factor- κΒ ligand (RANK-L) and macrophage inflammatory protein-1α mediation in bone resorption (Oyajobi, 2007). The most common metabolic complication in MM patients is hypercalcemia (Oyajobi, 2007), which causes symptoms that vary in severity according to a rise in serum calcium levels, such as constipation, muscle weakness, fatigue, and nausea.
In the nervous system, increased calcium in the blood causes a disturbance in the higher brain functions, apathy, coma, and even depression (Oyajobi, 2007) and (Inzucchi, 2004).
Management of hypercalcemia is dependent on its severity; in mild hypercalcemia it is possible to wait until laboratory investigations and diagnosis are completed. In moderate and severe hypercalcemia, the purpose is to eliminate calcium in all possible ways, by increasing its excretion through urine, preventing bone resorption, and inhibiting the intestinal absorption. The patient is treated empirically with Normal Saline 0.9% for dehydration, calcitonin and biphosphonate. If the patient does not respond to biphosphonate, he is given denosumab. Also, gallium nitrate and cenacalcet can be used as they are known to cause a few side effects compared to previous ones. (Asonitis et al, 2019).
HYPERVISCOSITY SYNDROME
There are three types of hyperviscosity syndrome that depend on pathogenesis. Polycythemia hyperviscosity is the result of an increase in the number of red blood cells more than normal, resulting in low blood flow and reduced blood capillaries supply. Hyperviscosity syndromes are caused by the deformation of red blood cells, which leads to clot formation and ischemia. This is exactly what happens in sickle cell anemia. Hyperviscosity syndrome is the product of the dramatically increased protein molecules in the serum, this is what happens in MM and we target it in this space (El Kassimi et al, 2018). The most common causes are IgM myeloma where the molecular weight of immunoglobulin M is 970 kDa and excessive paraprotein increase, which is happening in macroglobulinemia (Mehta & Singhal, 2003). But this does not deny that it can happen due to lightweight molecules such as IgG and IgA (Gertz, 2018). Hyperviscosity syndrome is often translated into symptoms such as epistaxis, retinal bleeding, gum bleeding, and even cerebral infarction (Baskind et al, 2018), (Ellen Mullen & Noel Mendez, 2008) and (Park et al, 2005).
Plasma exchange is the golden option for the treatment of hyperviscosity syndrome, as it reduces the viscosity level in one session by 30%-50% when exchanging one volume of the patient’s plasma. This session is sufficient to prevent bleeding from the mucous membrane.
The number of sessions can be increased to 3 when the viscosity exceeds 6 degrees. (Kaplan, 2017) (Ballestri et al, 2007).
There are two types of plasma exchange: Centrifugation, and double-membrane filtration. Both have the same efficacy, and side effects with low blood pressure and hypersensitivity. (Lemaire et al, 2017) Also, rapid response to systemic chemotherapy can be performed by bortezomib to reduce viscosity. Carfilzomib can be used to reduce 50% of IgM within two months, while only 25% is enough to disappear features of hyperviscosity. If the patient needs a rapid effect, ibrutinib is likely to be used. (Gavriatopoulou et al, 2017), (Treon et al, 2014) and (Dimopoulos et al, 2018).
UREMIA
Uremia can be defined very simply as increased protein residue, urea, in the blood (Meyer & Hostetter, 2007). It occurs due to the effect of cancer on the kidneys in many ways all ending in kidney injury, resulting in urea accumulation due to the failure of the responsible organ to dispose of them (Zemaitis et al, 2017).
This rise in urea toxins can lead to neurological disease · The mechanism of this problem has not yet been well understood, and is still subject to many theories as attempts to explain it, but the current explanation is that axons of the central nervous system are in chronic depolarization state in patients with renal failure before dialysis. The clinical image of uremic encephalopathy is confusion or even coma, mental changes, abnormal movements, and sleep disorders (Krishnan & Kiernan, 2007) and (Seifter & Samuels, 2011).
Patient with symptomatic uremia needs dialysis as soon as possible, but in an emergency, in case of uremic encephalopathy, hyperkalemia, acidosis, and pericardial effusion, a patient needs emergency renal dialysis with a gentle start to avoid disequilibrium syndrome. To improve survival and quality of life, it is best to do a kidney transplant. (Zemaitis et al, 2017)Iron supplements are necessary to compensate for lost iron with dialysis, and an erythropoietin stimulator can be given when the hemoglobin level is below 10 mg/dl. (Zemaitis et al, 2017).
INFILTRATIVE COMPLICATIONS
CRANIAL & INTRACRANIAL INVOLVEMENT
The involvement of the skull Base in MM is rare. 3% of MM patients’ initial presentation is related to cranial and intracranial involvement (Kashyap et al, 2010). MM is an aggressive disease and is characterized by diffuse bone marrow infiltration, which leads to the formation of extramedullary plasmacytoma within the head and neck (Lasocki et al, 2015). The symptoms of extramedullary plasmacytoma vary depending on where plasmacytoma has originated. It can be found in the base of the skull and compress on the anatomical structures there, causing symptoms such as double vision, paresthesia on one side of the face, headache, vertigo, or disequilibrium (Ustuner et al, 2003) and (Joshi et al, 2011). The tumor can also damage cranial nerves either by infiltration or by pressing them, causing cranial nerve palsy symptoms that appear according to the function of the affected nerve. When sixth nerve palsy occurs, the patient complains that he cannot adjust his eyes. (Kashyap et al, 2010).
The involvement of the cranium can be detected by brain CT or MRI, which often reveals deposits in meningeal layers, damaged brain tissue, and direct infiltration from the nearest part of the skull bone.In the cytology of cerebrospinal fluid, there is an expansion in plasma and monoclonal cells in the vast majority of patients. (Lee et al, 2019).
A mixture of proteasome inhibitors, conventional chemotherapy, radiotherapy, immunomodulatory imide drugs, and autologous stem cell transplant is often used for extramedullary MM treatment. Using systemic and intrathecal chemotherapy (e.g: methotrexate), and craniocaudal irradiation for the treatment of extramedullary CNS involvement is a hotline of debate among researchers for its ability to cross blood brain barrier and target the lesion. (Lee et al, 2019).
NUMB CHIN SYNDROME
Numb chin syndrome is a neurological disease caused by damage to the mental nerve by direct tumor spread or pressure on the nerve. This nerve is responsible for feeding the mandibular region, and since the said nerve is a sensory nerve, the patient suffers from the loss, lack of sensation, or even pain in that area (Jain et al, 2016), (Carbone et al, 2014) and (Elias et al, 2009).
The diagnosis of numb chin syndrome is based on clinical features. However, some investigations can confirm this, including the cone-beam computed tomography (CBCT), which provides a clear view of the inferior alveolar canal and mental foramina. Also, there is a gadolinium CT or MRI for the head and neck that gives an accurate picture of the inferior alveolar nerve and its surrounding structures. Numb chin syndrome patients are often treated by local radiotherapy. (Jain et al, 2016).
DISCUSSION
This article deals with the most prominent neurological complications of MM. It represents a new addition that increases, and reinforces the little knowledge related to the understanding of the mechanism. It lists their adjacency under large groups based on the common pathophysiology. It also shows how the symptoms can be logically inferred. The infiltrative complications can be caused in another way by extramedullary plasmacytoma compression on the same anatomical structures that have been infiltrated (Chang & Winkelstein, 2011).
This content is a logical support and sequencing of future research that will address diagnostic and treatment methods. Also, knowing what neuropathology is induced by MM helps medical practitioner to extend the circle of differential diagnoses in such cases..
CONCLUSION
In this review we discussed many diseases that can all be neurological complications in MM, and we have classified them according to the main mechanism of these diseases to make optimal use of them. Our goal is to provide a simplified pathophysiology understanding of the neurological disorders related to MM on which potential clinical manifestations are based, and which is the basis for effective treatment methods.
By the end of this review, we recommend that all doctors consider the diseases discussed in this paper and include them in the differential diagnostic list.
CONFLICT OF INTEREST
No Conflict of Interest.
REFERENCES
1. Antoine J. C, Camdessanché J. P 2007 Peripheral nervous system involvement in patients with cancer The Lancet Neurology 6 1 75–86
2. Argyriou A. A, Iconomou G, Kalofonos H. P 2008 Bortezomib-induced peripheral neuropathy in multiple myeloma:a comprehensive review of the literature Blood 112 5 1593–1599
3. Asonitis N, Angelousi A, Zafeiris C, Lambrou G. I, Dontas I, Kassi E 2019 Diagnosis, pathophysiology and management of hypercalcemia in malignancy:a review of the literature Hormone and Metabolic Research 51 12 770–778
4. Ballestri M, Ferrari F, Magistroni R, Mariano M, Ceccherelli G. B, Milanti G, Albertazzi A 2007 Plasma exchange in acute and chronic hyperviscosity syndrome:a rheological approach and guidelines study
5. Baskind M, Hilton R, Chandar A, Nagella N 2018 Hyperviscosity Syndrome:A Rare Cause of Multisystem Organ Dysfunction In B46. CRITICAL CARE CASE REPORTS:HEMATOLOGY, ONCOLOGY, RHEUMATOLOGY, AND IMMUNOLOGY (pp. A3424-A3424). American Thoracic Society
6. Bladé J, Rosiñol L 2007 Complications of multiple myeloma Hematology/oncology clinics of North America 21 6 1231–1246
7. Broyl A, Corthals S. L, Jongen J. L, van der Holt B, Kuiper R, de Knegt Y, Durie B. G 2010 Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma:a prospective analysis of data from the HOVON-65/GMMG-HD4 trial The lancet oncology 11 11 1057–1065
8. Carbone M, Della Ferrera F, Carbone L, Gatti G, Carrozzo M 2014 Numb chin syndrome as first symptom of diffuse large B- cell lymphoma Case reports in dentistry 2014
9. Cavaletti G, Marmiroli P 2010 Chemotherapy-induced peripheral neurotoxicity Nature Reviews Neurology 6 12 657–666
10. Chakraborty R, Majhail N. S 2020 Treatment and disease-related complications in multiple myeloma:Implications for survivorship American Journal of Hematology 95 6 672–690
11. Chang Y. W, Winkelstein B. A 2011 Schwann cell proliferation and macrophage infiltration are evident at day 14 after painful cervical nerve root compression in the rat Journal of Neurotrauma 28 12 24292438
12. Cowan A. J, Allen C, Barac A, Basaleem H, Bensenor I, Curado M. P, Jakovljevic M 2018 Global burden of multiple myeloma:a systematic analysis for the global burden of disease study 2016 JAMA oncology 4 9 1221–1227
13. Bladé J, Rosiñol L 2007 Complications of multiple myeloma Hematology/oncology clinics of North America 21 6 1231–1246
14. Delforge M, Ludwig H 2017 How I manage the toxicities of myeloma drugs Blood 129 17 2359–2367
15. Delforge M, Bladé J, Dimopoulos M. A, Facon T, Kropff M, Ludwig H, Sonneveld P 2010 Treatment-related peripheral neuropathy in multiple myeloma:the challenge continues The lancet oncology 11 11 1086–1095
16. Dimopoulos M. A, Hillengass J, Usmani S, Zamagni E, Lentzsch S, Davies F. E, Badros A 2015 Role of magnetic resonance imaging in the management of patients with multiple myeloma:a consensus statement J Clin Oncol 33 6 657–664
17. Dimopoulos M. A, Tedeschi A, Trotman J, García-Sanz R, Macdonald D, Leblond V, Palomba M. L 2018 Phase 3 trial of ibrutinib plus rituximab in Waldenstrom's macroglobulinemia New England journal of medicine 378 25 23992410
18. Dispenzieri A, Kyle R. A 2005 Neurological aspects of multiple myeloma and related disorders Best practice &research Clinical haematology 18 4 673–688
19. Caridi J. M, Pumberger M, Hughes A. P 2011 Cervical radiculopathy:a review HSS Journal® 7 3 265–272
20. Driessen C. M. L, de Kleine-Bolt K. M. E, Vingerhoets A. J. J. M, Mols F, Vreugdenhil G 2012 Assessing the impact of chemotherapy-induced peripheral neurotoxicity on the quality of life of cancer patients Supportive care in cancer 20 4 877–881
21. Durand J. P, Deplanque G, Montheil V, Gornet J. M, Scotte F, Mir O, Herait P 2012 Efficacy of venlafaxine for the prevention and relief of oxaliplatin-induced acute neurotoxicity:results of EFFOX, a randomized, double-blind, placebo-controlled phase III trial Annals of Oncology 23 1 200205
22. Elias H. G, Scott J, Metheny L, Quereshy F. A 2009 Multiple myeloma presenting as mandibular ill-defined radiolucent lesion with numb chin syndrome:a case report Journal of oral and maxillofacial surgery 67 9 1991–1996
23. El Kassimi I, Touab R, Elkoundi A, Khayar Y 2018 Blood Hyperviscosity Syndrome Revealing Multiple Myeloma in Emergency Department:Report of a New Case BMH Medical Journal-ISSN 2348-392X 5 3 8891
24. Ellen Mullen R. N, Noel Mendez R. N 2008 Hyperviscosity syndrome in patients with multiple myeloma In Oncology Nursing Forum 35 3 350 Oncology Nursing Society
25. Eubanks J. D 2010 Cervical radiculopathy:nonoperative management of neck pain and radicular symptoms American family physician 81 1 33–40
26. Gavriatopoulou M, García-Sanz R, Kastritis E, Morel P, Kyrtsonis M. C, Michalis E, Gika D 2017 BDR in newly diagnosed patients with WM:final analysis of a phase 2 study after a minimum follow-up of 6 years Blood 129 4 456–459
27. Gertz M. A 2018 Acute hyperviscosity:syndromes and management blood 132 13 1379–1385
28. Hiasa M, Okui T, Allette Y. M, Ripsch M. S, Sun-Wada G. H, Wakabayashi H, Yoneda T 2017 Bone pain induced by multiple myeloma is reduced by targeting V-ATPase and ASIC3 Cancer research 77 6 1283–1295
29. Hillengass J, Fechtner K, Weber M. A, Bauerle T, Ayyaz S, Heiss C, Ho A. D 2010 Prognostic significance of focal lesions in whole-body magnetic resonance imaging in patients with asymptomatic multiple myeloma J Clin Oncol 28 9 1606–1610
30. Holma K. M, Haukka J, Suominen K, Valtonen H. M, Mantere O, Melartin T. K, Isometsa E. T 2014 Differences in incidence of suicide attempts between bipolar I and II disorders and major depressive disorder Bipolar Disorders 16 6 652–661
31. Ippolito D, Besostri V, Bonaffini P. A, Rossini F, Di Lelio A, Sironi S 2013 Diagnostic value of whole-body low-dose computed tomography (WBLDCT) in bone lesions detection in patients with multiple myeloma (MM) European Journal of Radiology 82 12 2322–2327
32. Isoardo G, Bergui M, Durelli L, Barbero P, Boccadoro M, Bertola A, Cocito D 2004 Thalidomide neuropathy:clinical, electrophysiological and neuroradiological features Acta neurologica scandinavica 109 3 188–193
33. Jain N, Annigeri R. G, Chauhan H, Raizada S, Adhauliya N, Potlia I 2016 Numb Chin Syndrome-A Dentist Perspective synthesis 21 22
34. Joshi A, Jiang D, Singh P, Moffat D 2011 Skull base presentation of multiple myeloma Ear, Nose &Throat Journal 90 1 E6–E9
35. Kaplan A. A 2017 Moderator's view:High-volume plasma exchange:pro, con and consensus Nephrology Dialysis Transplantation 32 9 1464–1467
36. Kashyap R, Kumar R, Kumar S 2010 Cranial nerve palsy in multiple myeloma and solitary plasmacytoma Asia-Pacific Journal of Clinical Oncology 6 4 251–255
37. Keifer J. A, Guttridge D. C, Ashburner B. P, Baldwin A. S 2001 Inhibition of NF-κΒactivity by thalidomide through suppression of ΙκΒkinase activity Journal of Biological Chemistry 276 25 22382–22387
38. Krishnan A. V, Kiernan M. C 2007 Uremic neuropathy:clinical features and new pathophysiological insights Muscle &Nerve:Official Journal of the American Association of Electrodiagnostic Medicine 35 3 273–290
39. Kyle R. A, Yee G. C, Somerfield M. R, Flynn P. J, Halabi S, Jagannath S, Anderson K 2007 American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma Journal of Clinical Oncology 25 17 2464–2472
40. Landowski T. H, Megli C. J, Nullmeyer K. D, Lynch R. M, Dorr R. T 2005 Mitochondrial-mediated disregulation of Ca2+is a critical determinant of Velcade (PS- 341/bortezomib) cytotoxicity in myeloma cell lines Cancer research 65 9 3828–3836
41. Lasocki A, Gangatharan S, Gaillard F, Harrison S. J 2015 Intracranial involvement by multiple myeloma Clinical radiology 70 8 890–897
42. Lee W, Chen R. C, Swaminathan S. K, Ho C. L 2019 Extramedullary multiple myeloma with central nervous system and multiorgan involvement:Case report and literature review Journal of Radiology Case Reports 13 12 1
43. Lemaire A, Parquet N, Galicier L, Boutboul D, Bertinchamp R, Malphettes M, Schlemmer B 2017 Plasma exchange in the intensive care unit:technical aspects and complications Journal of Clinical Apheresis 32 6 405–412
44. Lu Y. Y, Chen J. H, Lin W. Y, Liang J. A, Wang H. Y, Tsai S. C, Kao C. H 2012 FDG PET or PET/CT for detecting intramedullary and extramedullary lesions in multiple myeloma:a systematic review and meta- analysis Clinical nuclear medicine 37 9 833837
45. Mak K. S, Lee L. K, Mak R. H, Wang S, Pile-Spellman J, Abrahm J. L, Balboni T. A 2011 Incidence and treatment patterns in hospitalizations for malignant spinal cord compression in the United States, 1998-2006 International Journal of Radiation Oncology1 Biology*Physics 80 3 824–831
46. Mehta J, Singhal S 2003 Hyperviscosity syndrome in plasma cell dyscrasias In Seminars in thrombosis and hemostasis 29 05 467–472 Copyright©2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.:+1 (212) 584-4662
47. Meregalli C, Canta A, Carozzi V. A, Chiorazzi A, Oggioni N, Gilardini A, Cavaletti G 2010 Bortezomib-induced painful neuropathy in rats:a behavioral, neurophysiological and pathological study in rats European Journal of Pain 14 4 343–350
48. Messiou C, Kaiser M 2015 Whole body diffusion weighted MRI-a new view of myeloma British journal of haematology 171 1 29–37
49. Meyer T. W, Hostetter T. H 2007 Uremia New England Journal of Medicine 357 13 1316–1325
50. Pianko M. J, Terpos E, Roodman G. D, Divgi C. R, Zweegman S, Hillengass J, Lentzsch S 2014 Whole-body low-dose computed tomography and advanced imaging techniques for multiple myeloma bone disease Clinical Cancer Research 20 23 5888–5897
51. Mohty B, El-Cheikh J, Yakoub-Agha I, Moreau P, Harousseau J. L, Mohty M 2010 Peripheral neuropathy and new treatments for multiple myeloma:background and practical recommendations haematologica 95 2 311–319
52. Nau K. C, Lewis W. D 2008 Multiple myeloma:diagnosis and treatment American family physician 78 7 853–859
53. O'Connor R. C, Andary M. T, Russo R. B, DeLano M 2002 Thoracic radiculopathy Physical medicine and rehabilitation clinics of North America 13 3 623–44
54. Oyajobi B. O 2007 Multiple myeloma/hypercalcemia Arthritis research &therapy 9 1 1–6
55. Inzucchi S. E 2004 Understanding hypercalcemia:its metabolic basis, signs, and symptoms Postgraduate medicine 115 4 6976
56. Paleologos N. A, Weathers A. L 2016 20 Neurological complications of multiple myeloma Neurological Complications of Systemic Cancer and Antineoplastic Therapy 365
57. Park M. S, Kim B. C, Kim I. K, Lee S. H, Choi S. M, Kim M. K, Cho K. H 2005 Cerebral infarction in IgG multiple myeloma with hyperviscosity Journal of Korean Medical Science 20 4 699–701
58. Qureshi A, Tariq M. J, Shah Z, Abu Zar M, Aslam S, Rafae A, Anwer F 2020 Evidence-based supportive care in multiple myeloma Journal of Community Hospital Internal Medicine Perspectives 10 4 313–317
59. Raje N, Roodman G. D 2011 Advances in the biology and treatment of bone disease in multiple myeloma Clinical Cancer Research 17 6 1278–1286
60. Raje N, Terpos E, Willenbacher W, Shimizu K, García-Sanz R, Durie B, Cheng P 2018 Denosumab versus zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma:an international, double-blind, double-dummy, randomised, controlled, phase 3 study The Lancet Oncology 19 3 370–381
61. Rajkumar S. V, Dimopoulos M. A, Palumbo A, Blade J, Merlini G, Mateos M. V, Landgren O 2014 International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma The lancet oncology 15 12 e538–e548
62. Rauniyar A. K Integrated Bioinformatics analysis of differentially expressed genes (DEGs) of multiple myeloma (MM) datasets from gene expression omnibus (GEO)
63. Seifter J. L, Samuels M. A 2011 Uremic encephalopathy and other brain disorders associated with renal failure In Seminars in neurology 31 02 139143 ©Thieme Medical Publishers
64. Silberman J, Lonial S 2008 Review of peripheral neuropathy in plasma cell disorders Hematological oncology 26 2 5565
65. Talamo G, Farooq U, Zangari M, Liao J, Dolloff N. G, Loughran T. P Jr, Epner E 2010 Beyond the CRAB symptoms:a study of presenting clinical manifestations of multiple myeloma Clinical Lymphoma Myeloma and Leukemia 10 6 464–468
66. Tamilarasan K. P, Kolluru G. K, Rajaram M, Indhumathy M, Saranya R, Chatterjee S 2006 Thalidomide attenuates nitric oxide mediated angiogenesis by blocking migration of endothelial cells BMC Cell Biology 7 1 17
67. Tirumani S. H, Shinagare A. B, Jagannathan J. P, Krajewski K. M, Munshi N. C, Ramaiya N. H 2014 MRI features of extramedullary myeloma American Journal of Roentgenology 202 4 803–810
68. Treon S. P, Tripsas C. K, Meid K, Kanan S, Sheehy P, Chuma S, Patterson C. J 2014 Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-sparing approach for treating Waldenstrom's macroglobulinemia Blood. The Journal of the American Society of Hematology 124 4 503–510
69. Ustuner Z, Basaran M, Kiris T, Bilgic B, Sencer S, Sakar B, Porter R. W 2003 Skull base plasmacytoma in a patient with light chain myeloma Skull Base 13 03 167–172
70. Van den Wyngaert T, Huizing M. T, Vermorken J. B 2007 Osteonecrosis of the jaw related to the use of bisphosphonates Current opinion in oncology 19 4 315–322
71. Zemaitis M. R, Foris L. A, Chandra S, Bashir K 2017 Uremia
