Neuromuscular complications in cancer

    Neuromuscular complications in cancer W. Grisold, A. Grisold, W.N. L¨oscher PII: DOI: Reference:

S0022-510X(16)30333-1 doi: 10.1016/j.jns.2016.06.002 JNS 14594

To appear in:

Journal of the Neurological Sciences

Received date: Revised date: Accepted date:

6 March 2016 8 May 2016 1 June 2016

Please cite this article as: W. Grisold, A. Grisold, W.N. L¨oscher, Neuromuscular complications in cancer, Journal of the Neurological Sciences (2016), doi: 10.1016/j.jns.2016.06.002

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Grisold W 1, Grisold A 2, Löscher WN 3 1 Department of Neurology, Kaiser Franz Josef hospital, Vienna, Austria

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2 Department of Neurology, Medical University of Vienna, Vienna, Austria

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Neuromuscular Complications in Cancer

3 Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria

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Corresponding author Wolfgang Grisold, MD Prof.

Kundratstr. 3, 1100 Vienna, Austria

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Department of Neurology, Kaiser Franz Josef hospital

Ludwig Boltzmann Institute for Experimental und Clinical Traumatology.

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[email protected]

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Keywords

Cancer, lymphoma, leukemia, neuromuscular complications, cranial nerves, peripheral

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Highlights

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nerves, neuromuscular junction, muscle

Neuromuscular complications in cancer are frequent. Mechanisms range from toxicity of drug treatment, neoplastic infiltration, paraneoplastic, metabolic and inflammatory syndromes. Precise differential diagnosis is essential for treatment. Drug toxicity can be a dose limiting factor of cancer therapy.

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The study was not funded. There is no conflict of interest.

ACCEPTED MANUSCRIPT Abstract

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Cancer is becoming a treatable and even often curable disease. The neuromuscular system can be affected by direct tumor invasion or metastasis, neuroendocrine, metabolic, dysimmune /inflammatory, infections and toxic as well as paraneoplastic conditions. Due to the nature of cancer treatment, which frequently is based on a DNA damaging mechanism, treatment related toxic side effects are frequent and the correct identification of the causative mechanism is necessary to initiate the proper treatment.

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The peripheral nervous system is conventionally divided into nerve roots, the proximal nerves and plexus, the peripheral nerves (mono- and polyneuropathies), the site of neuromuscular transmission and muscle. This review is based on the anatomic distribution of the peripheral nervous system, divided into cranial nerves (CN), motor neuron (MND), nerve roots, plexus, peripheral nerve, the neuromuscular junction and muscle. The various etiologies of neuromuscular complications – neoplastic, surgical and mechanic, toxic, metabolic, endocrine, and paraneoplastic/immune - are discussed separately for each part of the peripheral nervous system.

ACCEPTED MANUSCRIPT Introduction

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Neuromuscular complications in cancer have different etiologies in different anatomical regions. Although metastases as the cause of a neuromuscular syndrome is often the primary concern, several other pathogenic causes exist. CN lesions often have a neoplastic cause, in particular local metastases and meningeal infiltration. Nerve roots can be both damaged by mechanical and neoplastic causes, and the nerve plexi are predominantly affected by neoplastic lesions, and if radiated also radiation effects need to be considered. Peripheral neuropathies can be caused by paraneoplastic etiologies, usually at the time of diagnosis, during the course of therapy by toxic drug effects and much rarer by infrequent causes such as neoplastic infiltration, metabolic or inflammatory causes. The neuromuscular junction (NMJ) can be a site of paraneoplastic or dysimmune effects such as in myasthenia gravis, Lambert Eaton myasthenia syndrome (LEMS) or neuromyotonia. In muscle paraneoplastic and inflammatory lesions dominate. Direct neoplastic involvement is rare. The most frequent type of muscle involvement is cachexia. Neuromuscular complications can appear as the first sign of cancer, where often a tumor search is needed [1], or appear as a complication during the disease. An important aspect affecting the impact of neuromuscular complications is associated with age. Pediatric cancer, adult cancer and increasingly geriatric aspects of cancer [2], [3] have a diverse spectrum of complications. This distinction can be based on several issues such as tolerance of treatment, development of persisting or late toxicity, and also the influence of other concomitant diseases.

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Besides anatomical considerations, pathogenic mechanisms vary and are important for localization and development of treatment:

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Neoplastic Different tumors have different propensities to metastasize at different time points and into different organs (organotropism). Cancer is usually classified into hematological and solid tumors. Both types have the ability to convert from a solid into a liquid state (meningeal carcinomatosis) and vice versa (chloroma or myelosarcoma). Other mechanisms are local compression, focal or diffuse invasion, and even rarer anterograde and retrograde spread along nerves and rarely local tumor or metastasis into nerve and muscle. Surgical and mechanical The surgical approach to tumors or metastases can mechanically damage peripheral nerves, or less frequently muscles. Also perioperative procedures e.g. posturing can result in nerve lesions. Radiotherapy Side effects are usually classified by the timing of appearance, which can be early, delayed and late. Early and early delayed affects are usually rare [4].

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Delayed effects on peripheral nerves affect peripheral nerves and the nerve plexus, increasingly late effects on muscle tissue are noted. The pathogenic cause of late effects is radiation induced vascular pathology and fibrosis. Modern radiation techniques aim to avoid these side effects, although at some sites, e.g. such as the skull regional damage of CN can be unavoidable. Chemotherapy can cause an inflammatory reaction in prior radiated tissue, which is called „radiation recall syndrome“ [5].

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Toxicity from chemotherapy Neurotoxicity in the peripheral nervous system is one of the dose limiting factors. In peripheral nerves in addition to cumulative toxicity, increasingly persistent late toxicity is noted. The mechanisms of toxicity are not uniform and depend on the drug and its specific mechanism. Toxicity can be acute, cumulative or late. For several chemotherapies the susceptibility of the individuals varies and is most likely determined by genetic causes [6]. The increasingly used biological drugs can cause dysimmune conditions resulting in neuromuscular syndromes, by different pathogenic mechanisms.

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Metabolic/endocrine Metabolic conditions related to tumors, or treatment may cause dysfunction of the neuromuscular system. Hormonal and electrolyte disorders, endocrine effects either by production of paraendocrine hormones, dysregulation of endocrine hormone production, or effects of hormonal treatment (breast, prostate), can influence the neuromuscular system. Amyloid deposition can be present in multiple myeloma (MM) and paraproteinemia and may affect peripheral nerves as well as muscles.

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Paraneoplastic and immune - mediated The mechanism of paraneoplastic diseases are heterogenous. Autoimmune, metabolic, endocrine and unresolved mechanisms exist. The autoimmune paraneoplastic syndromes are caused by onconeuronal antibodies as well as by surface antibodies, and rarely combinations. The Euro-PNS study [7] identified the distribution of onconeural antibodies and paraneoplastic neurological syndromes. Frequently patients with cancer suffer from weight loss and in progressive stages of cachexia. Despite the frequency of this condition the mechanisms are still unresolved. Infections Infections occur in cancer patients due to immune suppression. The most frequent association is Herpes Zoster. Generalized infections and sepsis can cause critical illness neuropathy and myopathy. Other Various other causes such as pressure sores, weight loss, malabsorption can cause damage of the peripheral nervous system.

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Table 1 Likelihood of different pathogenic mechanisms causing neuromuscular complications in cancer.

Anatomically defined sites of lesions CN Anatomically, CN have a cerebral parenchymatous and an intracavitary part within the skull. They have a defined exit through the skull, followed by an extracranial course. The intracavitary part will not be considered here, with the exception of nerve infiltration or compression in leptomeningeal disease, as well as base of the skull tumors. Imaging is useful to demonstrate abnormalities of CNs [8]. Neoplastic lesions of CNs can be caused by a number of intracranial causes such as leptomeningeal carcinomatosis (LC) and local metastasis, as to the cavernous sinus, the orbital fissure, the Meckel`s cave , as well as local lesion at exit points of the CN outside of the skull [9].

ACCEPTED MANUSCRIPT Outside the intracranial cavity the CNs either travel within other cavities (eg orbita, nasal sinus) or the soft tissue parenchyma of the head and neck and even further such as the vagus nerve [10].

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Particular sites as metastases to the clivus [11] and the spread of malignant parotid tumors along nerves and centripitally into the cranial cavity. Several observations of retrograde spread from facial skin tumors via the CN V and VII have been made [12]. Perineurial invasion is usually slowly progressive and can be a diagnostic dilemma [13]. Facial pain can also be a presentation of skin cancer [14], as well as spread of pain to the head and cervical plexus by tumors in the neck. CN V and CN VII can be the site of antero- and retrograde tumor spread [10] and neoplastic infiltration can spread from one CN territory into the other, as in anastomoses between CN V and CN VII. The pyriform fossa [15] is a site of transgression from one nerve territory into the other. Local nerve infiltration can be erroneously considered to be a Bell`s palsy or trigeminal neuralgia [16].

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The orbits and eyes can be a site of direct involvement by cancer, either as metastasis to the eye and retina or spread of lymphoma in the vitreous fluid [17]. Also the orbits can be the site of local metastasis, either in the extraocular muscles [18] or as an intraorbital mass (eg. lymphoma or leukemia) [19] or scirrus like tumors producing enophthalmus [20], and the site of perineurial invasion [21].

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Several other causes of CN lesions include unilateral trigeminal motor neuropathy [22], trigeminal neuropathy secondary to perineural infiltration [23], mental neuropathy or numb chin syndrome [24], rarely brain tumors with local infiltration [25] and metastasis to the skin of the head in a zosteriform pattern [26], [27] .

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The lower CNs can be affected by LC, destruction of exit sites of the skull, local tumors or lymph nodes in the neck and rarely neurolymphomatosis [28]. Nasopharyngeal tumors can affect CN VI and CN XII and may have a response to radiotherapy [29]. Surgical/mechanical damage Surgical damage to CNs occurs by access to a tumor located in the head or related structures and causes focal damage, either by compression, ischemia or transection. Several Iatrogenic lesions have been described [30], [31]. Embolization of the neck arteries [32] such as the arteria pharyngea ascendens for tumor treatment, can cause ischemic damage to the vascular supply of the CNs. The concept of angiosoma [33] describes a specific vascular supply of the whole body including the skull and vascular supply of the CN is helpful in interventions at the base of the skull. The implementation of this anatomical concept is useful in saving the lower CN from vascular damage in intervention such as tumor embolization.

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Table 2 Cranial nerve (CN) lesions. Legend: In CN lesions, primarily a neoplastic cause needs to be ruled out. Sequelae of RT depend on the type of RT and focal application; toxic CN lesions occur; paraneoplastic CN are rare and almost confined to the visual system.

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Radiation therapy (RT) RT is an important treatment modality but despite great efforts to avoid CN lesions, they cannot always be avoided. In particular in some brain tumors the optic nerve [34] and the chiasm can be damaged by RT of the base of the skull, and in ENT tumors, also resulting in late complications [35]. Depending on the site of the lesion other CNs can be affected. RT of ENT tumors [36] can damage the hypoglossal nerve [37] resulting in myokymia [38]or the vocal fold [39] can be damaged. Also the trigeminal nerve [40] and facial nerve can be damaged in RT [41] as well as caudal CNs [42]. Toxic Toxic CN lesions are rare. The most frequently described toxic lesions are caused by vincristine [43]. Docetaxel can damage the optic nerve [44], [45], [46] , [45] but are rather a diagnosis of exclusion. Vision can also be compromised by other effects of chemotherapy [47]. Several causes of jaw pain have to be considered in oncology ([48]. Metabolic and endocrine Metabolic and endocrine CN dysfunctions are usually not encountered. Amyloid deposition in the form of amyloidomas can be found in CNs [49], [50] , [51], [52].

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Paraneoplastic/immune - mediated Paraneoplastic CN dysfunction is rare [53]. Several visual syndromes [54] ,[55] affecting the retina and the optic nerve have been described. The oculomotor system is rarely involved [56] , [57]. In LEMS only a mild ptosis and mild involvement of extraocular muscles compared with MG can be expected. Whether giant cell arteritis and polymyalgia rheumatica are considered cancer association is a matter of debate.

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Differential diagnosis The differential diagnosis of CN lesions include a variety of unrelated diseases, in the context of cancer, numerous infections which can be local, or in the mouth [58], [59] and upper digestive tract, causing swallowing difficulties. Radiation induced tumors of CNs occur (IgG related pseudotumors [60] ) causing CN damage are rare.

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Spinal cord: MND and tract degeneration The spinal cord can be involved in cancer in several ways. For this review the different types of spinal cord compression and metastasis will not be discussed. Changes due to paraneoplastic causes have been described [61]. Motor neurone diseases such as ALS and primary lateral sclerosis (PLS) type [62] and lower motor neuron diseases have been described [63] , [64] but are subjects of debate. In addition to these well defined entities, also individual tracts, such as the posterior columns in sensory neuronopathy and also other tract systems [65], such as the pyramidal tracts in PLS can be involved. Segmental myelopathies can be caused by local infections, in particular herpes zoster [66], [67]. RT can cause focal lesions of motor neurons the „ dropped head syndrome“ [68] or lower motor neurone disease [69], [64]. Paraneoplastic myelopathies, or motor neurone syndromes have been described as a paraneoplastic syndrome associated with onconeuronal antibodies [70][, 71] , [72]. The classical term of paraneoplastic encephalomyelitis (PEM) describes a combination of encephalitis with myelopathy. Stiff person syndromes 10% of the stiff person syndrome (SPS) cases are paraneoplastic. Stiff syndromes such as stiff person syndrome, or progressive encephalomyelitis with rigidity and myoclonus (PERM) [73], [74] are usually categorized as CNS effects. SPS and „stiff limb syndromes“ are autoimmune diseases often associated with GAD [74], [75] or amphiphysin antibodies [76]. The frequency of the association with cancer also including encephalopathies is a spectrum of diseases [77] GAD spectrum. In PERM an additional degeneration of motor neurons has been described [78]. Clinical syndrome Patients have fluctuating muscle stiffness, often with spasms, and focused to the trunk muscles. Continuous uncharacteristic muscle activity and muscle spasms appear. Autonomic features can be associated. GAD antibodies are present in up to 50 % of patients;

ACCEPTED MANUSCRIPT also amphiphysin antibodies have been described. In paraneoplastic conditions a more distal clinical distribution termed the „ Stiff limb syndrome“ [79] has been postulated.

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SPS can be found in breast cancer, SCLC, lymphoma, and thymoma. Treatment is immune modulation with steroids, IVIg, plasma exchange and with diazepam or clonazepam, dantrium, gabapentin or vigabatrin.

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Nerve Roots Nerve root involvement in cancer is a frequent finding. It can be caused by intrathecal root lesions such as leptomeningeal carcinomatosis (LC) or by local tumors. More frequently local root disease occurs due to vertebral metastasis, vertebral collapse, or local infiltration of tissue due to vertebral column metastasis. Usually a combination of a nociceptive and neuropathic pain syndrome occurs. Prostate cancer frequently presents with back pain and vertebral column metastases [80].

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Metastasis to nerve roots are infrequently reported [81], [82]. Lymphoma can mimick a nerve root schwannoma [83], and involve several nerve roots [84]. Also chloromas can present with radiculopathies [85]. Rarely a retrograde infiltration of the nerve roots can occur due to spread along the plexus [86], and invasion via the intervertebral foramina, without bone destruction [87]. Single cases of infiltration of the dorsal root ganglia (DRG) [88], [89] have been described. Also epidural haematopoesis [90] can cause local nerve root symptoms, as well as infiltration of the cauda equina and caudal nerve roots [91]. Also extremely rare cases of nerve root damage need to be considered [92].

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RT Focal damage to individual nerve roots can be caused by stereotactic treatment of cancer [93], [94]. Rarely RT damages roots but can mimic tumor recurrence (radiation induced lumbosacral radiculopathy) [95]. Metabolic/endocrine In cancer treatment with steroids, the development of epidural lipomatosis has been described [96] [97], [98], [99] or may result from Cushing`s syndrome [100]. Toxic Various drugs used for intrathecal treatment can cause focal neurotoxicity [101]. Infection Herpes is probably the most common infection in adult cancer patients [102], and presents with the typical skin rash and a varying degree of neuropathic pain. Rarely also a generalized herpes zoster (HZ) can appear [103]. Also spinal infections and spondylodiscitis [104], [105] have been described in cancer patients.

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Paraneoplastic/immune-mediated Paraneoplastic causes for radiculopathies are unlikely, but have been observed in conjunction with myelitis [106], and individually in lymphoma [107]. Selective enlargement of cauda equina fibers has been described in lung cancer [108]. Therapy induced multifocal polyradiculopathy has been observed with the immune check point inhibitor ipimilumab [109].

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Nerve Plexus The nerve plexus can be subject to several types of damage, which go beyond the classical differentiation between neoplastic and radiation induced plexopathy [110], [111]. Imaging can often detect most neoplastic lesions, and also electrophysiological examinations can be helpful to distinguish between denervation and RT induced changes (myokymia) [112]. RT techniques have significantly improved and radiation-induced lesions of the nerve plexus are less frequently expected. However also stereotaxic methods cause brachial plexus lesions [113]. Despite advanced imaging techniques [114] the distinction between tumor recurrence and radiation damage is not always clear [(115]. Therapies for RT induced damage are still lacking [116].

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Cervical plexus The cervical plexus receives fibers from C1 to C4. There are several anastomotic connections with CNs (e.g. the accessory [117] and hypoglossal nerve and the sympathetic trunk. Several branches as the greater auricular nerve, the transverse cervical nerve, the lesser occipital and supraclavicular nerves innervate the skin of the neck and posterior regions of the skull. In „neck dissection“ nerve lesions often cause local neuropathic pain. The dorsal nerves of the cervical plexus form their own anastomoses [118].

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Neoplastic lesion Lesions are most frequently caused by ENT tumors, or local metastasis. Rarely leukemia can present with focal tumors [119]. Neoplastic lesions clinically with a local dull pain and neuropathic components. Pain projection into the head and skull can be a misleading feature [120]. MR investigations are helpful [121]. In surgery, particularly following neck dissection pain is often the dominant feature [122], [123]. The preservation of nerve roots during this procedure improves [119] the clinical outcome. Brachial plexus Brachial plexus lesions in cancer can present with focal neurological deficits, as well as local pain syndromes presenting such as shoulder pain [124] and cervicobrachialgia [125]. These local pain syndromes can be misleading if they are the presentation of cancer. Neoplastic The brachial plexus is conventionally divided in the upper and lower brachial plexus or a panplexopathy. Due to the site of lymph nodes and the vicinity of the lung lower brachial

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plexus lesions are more frequent in neoplastic involvement [126]. Tumor infiltrations via the skin have been described [127]. The brachial plexopathy often presents with dull pain, and neuropathic components can be associated. The pain spreads to the medial and posterior aspect of the upper arm and medial forearm. Neurologic signs usually follow the pain. Weakness caused by lesions of the lower brachial plexus affects the hand muscles, and sensory loss often involves the 4th and 5th finger and the C8 innervated area of the medial forearm. Horner’s syndrome is caused by involvement of the sympathetic trunk.

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Breast: Breast cancer is the most frequent cause of brachial plexopathy and is often a late complication, even occurring years after cancer treatment. The spread of the tumor occurs from the lateral group of lymphatics. Proximal spread along the nerve roots can result in a tumor extension into the neural foramina and even cause additional spinal cord compression.

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Lung: Pancoast tumor is a well-defined syndrome, which usually is seen in conjunction with cancer of the apex of the lung. In addition to the commonly observed combination of ptosis, C8 symptoms and local pain, several varieties of presentation have been described [128], such as pain in the elbow or cervicobrachialgia [125]. In a large number of patients also spinal cord compression occurs [129].

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Lymphoma: the brachial plexus can be involved in a variety of ways [130, 131], [132]. Nerve compression from lymphoma or nerve invasion can occur. Also spread along the nerve roots with spinal cord compression has been observed [133]. In Hodgkin`s disease the brachial plexus is involved in 10-15 % of patients [134].

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Rarely tumor spread from other solid tumors is reported such as tumor spread from a mandibular tumor to the brachial plexus [135]. Intrinsic tumors of the brachial plexus include neuronal sheath tumors either benign or malignant. Radiation therapy The incidence of radiation-induced brachial plexopathy is decreasing due to improved RT techniques. Radiation injury is observed in breast cancer, ENT tumors, and in RT of tumors of the chest, neck or axillary region of any other tumor. The time of onset varies from months to years in the conventional radiation-induced brachial plexopathy and is dosedependent [136]. Conventionally 3 types of RT injury are distinguished: early transient plexopathy, [137], early delayed and delayed injury are distinguished [138]. Delayed toxicity is usually not expected to occur before 6 months after RT. Local Tinel Hoffmann sign can be elicitable, and paresthesias more frequent, than in patients with surgery [139]. Radiation-induced brachial plexopathy is a disabling disorder [140] and primarily involves the upper trunk, which may be explained by the closeness to the radiation port. Additional skin lesions and lymphedema can appear. MRI often finds edematous swelling of the brachial plexus [141].

ACCEPTED MANUSCRIPT An acute onset ischemic radiation-induced brachial plexopathy is controversial [142]. Studies of radiations of ENT tumors revealed an onset of neurological symptoms two years after RT [143].

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Rarely radiation-induced tumors occur [144], [145]. EMG can be helpful to demonstrate continuous muscle fiber activity and myokymia [146] as an indication of radiation damage.

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Paraneoplastic Paraneoplastic brachial plexopathy is rare [147], [148] and diagnosed by exclusion.

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Lumbar and sacral plexus Lumbar and sacral plexopathy are often termed „lumbosacral plexopathy“ [149]. Lumbar plexopathy is less frequent than sacral plexopathy. Despite their distinguished and separated location, both plexi are connected with the lumbosacral trunk (fibers from L4/5). For sacral plexopathies, the distinction between radiculopathy, plexopathy, and isolated nerve lesions is difficult, due to the vicinity of local tumors to all nervous structures [150].

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The lumbar plexus is less frequently involved than the sacral plexus. Invasion of the psoas muscle is termed malignant psoas syndrome [151]. Coagulation disorders can cause psoas and iliac haematoma, both can have an insidious onset and can present with uncharacteristic pain.

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Sacral The location of the sacral plexus is presacral near the midline, which makes bilateral damage possible. Often, osseous metastatic destructions of the sacrum can be found. The local neighbourhood of the plexus with nerve roots and the peripheral nerves makes a precise neuroanatomical diagnosis difficult. Regional and radiating pain syndromes, mimicking sciatic nerve lesions are often the clinical hallmark. Numbness in the perianal region, as well as involvement of the sympathetic fibers resulting in „hot and dry foot” [152] can be found. Local tumors and recurrences of gynecological and rectal carcinoma [153] are observed. Local tumor spread along regional nerves has been described in prostate cancer [154], [155], [156], [157], [158]. Pretreatment of the sacral plexus with RT is an important distinction. Usually RT lesions do not occur before several months, and are often painless and characterized by autonomic features. Several dose adaptions have been described in gynecological cervical cancer to avoid nerve damage [159]. Imaging is increasingly helpful; also EMG helps to characterize RT-induced electrical activity usually by appearance of myokymia. Lesions of the cauda equina are an important differential diagnosis. The full picture is a flaccid paraparesis, often with a motor predominance. The causes can be neoplastic infiltration of the nerve roots, focal tumors [160] local compression by metastasis, or vertebral collapse. Radiation of T10 to L4 vertebral column bodies can appear as a late effect some years after RT [161]. ´

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Polyneuropathy (PNP) Neuropathies in cancer patients occur most frequently as toxic neuropathies (chemotherapy induced polyneuropathy-CIPN), less frequently as paraneoplastic, immune-mediated and even rarer neoplastic neuropathies. Toxic neuropathies are often a dose limiting factor in cancer therapy. In addition to acute and cumulative effects increasingly late toxicity, or symptoms in cancer survivors are becoming an issue.

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Neoplastic Neurolymphomatosis [162], [163] , [84], [164] has been well described and appears in various forms [165], also mimicking CIDP [166] , [164]. Also intravascular lymphomas [167] and combinations [168] have been described. Rarely leukemia produces diffuse infiltrations [169] and also the invasion of dorsal root ganglia has been described, although no precise clinical correlation is known [164].

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Metabolic/endocrine Metabolic and endocrine causes of neuropathy can be due to underlying internal diseases such as diabetes, thyroid disorders and renal insufficiency. These conditions can probably predispose or worsen toxic neuropathies by cancer treatment and are important to consider. Amyloid deposition in peripheral nerves occurs in paraproteinemic neuropathies such as in multiple myeloma (MM) and Waldenstroem`s disease [170], [171].

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Paraneoplastic and dysimmune The classification of paraneoplastic neuropathies is a matter of debate [172], [173] . The analysis of the Euro PNS consortium study [7] identified sensory neuronopathy as the most frequent type of paraneoplastic neuropathy. The other types such as sensory neuropathies, acute and chronic demyelinating neuropathy, multifocal or multiplex neuropathy were less frequent. The term „dysimmune neuropathies“ has been recently [174] selected to describe a number of neuropathies occurring in conjunction with Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL). Most paraneoplastic neuropathies occur at the onset of cancer, or are the reason for its detection. The exceptions are inflammatory neuropathies such as acute inflammatory demyelinating neuropathy (AIDP) or chronic inflammatory demyelinating polyneuropathy (CIDP), which can appear during the disease, in particular in NHL and HD. Subacute sensory neuronopathy (SSN) is well characterized clinically [175] and neuropathologically [176]. SSN is characterized by an acute or subacute appearance, often asymmetric, often painful, onset with an upper extremity preference and severe sensory loss resulting in ataxia and often pseudo-athethosis. Rarely pruritus can be the first symptom [177]. In clinical descriptions and series, SSNs are sometimes confounded with sensory neuropathies. The most often associated antibodies are anti-Hu [178], and the most frequent cancer is SCLC, although all several cancers have been described [179], [180]. Once SSN has developed, it remains usually in a plateau phase and rarely improves. A Cochrane review

ACCEPTED MANUSCRIPT failed to disclose therapeutic options [181], a possible therapeutic window of treatment however has been suggested [182].

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Sensorimotor neuropathies are the most frequently observed type of neuropathy in adults with cancer. In a large epidemiological study of sensorimotor neuropathy [183] paraneoplastic neuropathy is not specifically mentioned. Most likely this will fit into „neuropathy with systemic disease“, which occurs in around 5 %. Other causes such as concomitant diabetes or toxicity, are often identified. Several observations describe sensorimotor neuropathies in association with onconeuronal antibodies [184].

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Inflammatory neuropathies (AIDP, CIDP) The association of AIDP and cancer is a matter of debate [7], several individual cases have been described [185]. CIDP can occur in association with plasma cell dyscrasia, hematological malignancies such as NHL and HD [186] and some of these presentations may be characterized as dysimmune neuropathies. Also, other demyelinating neuropathies have been described in association with other antibodies [187]. The Miller-Fisher syndrome is rare in cancer [188]. Vasculitic neuropathies have been described in individual cases [189, 190], [191].

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Autonomic neuropathy Autoimmune autonomic ganglionopathy and chronic intestinal pseudo-obstruction, can be associated with cancer [192]. Autonomic dysfunction can be part of other paraneoplastic syndromes such as SSN and LEMS.

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Diagnosis: the role of autoantibodies in the detection of paraneoplastic neuropathies is increasing [193] , [184], although the most useful and stringent association remain the anti-Hu antibodies in association with small cell lung cancer (SCLC) and SSN [184].

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Treatment: to assess the effects of treatment on paraneoplastic neuropathies is difficult due to several confounding factors such as different cancer types, lack of homogenous classification and small series and often individual observations. An attempt has been made with a Cochrane review, [181]. However in typical clinical syndromes such as AIDP and CIDP, as well as vasculitis, the conventional therapies should be used. Toxic neuropathies Toxic neuropathies have become a dose-limiting factor in cancer therapy. In addition to acute and cumulative effects, increasingly late toxicity is becoming an issue.

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Table 3: Chemotherapy-induced neuropathy, a summary of types of neuropathies and practical issues.

Acute toxicity occurs in oxaliplatin treatment. It can appear at the first exposure and is a cold-induced painful neuropathy often associated with muscle-cramps. The mechanism is different than from cumulative neurotoxicity and is caused by impaired neuronal calcium sensitive voltage-gated sodium channels [194]. Chronic cumulative toxicity [195], [196], [197] The most frequent type of CIPN is the cumulative type. For most drugs a cumulative dose is known, though predictors of susceptibility are still debated [198] . CIPN usually occurs after the 3rd or 4th cycle. Individual susceptibility plays a role and has not been clearly defined. The role of preexisting neuropathies, in particular diabetes, alcohol, hereditary neuropathies or previous pretreatments with chemotherapy, are not resolved. Usually axonal damage is observed, demyelinating neuropathies are observed with suramin treatment and also eribulin [199]. Table 4 differentiates between acute and chronic toxicity, however also late effects, and drug specific effects need to be considered. In addition to the classic drugs [195], [200],

ACCEPTED MANUSCRIPT [197], also more newly developed agents have neurotoxic potential [201], [202],[203], [204], [205].

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Clinically CIPNs in predominately an axonal sensory neuropathy, and a range from sensory symptoms to sensory ataxia is observed, which can also be painful. Motor and CN symptoms as well as autonomic symptoms are less frequent [206].

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Table 4: Chemotherapy induced neuropathy: types and other effects. This table describes acute, cumulative, late effects and other effects. Late effects have been described for vinca alkaloids, platinum drugs and paclitaxel. For several drugs the present evidence is not clear (n.c.). The evidence of late effects in Thalidomide, lenalodomide and bortezomib may be difficult to asses as multiple myeloma is more frequent in an elderly population, and “long term effects” may be obscured by multimorbidity. “No” in the table indicates that no evidence was found.

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Coasting Coasting is a phenomenon, which is characteristic for cisplatin neuropathies. It describes an increase of symptoms after termination of chemotherapy and can be disconcerting for both patients and their caregivers [196] . It occurs after the termination of chemotherapy and lasts up to 2 or 3 months and is self-terminating.

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Late effects Increasingly in long term survivors late toxicity is described presenting with sensory symptoms, pain [207], [208], clumsiness and often Raynaud`s [209] syndrome. Several drugs such as vincristine [210], [211] paclitaxel, vincristine [212] and oxaliplatin have been described in association with late toxicity.

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Immune-mediated Several immune mediated neuropathies have been termed „dysimmune neuropathies“ appearing in lymphoma and HD [174].

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In addition immune mediated neuropathies can appear with alemtuzumab [213], rituximab, carfilomib [214], [215] and immune check point inhibitors such as vemurafenib [216] .

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Presently the literature on the neurological side effects of immune modulators and immune check point inhibitors is still small. Also the drugs are less used frequently than conventional chemotherapy.

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Small fiber neuropathy Neuropathy has not been often described in the context of CIPN. It has been implicated in taxanes [217], [218] and possibly bortezomib [219], [220]. Rarely erythromelalgia has been described as a paraneoplastic syndrome [221]. Also in Waldenstroem`s associated small fiber neuropathies have been described [222]. Paraproteinenemic neuropathies [223], [224] Paraproteinemic neuropathies cover a wide range of presentations. MGUS is the most frequent appearance and patients need to be monitored regularly. In particular IgM paraproteinemia has a higher association with neuropathy. The association with myelin associated protein (MAG) causes a more specific sensory - ataxic syndrome and often painful neuropathy. MM, POEMS syndrome, Waldenstroem’s disease [225] Castleman’s disease and some types of lymphoma can be associated with paraproteinemia. Primary amyloidosis can occur in hematological diseases and is characterized by often sensory and autonomic features. POEMS syndrome POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasmaproliferative disorder, skin changes), also known as Crow-Fukase Syndrome or Takatsuki disease can present with a severe neuropathy developing into quadraparesis. The onset is marked by

ACCEPTED MANUSCRIPT distal sensory loss. CNs are usually not involved. Motor neuropathy has also been described in POEMS [226].

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Frequently osteosclerotic myeloma and paraproteinemia appears, and usually IgG or IgA λ light chain is found. VEGF is elevated in the serum and normal in the CSF, pro inflammatory cytokines such as TNF alpha can be up-regulated. CSF protein is elevated.

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The underlying tumor needs treatment [227] and also successful improvement of quadruparesis has been described [228]. Amyloidosis can be associated [229]. In addition, as in all hematologic conditions, neurotoxicity of treatment, has to be considered as a differential diagnosis.

Paraproteinemic neuropathies

neuropathy Sublinical ,

MGUS and anti MAG abs

Antibodies

Treatment

IgM, IgG and IgA

Debated for MGUS and sensorimotor neuropathy.

like

If CIDP like, similar to

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sensorimotor, rarely CIDP

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MGUS

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Characteristics of

Sensory more than

CIDP treatment. IgM anti MAG antibodies

attempts.

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motor, often painful

Multiple myeloma (MM)

Individual therapeutic Symptomatic treatment, Rituximab optional

Distal, sensorimotor

Treatment of myeloma-

symmetric neuropathies.

treatment often involves

Focal neuropathies as

neurotoxic drugs

CTS. Rarely: amyloid POEMS-syndrome

CIDP or other

IgG

manifestations,

Treatment of POEMS syndrome

Papilledema, autonomic features Waldenström`s disease

Large fiber ataxic

MAG, GMI, sulfatide,

Treatment of

neuropathy

GD1a, or GD1b.

Waldenström`s disease

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Several types of

Cryoglobulinema can be

Treatment of lymphoma

paraprotein associated

associated

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Table 5 Paraproteinemic neuropathies.

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Mononeuropathies Contrary to polyneuropathies, mononeuropathies are most frequently inflicted by mechanical damage, often by surgical procedures. Tumor spread, infiltration of surrounding tissue , rarely metastasis into peripheral nerves [230] and focal or intra-nerval hemorrhages are other causes. Toxic mononeuropathies have been described in vinca-alkaloids.

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Neoplastic Neoplastic involvement of individual nerves is rare. Rarely metastasis [230] , but also lymphoma and leukemia can infiltrate into individual nerves [231], [232], [233], [234]. Focal myelosarcomas affecting peripheral nerves („chloromas“) have been described [235], [236]. Also adjacent tumors can infiltrate into peripheral nerves [237], [238]. Mononeuropathies can also appear within a multiplex neuropathy in neoplastic conditions such as neurolymphomatosis or neuroleukemiosis [239, 240]. [241], [242]). Pseudotumors of peripheral nerves occur rarely [243], [244], [245], [246]. Surgical and mechanic Damage to individual nerves is the most frequent cause of CN lesions. This can be due to operative interventions on sites or due to postural pressure during interventions. Weight loss seems to increase the likelihood for focal nerve damage. Not only can sensorimotor deficits occur,( depending on the nerve involved), but also local neuropathic pain syndromes can be a serious problem for patients. An example is the intercostobrachial nerve, which can be damaged in breast cancer axillary surgery [247]. Surgical damage and rein nervation can produce involuntary movements such as in the „jumping breast“ after latissimus doors flap in breast reconstruction [248]. Hemorrhage Hemorrhage into peripheral nerves is often a neglected topic [249] , but can occur in coagulation disorders [250], in idiopathic thromobocytopenic purpura [251] and in cancer and in bone

ACCEPTED MANUSCRIPT marrow transplant procedures [252]. Focal hematomas in the psoas and iliac muscle have distinct clinical presentations.

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Radiation therapy (RT) Radiation of peripheral nerves results in RT fibrosis, [94]. A new term called „radiation fibrosis syndrome“ suggests that nerve and muscle can suffer permanent damage from RT. RT can be the cause of chronic neuropathic pain syndromes. Examples are phrenic nerve lesions after RT [253], [228]. In addition RT induced tumors [254] can occur in peripheral nerves.

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Toxic Chemotherapy induced mononeuropathies and also CN lesions, have been documented in vincristine treatment [255]. Chemotherapy induced mononeuropathies are rare. Phrenic nerve lesion from thalidomide treatment has been described [256].

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Metabolic and endocrine Anti-estrogen treatment (tamoxifen) and anti-aromatase inhibitors are associated with a higher incidence of carpal tunnel syndrome [257], [258], [259]. There is an ongoing controversy if the drugs tamoxifen and other aromatase inhibitors per se or lymphedema [260] [261] are the cause of CTS. Growth hormone treatment can also cause CTS [262] Amyloid deposition can occur as local amyloidomas and induce nerve compression [263].

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Paraneoplastic/immune Paraneoplastic involvement of individual nerves has been described, usually as case reports. They are usually not considered in the classical paraneoplastic syndromes [264]. In graft versus host disease (GVHD) multiple entrapment syndromes have been described [265].

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Infections Herpes Zoster is the most relevant infection of peripheral nerves in cancer. In addition to the sensory involvement but increasingly also motor involvement is described [266]. The risk for cancer after Herpes in the elderly seems lower than assumed [267]. Infections associated with sepsis can result critical illness neuropathy [268].

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Table 6 Involvement of peripheral nerves in cancer patients (direct cancer effect, therapy-related and other causes). ENT: ear nose and throat, RT: radiotherapy, ICU: intensive care unit, Any nerve that is surgically damaged can develop painful neuroma as a late effect. Rarely, radiation can induce malignant nerve sheath tumors.

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Neuromuscular Transmission (NMT) Disorders of neuromuscular transmission are conventionally grouped into pre- and postsynaptic types [269], [270].

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Myasthenia gravis (MG) is observed in association with thymoma, and usually not in association with other tumors, although single observations exist. MG as an autoimmune disease, has appeared during graft-versus-host disease, and possibly also during treatment with immune modifying therapies.

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Lambert Eaton (LE) syndrome is a presynaptic disorder caused by antibodies against the VGCC. It is „paraneoplastic „ in about half of the cases. In cancer it appears in association with lung cancer (SCLC) and is characterized by minor CN dysfunction, proximal weakness and autonomic features. Reflexes are often absent and can be facilitated [269].

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A third type of pathology is neuromyotonia, caused by potassium channel antibodies in the presynaptic region. In addition to neuromyotonia, these patients often have autonomic dysfunction.

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Neuromuscular Transmission Disorders Autoimmune disorders of the neuromuscular junction include Lambert Eaton myasthenic syndrome (LEMS), neuromyotonia and MG, all of which can occur as prototypical paraneoplastic disorders with defined antibodies.

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Lambert Eaton myasthenic Syndrom (LEMS) Typical clinical features of LEMS are proximal weakness, areflexia and autonomic dysfunction. LEMS is a rare disorder with an incidence of 0.48 – 0.75 / 1.000.000 [270] and about 50-60% of patients with LEMS have an underlying tumor, mostly a SCLC. An association with other tumors is extremely rare but has been reported, e.g. with prostate cancer [271]. Clinically, paraneoplastic and non-tumorous LEMS are indistinguishable, although the DELTA-P Score calculates the probability of SCLC in a patient with LEMS [272]. Besides clinical clues, the diagnosis rests upon electrodiagnostic studies and antibody testing. Nerve conduction studies show low amplitude compound motor action potentials following a single supramaximal stimulation, a decremental response during low-frequency stimulation (3 Hz) and an incremental response during 30 Hz stimulation or following a 10s maximum voluntary contraction [273]. Highly specific for LEMS are antibodies to the P/Q type VGKC, which are found in 85-90% of patients. Antibodies against SOX1 strongly suggest SCLC as they are present in 65% of SCLC-LEMS but only in 5% of non-tumorous LEMS [270]. Treatment of the cancer frequently also improves LEMS. When additional treatment is necessary, 3,4-diaminopyridine is the first choice of symptomatic treatment. The addition of pyridostigmine can help. When treatment response is incomplete, prednisone and azathioprine can be added. Additional immunosuppression with rituximab, plasma exchange and IVIg is rarely necessary.

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Neuromyotonia Neuromyotonia (NMT), or Isaac syndrome, is a peripheral nerve hyperexcitability disorder characterized by muscle stiffness, cramps, fasciculations, myokymia and hyperhidrosis [274], [275], [276] [277]. The combination of neuromyotonia with dysautonomia, insomnia, and signs of encephalopathy such as personality changes, hallucinations and disorientation has been called Morvan syndrome [275]. Rarely, NMT can co-occur with myasthenia and vice versa [278]. Needle EMG recordings typically show high-frequency neuromyotonic discharges, douplets, triplets and multiplets and myokymic discharges [274], [279] NMT and Morvan syndrome can be associated with cancer in up to 50% [278].

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The most frequent tumors are thymoma and SCLC, but lymphoma and plasmocytoma with Mprotein have also been reported [280], [281], [282], [283].

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Antibodies found in NMT and Morvan syndrome are not directed directly against VGKC, but against proteins, which form a complex with VGKC, namely CASPR-2 and LGI-1. CASPR-2 antibodies are more frequent than LGI-1 antibodies, which are more common in limbic encephalitis [284]. These antibodies can be found in up to 40% of patients with NMT, and even in up to 80% in NMT with thymoma [281]. The frequency of these antibodies in Morvan syndrome is approximately 80% [275]. First-line treatment is the treatment of the underling tumor and symptomatic treatment with sodium-channel blocking antiepileptic drugs (carbamazepine, phenytoin, valproic acid) is necessary in most cases. Additional immunosuppression, e.g. steroids, IVIg, plasma exchange or rituximab, is usually required in Morvan syndrome [275],[275], [285].

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Myasthenia gravis (MG) The clinical hallmark of MG is use-dependent fluctuating weakness, which primarily affects ocular and bulbar muscles, but also the extremities [286]. Clinically, paraneoplastic and nontumorous types of MG are indistinguishable. Electrophysiological studies reveal the typical findings of a postsynaptic neuromuscular transmission disorder [287]. Thymomas are only found in AChr-MG, not in MuSK- and LRP4-MG and only 3 cases of seronegative MG with thymoma have been reported [288]. In about 20% of AChR-MG a thymoma is found, more frequently at the age of >50 years. On the other hand, a recent study found that 55% of 302 patients with a thymoma had MG [289]. In thymoma, additional antibodies against striated muscle, rhyanodine, and titin are frequently found [290]. However, these antibodies are not very specific for paraneoplastic MG, as all of them, but especially titin-antibodies, are often found in very late onset (>60 years) nontumorous MG [291]. Thymectomy is indicated in thymoma but it is recommended to achieve optimal control of MG before thymectomy is performed to minimize anaesthetic complications [292]. Clinical improvement can occur following thymectomy but appears to be less common than in non-tumorous MG [293].

ACCEPTED MANUSCRIPT Symptomatic treatment is similar to that of non-tumorous MG, with pyridostigmine, steroids and azathioprine being first-line drugs, and an increasing number of second-line immunosuppressive agents such as mycophenolate mofetil, methotrexate, cyclosporine and rituximab [292].

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Muscle Muscle is frequently involved in cancer patients. Most commonly weight loss and cachexia are observed, although the mechanisms are not well defined. Neoplastic involvement is rare; however immune and paraneoplastic myopathies occur more often. Toxic and metabolic myopathies occur rarely.

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Neoplastic Neoplastic involvement of muscle is rare and several predilection sites have been identified [294], [295], [296]. In addition to solid metastases [297], also local continuous infiltration [298] occurs and muscle metastases can present with a hypertrophic [299] muscle. Diffuse muscle involvement in leukemia has been documented, isolated muscle lymphoma is rare [300], [301], [302], [303].

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Surgical and mechanic Surgical procedures in major surgery such as fore- and hindquarter amputations, and transection or sacrifice of important muscle groups can cause important implications for movement and associate with pain. These complex interventions are also of interest in cancer phantom pain, after amputation of cancer-associated parts of the body.

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RT RT of muscle can cause a delayed fibrosis of muscle [304]. An example is mantle field radiation [305]. Also focal calcifications termed myositis ossificans ([306] have been described, as well as the radiation recall syndrome [307], [308] , which affects radiated muscle and resembles the skin radiation recall . Paravertebral muscle damage by RT damage may cause camptocormia [309], also isolated focal RT sites causing „Dropped head syndrome“ [68]. Histologically a nemaline type of myopathy has been described [310]. Clinically, muscles are fibrotic and firm on palpation, associated with weakness. CK is normal. The distribution corresponds with the radiated field. Focal radiation complications of masseteric muscles can cause contractures of jaws, resulting in difficulties with nutrition.

Drug treatment and toxicity Steroids are used for many indications in oncology. Dependent on the type of steroid used and the dose and duration of treatment patients can develop a steroid induced myopathy [311], [312], [313] . This myopathy presents with proximal weakness, and frequently muscle atrophy. Fluorinated steroids are a higher risk for myopathy. Respiratory muscle can be rarely involved [. 314], [315]. Contrary to other types of myopathy, CK is normal and EMG changes are infrequent. The individual susceptibility to steroid side effects varies, however with daily dexamethasone doses of 16 mg, thigh weakness usually appears in 2-3 weeks of continuous treatment.

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Other cancer drugs can rarely induce myopathic syndromes including doxorubicine [316], taxanes [317], gemcitabine [318] and vincristine [319]. Transretinoic acid used in leukemia can cause a myositis like syndrome [320]. Isolated diaphragmatic weakness has been reported as an effect of chemotherapy [ 321]. Inflammatory changes were observed in ipimilumab therapy [322].

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Ischemic myopathies can occur in preradiated areas following chemotherapy [323], [324].

Table 7 Drugs and myopathy

Metabolic and endocrine Muscle weakness can be a feature of metabolic disturbances, such as electrolyte changes, and resulting from paraendocrine ACTH production [325] and Cushing’s syndrome. Hypercalciaemia can be associated with muscle weakness and can occur in conjunction with bone metastases or as a paraendocrine effect [326]. Amyloid deposition resulting in muscle hypertrophy and weakness has been described as a rare syndrome [327], [328], [329], [330]. Paraneoplastic/immune mediated

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Inflammatory: Dermatomyositis (DM), Polymyositis (PM) and immune-mediated necrotizing myopathies can appear in the context of cancer. Most frequently DM is observed in adults, and a search for a paraneoplastic course is warranted. The occurrence of PM in association with cancer is less clear. Necrotizing myopathies are increasingly described. [331], [332]. Necrotizing myopathy can present with a polymyositis like appearance, high CK, and proximal weakness. NM has been observed in various conditions, including cancer [333]. Several other types of muscle involvement such as type 2 fiber atrophy and carcinomatose neuromyopathy, have been observed. The latter is not well defined, and has been included in the older terminology, with little clinical relevance. A possible association with polymyalgia rheumatica has been suggested [334] but is not generally accepted.

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Graft versus host disease (GVhD) GVhD can be associated with immune neuropathies and myopathies and fasciitis [335]. Myositis in association with GVhD has been described [336], [337]. This complication can be expected with an increasing frequency of bone marrow (BMT) and stem cell trans-plantations.

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Other muscle conditions in cancer Rhabdomyolysis has been observed in gemcitabine treatment [338] and with cyclophosphamide [339], compartment syndromes in leukemia [340], and orbital myositis [341] .

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„Polymyalgia rheumatica” has been described in ipimilumab treatment [342], [343], [334] . Also trismus in ovarian cancer [344] have been observed in individual cases. Also rheumatoid pain in cancer [345], [346] has been described.

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Cachexia Loss of muscle volume is a frequent occurrence in cancer patients [347] , [348], [349]. In comparison to the frequency of cancer cachexia relatively little attention in regard to pathogenetic causes is made. This is attracting more attention as prevention of cachexia is supposed to be a predictive factor for cancer treatment and survival. Cachexia is a general muscle atrophy; also the diaphragm muscles can be involved [350]. Drugs have been suspected to increase cachexia [351]. Conversely, women with breast cancer can have weight gain, produced by an in crease of fat in the lower trunk and lower extremities [352]. These anti gravity muscles have an important role for stability, stance and gait. In addition with sensory loss, e.g. by chemotherapy the danger of falls increases in cachectic patients, which makes the prevention older persons necessary [353], [354]. Several strategies to treat cachexia are being developed [348], [355], [349], [356].

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Bone marrow transplantation (BMT) and stem cell- transplantation

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Bone marrow transplantation BMT a treatment used for the hematological tumors and treatment and other cancers. Side effects from chemotherapy, RT, infections and immune dysregulations due to GVHD are observed. GVHD can be associated with several neuromuscular complications of muscle (myositis) [357], disordered neuromuscular transmission (MG) [358] and neuropathies such as GBS and CIDP [359]. In al logeneic transplantations these complications are more frequent.

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Cancer Pain and the NM system

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Hematopoietic stem cell transplantation is used in the treatment of hematological malignancies. Also the these patients receive chemotherapy, and RT and can suffer the same toxicities and risk for infections as BMT Chronic GVHD can develop in the further course, and is associated with autoimmune neuromuscular disease such as DM, PM [360], MG and sensorimotor as well as autoimmune neuropathies [361], [362], [363].

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Cancer pain is an important issue which involves several types of pain as well as mechanisms and sites of involvement [364]. Involvement of the PNS at various sites can be the leading symptom of cancer pain. Increasingly sequelae of chemotherapy (CIPN) are observed [365], in particular in long term survivors. The table 8, serves as an overview on the types of cancer pain syndromes. The general treatment of cancer pain is beyond the scope of this review [ 366], [367], [368], [369]. For cancer pain in the peripheral nervous system, the concept of treatment of neuropathic pain is usually applied. This is primarily based on anticonvulsants, and antidepressants, but topical treatments and opioids are also used in addition to several other methods. Radiation and also anti tumor therapy is used in focal neoplastic conditions. In addition, physical medicine (e.g. temperature) and physiotherapy are often applied. Chronic pain syndromes are increasingly described as long-term effects, in cancer survivors [370]. These are predominately neuropathic pain syndromes in neuropathies, associated with other peripheral signs such as sensory disturbance, and coordination impairment. Pain in cancer survivors is the subject of several reviews [371], [372], [373], [374], [208].

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Table 8 (Cancer pain) The table correlates the affected structures with neoplastic and other causes.

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In addition to regional lesions [375] focal nerve lesions and neuropathies other painful conditions such as Raynaud`s syndrome ( in association with CIPN ), rheumatoid pain sometimes due to chemotherapy and possibly polymyalgia rheumatica have been associated with cancer pain [345], [346].

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Hand and foot syndrome is classified into several stages [376], and can be mistaken for neuropathy. Skin changes and pain are the diagnostic features. It is often associated with capecitabine treatment [377], and lipophilic doxyrubicin but can occur with several other types of chemotherapy.

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A particular type of pain which may be overlooked is „phantom pain“, which has been observed after amputations of the breast [378], [379], lung, penis, rectum [380] and eye. Also severe pain conditions occur after fore- and hindquarter amputations [381].

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Summary Neurologists are important in the management and treatment of patients with systemic cancer. In the PNS a large number of differential diagnoses have to be evaluated, and treatment of neuromuscular symptoms and signs needs different approaches, depending on the etiology of the lesion. As the spectrum of tumor therapies broadens the pathogenetic mechanisms vary. The success of several tumor therapies have increased the number of long term survivors, who may also suffer from previously unknown long term toxicity.

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