Paraneoplastic motor neuron disease

Clinical Neurophysiology of Motor Neuron Diseases Handbook of Clinical Neurophysiology, Vol. 4 A. Eisen (Ed.) q 2004 Elsevier B.V. All rights reserved

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CHAPTER 33

Paraneoplastic motor neuron disease Eduardo Nobile-Orazioa,* and Alberto Cappellarib a

“Giorgio Spagnol” Service of Clinical Neuroimmunology, Centro Dino Ferrari, Department of Neurological Sciences, University of Milan, IRCCS Ospedale Maggiore Policlinico and Humanitas Clinical Institute, 20089 Rozzano, Milan, Italy b Service of Clinical Neurophysiology, Centro Dino Ferrari, University of Milan, IRCCS Ospedale Maggiore Policlinico, 20122 Milan, Italy

33.1. Introduction: paraneoplastic syndromes Paraneoplastic neurological syndromes are a group of disorders which most often, though not invariably, present in association with malignancies and which are not due to metastatic invasion of neural tissue, side effect of radiation therapy or chemotherapy, metabolic, vascular and hormonal disturbances or opportunistic infections (recently reviewed by Darnell and Posner, 2003). Even if any neurological diseases may occur in patients who also have cancer, the term paraneoplastic syndromes is currently reserved for those diseases, which more frequently occur in patients with cancer than in those without it. The list of these syndromes has greatly expanded in the last few years and now include diseases affecting the central and peripheral nervous system as well as the neuromuscular junction and skeletal muscle (Table 1). The pathogenetic mechanism of these “remote effects of cancer” is still incompletely known but is supposed to be related to an immune response to antigen(s) also present in neural tissues (Voltz, 2002). This hypothesis has been reinforced by the frequent occurrence in paraneoplastic syndromes of a number of antibodies directed against antigens shared by the affected neural tissue and specific cancer and encompassed under the term of anti-onconeural antibodies. Overall, these are rare disorders affecting perhaps 0.01% of patients with cancer (Darnell and Posner, 2003) in whom they account for 1% of * Correspondence to: Eduardo Nobile-Orazio, Department of Neurological Sciences, University of Milan, Humanitas Clinical Institute, Via Manzoni 56, 20089 Rozzano, Milan, Italy. E-mail address: [email protected] (E. NobileOrazio). Tel.: þ39-0282242209; fax: þ 39-0282242298.

neurological manifestations (Clouston et al., 1992). Nevertheless, identification of a neurological disorder as paraneoplastic is important because it may lead to the early detection, and treatment of the tumor, which is still the most effective treatment for the neurological disease. At the same time it is necessary to establish which syndromes are truly paraneoplastic, to avoid widespread unnecessary and costly investigation (and aggressive therapies) in patients with disease of unknown etiology. Several studies have addressed the possible clinical and pathogenetic relevance of the association of amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND), with various neoplasms such as cancer, lymphoma or monoclonal gammopathies or with the presence in patients’ sera of anti-onconeural antibodies usually associated with paraneoplastic disease. The hypothesis of the existence of paraneoplastic MND was reinforced by the occasional report of MND patients responding to cytostatic therapies or tumor removal. The aim of this review is to verify whether available data on the association of MND with cancer, lymphoma, plasma cell dyscrasia, or anti-onconeural antibodies provide enough evidence to support the concept of paraneoplastic MND which would justify the use in these patients of an aggressive therapeutic approach to the underlying neoplasm in order to improve their MND.

33.2. MND and cancer The hypothesis of a possible association of MND with cancer was supported by some controversial reports on the increased frequency of cancer in patients with MND, the association of some types of cancer with particular MND presentations, the

570 Table 1 Paraneoplastic neurological syndromes. Central nervous system Encephalomyelitis: Limbic encephalitis Brain-stem encephalitis Subacute cerebellar degeneration Opsoclonus-myoclonus Cancer-associated retinopathy Necrotizing myelopathy Subacute motor neuronopathy Stiff-person syndrome Peripheral nervous system Subacute sensory neuronopathy Autonomic neuronopathy Vasculitic neuropathy Neuromyotonia Neuromuscular junction and muscle Lambert –Eaton myastenic syndrome Myastenia gravis Acute necrotizing myopathy Dermatomyositis (polymiositis?) Entries in italics, disease with an increased frequency of cancer but most frequently occurring in the absence of it. (Adapted from Darnell and Posner, 2003.)

frequent motoneuronal involvement in paraneoplastic encephalomyelitis (PEM), the occasional findings in MND of the same anti-neural antibodies found in other paraneoplastic disorders, and, last but not least, by the occasional response of MND patients to cancer therapy. 33.2.1. History and prevalence Wechsler et al. (1944) were probably the first to highlight the association of cancer and MND by reporting a patient with MND and pancreatic carcinoma among a total of 81 MND patients, introducing the concept of symptomatic MND in contradistinction to primary MND. It was, however, Lord Brain who first draw attention to the association between MND and cancer raising the issue of “carcinomatous” MND (Brain et al., 1965). The authors had enucleated this entity from a larger series of patients with cancer affected by various neurological diseases encompassed under the term of carcinomatous neuromyopathy, a condition that they

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found to occur in 96 patients (6.5%) out of 1465 patients with cancer neurologically examined over a period of 4 years (Croft and Wilkinson, 1965). Only three of these patients had features of MND, corresponding to a prevalence of MND in patients with cancer of 200 for 100,000 which is almost 30 times higher than that estimated in the general population. These three patients together with eight additional patients with the same association observed by the authors during the same period were the object of the seminal paper by Brain et al. (1965) on a total of 11 patients with MND who also had cancer of the lung (5 patients), breast (3), stomach (2) and sarcoma of the ileum. Even if the clinical presentation of the patients was consistent with MND, all patients had, compared to a concomitant series of MND patients without cancer, a slow progression of the disease. In addition, both patients undergoing autopsy showed some unusual findings for MND including a complete or relative sparing of upper motor neurons and a concomitant impairment of dorsal roots and column. These unusual features lead the authors to postulate that this association was not merely casual and that patients with an unusually slow progression of MND should be investigated for the presence of cancer. Several studies have been conducted on the prevalence of cancer among patients with MND with controversial results. Norris and Engel (1965) reported for instance that 13 of their 130 patients with MND had a malignancy, which was mostly diagnosed within 1 year of MND diagnosis, corresponding to a prevalence of 10%. In contrast, Shy and Silverstein (1965) found that the prevalence of cancer in MND (4.6%) did not differ significantly from that expected in the normal population. Similar results were obtained from several case – control studies (Juergens et al., 1980; Kurtzke and Beebe, 1980; Bharucha et al., 1983; Leone et al., 1987; Zisfein and Caroscio, 1988; Norris et al., 1989) in different countries published in the 1980s and by two systematic reviews on the incidence of cancer in MND (Barron and Rodichok, 1982; Rosenfeld and Posner, 1991). At odds with these findings, Gubbay et al. (1985) found that the prevalence of malignancy in MND in a population based study in Israel was 3.8% or even 7.2% when patients with some atypical features for MND were also included, compared to 2.4% in the general population. These results were not, however, confirmed in a subsequent population based study in

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Italy, that showed that even if the prevalence of cancer in patients with MND tended to be higher then previously reported (5.8%) it was not significantly higher than the expected prevalence of cancer in the general population (Chio` et al., 1988). It seems, therefore, that with the exception of only few studies, the prevalence of cancer is not increased in patients with MND making it unlikely that cancer is a risk factor for MND. 33.2.2. Association of some types of cancer with particular MND presentations If epidemiological studies provided little support for a pathogenic link between MND and malignancies in general, more recent studies draw attention to the possibility that specific forms of MND may be associated with particular cancers. The presence of these should therefore be investigated in patients with these clinical phenotypes of MND. These associations have been particularly emphasized for patients with MND and lymphoma or other monoclonal gammopathy, reviewed below. As already mentioned, Brain et al. (1965) reported that all their patients with MND and cancer had a relatively slow progression of MND compared to those without it, but did not find any significant difference between the two groups in term of clinical presentation. More recently Forsyth et al. (1997) reported five women who presented, at least at onset, with a predominantly upper motor neuron form of MND resembling primary lateral sclerosis (PLS) in close temporal association with the diagnosis or recurrence of breast cancer. Two of these patients ultimately developed lower motor neuron signs therefore proving to have ALS while none responded to cancer therapy. These observations led the author to hypothesize a paraneoplastic origin of the patients’ disorder and to suggest that women with this infrequent clinical presentation of MND should be investigated for breast cancer. The relevance of this association is, however, challenged by the fact that most reported patients with breast cancer and MND, including some with antibodies to neural antigens (see below), had different clinical presentation including LMNS and typical ALS, and that none of them consistently responded to cancer therapy (Hays et al., 1994; Rowland, 1997; Ferracci et al., 1999; Vigliani et al., 2000). In addition, in a recent survey of 49 patients with paraneoplastic syndromes and breast cancer the only two patients reported to have MND

had ALS (Rojas-Marcos et al., 2003). A case – control or population study is necessary to further clarify the significance of this association (Rowland, 1997); thus far there is insufficient evidence to support the hypothesis that women with PLS have an increased risk of breast cancer (or vice versa) justifying a screen for breast or other cancers in patients with this clinical presentation. Vigliani et al. (2000) reviewed the clinical features of 14 patients with ALS having a variety of tumors including breast (4 patients), lung (3), bowel (3), liver (1) or kidney cancer and mesothelioma, and found no significant difference in their clinical presentation, progression and outcome compared to those of 28 matched sporadic ALS patients without cancer. The data indicates that there is so far little evidence that MND in patients with cancer have distinctive features compared to those of classic Charcot ALS without cancer, or that there are features in MND that may suggest the presence of an underlying cancer. 33.2.3. MND, paraneoplastic syndromes and anti-onconeural antibodies The possibility that MND may have a paraneoplastic origin was further reinforced by the observation that motor neuron impairment may occur in the context of more widespread paraneoplastic syndromes. Forsyth et al. (1997), for instance, reported on three patients associated with SCLC or prostate cancer who developed rapidly progressive MND in the context of a less prominent involvement of other areas of the CNS suggestive of PEM. All these patients had indeed the same anti-onconeural antibodies usually associated with PEM or subacute sensory neuronopathy (SSN) in the context of lung carcinoma and variably named anti-Hu antibodies or anti-neuronal nuclei antibody, type (ANNA-1) (Dropcho, 1998). In a previous study on a large series of patients, symptoms or signs of lower motor involvement were reported in over 20% of 71 patients with PEM or SSN (Dalmau et al., 1992) where they were frequently associated with the presence of antiHu onconeuronal antibodies and lung cancer. Similarly, signs of lower motor neuron impairment were reported in two of the eight patients with SSN, SCLC and anti-Hu antibodies reported by Anderson et al. (1988), and in 25% of those with paraneoplastic syndrome and SCLC reported by Furneaux et al. (1990), most of whom had SSN. From all these

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studies it was, however, evident that, even if lower motor neuron involvement in PEM or SSN was sometime prominent, it was seldom, if ever, the only presenting symptoms, being almost invariably associated with features of a more diffuse CNS involvement. The occasional findings in MND of the same antibodies found in other paraneoplastic disorders also lead to the hypothesis that in some patients the disease may be pathogenically related to cancer. Beside the already mentioned presence of these antibodies in patients whose motor neuron impairment is associated with less prominent signs of diffuse central nervous system involvement consistent with PEM or SSN, there have been also occasional reports of patients with typical MND or even ALS bearing these antibodies. Verma et al. (1996) for instance reported a patient with pure MND associated with small cell lung cancer (SCLC) and repeatedly high anti-Hu antibodies. This patient died from respiratory failure after 2.5 years of a relentlessly progressive weakness leaving him bedridden despite immunoand chemotherapy. At autopsy this patient had a widespread loss of anterior horn cells, a slight decrease of Purkinje cells but no evidence of other system impairment including the corticospinal tracts. Even if the only evidence of a possible role of anti-Hu antibodies in the pathogenesis of MND was the presence of IgG immune reactivity in the clinically unaffected Purkinje cells and medullary tegmentum nuclei including the hypoglossal nuclei it is not possible to exclude that the same antibodies caused the widespread loss of anterior horn cells. Other antineuronal antibodies have been also occasionally associated with MND and cancer. Anti-Yo antibodies, usually associated with paraneoplastic cerebellar degeneration in the context of breast or gynecologic cancer, were reported in a 67-year-old woman with ovarian adenocarcinoma and an otherwise typical ALS whose relentless course was not affected by cancer removal (Khwaja et al., 1998). Antibodies to axon initial segments and nodes of Ranvier were found by immunocytochemistry in a 72-year-old woman with breast cancer and a lower motor neuron syndrome (Ferracci et al., 1999). Even if this pattern of staining was similar to that obtained with antisera raised against amphiphysin, another antigen often involved in paraneoplastic syndromes, the patient did not bear anti-amphiphysin antibodies, but was later found to react with bIV spectrin, a

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cytosolic protein which is particularly enriched at axon initial segments and nodes of Ranvier (Berghs et al., 2001). The patient partially improved after cancer removal while immunotherapy had no effect. Several features distinguished the disease of this patient from typical MND including an unusually rapid progression of weakness resulting in a severe areflexic tetra-paresis with facial and bulbar impairment in 3 months, the transient appearance of dizziness and vertigo, the presence of oligoclonal bands in the CSF and of hyper intensities in T2 sequences of cervical spinal cord by MRI. Another patient with ALS, breast cancer and IgA monoclonal gammopathy (see also later) had IgA antibodies to the 200 kDa high-molecular subunit of neurofilament protein and was found at autopsy to have intracellular accumulation of IgA in surviving motor neurons and in large neuritis of ventral horns (Hays et al., 1994). All these observations have prompted extensive though often unrewarding search for anti-neuronal antibodies in patients with MND. In our laboratory for instance we examined the presence of anti-Hu, -Yo and -Ri antibodies by western blot on human Purkinje cell extracts and by indirect immunofluorescence on mouse cerebellum in 64 consecutive MND patients, none of whom proved positive by either method (Nobile-Orazio et al., 2001). Similarly none of the 14 patients with ALS and cancer reported by Vigliani et al. (2000) had anti-onconeural antibodies. Overall, all these observations confirm that the presence of anti-neuronal antibodies are extremely rare in MND and that, even when present, their possible pathogenetic relationship to MND remains elusive. 33.2.4. MND and response to cancer therapy Even if clinical, epidemiological and immunological studies do not seem to support the concept of paraneoplastic MND, there are occasional reports of MND patients with cancer who improved or stabilized after cancer treatment. Two patients with renal adenocarcinoma and MND with only lower motor neuron deficit, improved after cancer removal (Buchanan and Malamud, 1973; Evans et al., 1990). Both patients had lower limb weakness with fasciculation, atrophy, normal reflexes and no Babinski sign, and one also had signs of a concomitant sensorimotor neuropathy (Buchanan and Malamud, 1973). Three patients with a different form of lung cancer

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also improved after cancer removal or irradiation. One of them, included in the series of Brain et al. (1965), had brisk reflexes, Babinski sign, diffuse fasciculations and hand muscle wasting, but no weakness before cancer removal; the improvement consisted in a more stable gait and improved use of his limbs. Prior to therapy he was reported to have had a normal gait and denied any limb disability. He subsequently developed moderate limb weakness upon recurrence of cancer. The other two patients had both lower and probable or definite upper motor neuron signs (Mitchell and Olczak, 1979; Peacock et al., 1979). One patient with thymoma and lower limb weakness, tongue fasciculation, absent reflexes, no Babinski sign and abnormal sensory examination stabilized after surgery (Gerling and Woosley, 1967). The already mentioned patient with breast cancer and anti-spectrin antibody had a very rapidly progressive lower motor neuron syndrome with areflexic tetra paresis, facial and bulbar impairment and unusual hyper intensities on cervical NMR (Ferracci et al., 1999). Her strength rapidly, but incompletely, improved after tumor excision. Overall, only two of these patients fulfilled the diagnosis of ALS while the other had mainly signs of lower motor neuron impairment associated in some patients with unusual features like sensory impairment or very rapid progression. One additional patient in the series of Forsyth et al. (1997) with uterine cancer and ALS was briefly mentioned to have a subjective improvement after cancer irradiation. In contrast to these findings there are many more patients with MND and cancer, including the other four treated patients in the series of Brain et al. (1965) and six in the series of Forsyth (1997), as well as all the other previously mentioned patients with anti-neural reactivity (Hays et al., 1994; Verma et al., 1996; Khwaja et al., 1998) whose MND failed to improve after cancer therapy. In the series of Vigliani et al. (2000), none of the 14 patients with ALS and cancer improved after cancer therapy and their mean survival (18 months) was similar to that of ALS patients without cancer. On the basis of this review and our personal experience we think that patients with typical ALS (MND) should not be investigated for cancer unless there are other pointers suggestive of cancer. Antineural antibodies should be probably tested (and a cancer screen performed) only in MND patients with signs of a more diffuse central nervous system involvement suggesting PEM. Similarly, we think

that, in order to avoid false hope, patients with otherwise typical ALS and cancer should be made aware that therapy for cancer is very unlikely to have any effect on the progression of their disease. 33.3. MND and lymphoproliferative diseases In recent years, several studies have drawn attention to the association of MND with lymphoma and other lymphoproliferative disorders, all characterized by a neoplastic proliferation of lymphocytes or their precursor. This association was initially restricted to a purely lower motor neuron syndrome named subacute motor neuronopathy, whereas in the following years more typical forms of MND were also reported. We will review in this section the forms associated with different forms of lymphoma and other malignant lymphoproliferative disease including macroglobulinemia and myeloma while those associated benign plasma cell dyscrasias will be addressed in the following section. 33.3.1. Subacute motor neuronopathy and lymphoma Rowland and Schneck (1963) first reported two young women who developed a severe progressive quadriparesis with reduced or absent tendon reflexes and normal sensation and cranial nerve function in association with Hodgkin’s lymphoma. Both patients died within 2 years from onset of the disease. Neuropathological examination in both patients revealed severe neuronal degeneration of the anterior horn cells with variable degree of gliosis, associated in both with moderate to severe demyelination of the posterior cord. In one patient, lymphocytic infiltrates of the anterior horns were also present together with demyelination and glial proliferation of adjacent anterior and lateral columns and of proximal nerve segments. A similar case was later reported by Walton et al. (1968), who described a young man with Hodgkin’s lymphoma who developed a rapidly progressive asymmetrical quadriparesis with fasciculation, wasting, reduced reflexes and normal sensation. The patient died 3 months after the onset of neurological symptoms. At autopsy, features reminiscent of acute anterior poliomyelitis were found with severe neuronal loss and degeneration in the anterior horns where gliosis, lymphocytic infiltration and virus like particles were also found by electron microscopy. Also in these cases there was some

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demyelination of dorsal column together with neuronal loss in the posterior horns. Schold et al. (1979) reviewed these cases and reported 10 additional patients with a subacute lower motor neuron syndrome and lymphoma, which they collected under the diagnosis of subacute motor neuronopathy. The disease was characterized by a subacute, progressive, asymmetric pure lower motor neuron weakness mainly affecting the lower limbs, sometimes associated with minimal sensory impairment. It most often presented a few months up to 6 years after the diagnosis of lymphoma, but at time heralded this diagnosis. All these patients had Hodgkin’s or non-Hodgkin’s lymphoma although a similar presentation had been reported in patients with oat cell carcinoma (Case Records of the Massachusetts General Hospital, 1970) or thymoma (Stoll et al., 1984). The disease stabilized or even spontaneously improved after a few months or years in seven of the 10 patients reported by Schold et al. (1979), but the progression did not parallel that of lymphoma or respond to any immuno- or chemotherapy. Similar to previously reported cases, neuropathological studies in the two patients undergoing autopsy showed prominent neuronal degeneration in the anterior horn of spinal cord with only mild signs of inflammation, associated with variable degree of demyelination in posterior column, spinal roots and brachial and lumbar plexus. The cause of this syndrome remains unclear. The possible role of radiation therapy seems unlikely as only eight of the 13 initially reported patients received mantle and paraaortic radiotherapy before the onset of neurological disease and it is unusual for post-irradiation motor neuron syndrome or radiculo-myelopathy to spontaneously improve. Alternatively, the presence of a viral particle in one patient and of opportunistic infections in two other patients (Schold et al., 1979) may suggest that an opportunistic infection or new infectious agent caused the two diseases as possibly indicated by the fact that some retrovirus may induce in mice both lymphoma and neuronal loss (Kay et al., 1993). 33.3.2. MND and lymphoma Several cases of typical ALS associated with lymphoma have been reported (Younger et al., 1991; Rubio et al., 1997; Leone and Phillips, 1998),

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prompting several authors to raise the hypothesis that this association might not be merely coincidental but pathogenically related. The prevalence of this association is uncertain and varies according to the methods used to ascertain the presence of lymphoma. Younger et al. (1990) found that two of the 120 MND patients who had performed serum protein electrophoresis or cerebrospinal fluid (CSF) analysis had lymphoma (1.6%), whereas in a subsequent prospective study of bone marrow biopsy two out of 37 patients with MND (5.4%) were found to have lymphoma, including one without paraproteinemia (Rowland et al., 1992). The latter figure was, however, probably overestimated by the fact that the authors interrupted the study after finding the first patient with lymphoma without paraproteinemia after 37 consecutive bone marrow biopsies. A subsequent larger study by the same group (Louis et al., 1996) showed that four of 161 MND patients (2.5%) had lymphoproliferative disease in the marrow, including one who also had a monoclonal gammopathy. These findings initially prompted the authors to suggest including bone marrow biopsy in the workup of MND, but later they proposed to reserve this for patients with either paraproteinemia, high CSF proteins, clinical or laboratory evidence of lymphoproliferative disease or atypical features for MND (Gordon et al., 1997). These conclusions need to be confirmed by case – control or population-based studies as it is not possible to exclude that the high prevalence of lymphoproliferative diseases in the mentioned studies are the results of a selection bias due to the referral in specialized Centers of patients with peculiar features or associated abnormalities (increased CSF proteins, paraproteinemia, etc.). Similarly inconclusive are the studies on the clinical features of MND associated with lymphoproliferative diseases. While earlier studies suggested an association of lymphoma mainly with lower MND, Gordon et al. (1997) in reviewing 56 MND/ALS patients observed at their Center or previously reported in the literature, found that more than half of reported or observed patients had typical ALS with both upper and lower motor neuron impairment while the others had lower motor neuron signs only. A similar proportion was found at autopsy studies. The hematological diagnoses in these patients included Hodgkin’s or non-Hodgkin’s lymphoma, multiple myeloma, Waldenstro¨m macroglobulinemia, and chronic lymphocytic leukemia and were equally distributed in relation to MND presentation. In half

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of the patients, the onset of MND preceded the discovery of a lymphoproliferative disorder that, in most of the patients observed by the authors, was asymptomatic being only revealed by the presence of a circulating paraprotein or increased CSF proteins or, at time, only found by bone marrow biopsy or even autopsy. The issue of the clinical association of lymphoma is further complicated by the fact that the clinical distinction in vivo between MND and motor neuropathy may not always be easy as illustrated by the reports of patients clinically presenting with symptoms and signs consistent with the diagnosis of a rapidly progressive and ultimately fatal lower MND associated with macroglobulinemia which proved at autopsy not to have MND but a proximal predominantly motor radiculo-neuropathy (Rowland et al., 1982) or a proximal motor axonopathy with lymphocytic infiltration of ventral roots (Parry et al., 1986). The presence of reduced conduction velocities might have suggested the correct diagnosis in the first patient, but not in the second one who had low amplitude motor responses with normal conduction velocities. If the prevalence and clinical features of MND associated with lymphoma associated remain unclear, even less convincing are the effects on MND of the treatment for lymphoma in these patients. In their review, Gordon et al. (1997) reported that only five of the 42 reported patients who had been treated for lymphoma, improved or stabilized after these treatments. All but one responding patients had, however, motor neuropathy (Younger et al., 1991) or lower MND, including one patient reported before nerve conduction studies (NCS) for conduction blocks were available (Peters and Clatanoff, 1968) but whose clinical features might have been consistent with the diagnosis of multifocal motor neuropathy (NobileOrazio, 2001). The fact that only one patient responding to lymphoma therapy had signs of both upper and lower motor neuron impairment (Norris and Engel, 1965), indicates that it is very unlikely for patients with typical MND to benefit from therapy of concomitant lymphoma. In conclusion available data may at best suggest that the association of MND with lymphoma is more than coincidental leading some authors to hypothesize there is a common etiology for the two disorders (Younger et al., 1991). Still, there is little evidence that this association has any pathogenic relevance in terms of considering MND a “remote effect” of

lymphoma. Until more convincing evidence is provided we do not think it is justified to submit patients with typical ALS to bone marrow biopsy in the search of an associated lymphoproliferative disorder or to submit them to toxic therapeutic regimens unless these are required by their hematological diseases. 33.4. MND and monoclonal gammopathy of undetermined significance A closely related issue is that of MND/ALS associated with benign plasma cell dyscrasia or monoclonal gammopathy of undetermined significance (MGUS), with the main difference that this hematological condition is benign and does not require treatment per se. This implies that treatment directed at reducing circulating levels of the monoclonal proteins (M-proteins or paraproteins) in MND/ALS patients with this associated conditions are only directed at curing MND/ALS. The prevalence of monoclonal gammopathy in patients with MND has been first examined by Shy et al. (1986) who found it in 10 of 206 (4.8%) consecutive patients with MND in whom serum protein electrophoresis had been performed compared to only one of 100 (1%) patients with other neurological diseases. This figure was also higher than the expected prevalence of monoclonal gammopathy in their MND series (0.8%) derived from population studies. Of the 10 patients with MND and monoclonal gammopathy, three had ALS, one had progressive bulbar palsy (PBP) and six had lower MND. The preferential association of monoclonal gammopathy with lower MND was not, however, confirmed in their review of 21 previously reported patients, most of whom had either ALS or PBP. Using a more sensitive method to detect serum M-proteins (immunofixation), Younger et al. (1990) reported that the prevalence of monoclonal gammopathy among 120 MND patients attained 9%; but, no control population was examined in that study. All but one patient with monoclonal gammopathy in the series had ALS with definite or probable upper motor neuron signs. Similarly high figures were subsequently reported by Sanders et al. (1993) and by Lavrnic et al. (1995), who found a prevalence of 8.6% among 110 patients and 9.6% among 52 patients, respectively. All the patients with monoclonal gammopathy in the first study had ALS while in the second one, two had ALS and three had

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lower MND. Using a more sensitive Western blot technique, Duarte et al. (1991) found that 18 (60%) of 30 consecutive ALS patients had one or more serum monoclonal immunoglobulins, mostly IgG, compared to four (13.3%) of 30 matched controls. All but two ALS patients examined, including 17 with monoclonal immunoglobulins, had both upper and lower motor neuron signs including Babinski sign while two, including one with monoclonal immunoglobulins, had lower motor neuron signs with brisk reflexes but no Babinski sign. These figures were not, however, confirmed in a population based case –control study of MND in Scotland which showed that the prevalence of monoclonal gammopathy by agarose gel electrophoresis followed by immunofixation was similar in MND patients (1.2%) and in age and sex matched community controls (2.4%) (Willison et al., 1993). These figures increased in the two groups to 28% and 27%, respectively, when a more sensitive isoelectrofocusing and immunoblotting method was used. From these studies it appears, therefore, that not only the data on the increased prevalence of monoclonal gammopathy is at least questionable, but also that this association is not restricted or prevalent for a specific presentation or form of MND as also indicated by the recent report of a patient in whom IgM paraproteinemia was associated with PLS (Desai and Swash, 1999). The possible role of monoclonal gammopathy in the pathogenesis of MND was, however, sustained by the reports of a number of patients with various forms of MND and monoclonal gammopathy who had the same anti-neural IgM antibodies found in some dysimmune neuropathies including anti-GM1 (Latov et al., 1988; Nardelli et al., 1988; Nobile-Orazio et al., 1990), anti-GD1a (Bollensen et al., 1989; Carpo et al., 1996), anti-MAG or -SGPG (Rowland et al., 1995; Van den Berg et al., 1996), and anti-sulfatide antibodies (Baud et al., 1998). These findings together with the occasional reports of patients with MND or LMNS and monoclonal gammopathy with or without anti-neural reactivity who responded to therapy directed at reducing M-protein levels (Peters and Clatanoff, 1968; Patten, 1984; Parry et al., 1986; Rudnicki et al., 1987; Latov et al., 1988; Bollensen et al., 1989; Younger et al., 1991; Carpo et al., 1996) has led to consider MND patients with monoclonal gammopathy as a separate group from those without it, and to exclude them from trials on non-immune therapies in ALS. Also in this case, however, almost all responding patients had a final diagnosis of motor

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neuropathy, lower motor neuron syndrome or lower MND while in only two of them the diagnosis was possibly consistent with typical ALS (Patten, 1984). We reached similar conclusions analyzing the clinical and immunological features and response to immune therapy in a series of 18 consecutive patients with a pure motor neuron syndrome associated with monoclonal gammopathy (11 IgM, 5 IgG and 2 IgA) including five with typical ALS, six with lower and probable upper motor neuron signs (ALS-PUMNS), two with lower MND, and five with a pure motor neuropathy (MN)(Nobile-Orazio et al. 2001). None of the patients with ALS, ALS-PUMNS or lower MND (including two with high anti-ganglioside antibodies) treated with immune therapies such as plasma exchange, high-dose intravenous immunoglobulins (IVIg), steroids, cyclophosphamide or chlorambucil, alone or in combination, responded to any of these therapies as compared to all those with MN. Even if, similarly to other series, IgM M-proteins were overexpressed in our MND patients with respect to the other Ig isotypes, their therapeutical reduction in patients with typical ALS or MND was not associated with a neurological improvement. Overall, in our opinion, all these findings support at the most a possible pathogenetic association between monoclonal gammopathy and some forms of lower motor neuron syndromes but do not provide enough evidence that this link also stands for typical ALS or MND. We therefore think that patients with otherwise typical ALS or MND and monoclonal gammopathy should not be treated differently from those without monoclonal gammopathy, nor should they be excluded from non-immune therapeutic trials in ALS. In addition, since in these patients the use of chemotherapy is not required because the associated hematological condition is usually benign, it seems premature to expose these patients to a potentially harmful therapy. 33.5. Electrophysiological findings Only few detailed studies are available on the electrophysiological features of MND/ALS associated with cancer, lymphoma or monoclonal gammopathies. More in general these findings are consistent with the final clinical diagnosis of the patients and there is so far little evidence that some electrophysiological features might help distinguishing

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these forms from non-paraneoplastic MND (Dumitru and Amato, 2002). The electrodiagnostic features required by El Escorial criteria for the diagnosis of ALS are reviewed elsewhere in this book. Briefly, they include the presence of (1) fibrillation potentials, (2) chronic neurogenic MUAPs, and (3) reduced MUAP recruitment in two muscles supplied by two different nerve roots and nerves in a limb (World Federation of Neurology Research Group on Neuromuscular Disease El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis, 1994). However, many patients with ALS do not fulfill these criteria and challenge the diagnosis. Sensory NCS are generally normal, although a few patients have some SNAP parameter abnormalities (Williams and Windebank, 1991). In the study of Younger et al. (1991), eight of the nine patients with lymphoma and MND had lower motor neuron signs along with probable or definite upper motor neuron signs, qualifying for the diagnosis of ALS. All these patients had normal NCS and needle EMG consistent with MND. Multifocal conduction blocks were detected in the only patient with a pure lower motor neuron syndrome (resolving after therapy for the lymphoma) and in one patient with ALS syndrome. Eight of these patients were included in a subsequent study by Gordon et al. (1997) on a total of 26 patients with lymphoproliferative disorders and MND selected on the basis of clinical and EMG signs of lower motor neuron dysfunction in at least three limbs, normal NCS, no clinical sensory loss nor isolated bulbar signs. Twenty-three patients were designated as having definite ALS or ALS with probable upper motor neuron signs, and the remaining three were categorized as suffering from progressive spinal muscular atrophy (PSMA). None of the patients had evidence of motor neuropathy at the electrophysiological examination, including proximal NCS to detect conduction blocks. Two subjects, one with ALS and one with PSMA, previously included among patients with multifocal conduction blocks (Younger et al., 1990), were subsequently reassessed by more stringent electrophysiological criteria that ascribed the changes to temporal dispersion and phase cancellation (Lange et al., 1992). None of these patients responded to the therapy of lymphoma, confirming that when patients with MND or ALS in the course

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of lymphoma are carefully examined they have the same electrophysiological findings and lack of response to therapy of those without it. In patients with subacute motor neuropathy, electrophysiologic studies demonstrated the involvement of both the motor and sensory systems. NCS usually showed mild reduction of motor and sensory nerve conduction velocities, although they were reported to be normal in some patients (Walton et al., 1968; Dumitru and Amato, 2002). At needle EMG, features of acute denervation (positive sharp waves and fibrillation potentials), chronic denervationreinnervation (increased MUAP duration and amplitude), and reduced MUAP recruitment were detected. In the study of Schold et al. (1979) on 10 lymphoma patients, NCS revealed minimal prolongation of distal sensory latencies but, unfortunately, sensory nerve action potential (SNAP) amplitudes were not reported. Clinically, two patients had unequivocal sensory abnormalities in the affected extremities, whereas the other eight had mild or absent sensory symptoms and signs. NCS studies showed slight slowing of motor conduction velocity, and needle EMG disclosed patchy evidence of acute and chronic denervation in the affected limbs. When motor neuron involvement represents a component of PEM (see above), it is usually associated with clinical signs of more widespread paraneoplastic syndromes. Subclinical signs of motor neuron impairment can also be, however, detected by needle EMG in patients with PEM only with reduced MUAP recruitment and occasional fibrillation potentials. In these patients, NCS may show borderline or normal velocities (Dorfman and Forno, 1972). In patients with a concomitant SSN, where the sensory cell body is primarily involved, NCS show low amplitude or absent SNAPs (Horwich et al., 1977; Anderson et al., 1988; Dalmau et al., 1992). SNAP abnormalities can be asymmetric and restricted to the upper limb nerves. The latter features distinguish a ganglionopathy from a length-dependent axonopathy, in which SNAPs of the legs are particularly affected (Amato and Dumitru, 2002). While motor NCS are usually normal in patients with SSN, they can be abnormal in the presence of a concomitant paraneoplastic disorder of the neuromuscular junction such as Lambert – Eaton syndrome. Similarly, needle EMG is usually normal in SSN, although some abnormalities such as enlarged MUAPs or low-grade fibrillation potentials can be detected in the distal

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limb muscles of patients with a concomitant, though often subclinical, motor neuron involvement. Of the four patients with SSN investigated by Horwich et al. (1977), SNAPs were absent in 2/2, motor NCS were normal in 3/4, and needle EMG performed on three patients showed variable results (one was normal, one had chronic abnormal MUAPs, and one showed both acute and chronic denervation). In the study of Anderson et al. (1988), SNAPs were absent or low in amplitude, motor nerve conduction velocities were either normal or mildly slowed, and, except in patients with a clinical evidence of lower motor neuron syndrome, EMG did not detect signs of denervation. The electrophysiological findings of patients with MND who were reported to improve after cancer therapy are somehow confusing. As already mentioned, most of them had mainly clinical signs of lower motor neuron impairment associated in some with a concomitant sensory impairment (Buchanan and Malamud, 1973). In addition, electrophysiological studies, in most of these patients, particularly those in the early reports, were often incomplete and did not contain data (SNAP amplitudes, search for motor conduction blocks, F-wave features) necessary to exclude a peripheral neuropathy (Preston and Kelly, 1993). Chronic demyelinating motor neuropathies may, for instance, sometime masquerade as MND (Parry and Clarke, 1988), and their distinction may be difficult unless detailed electrophysiological studies including very proximal conduction studies (stimulation at Erb’ point or root level) are performed. Similarly difficult may be the distinction between motor neuropathy and MND when conduction block or other electrodiagnostic features of demyelination and antineural antibodies are absent (Pakiam and Parry, 1998; Gorson et al., 1999). Some patients have been for instance recently reported with slowly or non-progressive multifocal motor neuropathy and purely axonal electrodiagnostic features who improved after IVIg therapy (Katz et al., 2002), blurring the lines distinguishing motor neuropathies from neuronopathies. All these observations highlight the need for serial and widespread electrophysiological studies in patients presenting with only signs of lower motor neuron involvement to help distinguishing those with a pure motor neuropathy from those with MND.

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33.6. Conclusion From the data available to date, there is little evidence supporting a pathogenic role of cancer, lymphoma or monoclonal gammopathy in patients with ALS/MND and that immuno- or chemotherapy in these patients may alter disease progression, even in the presence of antibodies to neural antigens. The very occasional response of ALS or MND to immuno- or chemotherapy in some patients with ALS, raised doubts to the diagnosis. In general, aggressive treatment of this sort is more likely to be harmful than helpful. Until there is more convincing evidence that any of these therapies has any effect on ALS, their use should also be avoided for conditions not requiring any treatment per se, like benign monoclonal gammopathy. A different issue is that of patients presenting with pure lower motor neuron impairment. In these patients, a careful diagnostic investigation is necessary to identify potentially treatable purely motor neuropathies such as MMN where immune therapies are often effective (Nobile-Orazio, 2001), and which mimic MND (Chad et al., 1986; Parry and Clarke, 1988; Di Bella et al., 1991; Bentes et al., 1999; Kaji, this volume). In some of these patients, electrophysiological studies may not reveal the presence of conduction abnormalities including conduction block or slowing (Katz et al., 1997; Pakiam and Parry, 1998; Van den Berg-Vos et al., 2000; Katz et al., 2002; Nobile-Orazio et al., 2002), highlighting the need for better diagnostic criteria to distinguish patients with a purely motor neuropathy which might respond to immune therapies from patients with lower MND. Acknowledgements This work was made possible by the financial support of Associazione Amici Centro Dino Ferrari and by grants from IRCCS Ospedale Maggiore Policlinico, Milan, Italy. I wish to thank Dr Fabrizia Terenghi for her valuable help. References Amato, AA and Dumitru, D (2002) Acquired neuropathies. In: D Dumitru, AA Amato and MJ Zwarts (Eds.), Electrodiagnostic Medicine. Hanley & Belfus, Inc, Philadelphia, 2nd ed., pp. 937 – 1041.

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