POSTGRAD. MED. J. (i 961), 37, 282

NEUROLOGICAL DISORDERS ASSOCIATEDWITH MALIGNANT DISEASE

W. THOMAS SMITH, M.D. (BIRM.)Department of Pathology, University of Birmingham

CEREBRAL metastases occur in approximately 5%of all fatal cases of malignant disease (Willis, I952)and the effects of discrete macroscopical depositsare well known. On the other hand, disorders ofthe nervous system resulting from either diffusemicroscopical infiltration or other associatedchanges are less familiar and are the main concernof this survey.

In recent years it has been shown that carcinomais sometimes associated with neuromuscular lesionswhich are not due to metastases. The resultantdisorders are commonly termed carcinomatousneuropathy, myopathy or neuromyopathy, accord-ing to the site of the lesion. Although the adjectivecarcinomatous is also applicable to other neuro-logical complications of carcinoma, such as thosedue to metastases, the term carcinomatous neuro-pathy is used in this paper with its current arbitrarynon-metastatic connotation.

Diffuse carcinomatous infiltration of the brain,nerve roots or meninges may' produce a clinicalpicture which resembles carcinomatous neuro-pathy; this can only be established microscopicallyand precise diagnosis may therefore depend onpathological examination. Furthermore, neuro-logical complications occasionally result from car-cinoma emboli, from an associated thromboticsyndrome or from induced dietary or metabolicdefects. Neurological lesions which are not due togross metastases and sometimes complicate thediseases broadly classified as malignant reticuloseshave also been described recently and meritconsideration.

Carcinomatous NeuromyopathyNeuromuscular syndromes occur in pure forms

or in varying combinations, as has been shown inthe detailed reports of Henson, Russell and Wilkin-son (I954), Heathfield and Williams (1954) andBrain and Henson (1958). Although the disordersdescribed below are distinguished for descriptivepurposes, many gradations are found, dependingon the relative involvement of brain, spinal cord,peripheral nerves and muscles, and there is noreason to regard them as different diseases. Clinical

diagnosis depends on the dominant feature(s)present.

Cerebellar Cortical Degeneration (Brain, Danieland Greenfield, 1951; Greenfield, 1954). Thedisease commonly runs a course of less than a year,occasionally only a few weeks and rarely morethan two years. In published reports it has beenassociated with ' pelvic sarcoma ' (Brouwer, I9I9),ovarian, bronchial, mammary and uterine car-cinomas; our two pathologically confirmed caseshad primaries in bronchus and colon.The first symptom is usually unsteadiness of

gait, which is followed by clumsiness of hands,vertigo, dysarthria, diplopia or nystagmus. Mentalchanges are often prominent and there may bepyramidal tract lesions, polyneuritic symptoms orinvoluntary movements. Arrest of the process butnot remission is reported. The CSF may show anexcess of cells, increased protein or a paretic Langecurve. Because of the rapid onset and course of thedisease cerebellar tumour or multiple sclerosis issometimes suspected.

Histologically there is generalized atrophy andloss of Purkinje cells throughout the cerebellum.Degeneration of the lateral and dorsal columns ofthe spinal cord, and meningeal and perivascularinfiltration with lymphocytes have also beendescribed. The clinical and pathological featureswhich distinguish this from other cortical cere-bellar atrophies are discussed by Victor, Adamsand Mancall (I959).

Sensory Neuropathy (Denny-Brown, 1948). Char-acteristically this disorder reaches its maximum in afew weeks, but it may progress slowly over aperiod of months or even years. Clinically there isloss of joint and position senses and impairment ofskin sensation without motor weakness. Tendonreflexes are diminished or absent, and severe rootpains similar to the ' lightning pains ' of tabesdorsalis may occur. Neurological symptoms andsigns sometimes appear long before the associatedneoplasm is detected, 3' years elapsing in the casedescribed by Dyck, Bailey and Olszewski (I958).

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Apart from the case with cesophageal carcinomareported by Dodgson and Hoffman (1953), theprimary has always been bronchial.

Histologically the dorsal root ganglia show de-generation of nerve cells, many being replaced bynodules (' residual nodules') consisting of small,darkly staining cells. The central and peripheralprocesses of the degenerate sensory neuronesundergo Wallerian degeneration, resulting in de-myelination of the dorsal roots and columns of thespinal cord and patchy demyelination of the peri-pheral nerve sensory fibres. Our three cases alsoshowed a variable degree of round-celled infiltra-tion in the subarachnoid space over the cerebraland cerebellar hemispheres and in the perivascularspaces of the brain-stem. In one case there were'residual nodules' in the oculomotor, trigeminaland dentate nuclei.

Polyneuritis (Sensory-Motor Neuropathy). Thissyndrome has always been associated with bron-chial carcinoma. Lennox and Pritchard (1950)reported five cases with a peripheral neuritis ofpredominantly motor type, but with some sensorychanges, the neuropathy always being the present-ing clinical feature. Brain and Henson (1958)noted complete remissions in two out of five cases,in one instance six months before definite evidenceof the carcinoma appeared; partial remissionshave been described. Lea (1952) found evidenceof polyneuritis in 2.2% of a series of 50I cases ofbronchial carcinoma. One of our two cases showedpatchy demyelination in the peripheral nerves andboth showed chromatolysis in the anterior horncells of the spinal cord. Other reported casesshowed similar or no histological lesions. Coersand Woolf (1959), using vital staining with methy-lene blue and also cholinesterase stains on musclebiopsies, found changes in the subterminal nervefibres and subneural apparatus, and evidence ofcollateral reinnervation, in both polyneuritic andsensory disorders.

Neuromuscular Disorders. In this group thereis often a progressive atrophic paresis of lowermotor neurone type involving mainly the pelvicand shoulder girdles and proximal limb muscles.Tendon reflexes are diminished or lost in theaffected areas and sometimes beyond it. Remissionsmay occur. Stem lesions (ptosis, diplopia, aphonia,palatal paralysis) and extensor plantar responseshave been described. There may be pains in thelimbs, cramps and parxsthesix, but objectivesensory involvement is unusual.

Muscle weakness of either myopathic or myas-thenic type may accompany the neuropathy.Amongst Brain and Henson's 15 patients withneuromuscular disorders eight showed myopathy

without clinical evidence of neural lesions. Myas-thenia with bronchial carcinoma was first reportedby Anderson, Churchill-Davidson and Richardson(1953), oral neostigmine benefiting their patient;Mackenzie (I954), Shafar (I954), Borrelli andKeen (I954), Eaton and Lambert (I957) and Brainand Henson (1958) also described myastheniccases. Croft (1958) found that patients withcarcinomatous neuropathy but without overtmyasthenia were hypersensitive to muscle re-laxants.The associated carcinomas have usually been

bronchial, although Hart (I954) reported two cases,one with squamous carcinoma of antrum and theother with breast carcinoma, and amongst Brainand Henson's patients were ' examples of rectaland prostatic growths '. Two cases with bronchialcarcinoma examined in this Department showedclinical features resembling myasthenia gravis andmotor neurone disease respectively; a third pre-dominantly myopathic case was associated withhepatic carcinoma and haemochromatosis, but isonly tentatively included in this category becauseof these complex findings.The site of the lesion responsible for muscle

wasting has not been found from biopsy ornecropsy studies and Brain and Henson suggestedthat the disturbances may arise at more than onelevel in the neuromuscular system. Histology hasshown non-specific muscle atrophy, degenerationand loss of neurones in the spinal cord and brain-stem, and loss of fibres in the peripheral nerves.The differential diagnosis may be difficult and

includes dermatomyositis, polymyositis, myopathyof late onset, myasthenia gravis and motor neuronedisease.

Mental Changes. These may be the first in-dication ofcarcinomatous neuropathy and occasion-ally persist alone. More commonly they areassociated with other evidence of neuropathy,especially cerebellar dysfunction. Brain andHensohi described 17 patients with mental dis-turbances and I0 of these had cerebellar symptoms.Meerloo (I944) described nine patients with mentaldisorders and 'pulmonary carcinoma'; severalprobably had peripheral neuritis. Charatan andBrierley (1956), who reported three cases ofbronchial carcinoma with toxic confusional psy-chosis, considered that extensive liver metastaseswere a causative factor. But McGovern, Miller andRobertson (1959) described two cases with mentalchanges in which there were no liver metastasesand I have also examined a similar case. Savageand Noble (1954) reported two cases of pancreaticcarcinoma with a psychiatric illness, reviewed theliterature and found that 26 similar cases hadpreviously been described; the mental changes

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are apparently not related to interference withinsulin secretion.

Mixed Disorders. In some patients gradationsbetween the above groups occur, a dominantclinical picture does not emerge and precise classi-fication is difficult. Cerebellar dysfunction isusually present in such patients, but is less severe-than in the first group. Other features are super-imposed, such as peripheral neuritis, neuro-muscular and upper motor neurone lesions, bulbarpalsies, involuntary movements and disturbances,of sensation. In the mixed cases described byBrain and Henson inflammatory changes were anoteworthy pathological change. McCaughey andMillar (1955) reported a case in which there wassensory neuropathy, involuntary movements,dorso-lateral demyelination in the spinal cord andcalcified concretions in the dorsal-root ganglia.

Diffuse Carcinomatous Infiltration of theNervous System

Diffuse infiltration of the spinal nerve roots andperipheral nerves with metastatic carcinoma canpresent clinically as polyneuritis (Selinsky, 1930;Barron, Rowland and Zimmerman, I960) andresemble the polyneuritic variety of carcinomatousneuropathy. The ultimate diagnosis may dependupon histological examination, macroscopicalchanges being absent in some cases.

Clinical signs may also result from diffuse micro-scopical infiltration of the brain with carcinomacells. Three cases associated with bronchialcarcinoma were reported by Madow and Alpers(195I) as ' encephalitic metastatic carcinoma' andthere were no naked-eye changes. Isolated clumpsof anaplastic carcinoma cells, especially whenderived from an ' oat-cell ' bronchial carcinoma,can be difficult to identify, and the pathologist mayfind it hard to decide whether lesions are due todiffuse infiltration or non-metastatic carcinomatousneuropathy. With Dr. A. G. Whitfield (Smithand Whitfield, I955) I reported a case of carcino-matous sensory neuropathy in which it seemedthat the cellular nodules in the spinal gangliamight include anaplastic carcinoma cells, and Ihave since seen two similar cases.The sub-arachnoid space is sometimes diffusely

infiltrated with carcinoma cells (' carcinomatousmeningitis') which have not spread from adjacentneural or osseous deposits. Fischer-Williams,Bosanquet and Daniel (I955) found that the mainclinical features were vague ill-health followed byneurological symptoms and signs (headache,meningism, fits, mental deterioration, visual failure,loss of tendon jerks, cranial nerve palsies) whichmay appear suddenly and progress rapidly. Ex-amination of the CSF sometimes shows malignant

cells or a reduced sugar content. Carcinomatousneuropathy may again be simulated. Thus, Alpersand Smith (1938) and Alajouanine, Boudin, Nickand Contamin (1950) described polyneuritic casesand Greenfield (1938) noted dementia as a pre-senting clinical feature. Fischer-Williams et al.(1955) stated that the optic nerve degeneration intheir cases might be related to the degenerativelesions described in carcinomatous neuropathy.The way in which carcinoma cells reach the sub-arachnoid space in 'carcinomatous meningitis'is undecided: perineural lymph-borne infiltration,retrograde venous spread and direct hlimicmetastasis have all been suggested.Although the gastro-intestinal tract and bronchus

are the commonest site of the primary growth,reports indicate that most carcinomas can involvethe leptomeninges in this way.

Neurological Complications of Emboli ofCarcinoma Cells

Cerebral softening due to blood-borne neoplasticemboli is recorded by Thompson and Evans(1929), Storjohann (I932), Eason (1950), Madowand Alpers (1952), Miller and Jackson (I954) andothers. Smith and Whitfield (I954) found focalsoftenings related to microscopical carcinomaemboli in the brain of a woman dying 7j yearsafter radical excision of a breast carcinoma; in-filtrative metastases were not present. A case oflepto-meningeal carcinomatosis described by Smith(1957) showed carcinoma emboli occluding smallarteries penetrating the spinal cord, with resultantfocal myelomalacia.

Smith (I957) also made a detailed histologicalstudy of 27 macroscopically normal brains frompatients suffering from carcinoma who had notshowed clinical evidence of neurological disease.Two out of i i cases of bronchial carcinoma showedmany intra-vascular carcinoma emboli, withminimal extra-vascular infiltration. One out ofsix cases of breast carcinoma showed a single focusof leptomeningeal infiltration. The remaining iocases (two prostatic, three gastric, two uterine,two vesical and one pancreatic carcinomas) did notshow cerebral deposits. Although the number ofcases examined in this series was limited becauseof the work involved in examining each brain insufficient detail, it seems probable that more thanio% of fatal cases of bronchial carcinoma willshow intra-cerebral carcinoma emboli which areclinically latent. Clinical signs may, however,occasionally be produced in this way, as illustratedby another case examined by Smith (I957).Bulbar palsies and ataxia led to a tentative diagnosisduring life of primary brain tumour, but when amacroscopically normal brain and an unsuspectedbronchial carcinoma were found at necropsy the

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diagnosis was changed to carcinomatous neuro-pathy. Histology subsequently showed thatabundant carcinoma emboli and minute metastasesin the cerebral cortex, brain-stem and cerebellumwere responsible for the clinical signs.

Neurological complications may also result frommassive carcinoma emboli, sometimes recog-nizable macroscopically, and I have seen three suchcases. In the first case a carcinoma embolus wasdisplaced into a pulmonary vein during pneumo-nectomy for bronchial carcinoma and caused a fatalcerebral softening. In the second case a bronchialcarcinoma infiltrated along a pulmonary vein intothe left auricle, forming a necrotic intra-auricularmass, from which a cerebral embolus originated.In the third case a fragment of renal carcinoma,liberated into the venous system during nephrec-tomy, passed into the left auricle through a patentforamen ovale and a paradoxical tumour embolusfinally occluded a middle cerebral artery.

Cerebral Lesions Associated with MalignantThrombosis

Trousseau (I873) first described recurrentvenous thrombosis as a sign of obscure carcinoma;recently it has been found that arterial occlusionmay also occur in such cases (Oelbaum and Strich,1953; Williams, I954; Fisher and Baird, I956).The thrombosis is not attributable to recumbency,or invasion of or pressure on blood-vessels by thecarcinoma. Cerebral thrombosis has occasionallybeen mentioned in previous reports. Some casesalso develop non-bacterial thrombotic vegetationson the heart valves (Sproul, 1938; Smith andYates, 1955). The syndrome most commonlyoccurs with pancreatic carcinoma, but has alsobeen found with many other primaries, particularlybronchial and gastro-intestinal.

Smith (I957) found that neurological disordersattributable to the malignant thrombosis syndromeoccurred in I0oOut of 993 consecutive fatal casesof carcinoma. The primary carcinomas were asfollows: four pancreatic, two uterine, two gastric,one mammary, one bronchial. In six cases neuro-logical complications (hemiplegia, convulsions,involuntary movements, ataxia, mental changes)first appeared within a week of death and in theother four cases, four, six and twenty weeks, andfour years before death. Multiple venous and/orarterial thromboses of major extra-cerebral vesselswere found in all cases and coincident athero-sclerosis predisposed to arterial occlusion. Insix cases neuropathy resulted from micro-thrombosis of the cerebral arteries or veins andin four cases from gross occlusion of theinternal carotid artery or its proximal branches.In five cases microthrombosis was also found in themyocardium, spleen, liver, lungs or adrenals. Four

cases (three pancreatic, one gastric) showed cardiacvegetations. McDonald and Robbins (I957) andBarron, Siqueira and Hirano (I960) drew attentionto the clinical significance of non-bacterial throm-botic endocarditis and confirmed the finding ofAdams (1955) that cerebral embolism secondaryto it may be the first indication of an occultcarcinoma.

In the malignant thrombosis syndrome somemicrothrombi appear to be arrested embolic frag-ments of cardiac vegetations, although auto-chthonous microthrombosis also occurs in caseswithout vegetations. The microthrombi and thecardiac vegetations consist of material which isprobably a mixture of fibrin, altered fibrin andfused platelet masses; they are not superimposedon carcinoma emboli (Smith, 1957). There is amorphological similarity between the micro-thrombi seen in this syndrome and in thromboticmicroangiopathy (' platelet thrombosis syndrome').The occlusion of small cerebral blood vessels

results in focal areas of degeneration of variablesize which have no specific features. Recent lesionsconsist of pale zones of coagulative necrosis; olderlesions show infiltration with lipophages and areeventually transformed into gliotic scars. Vascularcongestion and perivascular hamorrhages arefrequently found when veins are occluded.

Neurological disorders resulting from the malig-nant thrombosis syndrome deserve wider recog-nition and may be the first indication of an occultcarcinoma.

Neuropathy Due to Dietary or MetabolicDefects Induced by Carcinoma

Neuropathy induced in this way needs onlybrief mention. Nutritional neuropathy (particu-larly Wernicke's encephalopathy) associated withgastro-intestinal carcinoma is a well-known ex-ample. Neoplastic destruction of organs essentialto metabolism may also result in neurological dis-orders, e.g. hepatic encephalopathy with primaryor secondary liver carcinoma. There is, however,no reason to believe that any of the cases ofcarcinomatous neuropathy studied in this Depart-ment resulted from similar dietary or metabolicdefects.

Neurological Complications of MalignantReticuloses

Changes in the brain, spinal cord and peripneralnerves which result from either diffuse infiltra-tion or compression by osseous or dural metastasesmay occur in leukxmia, lymphosarcoma, reticulo-sarcoma, Hodgkin's disease and multiple myeloma(see Sparling, Adams and Parker, 1947; Clarke,1954; Morrell, 1958; Williams, Diamond andCraver, I958; Hunt, Bouroncle and Meagher,

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1959; Barron et al., I960, and others). In somecases the affected areas appear normal macro-scopically. Cerebral limorrhage and (edema arealso frequent causes of neurological complicationsin leukiemia (Hunt et al., 1959).

Demyelination in the brain, spinal cord andperipheral nerves, which is unrelated to tumourinfiltration, has recently been described in thisgroup of diseases and is of particular interest.Victor, Banker and Adams (1958) described fivecases of demyelinating polyneuropathy associatedwith multiple myeloma and found that it resembledsensory-motor carcinomatous neuropathy.Cameron, Howell and Hutchison (1958) describeddemyelination of the peripheral nerves in Hodg-kin's disease, as did Hutchinson, Leonard,Maudsley and Yates (1958), who also found de-myelination in the spinal cord. Cerebral disordersassociated with demyelination in Hodgkin's diseaseand lymphatic leukimia were reported by Astrom,Mancall and Richardson (1958) and Cavanagh,Greenbaum, Marshall and Rubinstein (I959) andin lymphosarcoma by Lloyd and Urich (1959).The cerebral demyelination in most cases wasmulti-focal, tended to become confluent and wasassociated with bizarre changes in the glial nuclei.The clinical picture may closely resemble acuteSchilder's disease and in one of the cases ofCavanagh et al. (I959) the pathological findingswere those of Schilder's disease. There is noevidence that demyelination in the malignantreticuloses results from treatment with radio-therapy, radiomimetic drugs or any other form oftherapy.

DiscussionIt is clear that some neurological disorders

associated with carcinoma result from diffuse meta-static infiltration of various parts of the nervoussystem and are only recognizable histologically.In other cases occlusion of blood vessels of micro-scopical size by carcinoma emboli produces focallesions. The reason why such micro-emboli donot develop into distinct macroscopical metastasesand either remain intra-vascular or else spreaddiffusely in the neural tissue or meninges is afundamental question related to factors such as theinvasive properties of tumour cells and stromalresponse. The important practical point is thatthe spread of tumours in the nervous system is soprotean that even in the absence of naked-eyechanges histological study is usually obligatorybefore making a definite diagnosis of carcinomatousneuropathy. Fatal cerebral infarction due to grosstumour embolism, although interesting, is appar-ently a chance event which may occur spon-taneously or as a complication of cancersurgery.

The cause of the non-metastatic neuropathiesassociated with malignant disease remains obscure.It has been suggested that carcinomatous neuro-pathy may be due to ' carcinotoxins ', vitamindeficiencies or metabolic disorders conditioned bythe carcinoma, virus infection, endocrine abnor-malities or the production of auto-antibodies tonerve tissue. Other possibilities are that thecarcinoma and the neuropathy are induced by acommon ietiological agent, or even that multiplefactors are concerned. All of these hypotheses arespeculative and no single explanation will sufficein all cases.

Cerebral demyelination complicating malignantreticuloses differs clinically and pathologically fromthe cerebral lesions described in carcinomatousneuropathy, although there are similarities as faras peripheral nerve involvement is concerned.Theories explaining reticulotic neuropathy havebeen similar to those advanced in carcinomatousneuropathy, but it is debatable whether the patho-genesis is similar in both groups.The association of carcinoma with diseases other

than neuropathy, such as polymyositis, dermato-myositis, scleroderma, acanthosis nigricans, pur-pura and thrombosis, is now well known. Thepathological effects in some cases can be complex,as illustrated by the cerebral lesions resulting fromthe syndrome of carcinoma and thrombosis. Ter-minology is not yet standardized and Walton andAdams (1958) considered that there are groundsfor considering dermatomyositis, polymyositis andmyopathy in patients with malignant disease col-lectively rather than as separate syndromes. Thenature of the connection between cancer, neuro-pathy and diseases of the connective tissues is aformidable problem, the investigation of whichcould well be rewarding and disclose factors whichare important both in carcinogenesis and in main-taining the form and function of neural and othertissues.

Summaryi. Various neurological disorders associated

with malignant disease are discussed, including:non-metastatic carcinomatous neuropathy; com-plications resulting from diffuse carcinomatous orreticulotic infiltration, from carcinoma emboli, orfrom an associated thrombotic syndrome; anddemyelination associated with malignant reticu-loses. The effects of discrete macroscopical meta-stases are not considered in this survey.

z. IEtiological mechanisms are only brieflymentioned because at the present time these areconjectural. It is stressed that there may be aclue in the non-metastatic disorders to factorsimportant both in carcinogenesis and in maintain-ing the integrity of neural and other tissues.

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ERRATUM'THE THIRD STAGE OF LABOUR', by F. DENNY, A. E. B. MATTHEWS, and R. M. WILD

February issue I96I. Page 86, Table 5:Column giving totals-for 1,I67 read i,8IS; for 1,047 read I,127; for 2,214 read 2,942.

Page 87, Table 9:Total of control group-for 2,942 read i,815.

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