Postgrad Med J: first published as 10.1136/pgmj.33.377.121 on 1 March 1957. Downloaded from

I1I

NEUROLOGICAL COMPLICATIONS IN By S. FAZLULLAH, M.B.(Osmania), D.T.M. & H. Late Medical Registrar, Barrow-in-Furness Group of Hospitals, Lancs.; Medical Registrar, Pontefract and Castleford Group of Hospitals, Yorks.

Hypersensitivity state is the altered activity of from acute and self-limited collagen disease in cells to any foreign substances, a normal physio- that the course is protracted over many years, logical phenomenon of protective adaptation. and if they are diseases of hypersensitivity we and hypersensitivity are our saviour for must postulate that the antigenic substance must which we should be grateful to nature. Allergy be present in the body throughout this long period is now being applied commonly to the pathological of activity, probably not being neutralized due to variants of the physiological process. Allergy, defective process of the . The same physiologically, allows the organism to react to can be applied to disseminated sclerosis in which antigenic substances to neutralize them. myelin sheath is involved instead of connective reaction, in certain people, tissue. may end naturally without any after-effects and in others may terminate in pathological process, Hypersensitivity and Collagen Diseases presumably due to inherent individual consti- Pirquet's original concept (I903) of allergy has copyright. tutional defect and defective enzyme system in withstood the test for 50 years and is substantially certain tissues or defect in the natural process of true today. The clinical manifestations of hyper- the immunity with the production of abnormal sensitivity now can be classified in four main , possessing affinity to certain tissues groups: with a capability of injuring them. Identification i. , hay and infantile eczema. of antibodies, other than those occurring in 2. sickness, and contact streptococcal infection, has not been often estab- dermatitis. lished, though some have reported antireticulin, 3. Bacterial and viral allergy (yet in infancy). antimyocardial and antirenal antibodies.* At the 4. Autoimmunization, , thrombocytopenia, http://pmj.bmj.com/ moment we know little about cell-fixed antibodies. haemolytic anaemia and hyperfunction of reticulo- endothelial system. with auto-antibodies formation Autosensitization (Bywaters, I956). In certain- people, autoimmunization, following There is widespread assumption that collagen autosensitivity to certain endogenous products, diseases are probably due to hypersensitivity might play a part in the production of multiple (Rich, 1946). Fibrinoid necrosis of collagen, such antibodies. A good clinical example of auto- as seen in acute

rheumatism, polyarteritis following on October 2, 2021 by guest. Protected immunization is found probably in lupus erythe- infection and (Rich, 1946), can matosus, which is presented with haemolytic also be found in mechanical injury to collagen anaemia in association with circulating antibodie§ such as in malignant hypertension, peptic ulcer proved by positive Coombs' test, thrombocyto- and acute pancreatitis (Klemperer, 1948). There penic purpura, false positive W.R., increase is no convincing evidence that collagen itself is gamma-globulin and multiple antibodies formation involved. Klemperer himself now believes that following transfusion. If lupus is regarded fibrinoid of lupus is probably derived from the as a disease of autoimmunization, we do not know breakdown of nucleic acid, supposed to be set in what antigenic substance is involved nor how process by gamma-globulin, a serum factor pro- it is rendered autoantigenic. Lupus, rheumatoid duced during autoimmunization. Gamma-globulin arthritis, polyarteritis and dermatomyositis differ inactivate the desoxyribonuclease inhibitor enzyme and allow nuclear of *Globulin fraction on antikidney serum tagged with degeneration leucocytes Il3 is localized primarily in the glomeruli as determined which consequently is ingested by polymorphs. by radioautograph. These deep purple staining bodies are found in Postgrad Med J: first published as 10.1136/pgmj.33.377.121 on 1 March 1957. Downloaded from I22 POSTGRADUATE MEDICAL JOURNAL March 1957 connective tissues identified by Klemperer (1948) Involvement of the central nervous system has as desoxyribonucleic acid. The same was found also been observed in Behcet syndrome (Behcet, in lupus erythematosus cell and marrow by Har- I937, I939, I940) and in Steven Johnson syndrome graves et al. (I948). (Ashby and Lazar, 195I) resembling disseminated The efficiency of cortisone and ACTH in sclerosis, presenting the same basic as arresting the disease process in rheumatoid seen in hypersensitivity. arthritis and lupus may depend upon the ability There is a growing evidence to believe that of these hormonal agents to reverse this destruc- post-infectious perivenous demyelinating encepha- tive enzymatic process in the affected cells lomyelitis and post-infective polyradiculoneuritis rather than upon the unknown cause of the (Landry-Guillain-Barre syndrome) are allergic disease. This hypothesis is supported by the reactions. These diseases are manifested 7-14 prompt effect of the therapy and equally prompt days following the infection, at a time when anti- recurrence of illness upon withdrawal of these bodies are being formed with a tendency to agents. spontaneous recovery. Miller (1956) believes that Hydralazine (apresoline), used for hypertension, these are secondary to the initial vascular insult, can also produce mesenchymal reaction simulating probably due to hypersensitivity. This toxic- lupus and rheumatoid arthritic features in asso- allergic complication had been for many years ciation with lupus erythematosus cell phenomenon. the explanation of and glomerulo- These lupus erythematosus cells are also found in nephritis following streptococcal infection. In sensitivity and virus hepatitis. Apreso- post-infectious neurological disorders there is a line has a strong affinity to combine with carbonyl damage to the melin sheath, while in the collagen and sulph-hydryl groups. Thus we can produce disorders connective tissue is injured. We do not the disease at will in animals and can study its know the exact mechanism of these syndromes of pathology. unknown cause. Many clinical and pathological features are common to all collagen diseases, with some varia- Clinical Material tion in intensity and distribution. Hypersensitivity The present paper deals with the neurological is a common factor to all. Disease may start disorders observed in cases with hypersensitivity copyright. with one syndrome predominating; as it pro- manifestations: drug allergy, polyarteritis, sys- gresses, this is replaced by another. In each case temic lupus, hypersensitivity angiitis and post- cellular infiltration and fibrinoid necrosis is asso- infection allergy. Twenty-one cases have been ciated with lymphoid hyperplasia and gamma- observed; signs and symptoms are analysed. globulinaemia. Increase gamma-globulin is re- garded as a response to antigen antibody reaction TABLE I No. of Diseases cases (Aegerter and Long, I949; Long, 1954, 1955). Polyarteritis ...... 3 The pathology of early stage is unknown. In an vasculitis .. Schonlein-Henoch allergic ..I http://pmj.bmj.com/ experimental analogous disease the earliest lesion, Hypersensitivity angiitis ...... I in guinea-pig, is oedema (Long, 1954, I955), and Allergic granulomatous angiitis .. ..I Pulmonary lupus ...... 2 this is shown in (Kulka et al., Allergic polyradiculoneuritis .. .. 4 1955) which is soon associated with cellular Spontaneous acute disseminated encephalo- infiltration and vascular insult. myelitis: (a) Myelitis type ...... 3 Neurological Complications in (b) Encephalomyelitis type .. .. 2 Glandular fever syndrome...... I- Hypersensitivity Meningococcal meningitis ...... on October 2, 2021 by guest. Protected Mayo Clinic has played an important role in Drugs allergy ...... 2 advancing the knowledge of lupus. Clark and Bailey (I956), of the same institute, have drawn 21 attention to the frequency with which mental and TABLE 2 No. of neurological complications occur in this disease. Hypersensitivity States cases They reviewed the neurological complications in Upper respiratory tract non-specific infections io systemic lupus observed at Mayo Clinic; these Asthma with eosinophilia (48% in one case) (io% in other case) ...... 2 included convulsions, mental disease, hemiplegia, Meningococcal infection ...... polyneuritis, subarachnoid haemorrhage, vertigo, Staphylococcal ...... nystagmus, chorea, monoplegia. Pathological Streptococcal ...... study revealed widespread vascular lesions in the Drugs allergy ...... central nervous system. Similar neurological Unknown ...... 4 complications have also been observed in poly- ZI arteritis. Postgrad Med J: first published as 10.1136/pgmj.33.377.121 on 1 March 1957. Downloaded from March 1957 FAZLULLAH: Neurological Complications in Hvpersensitivity 123

TABLE 3 was maintained for a further six weeks. Two No. of Neurological disorders cases months later she was seen when complete regres- Neuropathies: sion of the transverse myelitis was found. C.S.F. (a) Symmetrical polyneuritis in the legs 3 was normal, except raised up to 50 mg. (b) A symmetrical polyneuritis (mononeuritis per ioo ml. multiplex) ...... 3 Case.-Female, aged 32, developed spontaneous Asymmet. polyradiculoneuritis .. 4 Hyper-reflexia followed by areflexia 3 acute disseminated encephalomyelitis following a Transversemyelitis ...... 4 non-specific upper respiratory tract infection two Encephalitis ...... I weeks prior to the illness, in association with Mononeuritis (R. ext. popliteal palsy) 2 pyrexia I020 F., headache, neck stiffness, diplopia, Convulsions ...... I severe dysarthria, cerebellar ataxia, flaccid limbs 21 without changes in the reflexes and tachycardia. C.S.F. examination revealed normal pressure with TABLE 4 ioo and cells No. of cases raised (I20 mg. per ml.) Age in Years Male Female (I50 mononuclear cells per c.mm.). She was 0-10 0 0 treated symptomatically with complete recovery I0-20 .. .. 3 0 in six weeks. In such cases pleocytosis is due to 20-30 0 I meningeal involvement, otherwise proteins are 30-40 0 4 40-50 3 3 raised and sometimes C.S.F. is normal. 5o-60 .. 2 Some cases are presented with hemiplegia, 60-70 .. 2 I hemianopia, aphasia, convulsions, and focal neuro- 70-80 .. .. 0 I logical signs (McAlpine, I93I). Motor weakness A. Spontaneous Acute Disseminated in the lower limbs may progress to complete Encephalomyelitis paraplegia as occurred in the above-described A form of acute disseminated encephalomyelitis first case, in a day or two of the onset, but may be clinically and pathologically identical with post- delayed up to three weeks. The way in which exanthematous and post-vaccinal encephalomye- fresh neurological symptoms appear, within the copyright. litis may occur following on an influenzal type of first three weeks, but in rare instances up to few febrile illness. McAlpine reviewed the clinical months from the onset, as in the first case, is picture and described a cerebral and a spinal regarded highly characteristic. Mortality rate is clinical type (I93I). Miller and Evans (I953) low. Recovery is complete, though in some cases regard this illness as a non-specific allergic sequelae remain. encephalitis reaction of the C.N.S. to various , chiefly usually terminates fatally, but may become bacterial and virus infection, and possibly other arrested. kinds as well. Radicular type of pain in the back was com-

plained by four cases. This is an important http://pmj.bmj.com/ Clinical Features characteristic feature of acute disseminated mye- In the five presented cases onset of the neuro- litis which differentiates it from disseminated logical complications was sudden, following a sclerosis. non-specific upper respiratory tract infection, two Headache, fever and tachycardia with absence to three weeks previously, at a time when anti- of euphoria were present in all. Extensive sensory bodies loss to vibration, joint sense, pain temperature are formed. with acute paraplegia was noted in four cases- of Case.-Female, age'd 45, developed spontaneous disseminated myelitis which is rarely observed in on October 2, 2021 by guest. Protected ,cute disseminated myelitis in association with disseminated sclerosis. pyrexia I00° F., tachycardia, headache, depression In cases of disseminated myelitis, if residual and transverse myelitis. She exhibited unusual signs persist after acute stage, then diagnosis hyperalgesia to cold on the left leg. She was from disseminated sclerosis is extremely difficult. showing remissions and relapses of motor paralysis The diagnosis is based upon history of onset in the legs successively within a short time for following infection, characteristic symptoms and two months. These were controlled by a course absence of any extension of the physical signs of ACTHt gel. 40 units b.d. for one week, followed after first three weeks of illness. Occasionally by cortisone ioo mg. daily which was reduced disseminated encephalomyelitis and acute dis- gradually to 12.5 mg. in a six weeks' time, which seminated myelitis follow a relapsing course (McAlpine, I93I; Miller and Evans, 1953). This tACTH and cortisone may be dangerous in cases of virus diseases such as polio, bacterial infection of C.N.S. was noted in one case up to two months which (abscess) and T.B. meningitis. These diseases should was controlled by cortisone and ACTH therapy. be excluded before their administration. Miller (I953) has used ACTH for the treatment; Postgrad Med J: first published as 10.1136/pgmj.33.377.121 on 1 March 1957. Downloaded from 124 POSTGRADUATE MEDICAL JOURNAL March 1957 of acute disseminated encephalomyelitis. McAl- Russell (I955) described fibrinoid necrosis of pine (I93i) has drawn attention to the following the vessels in acute haemorrhagic leucoencepha- points as diagnostic for acute disseminated litis and polyarteritis type of vascular lesions in encephalomyelitis:- acute disseminated myelitis. She also described i. A temperature of over I000 F. plasma cells and their precursors in the spleen of 2. Severe shooting pain. both type of cases and concluded that ' allergy ' is 3. Absence of euphoria. the basis of reactions in the central nervous 4. Loss of pain and thermal sensibility, or system. Campbell and Good (1950) also described diminution of all sensation below the sensory plasma cells in the spleen of guinea-pigs with level, or presence of dissociated anaesthesia. experimental allergic encephalitis. Encephalitis 5. Motor weakness in the lower limbs with para- following arsphenamine (Russell, 1937), strepto- plegia is usually noticed within a day or two of mycin and P. aminosalicylic acid (Cavanagh, illness, or delayed till the end of two or three I953) is possibly the result of hypersensitivity. weeks. Reflexes are exaggerated or abolished. Acute haemorrhagic leucoencephalitis charac- Fresh neurological signs appear within the first terized by febrile illness, headache, vomiting, three weeks or delayed up to few months with stupor with or without hemiparesis with poly- complete recovery. Sphincter disturbance is morphonuclear leucocytosis in blood and high common. Ataxia with rapid and fine nystagmus cell counts in the cerebrospinal fluid with many is present. Bilateral optic neuritis with myelitis polymorphs and signs of acute disseminated simulate Devic's disease, which is also observed encephalomyelitis represent different grades of after measles and vaccination. intensity of reaction to a similar pathological The presented five cases were fulfilling the process (Greenfield, I950; Russell, I955). criteria described by McAlpine. Three cases Miller and Evans (I953) believe that acute developed paraplegia within two weeks of the disseminated encephalomyelitis is the result of onset of illness with extensive sensory loss, and in non-specific allergic reaction in the central nervous one case onset was delayed to three weeks and system, to various antigens-bacterial, virus and

fresh neurological signs were appearing up to other kinds. Acute disseminated encephalo-copyright. two months with paraplegia and extensive sensory myelitis and acute haemorrhagic leucoencephalitis loss in the legs. are similar to the experimental allergic encepha- litis, post-vaccinal and post-exanthematous peri- Aetiology venous demyelinating diseases, serum sickness, The development of encephalomyelitis following angio-neurotic oedema, and specific , vaccination and during antirabic purpura (Miller and Evans, I953). Miller (1956) treatment has long been recognized. Post-vaccinal believes that the neurological disorders are and post-infectious neurological complications secondary to the initial vascular insult in post- (1956) have an identical pathology. Although this is exanthematous encephalitis. Blackwood http://pmj.bmj.com/ designated as encephalomyelitis,'an infective agent concluded that the histopathology is too slender has never been isolated from the central nervous to exclude or confirm allergy in the pathogenesis system. Recent experiments with the injections of post-exanthematous encephalomyelitis. of homologous and heterologous brain tissue with Recurrence in post-exanthematous encephalo- adjuvants (dead tubercle bacilli and mineral oil) myelitis is unknown and also in illness following produced the pathological picture resembling the specific fevers. If nervous disorder follow a minor post-infective encephalomyelitis and throw doubt non-specific infection of upper respiratory tract, on infectious aetiology of the disease (Kabat et al., lasting immunity, in such cases, is lacking and on October 2, 2021 by guest. Protected I1954; Wolf et al., I947; Lumsden, 1I949, I956). repeated such antigenic insults play a part in the The nature of. the antigen and the mechanism of pathogenesis of recurrence of neurological dis- brain damage has not yet been elucidated. Colover orders (Miller and Evans, 1953). This fact (1954-56) and Colover and Consden (I955) have explains the recurrence of neurological disorder demonstrated that the active agent in the dead in one of the presented cases up to two months. tubercle bacilli is an insoluble somatic protein Perhaps this, also, explains the relapses in dis- bound compound which is mainly formed of seminated sclerosis. amiino-acids with a long chain fatty acid rather Recently the aetiology of disseminated sclerosis than lipid or wax or polysaccharides. The role is narrowed down to infection and allergy of adjuvants is described as purely potentiating (McAlpine, I956). The possible source of infec- and it must be given at the same site. Lumsden tion is the upper respiratory infection to which .949) also demonstrated that active agent in the lasting immunity is lacking. Abrupt onset, relaps- injected brain was protein or protein-bound com- ing, remitting course, increased globulin in the pound rather than a lipid. C.S F., occasional association with the other form Postgrad Med J: first published as 10.1136/pgmj.33.377.121 on 1 March 1957. Downloaded from March 1957 FAZLULLAH: Neurological Coinplications in Hypersensitivity of allergy and recurrence of the attacks following paresis, myositis tend to be conspicuous symp- infection, fatigue, lowered state of general health, toms and signs. Particular reference may be made trauma and emotional upset favour allergy. to the occurrence of unexplained foot drop, wrist Perhaps the silent reactivated allergens or the new drop in *association with pyrexia, 'microcytic allergens, due to the defective immunity, produce anaemia, albuminuria, raised E.S.R., increased fresh crops of antibodies, consequently new gamma-globulin, altered liver functions, raised lesions are produced in the C.N.S. Autoimmuniza- B.P., leucocytosis and wasting of muscles which tion seems as good as any at the moment. are highly suggestive of polyarteritis nodosa. Many potential allergic patients who keep good Variety of neurological disorders are described health and live in a favourable environment in cases of polyarteritis nodosa: fits (Malamud escape allergic symptoms. They remain in so- and Foster, 1942), hemiparesis (Malamud an'd called allergic balance, so that their symptoms Foster, I942), chorea (Neale and Whitfield, I934), remain subclinical. Once the natural defences Parkinsonism (Sheinker, I945), subarachnoid have been lowered by infections, nutritional dis- haemorrhage (Malamud and Foster, I942), bulb"ar turbances, hormonal imbalance stress, marked syndrome (Runge and Melzer, 1930), Ramsay and weather changes, habits, drugs, and Hunt syndrome (Spiegel, 1936), clinical picture of psychosomatic disorders which impair their well- intracranial neoplasm (Diaz-Rivera and Miller, being, allergic manifestations emerge in severe I946). forms, and if not corrected early lead to a Symmetrical neuropathy in the legs was ob- crippling invalidism. served in two cases of polyarteritis and mono- In recent studies in U.S.A., Lubens (I955) neuritis multiplex: right foot drop, wasting of reports on 300 cases of poliomyelitis, and states the small muscles of the hands, asymmetrical loss that the incidence of bulbarpolio was found to be of reflexes in the legs with subarachnoid haemor- as much as five times as great among those with rhage, diplopia, 48 per cent. eosinophilia with an allergic history as among those without such asthma in one case; another case was suffering background. The mortality from polio was also from asthma before the onset of neuropathy in

greater among allergic than among the non- the legs. One case, following meningococcal copyright. allergic. infection and sulpha drug therapy, developed mononeuritis multiplex: right Bell's, left ulnar and B. Neuropathies and Hypersensitivity right external popliteal palsies which improved (a) Polyarteritis Nodosa gradually. In two cases mononeuritis neuropathy Kussmaul and Maier (i866) described neuro- (right external popliteal N. palsy) was asso- pathy in their original case of periarteritis nodosa. ciated with pyrexia, microcytic anaemia, raised Since then the incidence of it, in different series, E.S.R. and pain in legs. In one of them infective has varied from 8 to io per cent. Kernohan and focus of staphylococcus was established,' but was ineffective. Woltman (I938) first differentiated the successive appropriate chemotherapy http://pmj.bmj.com/ involvement of peripheral nerves (mononeuritis One case (female, aged 74) exhibited a mixed multiplex) from symmetrical involvement of the picture of polyarteritis and systemic lupus with peripheral nerves in polyarteritis nodosa. Miller symmetrical neuropathy in the legs. She was thought that the symmetrical type of polyneuritis having recurrent attacks of conjunctivitis between is common (I949). Heathfield and William (I954) I95I and 1955, pleuritic pain with pulmonary described one case of mononeuritis multiplex and rales at right base of the lung, off and on, jaundice, seven cases of symmetrical polyneuritis, and giddy turns and developed diabetes which was placed diabetic neuropathy first, infective poly- treated symptomatically. She developed coronary on October 2, 2021 by guest. Protected neuritis second and polyarteritis nodosa neuro- thrombosis 'on March 28, 1955, with congestive pathy third in order of frequency. heart failure; now conjunctivitis recurred. She Necropsy of cases of polyarteritis nodosa reveals was treated by the anticoagulants, digoxin and macroscopic arterial lesions in the heart, kidney, mercurial diuretics. On April 23, I955, she liver and intestinal tract with yellowish mottlings developed generalized measly and urticarial , (infarctions) due to arterial occlusion. Histology angular stomatitis was noted on May 5s '955; this of peripheral nerves shows polyarteritis nodosa was followed by glossitis, vitamin B and nicotinic like lesions in vasa nervorum and nutrient vessels acid was ineffective. Two weeks later she passed of the peripheral nerves with their occlusion and large offensive malaenous stools with abdominal inflammatory oedema (Kernohan and Woltman, colic. This was followed by dysphagia; skin 1938; Miller, 1949; Lovshin and Kernohan, I948; lesions now were changed into healed polymorphic, Heathfield and William, 1954). purpuric and papulogranulomatous appearances; In all such cases local pain, loss of tendon exfoliation was observed, later on, in the legs, reflexes, subjective and objective sensory loss, peripheral arterial pulsations were absent in legs Postgrad Med J: first published as 10.1136/pgmj.33.377.121 on 1 March 1957. Downloaded from jiz6 POSTGRADUATE MEDICAL JOURNAL March 1957 with loss of deep reflexes; loss of sensation to (Selye, I944), and large doses of ergosterol diet pain, touch and vibration. Serum globulin and rich in calcium and phosphorus (Ham, I940). E.S.R. were raised. L.E. cells (lupus erythe- Cortisone and ACTH opened a new field for matosus cells) were absent from peripheral blood, the investigation of various types of necrotizing and biopsy was negative. In view of above findings arterial lesions. Ehrenreich and Olmstead (195I) lupus-polyarteritis complex was considered and reviewed the detrimental and beneficial effect of she was put on cortisone ioo mg. daily. Two these in periarteritis nodosa. The weeks later a dramatic improvement was noted in variable effects of these hormones suggest more her abdominal pain, dysphagia, diarrhoea and than one kind of necrotizing angiitis and need frequency of malaenous stools, which decreased more clinical and experimental observations, gradually. Cortisone was decreased gradually and whether one kind is benefited and other is harmed was stopped on July 26, I955. She developed (Zeek, 1952). Polley (I956) of Mayo Clinic, relapse of cardio-pulmonary symptoms four home of cortisone, discussing the status of these months later on; and cortisone was restarted. hormones, described that overdose and chronic Now her neuropathy in the legs improved, but hormonal excess can produce mesenchymal reac- loss of deep reflexes persisted and skin was glassy tionst simulating lupus, polyarteritis, light sensi- in appearance. She became bald. tivity, transfusion reaction, false serological reac- Three cases of drug sensitivity showed hyper- tions during blood grouping, articular pain and reflexia followed by areflexia, paraesthesiae in the muscular ache. Edge, Fazlullah and Ward (I955) legs, conjunctivitis, measly rash, abdominal pain noted variable effect of cortisone in a case of and . Asymmetrical loss of hypersensitivity angiitis. There may be some reflexes was also observed in three cases (glandular types in the group of necrotizing angiitides, fever, pulmonary lupus, hypersensitivity angiitis). reacting differently to these hormones. Perivascular retinal exudate was observed in the Recently Zeek (I952-53; Knowles et al., I953) case of hypersensitivity angiitis. suggested a new terminology, collectively, for Aetiology.-Aetiology is still unknown. Further various types of polyarteritis as necrotizing

investigations are needed in the sphere of histo- angiitides which is a non-committal as far ascopyright. chemistry and electron microscopy to throw more aetiology is concerned. They classified necro- light on the pathogenesis of idiopathic necrotizing tizing angiitides into five clinical types. There angiitides. Gruber (1925) suggested that it may may be other types still unclassified. The following be a manifestation of hyperergic reaction to is modified from Zeek classification: variety of antigens: infections, toxic agents and i. Hypersensitivity angiitis. drugs to which blood vessels had been previously 2. Allergic granulomatous angiitis. exposed. 3. Polyarteritis: (a) Primary polyarteritis, (b) Ophuls (1923) expressed that individual types secondary polyarteritis. the and develop disease suggested that the lesions 4. Rheumatic arteritis: (a) Acute type, (b) http://pmj.bmj.com/ are the result of actions of various infections and chronic type. toxic agents on the predisposed vessels. The 5. Temporal arteritis. observation that the disease often follows some 6. Shonlein-Henoch allergic vasvulitis. infections, particularly streptococcal infection, and Winkelman and Eckel (1932) described cerebral a similarity between it and acute rheumatism arteritis simulating the changes seen in acute suggests that polyarteritis may be a result of disseminated lupus, in cases of rheumatism and allergy iti a constitutionally defective individual. chorea of moderate chronicity. Benda (1949) and

Association of asthma favours allergy as an Breutsch (I942) described cerebral arteritis with on October 2, 2021 by guest. Protected aetiological factor. subintimal proliferation, filling lumen of small Subsequently experimental production of hyper- arteries, in cases of chronic rheumatism. Similar sensitivity in animals revealed necrotizing lesions lesions are seen in the heart. These changes may in the blood vessels (Klinge, I929; Clark and Kaplan, 1937; Rich, I942; Rich and Gregory, + In some cases these reactions are the manifestations 1943). Such lesions and those produced by drug of exacerbation of the disease process (polyarteritis or allergy differ to some extent from the classical lupus) for which these hormones were used. Some years ago it was found that periarteritis nodosa lesions, type of periarteritis nodosa of Kussmaul and Maier produced by DOCA, can be duplicated by Pit. Somato- (i866), and are termed hypersensitivity angiitis trophic (H. Selye, 195i, Lancet, i, 483). This (Zeek, 1952-53; Knowles et al., 1953). effect is inhibited by cortisone but only under conditions Fibrinoid necrosis is also observed in non- which induce marked adrenocortical atrophy. He also showed that cortisone prevents periarteritis nodosa in specific injury: malignant hypertension, peptic the mesenteric vessels, induced by DOCA, but does not ulcer, acute pancreatitis (Klemperer, I948), over- exert such preventive action on the arteries of heart, dose of DOCA and salt, large dose of ACTH kidney and certain organs. Postgrad Med J: first published as 10.1136/pgmj.33.377.121 on 1 March 1957. Downloaded from March I957 FAZLULLAH: Neurological Complications in Hypersensitivity 127 reasonably be regarded as slow inactive sensitiza- hypersensitivity angiitis caused by phenylbutazone tion of vascular tissue. hypersensitivity. On necropsy histology, poly- Before I900 published cases of polyarteritis arteritis, granulomatous lesions and hypersensi- revealed macroscopic nodular lesions in every tivity angiitis were found. case; there was a microscopic confirmation. In Edge, Fazlullah and Ward (I955) described a I903 Veszpremi and Jancso described a case of case of hypersensitivity angiitis caused by peni- polyarteritis without macroscopic nodular lesions cillin, streptomycin, isoniazid and cortisone. which was diagnosed microscopically (microscopic Hypersensitivity angiitis is characterized by short polyarteritis). In 1923 Ophuls was the first to fatal course, involvement of arterioles, venules, describe the case of hypersensitivity angiitis, in capillaries, interstitial inflammation in the involved which pulmonary small vessels were badly viscera, and necrotizing glomerulonephritis. The damaged, and there were widespread eosinophilic lesions are of the same age with no healing stage granulomatous lesions. Recently Edge, Fazlullah on the microscopy. Vessels of kidney, heart, and Ward (I955) described a case of hyper- lungs and splenic follicular arterioles are specially sensitivity angiitis in which pulmonary arteries involved. The arterial lesions are uncommon in were extensively involved. the intestinal tract. Usually there is a history of Primary Polyarteritis Nodosa. This group of sensitivity to serum, sulpha drugs and other polyarteritis comprises the clinical type of poly- drugs. There may be other types of hypersensi- arteritis described by Kussmaul and Maier (i866), tivity angiitis. Knowles et al. (I953) noted, in one characterized by a long course, remissions, of ten cases of hypersensitivity angiitis, early exacerbations, nodular macroscopic lesions, poly- wire loop lesions of lupus in the renal tissues, in ,neuritis, fever, anaemia and multi-systems involve- which course of the disease was delayed. Lupus ment. Necropsy reveals nodular lesion at the disseminata and systemic lupus may be a form of point of branching of small and medium size hypersensitivity angiitis (visceral necrotizing angi- arteries, widespread in distribution in the vessels itis). Recovery can occur in mild cases of hyper- of mesentery, pancreas, liver, kidney, coronary, sensitivity angiitis with exacerbation.

peripheral vessels and absent from the pulmonary copyright. vessels unless pulmonary hypertension is asso- Allergic Granulomatous Angiitis. This type of ciated. Splenic follicular arterioles are also in- angiitis is a systemic granulomatous condition and volved. Arterial lesions of various ages are seen occasionally is described as a polyarteritis which with the sequelae of renal hypertension and eventually results after pulmonary eosinophilia arterial obstruction. -and asthma with high eosinophilia, one to seven Secondary Polyarteritis Nodosa. In this type of or many years later on. polyarteritis lesions in the arteries develop shortly Allergic angiitis was described by Churg and before death in cases of severe renal disease and Strauss (1951), which is characterized by fever, in hypertension or of both. In cases of malignant asthma, eosinophilia, multinucleated giant cells hypertension necrotizing lesions are seen in the granuloma in the extravascular tissues and serous http://pmj.bmj.com/ kidneys, but inflammatory reactions are absent or membrane. The lesions are seen at various stages minimal, while in the secondary polyarteritis there with eosinophilic exudates widespread in distri- will be an inflammatory reaction (Knowles et al., bution, often in the lungs and spleen. The 1953). Recently Darmady et al. (I955) described lesions are seen in any size of vessels with special a case of renal failure (tubular failure) due to affinity to small size arteries and veins. One of polyarteritis in a woman of 31 years who had the presented cases was exhibiting recurrent onset nephritis at the age of 12 and toxaemia of preg- of purpura without any cause, with transient on October 2, 2021 by guest. Protected nancy at the age of 26, her necropsy revealing renal jaundice, intermittent pyrexia, microcytic anaemia, polyarteritis with interstitial inflammation. raised E.S.R. and leucocytosis for two years; the Hypersensitivity Angiitis. This type of angiitis sinus infection was established and drained; a was first described by Ophiil (I923), who empha- course of appropriate antibiotics was given. He sized the ten characteristic clinical features of the also used to get attacks of asthma off and on. disease. Couple of months later he was seen with enlarged Previously described lesions of polyarteritis due and tender liver in association with microcytic to sensitivity to serum, sulpha drugs and other anaemia, leucocytosis pyrexia and raised E.S.R.; drugs: Dilantin (Rich, 1947), thiouracil (McCor- simulating subdiaphragmatic abscess. On laparo- mick, I950), iodine (Rich, 1947), differ to some tomy liver was enlarged and full of granulomatous extent from classical polyarteritis and are termed lesions. Similar granulomas were found all over hypersensitivity angiitis (Zeek, I952; Knowles the peritoneum. Histology revealed multi- et al., 1953). nucleated giant cells, granulomatous lesions O'Brien and Story (1954) recorded a case of around necrotic masses. In some cases giant cells Postgrad Med J: first published as 10.1136/pgmj.33.377.121 on 1 March 1957. Downloaded from 128 POSTGRADUATE MEDICAL JOURNAL March 1957 are arranged in radial fashion around necrotic was observed and now the diagnosis of Sch6nlein- eosinophilic masses or the small necrotic vessel. Henoch syndrome was made. A week later he Rheumatic arteritis. This type of arteritis is developed acute haemorrhagic nephritis with seen in acute fulminating rheumatism with painful joints, fulfilling the criteria of the syn- carditis, involving the vessels of heart and lungs drome. He was treated symptomatically and by with Aschoff bodies and otherwise simulates . This is an example of allergic hypersensitivity angiitis. In the cases of chronic vasculitis, produced by the streptococcal allergy rheumatism lupus-like lesions are seen in the involving vessels of the intestine, brain, skin and small cerebral vessels, first observed by Winkel- kidneys. man and Eckel (I932). It must be remembered that the site of allergic Temporal Arteritis. Horton et al. (I932) first reactions to the antigen varies remarkably. In recognized temporal arteritis. This is a benign one case the same pathological process involves member of the family with self-limiting course, the arteries (polyarteritis) and in the other the characterized by pain over the temporal arteries capillaries (Sch6nlein-Henoch vasculitis); the latter with soreness, fever and , pathologically should also be added to the group of necrotizing subacute spreads longitudinally angiitides. Thromboangiitis may be a form of slow from vasa vasorum to the media along the vessels reactive angiitis. in contrast to the lesion in the polyarteritis nodosa with the sequel of thrombosis due to intimal (b) Allergic Polyradiculoneuritis (Landry-Guillain- hypertrophy. Similar lesions are found in the Barre Syndrome) internal carotid arteries (Cloake, 1953), intra- This syndrome is de'scribed under various cranial arteries, aorta, femoral, mesenteric, renal titles. None is self-explanatory. Although this and coronary arteries (Cooke et al., I946). Ocular is called an infective polyneuritis, infective agents disorders, such as ptosis, diplopia, retinal exudates, have never been isolated. In the present state of papilloedema and loss of vision, which ultimately knowledge it is reasonable to call it 'allergic improves or is lost permanently in one-third of polyradiculoneuritis' until definite aetiology is

cases (Cooke et al., 1946). Sometimes pain in the known. Attention has been drawn that 50 per'copyright. limbs is followed by impaired or loss of tendon cent. of the cases manifest the disease two to three reflexes, transient impairment of vibration, pos- weeks after the non-specific upper respiratory tural sense and cerebellar inco-ordination have tract infection or gastro-intestinal infection at a been recorded (Cloake, 1953). time when antibodies are formed and its asso- Sch6nlein-Henoch Allergic Vasculitis. Gairdner ciation withr post-vaccinal, post-exanthematous (1948) described that the Sch6nlein-Henoch syn- and drugs hypersensitivity illnesses, also, with poly- drome, acute nephritis, rheumatic fever and poly- arteritis (Liversedge and Leather, I953> and rh-eu- arteritis, together form a family of disease linked matoid arthritis (Grant and Leopold, 1954) by the tendency for one member to co-exist with suggests hyperergic manifestation to these noxious the other. In one of his cases of this syndrome agents. Recently this is supported by the experi- http://pmj.bmj.com/ necrotizing arteritis was found in the brain. He mental production of an identical disease in regards intensive allergic vasculitis as the basis of rabbits by intradermal injection of rabbit sciatic the Sch6nlein-Henoch syndrome. nerve or spinal'ganglia with heat-killed tubercle Allergic agent, usually, is a protein. The exciting bacilli, as an adjuvant, and this disease was asso- factor may be found in the food (Squier and ciated with high protein in the C.S.F. without Madison, 1937), chocolate (Diamond, 1936), and pleocytosis (Waksman and Adams, I955). This tomatoes (Gairdner, 1948). Streptococcal infec- allergic experimental polyneuritis of Waksman on October 2, 2021 by guest. Protected tion, frequently, is incriminated. and Adams has made a momentous advancement Case.-A boy, I2 years old, with primary in our knowledge about diseases of the peripheral complex developed otitis media, which was treated nervous system of unknown origin, and also shows by penicillin and sulpha drug. A week later he that there are different kinds of the antigens in complained of abdominal colic, vomiting and the peripheral and central nervous system; the diarrhoea, which continued for one week and former produce allergic polyneuritis and the latter followed by malaena. Three days later he passed allergic encephalomyelitis in the experimental a large offensive malaena. Hess test was negative animals. and were normal. Laparotomy revealed Guillain et al. (I9I6) emphasized raised protein no evidence of surgical conditions except swollen without pleocytosis in the C.S.F. of patients and congested intestines. A week later he sud- suffering from this disease, as the diagnostic denly became unconscious with status epilepticus feature of the disease. Sometimes, in the early for four hours. Lu'mbar puncture revealed stage of the disease, C.S.F. is normal and proteins normal C.S.F. A week later diffuse purpura increase gradually as the disease progresses. The Postgrad Med J: first published as 10.1136/pgmj.33.377.121 on 1 March 1957. Downloaded from March 1957 FAZLULLAH: Neurological Complications in Hypersensitivity 129 amount of proteins depends upon the obstruction Sometimes a combination of one of these has of exit of the C.S.F. due to oedema, congestion been observed. Recently Fazlullah (I956) reported of the roots, as they pass through the inter- three cases of Landry-Guillain-Barre syndrome, vertebral canals, and increased vascular perme- fulfilling the critera of the above-mentioned ability (Haymaker and Kernohan, I949). Roots type 4. One of the presented cases exhibited entery zones are frequently involved and these glandular fever syndrome with asynmetrical are bathed freely in the C.S.F. Aring (I945) n.uropathy, simulating, partly, type 3. syndrome. described changes in the C.S.F. proteins collected Case.-A female, aged 34, following sore throat, at various levels: Li vertebral: 330 mg. per IOO two weeks later, developed generalized erythema, ml.; cisternal level: 14 mg. per ioo ml. L2ver- itching, oedema of face and limbs with paraes- tebral: 380 mg. per ioo ml.; cisternal level: thesiae. This was followed by jaundice, cervical 88 mg. per iOO ml. L3 vertebral: 1,400 mg. per lymphadenopathy, splenic enlargement, poly- ioo ml.; cisternal level: i82 mg. per ioo ml. arthritis, conjunctivitis, intermittent pyrexia and Spinal block has been shown by intrathecal- tachycardia. Asymmetrical loss of deep reflexes thorotrast. Pleocytosis in the C.S.F. is noted with loss of sensation to pain, touch and vibration when meninges are involved. Recently Fazlullah were noted in the legs. C.S.F. was normal. (1956) reported a case of Landry-Guillain-Barre Paul Bunnell test was repeatedly negative. Ab- syndrome with extensive flaccid motor paralysis, normal were found in the peri- peripheral sensory neuropathy and pleocytosis- pheral blood. L.E. cells were absent from the 8o cells per c.mm. with evidence of meningeal peripheral blood. Muscle and gland biopsy was involvement. Haymaker and Kernohan (I949) negative for polyarteritis. Serum globulin was described pleocytosis up to 514 per c.mm., and normal. Her condition was deteriorating on ascribed pleocytosis to meningeal involvement. symptomatic treatment, and she developed severe Waksman and Adams (I955) also observed pleo- exfoliative dermatitis with haemorrhagic tendency cytosis in their allergic experimental polyneuritis in the hands, conjunctivitis, persisting obstructive in case of meningeal lesions. type of jaundice, angular stomatitis and glossitis. There is no complete agreement about the

She also complained of pain in the right hypo- copyright. pathology of this disease. In some fatal cases no chondrium, and liver was palpable and tender. definite pathological changes have been found. In She was put on cortisone ioo mg. daily two weeks some cases degeneration of myelin sheath with after the onset of the present illness. Dramatic perivenous infiltration of plasma cells, lympho- improvement was noted in her clinical condition. cytes and mononuclear cells in the spinal ganglia, Cortisone was reduced gradually as her clinical roots, and peripheral nerves has been observed. condition improved without any evidence of In mild cases myelin degeneration is limited to a relapse. Two months after discontinuation of few segments with sparing of axis cylinder, while cortisone, she developed relapse of her previous in severe cases whole sensory neurone is damaged. symptoms: generalized itching, erythema and Notable feature of the disease is perivascular or fascial oedema, which were controlled by anti- http://pmj.bmj.com/ perivenous inflammatory cells infiltration in the histamines. Her eosinophilia count was 2,000. peripheral nerves which is similar to the reaction Recently Towers (I955) reported two cases of of delayed tuberculin sensitivity and other allergic similar glandular fever syndrome due to PAS states. Similar perivascular cellular infiltration is sensitivity. One of his cases developed Guillain- seen in the heart, lungs, liver, kidneys and supra- Barre type of polyneuritis with raised C.S.F. renals. protein without pleocytosis. Barnes and Barnes

Variable clinical picture and course suggest on October 2, 2021 by guest. Protected that a single disease entity manifests under the (I955) suggested that the drug containing primary guise of several slightly different clinical syn- aromatic amines like PAS can produce glandular dromes. Recently Adams (I955) classified this fever syndrome. idiopathic polyneuritis into the following clinical Glandular fever syndrome with neuropathy, types:- following non-specific upper respiratory infection i. Syndrome of symmetrical ascending motor and drug sensitivity, favours an allergic reaction paralysis with minimal sensory change. to these noxious agents and throws light on the a. Syndrome of ophthalmoplegia, fascial di- pathogenesis of the so-called glandular fever. plegia, bulbar palsy and descending motor para- Though infective aetiology is suggested, no infec- lysis of the trunk and limbs. tive agent is confirmed. Evans (1947), in human 3. Glandular fever syndrome with ascending beings, had negative results as regards transmission motor and sensory paralysis. of the disease. Dramatic response to cortisone, 4. Asymmetrical sensorimotor spinal-cranial in the above case, with evidence of tuberculin polyneuritis of subacute onset. type of sensitivity and production of an identical Postgrad Med J: first published as 10.1136/pgmj.33.377.121 on 1 March 1957. Downloaded from I30 POSTGRADUATE MEDICAL JOURNAL March 1957 syndrome by drug sensitivity, support an allergic the sensitivity to bacterial allergens (Long, 1954, mechanism. Further clinical and experimental I955, 1956). These hormones probably reverse evidences are needed to evaluate this problem. the destructive enzymatic processes in the affected cells iather than the unknown cause or suppressing Conclusions the antibodies formation, since cortisone acts In hypersensitivity states the neurological dis- more rapidly than an effect on the antibodies orders are ischaemic in origin, probably due to would be expected and the equal prompt recur- primary vascular insult, allergic oedema and dis- rence of the illness after its discontinuance.§ turbed neuronal biochemistry resulted by the immunological process, otherwise we cannot Acknowledgments comprehend the pathological findings, clinical sequence of non-specific infection followed by I wish to record my sincere thanks to Dr. B. neurological disorders after an interval of two to Morgan, Dr. K. A. Latter, Dr. A. P. B. Waind three weeks, at a time when antibodies are formed and Dr. L. Watson, consulting , for and prompt recovery by ACTH or cortisone. their advice during the study of these cases. It is a high probability that there are many Continued on page i44 antibodies having an affinity to injure different tissues such as vessels, myelin, kidney, myo- §Selye (I95I) contends that the pathogenic basis of cardium and mesenchymal tissues alternatively, collagenous disorders may be a disturbance in the ratio of minerals and glucocorticoids, ACTH and cortisone autoimmunization with multiple autoantibodies on the one hand, pit. somatotrophic hormone and DOCA seems as good as any at the moment. We know on the other hand, exert diametrically opposed effect little about the cell-fixed antibodies and other and cardiovascular-renal lesions, caused by the pit. antitissues antibodies. somatotrophic hormones, are aggravated by simul- taneous administration of cortisone. This fails to do In the allergic disorders of the central and so in the adrenalectomized rats. peripheral nervous system the earliest pathological Investigations, on steroids in the urine of patients changes are perivascular cellular infiltration and with rheumatoid arthritis, show no evidence of adrenal oedema, amelioration of which gives rise to com- insufficiency. It has been postulated that a relative adrenal insufficiency is produced due to an increasedcopyright. plete regression of neurological disorders, but if hormone demand in tissues involved in this disease. In the reaction to the certain allergens is very violent such cases ant. pit. stimulus, although increased, would then this reaction will follow with necrotizing not result in an increased plasma level of the hormones. vascular lesions with severe neuronal damage. In cases of rheumatic fever high plasma ACTH and low cortisone has been reported (V. C. Kelly, 1955, The disease process may produce different Ann. N. Y. Acad. Sci., 6i, 369). This might be due to clinical syndromes by attacking in one case adrenal exhaustion, possibly as a result of increased arteries (polyarteritis), in another capillaries steroids demand in the tissues. (Sch6nlein-Henoch vasculitis), in other veins and In cases of rheumatoid arthritis, low plasma corti- perivenous neurone (allergic encephalomyelitis of coids (J. E. Warren, I956, Ann. rheum. Dis., 15, 70) and

decreased urinary steroids excretion (S. R. Hill, Jr., http://pmj.bmj.com/ Lumsden, post-exanthematous and spontaneous H. L. Holley, W. R. Stames, and L. L. Hibbett, I956, disseminated encephalomyelitis), and in another Ann. rheum. Dis., I5, 69) in the early morning can be peripheral nerves, spinal roots and ganglia correlated with the early morning exacerbation of muscular stiffness. This might reflect a change in the (allergic experimental polyneuritis of Waksman hypathalamus-pituitary-adrenal axis. and Adams or Landry-Guillain-Barre syndrome). Recently abnormal steroid metabolites have been There may be two kinds of antigenic processes, isolated from urine of cases with rheumatoid arthritis one attacking the peripheral neurone and the other which disappear after ACTH administration (H. Wilson, 1956, Ann. rheum. Dis., X5, 70). Patients with post- central neurone of the central nervous system partum pit. necrosis are unduly liable to develop rheu- on October 2, 2021 by guest. Protected which is supported by the experiments ofWaksman matism in knee (H. L. Sheehan, 1939, Quart. J. Med., and Adams (I955) and Lumsden (I948), or both 8, 277). The changes in the cellular structure of rheu- may co-exist. Eventually these syndromes will matoid and lupus hypophysis consist of degranulation of mucoid cells (A. G. E. Pearse, 1950, Lancet, i, 954). emerge as variants of a single disease process and There is an increasing evidence that ant. pit. may be it is possible that a common aetiology may be implicated in the aetiology of collagenous disorders. established. It seems that there may be some quantitative or quali- Persistent low-grade infection induces delayed tative abnormality in the endogenous corticotrophin. However, there is no increased incidence of rheumatoid type of hypersensitivity with cell-fixed antibodies, arthritis in cases of Addison's disease or in chromophobe eventually produces necrotizing inflammation adenoma with pit. insufficiency. It is impossible, at which commonly occurs in the diseases of collagen present, to ascertain whether this alteration in the hypo- (Long, I956). If bacteria persist in the body, thalamus-pituitary-adrenal mechanism is a cause or the result of chronic disease state. Further clinical and immunity to toxins and hypersensitivity to biochemical investigations are needed to confirm the allerg. ns are associated phenomena; at this stage role 6f ' hormonal imbalance ' in the pathogenesis of administration of cortisone and ACTH depresses collagenous diseases. Postgrad Med J: first published as 10.1136/pgmj.33.377.121 on 1 March 1957. Downloaded from POSTGRADUATE MEDICAL JOURNAL March I957 It would appear from the above that the reflex explore three weeks later and excise the tumour is indeed abolished when some of the more potent together with the bifurcation of the carotid. anaesthetics such as ether are used. Unfor- 6. If possible, insert an arterial graft, but if not tunately, these have usually some other disadvan- anastomose the distal cut ends of the internal and tages, such as toxicity or inflammability, and at external carotids. the present time with the widespread use of the 7. Carry out a stellate ganglion block with local diathermy, etc., they are usually contraindicated. anaesthetic. The fact that less potent agents and combinations 8. Give anticoagulants post-operatively. such as gas, Pethidine and light Trilene do not 9. Nurse in head-down position in an oxygen greatly depress the reflex was well demonstrated tent for several days. in this case. That this is of little consequence, however, is equally clear since it is comparatively Summary simple to nullify the effects of the reflex by em- A case of carotid body tumour with marked ploying drugs with vagolytic and sympatho- sinus syncope is described. mimetic properties. The agents of choice would The problem of treatment of these tumours is seem to be Atropine and Nor-adrenaline. discussed and a plan of treatment is given. The effects of various drugs on the syncopal Suggested Scheme of Treatment attacks are discussed. t. Preliminary assessment of state of collateral Our thanks are due to Dr. R. R. Hughes, under cerebral circulation by electroencephalogram and whose care the patient was admitted, and to crossed carotid angiogram. Mr. J. Cosbie Ross, who performed the operation, 2. Exploration of tumour through a long in- for permission to publish this case. cision along the anterior border of sterno-mastoid to give a wide exposure. 3. If possible to remove the tumour without BIBLIOGRAPHY CONLEY, J. J., and PACK, G. T. (1952), SurgerY, 3I, 845. jeopardizing the internal and common carotid DANDY, W. E. (I942), Arch. Surg., 45, 52I. GOLDBERG, H. M. (I947), Brit. J. Surg., 34, 29S. vessels, do so. GRATIOT, J. H. (1943), quoted by Lahey and Warren. 4. If not, apply a temporary ligature to the HENDRICK, J. W. (i9s2), Surgery, 31, 385. copyright. LAHEY, F. H., and WARREN K. W. (I9I), 'Surgical Practice common carotid, partially occluding it, and biopsy of the Lahey Clinic', P9,hiladelphia. McSWAINE, B., and SPENCER, F. L. (1947), Surgery, 22, 222. the tumour. MATAS, R. (I934), Amer. J. Surg., 24, 692. 5. If the -biopsy shows the tumour to be MIGNINIAC, M. (I937), Mem. Acad. Chir. (Paris), 63, I65. MONRO, R. S. (1950), Brit. J. Surg., 37, 445. malignant, or if the symptoms warrant it, re- ROGERS, L. (I947), ibid., 35, 43.

Bibliography continuedfrom page 13o-S. Fazlullah, M.B.(Osmania), D.T.M. & H. http://pmj.bmj.com/ BIBLIOGRAPHY DIAZ-RIVERA, R. S., and MILLER, A. J. (1946), Ann. Intern. ADAMS, R. D. (I955),' Text Book of Medicine,' by CECIL, R. .L, Med., 2I, 628. and LOEB, R. F., 1548. EDGE, J. R., FAZLULLAH, S., and WARD, J. (I9ss), Lancet, AEGERTER, E., and LONG, J. H. (I949), Amer. J. med. Sci., i, "153. 218, 324. EHRENREICH, T., and OLMSTEAD, E. V. (I95I), Arch. Path., 52, 145- ARING, C D. (I945), Internat. Clin., 4, 262. EVANS, A. (I947), Yale J. Biol. Med., 20, 19. ASHBY, D. W., and LAZAR, T. (I95I), Lancet, i, I09I. FAZLULLAH, S. (1956), Postgrad. med. J., 32, 150. BARNES, J., and BARNES, E. ('955), Lancet, i, 455. GAIRDNER, D. (1948), Quart. Y. Med., 17, 95. BEHCET, H. (1937), Derm. Wschr., 105, 1152. GRANT, H., and LEOPOLD, H. N. (195s), Y. Amer. med. Ass., BEHCET, H. (I939), Bull. Soc. franc. Derm. Syph., 46, 674. 155, 252. BEHCET, H. (1940), Dermatologica. Basel, 8I, 73. GREENFIELD, J. G. (I950), Brain, 73, 141. BENDA, C. E. (I949). Arch. Neurol. Psychiat., 6x, 137. on October 2, 2021 by guest. Protected BLACKWOOD, W. (I956), P1oc. Roy. Soc. Med., 49, 146. GRUBER, G. B. (1925), Arch. f. Path. Anat., 258, 441. BREUTSCH, W. L. (1942), Trans. Amer. neurol. Ass., 68, 17. GUILLAIN, G., BARRP-, J. A., and STROHL, A. (I9I6), Bull. et BYWATERS, E. G. L. (I956), Proc. roy. Soc. Med., 49, 287. mim. Soc. mid. d. h6p. de Paris, 40, 1462. CAMPBELL, B., and GOOD, R. A. (I950), Arch. Neurol. Psychiat., HAM, A. W. (1940), Arch. Path., 29, 73I. 63, 298. HARGRAVES, M. M., RICHMOND, H., and MORTON, R. CAVANAGH, J. B. (I953), J. clin. Path., 6, 128. (1948), Proc. Staff Meeting, Mayo Clin., 23, 25. L. HAYMAKER, W., and KERNOHAN, J. W. (1949), Medicine, CHURG, J., and STRAUSS, (i95I), Amer. J. Path., 27, 277. 28, 59. CLARK, E. C., and BAILEY, A. A. (I956), J. Amer. med. Assoc., K. W. G., and WILLIAM, J. R. B. x6o, 455. HEATHFIELD, (1954), CLARK, E., and KAPLAN, B. I. (I937), Arch. Path., 24,458. Lancet, ii, 673. CLOAKE, P. C. P. (i95i), 'Modern Trends in Neurology,' by HORTON, B. T., MAGATH, T. B., and BROWN, G. E. (1932), Feiling, A., 466. Proc. Mayo. Clin., 7, 700. CLOAKE, P. C. P. (I953), V. Internat. Neurol. Congress, I, 25. KABAT, E. A., WOLF, A., and BEZER, A. E. (I947),. exp. Med., COLOVER, J. (I954), Brain, 77, 435. 85, 117- COLOVER, J., and CONSDEN, R. (I955), Excerpta. med. (Amst.), KERNOHAN, J. W., and WOLTMAN, H. W. (1938), Arch. Sect. VIII, 8, 8o8. Neurol. Psychiat., 39, 655. COLOVER, J. (1956), Proc. roy. Soc. Med., 49, 154. KLEMPERER, P. (1948), Atn. intern. Med., 28, I. COOKE, W. T., CLOAKE, P. C. P., GOVAN, A. D. T., and KLINGE, F. (1929), Beitr. path. Anat., 83, x85. COLBECK, J. C. (1946), Quart. Y. Med., 15, 47. KNOWLES, H. C., ZEEK, P. M., and BLANKENHORN, M. A. DARMADY, E. M., GRIFFITHS, W. J., SPENCER, H., MAT- (I953), Arch. Int. Med., 92, 789. TINGLY, D., STRANAK, F., and WARDENER, H. E. DE KULKA, J. P., BOCKING, D., ROPES, M. W., and BAUER, W. (I95s), Lancet, i, 378. (955), Ardh. Path., 59, 129. DIAMOND, J. (1936),J. Pediat., 8, 697.