NEUROLOGICAL COMPLICATIONS IN HYPERSENSITIVITY · I1I NEUROLOGICAL COMPLICATIONS IN HYPERSENSITIVITY By S. FAZLULLAH, M.B.(Osmania), D.T.M. &H. Late MedicalRegistrar, Barrow-in-Furness

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NEUROLOGICAL COMPLICATIONSIN HYPERSENSITIVITYBy S. FAZLULLAH, M.B.(Osmania), D.T.M. & H.

Late Medical Registrar, Barrow-in-Furness Group of Hospitals, Lancs.; Medical Registrar, Pontefract and CastlefordGroup of Hospitals, Yorks.

Hypersensitivity state is the altered activity ofcells to any foreign substances, a normal physio-logical phenomenon of protective adaptation.Allergy and hypersensitivity are our saviour forwhich we should be grateful to nature. Allergyis now being applied commonly to the pathologicalvariants of the physiological process. Allergy,physiologically, allows the organism to react toantigenic substances to neutralize them.

Antigen antibody reaction, in certain people,may end naturally without any after-effects andin others may terminate in pathological process,presumably due to inherent individual consti-tutional defect and defective enzyme system incertain tissues or defect in the natural process ofthe immunity with the production of abnormalantibodies, possessing affinity to certain tissueswith a capability of injuring them. Identificationof antibodies, other than those occurring instreptococcal infection, has not been often estab-lished, though some have reported antireticulin,antimyocardial and antirenal antibodies.* At themoment we know little about cell-fixed antibodies.

AutosensitizationIn certain- people, autoimmunization, following

autosensitivity to certain endogenous products,might play a part in the production of multipleantibodies. A good clinical example of auto-immunization is found probably in lupus erythe-matosus, which is presented with haemolyticanaemia in association with circulating antibodie§proved by positive Coombs' test, thrombocyto-penic purpura, false positive W.R., increasegamma-globulin and multiple antibodies formationfollowing blood transfusion. If lupus is regardedas a disease of autoimmunization, we do not knowwhat antigenic substance is involved nor howit is rendered autoantigenic. Lupus, rheumatoidarthritis, polyarteritis and dermatomyositis differ

*Globulin fraction on antikidney serum tagged withIl3 is localized primarily in the glomeruli as determinedby radioautograph.

from acute and self-limited collagen disease inthat the course is protracted over many years,and if they are diseases of hypersensitivity wemust postulate that the antigenic substance mustbe present in the body throughout this long periodof activity, probably not being neutralized due todefective process of the immunity. The samecan be applied to disseminated sclerosis in whichmyelin sheath is involved instead of connectivetissue.

Hypersensitivity and Collagen DiseasesPirquet's original concept (I903) of allergy has

withstood the test for 50 years and is substantiallytrue today. The clinical manifestations of hyper-sensitivity now can be classified in four maingroups:

i. Asthma, hay fever and infantile eczema.2. Serum sickness, drug allergy and contact

dermatitis.3. Bacterial and viral allergy (yet in infancy).4. Autoimmunization, lupus, thrombocytopenia,

haemolytic anaemia and hyperfunction of reticulo-endothelial system. with auto-antibodies formation(Bywaters, I956).There is widespread assumption that collagen

diseases are probably due to hypersensitivity(Rich, 1946). Fibrinoid necrosis of collagen, suchas seen in acute rheumatism, polyarteritis followinginfection and serum sickness (Rich, 1946), canalso be found in mechanical injury to collagensuch as in malignant hypertension, peptic ulcerand acute pancreatitis (Klemperer, 1948). Thereis no convincing evidence that collagen itself isinvolved. Klemperer himself now believes thatfibrinoid of lupus is probably derived from thebreakdown of nucleic acid, supposed to be set inprocess by gamma-globulin, a serum factor pro-duced during autoimmunization. Gamma-globulininactivate the desoxyribonuclease inhibitor enzymeand allow nuclear degeneration of leucocyteswhich consequently is ingested by polymorphs.These deep purple staining bodies are found in

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connective tissues identified by Klemperer (1948)as desoxyribonucleic acid. The same was foundin lupus erythematosus cell and marrow by Har-graves et al. (I948).The efficiency of cortisone and ACTH in

arresting the disease process in rheumatoidarthritis and lupus may depend upon the abilityof these hormonal agents to reverse this destruc-tive enzymatic process in the affected cellsrather than upon the unknown cause of thedisease. This hypothesis is supported by theprompt effect of the therapy and equally promptrecurrence of illness upon withdrawal of theseagents.

Hydralazine (apresoline), used for hypertension,can also produce mesenchymal reaction simulatinglupus and rheumatoid arthritic features in asso-ciation with lupus erythematosus cell phenomenon.These lupus erythematosus cells are also found inpenicillin sensitivity and virus hepatitis. Apreso-line has a strong affinity to combine with carbonyland sulph-hydryl groups. Thus we can producethe disease at will in animals and can study itspathology.Many clinical and pathological features are

common to all collagen diseases, with some varia-tion in intensity and distribution. Hypersensitivityis a common factor to all. Disease may startwith one syndrome predominating; as it pro-gresses, this is replaced by another. In each casecellular infiltration and fibrinoid necrosis is asso-ciated with lymphoid hyperplasia and gamma-globulinaemia. Increase gamma-globulin is re-garded as a response to antigen antibody reaction(Aegerter and Long, I949; Long, 1954, 1955).The pathology of early stage is unknown. In anexperimental analogous disease the earliest lesion,in guinea-pig, is oedema (Long, 1954, I955), andthis is shown in rheumatoid arthritis (Kulka et al.,1955) which is soon associated with cellularinfiltration and vascular insult.

Neurological Complications inHypersensitivityMayo Clinic has played an important role in

advancing the knowledge of lupus. Clark andBailey (I956), of the same institute, have drawnattention to the frequency with which mental andneurological complications occur in this disease.They reviewed the neurological complications insystemic lupus observed at Mayo Clinic; theseincluded convulsions, mental disease, hemiplegia,polyneuritis, subarachnoid haemorrhage, vertigo,nystagmus, chorea, monoplegia. Pathologicalstudy revealed widespread vascular lesions in thecentral nervous system. Similar neurologicalcomplications have also been observed in poly-arteritis.

Involvement of the central nervous system hasalso been observed in Behcet syndrome (Behcet,I937, I939, I940) and in Steven Johnson syndrome(Ashby and Lazar, 195I) resembling disseminatedsclerosis, presenting the same basic pathology asseen in hypersensitivity.There is a growing evidence to believe that

post-infectious perivenous demyelinating encepha-lomyelitis and post-infective polyradiculoneuritis(Landry-Guillain-Barre syndrome) are allergicreactions. These diseases are manifested 7-14days following the infection, at a time when anti-bodies are being formed with a tendency tospontaneous recovery. Miller (1956) believes thatthese are secondary to the initial vascular insult,probably due to hypersensitivity. This toxic-allergic complication had been for many yearsthe explanation of rheumatic fever and glomerulo-nephritis following streptococcal infection. Inpost-infectious neurological disorders there is adamage to the melin sheath, while in the collagendisorders connective tissue is injured. We do notknow the exact mechanism of these syndromes ofunknown cause.

Clinical MaterialThe present paper deals with the neurological

disorders observed in cases with hypersensitivitymanifestations: drug allergy, polyarteritis, sys-temic lupus, hypersensitivity angiitis and post-infection allergy. Twenty-one cases have beenobserved; signs and symptoms are analysed.

TABLE I No. ofDiseases cases

Polyarteritis .. .. .. .. .. 3Schonlein-Henoch allergic vasculitis .. ..IHypersensitivity angiitis .. .. .. IAllergic granulomatous angiitis .. ..IPulmonary lupus .. .. .. .. .. 2Allergic polyradiculoneuritis .. .. 4Spontaneous acute disseminated encephalo-

myelitis:(a) Myelitis type .. .. .. 3(b) Encephalomyelitis type .. .. 2

Glandular fever syndrome.. I-.. ..Meningococcal meningitis .. .. .. ..Drugs allergy .. .. .. .. .. 2

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TABLE 2 No. ofHypersensitivity States cases

Upper respiratory tract non-specific infections ioAsthma with eosinophilia (48% in one case) (io%

in other case) .. .. .. .. .. 2Meningococcal infection .. .. .. ..Staphylococcal .. .. .. .. ..Streptococcal .. .. .. .. ..Drugs allergy .. .. .. .. ..Unknown .. .. .. .. .. .. 4

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March 1957 FAZLULLAH: Neurological Complications in Hvpersensitivity 123

TABLE 3No. of

Neurological disorders casesNeuropathies:

(a) Symmetrical polyneuritis in the legs 3(b) A symmetrical polyneuritis (mononeuritis

multiplex) .. .. .. . 3Asymmet. polyradiculoneuritis .. 4Hyper-reflexia followed by areflexia 3Transversemyelitis .. .. .. 4Encephalitis . . .. .. .. IMononeuritis (R. ext. popliteal palsy) 2Convulsions .. .. .. .. I

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TABLE 4No. of cases

Age in Years Male Female0-10 0 0I0-20 .. .. 3 020-30 0 I

30-40 0 440-50 3 35o-60 .. 260-70 .. 2 I70-80 .. .. 0 I

A. Spontaneous Acute DisseminatedEncephalomyelitisA form of acute disseminated encephalomyelitis

clinically and pathologically identical with post-exanthematous and post-vaccinal encephalomye-litis may occur following on an influenzal type offebrile illness. McAlpine reviewed the clinicalpicture and described a cerebral and a spinalclinical type (I93I). Miller and Evans (I953)regard this illness as a non-specific allergicreaction of the C.N.S. to various antigens, chieflybacterial and virus infection, and possibly otherkinds as well.

Clinical FeaturesIn the five presented cases onset of the neuro-

logical complications was sudden, following anon-specific upper respiratory tract infection, twoto three weeks previously, at a time when anti-bodies are formed.

Case.-Female, age'd 45, developed spontaneous,cute disseminated myelitis in association withpyrexia I00° F., tachycardia, headache, depressionand transverse myelitis. She exhibited unusualhyperalgesia to cold on the left leg. She wasshowing remissions and relapses of motor paralysisin the legs successively within a short time fortwo months. These were controlled by a courseofACTHt gel. 40 units b.d. for one week, followedby cortisone ioo mg. daily which was reducedgradually to 12.5 mg. in a six weeks' time, which

tACTH and cortisone may be dangerous in cases ofvirus diseases such as polio, bacterial infection of C.N.S.(abscess) and T.B. meningitis. These diseases shouldbe excluded before their administration.

was maintained for a further six weeks. Twomonths later she was seen when complete regres-sion of the transverse myelitis was found. C.S.F.was normal, except raised proteins up to 50 mg.per ioo ml.

Case.-Female, aged 32, developed spontaneousacute disseminated encephalomyelitis following anon-specific upper respiratory tract infection twoweeks prior to the illness, in association withpyrexia I020 F., headache, neck stiffness, diplopia,severe dysarthria, cerebellar ataxia, flaccid limbswithout changes in the reflexes and tachycardia.C.S.F. examination revealed normal pressure withraised protein (I20 mg. per ioo ml.) and cells(I50 mononuclear cells per c.mm.). She wastreated symptomatically with complete recoveryin six weeks. In such cases pleocytosis is due tomeningeal involvement, otherwise proteins areraised and sometimes C.S.F. is normal.Some cases are presented with hemiplegia,

hemianopia, aphasia, convulsions, and focal neuro-logical signs (McAlpine, I93I). Motor weaknessin the lower limbs may progress to completeparaplegia as occurred in the above-describedfirst case, in a day or two of the onset, but may bedelayed up to three weeks. The way in whichfresh neurological symptoms appear, within thefirst three weeks, but in rare instances up to fewmonths from the onset, as in the first case, isregarded highly characteristic. Mortality rate islow. Recovery is complete, though in some casessequelae remain. Inclusion bodies encephalitisusually terminates fatally, but may becomearrested.

Radicular type of pain in the back was com-plained by four cases. This is an importantcharacteristic feature of acute disseminated mye-litis which differentiates it from disseminatedsclerosis.

Headache, fever and tachycardia with absenceof euphoria were present in all. Extensive sensoryloss to vibration, joint sense, pain temperaturewith acute paraplegia was noted in four cases- ofdisseminated myelitis which is rarely observed indisseminated sclerosis.

In cases of disseminated myelitis, if residualsigns persist after acute stage, then diagnosisfrom disseminated sclerosis is extremely difficult.The diagnosis is based upon history of onsetfollowing infection, characteristic symptoms andabsence of any extension of the physical signsafter first three weeks of illness. Occasionallydisseminated encephalomyelitis and acute dis-seminated myelitis follow a relapsing course(McAlpine, I93I; Miller and Evans, 1953). Thiswas noted in one case up to two months whichwas controlled by cortisone and ACTH therapy.Miller (I953) has used ACTH for the treatment;



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of acute disseminated encephalomyelitis. McAl-pine (I93i) has drawn attention to the followingpoints as diagnostic for acute disseminatedencephalomyelitis:-

i. A temperature of over I000 F.2. Severe shooting pain.3. Absence of euphoria.4. Loss of pain and thermal sensibility, or

diminution of all sensation below the sensorylevel, or presence of dissociated anaesthesia.

5. Motor weakness in the lower limbs with para-plegia is usually noticed within a day or two ofillness, or delayed till the end of two or threeweeks. Reflexes are exaggerated or abolished.Fresh neurological signs appear within the firstthree weeks or delayed up to few months withcomplete recovery. Sphincter disturbance iscommon. Ataxia with rapid and fine nystagmusis present. Bilateral optic neuritis with myelitissimulate Devic's disease, which is also observedafter measles and vaccination.The presented five cases were fulfilling the

criteria described by McAlpine. Three casesdeveloped paraplegia within two weeks of theonset of illness with extensive sensory loss, and inone case onset was delayed to three weeks andfresh neurological signs were appearing up totwo months with paraplegia and extensive sensoryloss in the legs.

AetiologyThe development of encephalomyelitis following

specific fevers, vaccination and during antirabictreatment has long been recognized. Post-vaccinaland post-infectious neurological complicationshave an identical pathology. Although this isdesignated as encephalomyelitis,'an infective agenthas never been isolated from the central nervoussystem. Recent experiments with the injectionsof homologous and heterologous brain tissue withadjuvants (dead tubercle bacilli and mineral oil)produced the pathological picture resembling thepost-infective encephalomyelitis and throw doubton infectious aetiology of the disease (Kabat et al.,I1954; Wolf et al., I947; Lumsden, 1I949, I956).The nature of. the antigen and the mechanism ofbrain damage has not yet been elucidated. Colover(1954-56) and Colover and Consden (I955) havedemonstrated that the active agent in the deadtubercle bacilli is an insoluble somatic proteinbound compound which is mainly formed ofamiino-acids with a long chain fatty acid ratherthan lipid or wax or polysaccharides. The roleof adjuvants is described as purely potentiatingand it must be given at the same site. Lumsden.949) also demonstrated that active agent in theinjected brain was protein or protein-bound com-pound rather than a lipid.

Russell (I955) described fibrinoid necrosis ofthe vessels in acute haemorrhagic leucoencepha-litis and polyarteritis type of vascular lesions inacute disseminated myelitis. She also describedplasma cells and their precursors in the spleen ofboth type of cases and concluded that ' allergy ' isthe basis of reactions in the central nervoussystem. Campbell and Good (1950) also describedplasma cells in the spleen of guinea-pigs withexperimental allergic encephalitis. Encephalitisfollowing arsphenamine (Russell, 1937), strepto-mycin and P. aminosalicylic acid (Cavanagh,I953) is possibly the result of hypersensitivity.Acute haemorrhagic leucoencephalitis charac-terized by febrile illness, headache, vomiting,stupor with or without hemiparesis with poly-morphonuclear leucocytosis in blood and highcell counts in the cerebrospinal fluid with manypolymorphs and signs of acute disseminatedencephalomyelitis represent different grades ofintensity of reaction to a similar pathologicalprocess (Greenfield, I950; Russell, I955).

Miller and Evans (I953) believe that acutedisseminated encephalomyelitis is the result ofnon-specific allergic reaction in the central nervoussystem, to various antigens-bacterial, virus andother kinds. Acute disseminated encephalo-myelitis and acute haemorrhagic leucoencephalitisare similar to the experimental allergic encepha-litis, post-vaccinal and post-exanthematous peri-venous demyelinating diseases, serum sickness,angio-neurotic oedema, glomerulonephritis andpurpura (Miller and Evans, I953). Miller (1956)believes that the neurological disorders aresecondary to the initial vascular insult in post-exanthematous encephalitis. Blackwood (1956)concluded that the histopathology is too slenderto exclude or confirm allergy in the pathogenesisof post-exanthematous encephalomyelitis.

Recurrence in post-exanthematous encephalo-myelitis is unknown and also in illness followingspecific fevers. If nervous disorder follow a minornon-specific infection of upper respiratory tract,lasting immunity, in such cases, is lacking andrepeated such antigenic insults play a part in thepathogenesis of recurrence of neurological dis-orders (Miller and Evans, 1953). This factexplains the recurrence of neurological disorderin one of the presented cases up to two months.Perhaps this, also, explains the relapses in dis-seminated sclerosis.

Recently the aetiology of disseminated sclerosisis narrowed down to infection and allergy(McAlpine, I956). The possible source of infec-tion is the upper respiratory infection to whichlasting immunity is lacking. Abrupt onset, relaps-ing, remitting course, increased globulin in theC.S F., occasional association with the other form



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March 1957 FAZLULLAH: Neurological Coinplications in Hypersensitivity

of allergy and recurrence of the attacks followinginfection, fatigue, lowered state of general health,trauma and emotional upset favour allergy.Perhaps the silent reactivated allergens or the newallergens, due to the defective immunity, producefresh crops of antibodies, consequently newlesions are produced in the C.N.S. Autoimmuniza-tion seems as good as any at the moment.Many potential allergic patients who keep good

health and live in a favourable environmentescape allergic symptoms. They remain in so-called allergic balance, so that their symptomsremain subclinical. Once the natural defenceshave been lowered by infections, nutritional dis-turbances, hormonal imbalance stress, markedweather changes, habits, drugs, vaccines andpsychosomatic disorders which impair their well-being, allergic manifestations emerge in severeforms, and if not corrected early lead to acrippling invalidism.

In recent studies in U.S.A., Lubens (I955)reports on 300 cases of poliomyelitis, and statesthat the incidence of bulbarpolio was found to beas much as five times as great among those withan allergic history as among those without suchbackground. The mortality from polio was alsogreater among allergic than among the non-allergic.

B. Neuropathies and Hypersensitivity(a) Polyarteritis NodosaKussmaul and Maier (i866) described neuro-

pathy in their original case of periarteritis nodosa.Since then the incidence of it, in different series,has varied from 8 to io per cent. Kernohan andWoltman (I938) first differentiated the successiveinvolvement of peripheral nerves (mononeuritismultiplex) from symmetrical involvement of theperipheral nerves in polyarteritis nodosa. Millerthought that the symmetrical type of polyneuritisis common (I949). Heathfield and William (I954)described one case of mononeuritis multiplex andseven cases of symmetrical polyneuritis, andplaced diabetic neuropathy first, infective poly-neuritis second and polyarteritis nodosa neuro-pathy third in order of frequency.

Necropsy of cases of polyarteritis nodosa revealsmacroscopic arterial lesions in the heart, kidney,liver and intestinal tract with yellowish mottlings(infarctions) due to arterial occlusion. Histologyof peripheral nerves shows polyarteritis nodosalike lesions in vasa nervorum and nutrient vesselsof the peripheral nerves with their occlusion andinflammatory oedema (Kernohan and Woltman,1938; Miller, 1949; Lovshin and Kernohan, I948;Heathfield and William, 1954).

In all such cases local pain, loss of tendonreflexes, subjective and objective sensory loss,

paresis, myositis tend to be conspicuous symp-toms and signs. Particular reference may be madeto the occurrence of unexplained foot drop, wristdrop in *association with pyrexia, 'microcyticanaemia, albuminuria, raised E.S.R., increasedgamma-globulin, altered liver functions, raisedB.P., leucocytosis and wasting of muscles whichare highly suggestive of polyarteritis nodosa.

Variety of neurological disorders are describedin cases of polyarteritis nodosa: fits (Malamudand Foster, 1942), hemiparesis (Malamud an'dFoster, I942), chorea (Neale and Whitfield, I934),Parkinsonism (Sheinker, I945), subarachnoidhaemorrhage (Malamud and Foster, I942), bulb"arsyndrome (Runge and Melzer, 1930), Ramsay andHunt syndrome (Spiegel, 1936), clinical picture ofintracranial neoplasm (Diaz-Rivera and Miller,I946).

Symmetrical neuropathy in the legs was ob-served in two cases of polyarteritis and mono-neuritis multiplex: right foot drop, wasting ofthe small muscles of the hands, asymmetrical lossof reflexes in the legs with subarachnoid haemor-rhage, diplopia, 48 per cent. eosinophilia withasthma in one case; another case was sufferingfrom asthma before the onset of neuropathy inthe legs. One case, following meningococcalinfection and sulpha drug therapy, developedmononeuritis multiplex: right Bell's, left ulnar andright external popliteal palsies which improvedgradually. In two cases mononeuritis neuropathy(right external popliteal N. palsy) was asso-ciated with pyrexia, microcytic anaemia, raisedE.S.R. and pain in legs. In one of them infectivefocus of staphylococcus was established,' butappropriate chemotherapy was ineffective.One case (female, aged 74) exhibited a mixed

picture of polyarteritis and systemic lupus withsymmetrical neuropathy in the legs. She washaving recurrent attacks of conjunctivitis betweenI95I and 1955, pleuritic pain with pulmonaryrales at right base of the lung, off and on, jaundice,giddy turns and developed diabetes which wastreated symptomatically. She developed coronarythrombosis 'on March 28, 1955, with congestiveheart failure; now conjunctivitis recurred. Shewas treated by the anticoagulants, digoxin andmercurial diuretics. On April 23, I955, shedeveloped generalized measly and urticarial rash,angular stomatitis was noted on May 5s '955; thiswas followed by glossitis, vitamin B and nicotinicacid was ineffective. Two weeks later she passedlarge offensive malaenous stools with abdominalcolic. This was followed by dysphagia; skinlesions now were changed into healed polymorphic,purpuric and papulogranulomatous appearances;exfoliation was observed, later on, in the legs,peripheral arterial pulsations were absent in legs



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with loss of deep reflexes; loss of sensation topain, touch and vibration. Serum globulin andE.S.R. were raised. L.E. cells (lupus erythe-matosus cells) were absent from peripheral blood,and biopsy was negative. In view of above findingslupus-polyarteritis complex was considered andshe was put on cortisone ioo mg. daily. Twoweeks later a dramatic improvement was noted inher abdominal pain, dysphagia, diarrhoea andfrequency of malaenous stools, which decreasedgradually. Cortisone was decreased gradually andwas stopped on July 26, I955. She developedrelapse of cardio-pulmonary symptoms fourmonths later on; and cortisone was restarted.Now her neuropathy in the legs improved, butloss of deep reflexes persisted and skin was glassyin appearance. She became bald.Three cases of drug sensitivity showed hyper-

reflexia followed by areflexia, paraesthesiae in thelegs, conjunctivitis, measly rash, abdominal painand lymphadenopathy. Asymmetrical loss ofreflexes was also observed in three cases (glandularfever, pulmonary lupus, hypersensitivity angiitis).Perivascular retinal exudate was observed in thecase of hypersensitivity angiitis.

Aetiology.-Aetiology is still unknown. Furtherinvestigations are needed in the sphere of histo-chemistry and electron microscopy to throw morelight on the pathogenesis of idiopathic necrotizingangiitides. Gruber (1925) suggested that it maybe a manifestation of hyperergic reaction tovariety of antigens: infections, toxic agents anddrugs to which blood vessels had been previouslyexposed.Ophuls (1923) expressed that individual types

develop the disease and suggested that the lesionsare the result of actions of various infections andtoxic agents on the predisposed vessels. Theobservation that the disease often follows someinfections, particularly streptococcal infection, anda similarity between it and acute rheumatismsuggests that polyarteritis may be a result ofallergy iti a constitutionally defective individual.Association of asthma favours allergy as anaetiological factor.

Subsequently experimental production of hyper-sensitivity in animals revealed necrotizing lesionsin the blood vessels (Klinge, I929; Clark andKaplan, 1937; Rich, I942; Rich and Gregory,1943). Such lesions and those produced by drugallergy differ to some extent from the classicaltype of periarteritis nodosa of Kussmaul and Maier(i866), and are termed hypersensitivity angiitis(Zeek, 1952-53; Knowles et al., 1953).

Fibrinoid necrosis is also observed in non-specific injury: malignant hypertension, pepticulcer, acute pancreatitis (Klemperer, I948), over-dose of DOCA and salt, large dose of ACTH

(Selye, I944), and large doses of ergosterol dietrich in calcium and phosphorus (Ham, I940).

Cortisone and ACTH opened a new field forthe investigation of various types of necrotizingarterial lesions. Ehrenreich and Olmstead (195I)reviewed the detrimental and beneficial effect ofthese hormones in periarteritis nodosa. Thevariable effects of these hormones suggest morethan one kind of necrotizing angiitis and needmore clinical and experimental observations,whether one kind is benefited and other is harmed(Zeek, 1952). Polley (I956) of Mayo Clinic,home of cortisone, discussing the status of thesehormones, described that overdose and chronichormonal excess can produce mesenchymal reac-tionst simulating lupus, polyarteritis, light sensi-tivity, transfusion reaction, false serological reac-tions during blood grouping, articular pain andmuscular ache. Edge, Fazlullah and Ward (I955)noted variable effect of cortisone in a case ofhypersensitivity angiitis. There may be sometypes in the group of necrotizing angiitides,reacting differently to these hormones.

Recently Zeek (I952-53; Knowles et al., I953)suggested a new terminology, collectively, forvarious types of polyarteritis as necrotizingangiitides which is a non-committal as far asaetiology is concerned. They classified necro-tizing angiitides into five clinical types. Theremay be other types still unclassified. The followingis modified from Zeek classification:

i. Hypersensitivity angiitis.2. Allergic granulomatous angiitis.3. Polyarteritis: (a) Primary polyarteritis, (b)

secondary polyarteritis.4. Rheumatic arteritis: (a) Acute type, (b)

chronic type.5. Temporal arteritis.6. Shonlein-Henoch allergic vasvulitis.Winkelman and Eckel (1932) described cerebral

arteritis simulating the changes seen in acutedisseminated lupus, in cases of rheumatism andchorea of moderate chronicity. Benda (1949) andBreutsch (I942) described cerebral arteritis withsubintimal proliferation, filling lumen of smallarteries, in cases of chronic rheumatism. Similarlesions are seen in the heart. These changes may

+ In some cases these reactions are the manifestationsof exacerbation of the disease process (polyarteritis orlupus) for which these hormones were used. Someyears ago it was found that periarteritis nodosa lesions,produced by DOCA, can be duplicated by Pit. Somato-trophic hormone (H. Selye, 195i, Lancet, i, 483). Thiseffect is inhibited by cortisone but only under conditionswhich induce marked adrenocortical atrophy. He alsoshowed that cortisone prevents periarteritis nodosa inthe mesenteric vessels, induced by DOCA, but does notexert such preventive action on the arteries of heart,kidney and certain organs.



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reasonably be regarded as slow inactive sensitiza-tion of vascular tissue.

Before I900 published cases of polyarteritisrevealed macroscopic nodular lesions in everycase; there was a microscopic confirmation. InI903 Veszpremi and Jancso described a case ofpolyarteritis without macroscopic nodular lesionswhich was diagnosed microscopically (microscopicpolyarteritis). In 1923 Ophuls was the first todescribe the case of hypersensitivity angiitis, inwhich pulmonary small vessels were badlydamaged, and there were widespread eosinophilicgranulomatous lesions. Recently Edge, Fazlullahand Ward (I955) described a case of hyper-sensitivity angiitis in which pulmonary arterieswere extensively involved.Primary Polyarteritis Nodosa. This group of

polyarteritis comprises the clinical type of poly-arteritis described by Kussmaul and Maier (i866),characterized by a long course, remissions,exacerbations, nodular macroscopic lesions, poly-,neuritis, fever, anaemia and multi-systems involve-ment. Necropsy reveals nodular lesion at thepoint of branching of small and medium sizearteries, widespread in distribution in the vesselsof mesentery, pancreas, liver, kidney, coronary,peripheral vessels and absent from the pulmonaryvessels unless pulmonary hypertension is asso-ciated. Splenic follicular arterioles are also in-volved. Arterial lesions of various ages are seenwith the sequelae of renal hypertension andarterial obstruction.

Secondary Polyarteritis Nodosa. In this type ofpolyarteritis lesions in the arteries develop shortlybefore death in cases of severe renal disease andin hypertension or of both. In cases of malignanthypertension necrotizing lesions are seen in thekidneys, but inflammatory reactions are absent orminimal, while in the secondary polyarteritis therewill be an inflammatory reaction (Knowles et al.,1953). Recently Darmady et al. (I955) describeda case of renal failure (tubular failure) due topolyarteritis in a woman of 31 years who hadnephritis at the age of 12 and toxaemia of preg-nancy at the age of 26, her necropsy revealing renalpolyarteritis with interstitial inflammation.

Hypersensitivity Angiitis. This type of angiitiswas first described by Ophiil (I923), who empha-sized the ten characteristic clinical features of thedisease.

Previously described lesions of polyarteritis dueto sensitivity to serum, sulpha drugs and otherdrugs: Dilantin (Rich, 1947), thiouracil (McCor-mick, I950), iodine (Rich, 1947), differ to someextent from classical polyarteritis and are termedhypersensitivity angiitis (Zeek, I952; Knowleset al., 1953).

O'Brien and Story (1954) recorded a case of

hypersensitivity angiitis caused by phenylbutazonehypersensitivity. On necropsy histology, poly-arteritis, granulomatous lesions and hypersensi-tivity angiitis were found.

Edge, Fazlullah and Ward (I955) described acase of hypersensitivity angiitis caused by peni-cillin, streptomycin, isoniazid and cortisone.Hypersensitivity angiitis is characterized by shortfatal course, involvement of arterioles, venules,capillaries, interstitial inflammation in the involvedviscera, and necrotizing glomerulonephritis. Thelesions are of the same age with no healing stageon the microscopy. Vessels of kidney, heart,lungs and splenic follicular arterioles are speciallyinvolved. The arterial lesions are uncommon inthe intestinal tract. Usually there is a history ofsensitivity to serum, sulpha drugs and otherdrugs. There may be other types of hypersensi-tivity angiitis. Knowles et al. (I953) noted, in oneof ten cases of hypersensitivity angiitis, earlywire loop lesions of lupus in the renal tissues, inwhich course of the disease was delayed. Lupusdisseminata and systemic lupus may be a form ofhypersensitivity angiitis (visceral necrotizing angi-itis). Recovery can occur in mild cases of hyper-sensitivity angiitis with exacerbation.

Allergic Granulomatous Angiitis. This type ofangiitis is a systemic granulomatous condition andoccasionally is described as a polyarteritis whicheventually results after pulmonary eosinophilia-and asthma with high eosinophilia, one to sevenor many years later on.

Allergic angiitis was described by Churg andStrauss (1951), which is characterized by fever,asthma, eosinophilia, multinucleated giant cellsgranuloma in the extravascular tissues and serousmembrane. The lesions are seen at various stageswith eosinophilic exudates widespread in distri-bution, often in the lungs and spleen. Thelesions are seen in any size of vessels with specialaffinity to small size arteries and veins. One ofthe presented cases was exhibiting recurrent onsetof purpura without any cause, with transientjaundice, intermittent pyrexia, microcytic anaemia,raised E.S.R. and leucocytosis for two years; thesinus infection was established and drained; acourse of appropriate antibiotics was given. Healso used to get attacks of asthma off and on.Couple of months later he was seen with enlargedand tender liver in association with microcyticanaemia, leucocytosis pyrexia and raised E.S.R.;simulating subdiaphragmatic abscess. On laparo-tomy liver was enlarged and full of granulomatouslesions. Similar granulomas were found all overthe peritoneum. Histology revealed multi-nucleated giant cells, granulomatous lesionsaround necrotic masses. In some cases giant cells



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are arranged in radial fashion around necroticeosinophilic masses or the small necrotic vessel.

Rheumatic arteritis. This type of arteritis isseen in acute fulminating rheumatism withcarditis, involving the vessels of heart and lungswith Aschoff bodies and otherwise simulateshypersensitivity angiitis. In the cases of chronicrheumatism lupus-like lesions are seen in thesmall cerebral vessels, first observed by Winkel-man and Eckel (I932).

Temporal Arteritis. Horton et al. (I932) firstrecognized temporal arteritis. This is a benignmember of the family with self-limiting course,characterized by pain over the temporal arterieswith soreness, fever and malaise, pathologicallysubacute giant cell arteritis spreads longitudinallyfrom vasa vasorum to the media along the vesselsin contrast to the lesion in the polyarteritis nodosawith the sequel of thrombosis due to intimalhypertrophy. Similar lesions are found in theinternal carotid arteries (Cloake, 1953), intra-cranial arteries, aorta, femoral, mesenteric, renaland coronary arteries (Cooke et al., I946). Oculardisorders, such as ptosis, diplopia, retinal exudates,papilloedema and loss of vision, which ultimatelyimproves or is lost permanently in one-third ofcases (Cooke et al., 1946). Sometimes pain in thelimbs is followed by impaired or loss of tendonreflexes, transient impairment of vibration, pos-tural sense and cerebellar inco-ordination havebeen recorded (Cloake, 1953).

Sch6nlein-Henoch Allergic Vasculitis. Gairdner(1948) described that the Sch6nlein-Henoch syn-drome, acute nephritis, rheumatic fever and poly-arteritis, together form a family of disease linkedby the tendency for one member to co-exist withthe other. In one of his cases of this syndromenecrotizing arteritis was found in the brain. Heregards intensive allergic vasculitis as the basis ofthe Sch6nlein-Henoch syndrome.

Allergic agent, usually, is a protein. The excitingfactor may be found in the food (Squier andMadison, 1937), chocolate (Diamond, 1936), andtomatoes (Gairdner, 1948). Streptococcal infec-tion, frequently, is incriminated.Case.-A boy, I2 years old, with primary

complex developed otitis media, which was treatedby penicillin and sulpha drug. A week later hecomplained of abdominal colic, vomiting anddiarrhoea, which continued for one week andfollowed by malaena. Three days later he passeda large offensive malaena. Hess test was negativeand platelets were normal. Laparotomy revealedno evidence of surgical conditions except swollenand congested intestines. A week later he sud-denly became unconscious with status epilepticusfor four hours. Lu'mbar puncture revealednormal C.S.F. A week later diffuse purpura

was observed and now the diagnosis of Sch6nlein-Henoch syndrome was made. A week later hedeveloped acute haemorrhagic nephritis withpainful joints, fulfilling the criteria of the syn-drome. He was treated symptomatically and byantihistamines. This is an example of allergicvasculitis, produced by the streptococcal allergyinvolving vessels of the intestine, brain, skin andkidneys.

It must be remembered that the site of allergicreactions to the antigen varies remarkably. Inone case the same pathological process involvesthe arteries (polyarteritis) and in the other thecapillaries (Sch6nlein-Henoch vasculitis); the lattershould also be added to the group of necrotizingangiitides. Thromboangiitis may be a form of slowreactive angiitis.

(b) Allergic Polyradiculoneuritis (Landry-Guillain-Barre Syndrome)

This syndrome is de'scribed under varioustitles. None is self-explanatory. Although thisis called an infective polyneuritis, infective agentshave never been isolated. In the present state ofknowledge it is reasonable to call it 'allergicpolyradiculoneuritis' until definite aetiology isknown. Attention has been drawn that 50 per'cent. of the cases manifest the disease two to threeweeks after the non-specific upper respiratorytract infection or gastro-intestinal infection at atime when antibodies are formed and its asso-ciation withr post-vaccinal, post-exanthematousand drugs hypersensitivity illnesses, also, with poly-arteritis (Liversedge and Leather, I953> and rh-eu-matoid arthritis (Grant and Leopold, 1954)suggests hyperergic manifestation to these noxiousagents. Recently this is supported by the experi-mental production of an identical disease inrabbits by intradermal injection of rabbit sciaticnerve or spinal'ganglia with heat-killed tuberclebacilli, as an adjuvant, and this disease was asso-ciated with high protein in the C.S.F. withoutpleocytosis (Waksman and Adams, I955). Thisallergic experimental polyneuritis of Waksmanand Adams has made a momentous advancementin our knowledge about diseases of the peripheralnervous system of unknown origin, and also showsthat there are different kinds of the antigens inthe peripheral and central nervous system; theformer produce allergic polyneuritis and the latterallergic encephalomyelitis in the experimentalanimals.

Guillain et al. (I9I6) emphasized raised proteinwithout pleocytosis in the C.S.F. of patientssuffering from this disease, as the diagnosticfeature of the disease. Sometimes, in the earlystage of the disease, C.S.F. is normal and proteinsincrease gradually as the disease progresses. The



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March 1957 FAZLULLAH: Neurological Complications in Hypersensitivity 129

amount of proteins depends upon the obstructionof exit of the C.S.F. due to oedema, congestionof the roots, as they pass through the inter-vertebral canals, and increased vascular perme-ability (Haymaker and Kernohan, I949). Rootsentery zones are frequently involved and theseare bathed freely in the C.S.F. Aring (I945)described changes in the C.S.F. proteins collectedat various levels: Li vertebral: 330 mg. per IOOml.; cisternal level: 14 mg. per ioo ml. L2ver-tebral: 380 mg. per ioo ml.; cisternal level:88 mg. per iOO ml. L3 vertebral: 1,400 mg. perioo ml.; cisternal level: i82 mg. per ioo ml.

Spinal block has been shown by intrathecal-thorotrast. Pleocytosis in the C.S.F. is notedwhen meninges are involved. Recently Fazlullah(1956) reported a case of Landry-Guillain-Barresyndrome with extensive flaccid motor paralysis,peripheral sensory neuropathy and pleocytosis-8o cells per c.mm. with evidence of meningealinvolvement. Haymaker and Kernohan (I949)described pleocytosis up to 514 per c.mm., andascribed pleocytosis to meningeal involvement.Waksman and Adams (I955) also observed pleo-cytosis in their allergic experimental polyneuritisin case of meningeal lesions.There is no complete agreement about the

pathology of this disease. In some fatal cases nodefinite pathological changes have been found. Insome cases degeneration of myelin sheath withperivenous infiltration of plasma cells, lympho-cytes and mononuclear cells in the spinal ganglia,roots, and peripheral nerves has been observed.In mild cases myelin degeneration is limited to afew segments with sparing of axis cylinder, whilein severe cases whole sensory neurone is damaged.Notable feature of the disease is perivascular orperivenous inflammatory cells infiltration in theperipheral nerves which is similar to the reactionof delayed tuberculin sensitivity and other allergicstates. Similar perivascular cellular infiltration isseen in the heart, lungs, liver, kidneys and supra-renals.

Variable clinical picture and course suggestthat a single disease entity manifests under theguise of several slightly different clinical syn-dromes. Recently Adams (I955) classified thisidiopathic polyneuritis into the following clinicaltypes:-

i. Syndrome of symmetrical ascending motorparalysis with minimal sensory change.

a. Syndrome of ophthalmoplegia, fascial di-plegia, bulbar palsy and descending motor para-lysis of the trunk and limbs.

3. Glandular fever syndrome with ascendingmotor and sensory paralysis.

4. Asymmetrical sensorimotor spinal-cranialpolyneuritis of subacute onset.

Sometimes a combination of one of these hasbeen observed. Recently Fazlullah (I956) reportedthree cases of Landry-Guillain-Barre syndrome,fulfilling the critera of the above-mentionedtype 4. One of the presented cases exhibitedglandular fever syndrome with asynmetricaln.uropathy, simulating, partly, type 3. syndrome.Case.-A female, aged 34, following sore throat,

two weeks later, developed generalized erythema,itching, oedema of face and limbs with paraes-thesiae. This was followed by jaundice, cervicallymphadenopathy, splenic enlargement, poly-arthritis, conjunctivitis, intermittent pyrexia andtachycardia. Asymmetrical loss of deep reflexeswith loss of sensation to pain, touch and vibrationwere noted in the legs. C.S.F. was normal.Paul Bunnell test was repeatedly negative. Ab-normal lymphocytes were found in the peri-pheral blood. L.E. cells were absent from theperipheral blood. Muscle and gland biopsy wasnegative for polyarteritis. Serum globulin wasnormal. Her condition was deteriorating onsymptomatic treatment, and she developed severeexfoliative dermatitis with haemorrhagic tendencyin the hands, conjunctivitis, persisting obstructivetype of jaundice, angular stomatitis and glossitis.She also complained of pain in the right hypo-chondrium, and liver was palpable and tender.She was put on cortisone ioo mg. daily two weeksafter the onset of the present illness. Dramaticimprovement was noted in her clinical condition.Cortisone was reduced gradually as her clinicalcondition improved without any evidence ofrelapse. Two months after discontinuation ofcortisone, she developed relapse of her previoussymptoms: generalized itching, erythema andfascial oedema, which were controlled by anti-histamines. Her eosinophilia count was 2,000.

Recently Towers (I955) reported two cases ofsimilar glandular fever syndrome due to PASsensitivity. One of his cases developed Guillain-Barre type of polyneuritis with raised C.S.F.protein without pleocytosis. Barnes and Barnes(I955) suggested that the drug containing primaryaromatic amines like PAS can produce glandularfever syndrome.

Glandular fever syndrome with neuropathy,following non-specific upper respiratory infectionand drug sensitivity, favours an allergic reactionto these noxious agents and throws light on thepathogenesis of the so-called glandular fever.Though infective aetiology is suggested, no infec-tive agent is confirmed. Evans (1947), in humanbeings, had negative results as regards transmissionof the disease. Dramatic response to cortisone,in the above case, with evidence of tuberculintype of sensitivity and production of an identical



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syndrome by drug sensitivity, support an allergicmechanism. Further clinical and experimentalevidences are needed to evaluate this problem.

ConclusionsIn hypersensitivity states the neurological dis-

orders are ischaemic in origin, probably due toprimary vascular insult, allergic oedema and dis-turbed neuronal biochemistry resulted by theimmunological process, otherwise we cannotcomprehend the pathological findings, clinicalsequence of non-specific infection followed byneurological disorders after an interval of two tothree weeks, at a time when antibodies are formedand prompt recovery by ACTH or cortisone.

It is a high probability that there are manyantibodies having an affinity to injure differenttissues such as vessels, myelin, kidney, myo-cardium and mesenchymal tissues alternatively,autoimmunization with multiple autoantibodiesseems as good as any at the moment. We knowlittle about the cell-fixed antibodies and otherantitissues antibodies.

In the allergic disorders of the central andperipheral nervous system the earliest pathologicalchanges are perivascular cellular infiltration andoedema, amelioration of which gives rise to com-plete regression of neurological disorders, but ifthe reaction to the certain allergens is very violentthen this reaction will follow with necrotizingvascular lesions with severe neuronal damage.The disease process may produce different

clinical syndromes by attacking in one casearteries (polyarteritis), in another capillaries(Sch6nlein-Henoch vasculitis), in other veins andperivenous neurone (allergic encephalomyelitis ofLumsden, post-exanthematous and spontaneousdisseminated encephalomyelitis), and in anotherperipheral nerves, spinal roots and ganglia(allergic experimental polyneuritis of Waksmanand Adams or Landry-Guillain-Barre syndrome).There may be two kinds of antigenic processes,one attacking the peripheral neurone and the othercentral neurone of the central nervous systemwhich is supported by the experiments ofWaksmanand Adams (I955) and Lumsden (I948), or bothmay co-exist. Eventually these syndromes willemerge as variants of a single disease process andit is possible that a common aetiology may beestablished.

Persistent low-grade infection induces delayedtype of hypersensitivity with cell-fixed antibodies,eventually produces necrotizing inflammationwhich commonly occurs in the diseases of collagen(Long, I956). If bacteria persist in the body,immunity to toxins and hypersensitivity toallerg. ns are associated phenomena; at this stageadministration of cortisone and ACTH depresses

the sensitivity to bacterial allergens (Long, 1954,I955, 1956). These hormones probably reversethe destructive enzymatic processes in the affectedcells iather than the unknown cause or suppressingthe antibodies formation, since cortisone actsmore rapidly than an effect on the antibodieswould be expected and the equal prompt recur-rence of the illness after its discontinuance.§Acknowledgments

I wish to record my sincere thanks to Dr. B.Morgan, Dr. K. A. Latter, Dr. A. P. B. Waindand Dr. L. Watson, consulting physicians, fortheir advice during the study of these cases.Continued on page i44

§Selye (I95I) contends that the pathogenic basis ofcollagenous disorders may be a disturbance in the ratioof minerals and glucocorticoids, ACTH and cortisoneon the one hand, pit. somatotrophic hormone and DOCAon the other hand, exert diametrically opposed effectand cardiovascular-renal lesions, caused by the pit.somatotrophic hormones, are aggravated by simul-taneous administration of cortisone. This fails to doso in the adrenalectomized rats.

Investigations, on steroids in the urine of patientswith rheumatoid arthritis, show no evidence of adrenalinsufficiency. It has been postulated that a relativeadrenal insufficiency is produced due to an increasedhormone demand in tissues involved in this disease. Insuch cases ant. pit. stimulus, although increased, wouldnot result in an increased plasma level of the hormones.In cases of rheumatic fever high plasma ACTH andlow cortisone has been reported (V. C. Kelly, 1955,Ann. N. Y. Acad. Sci., 6i, 369). This might be due toadrenal exhaustion, possibly as a result of increasedsteroids demand in the tissues.

In cases of rheumatoid arthritis, low plasma corti-coids (J. E. Warren, I956, Ann. rheum. Dis., 15, 70) anddecreased urinary steroids excretion (S. R. Hill, Jr.,H. L. Holley, W. R. Stames, and L. L. Hibbett, I956,Ann. rheum. Dis., I5, 69) in the early morning can becorrelated with the early morning exacerbation ofmuscular stiffness. This might reflect a change in thehypathalamus-pituitary-adrenal axis.

Recently abnormal steroid metabolites have beenisolated from urine of cases with rheumatoid arthritiswhich disappear afterACTH administration (H. Wilson,1956, Ann. rheum. Dis., X5, 70). Patients with post-partum pit. necrosis are unduly liable to develop rheu-matism in knee (H. L. Sheehan, 1939, Quart. J. Med.,8, 277). The changes in the cellular structure of rheu-matoid and lupus hypophysis consist of degranulationof mucoid cells (A. G. E. Pearse, 1950, Lancet, i, 954).There is an increasing evidence that ant. pit. may beimplicated in the aetiology of collagenous disorders.It seems that there may be some quantitative or quali-tative abnormality in the endogenous corticotrophin.However, there is no increased incidence of rheumatoidarthritis in cases of Addison's disease or in chromophobeadenoma with pit. insufficiency. It is impossible, atpresent, to ascertain whether this alteration in the hypo-thalamus-pituitary-adrenal mechanism is a cause or theresult of chronic disease state. Further clinical andbiochemical investigations are needed to confirm therole 6f ' hormonal imbalance ' in the pathogenesis ofcollagenous diseases.



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It would appear from the above that the reflexis indeed abolished when some of the more potentanaesthetics such as ether are used. Unfor-tunately, these have usually some other disadvan-tages, such as toxicity or inflammability, and atthe present time with the widespread use of thediathermy, etc., they are usually contraindicated.The fact that less potent agents and combinationssuch as gas, Pethidine and light Trilene do notgreatly depress the reflex was well demonstratedin this case. That this is of little consequence,however, is equally clear since it is comparativelysimple to nullify the effects of the reflex by em-ploying drugs with vagolytic and sympatho-mimetic properties. The agents of choice wouldseem to be Atropine and Nor-adrenaline.

Suggested Scheme of Treatmentt. Preliminary assessment of state of collateral

cerebral circulation by electroencephalogram andcrossed carotid angiogram.

2. Exploration of tumour through a long in-cision along the anterior border of sterno-mastoidto give a wide exposure.

3. If possible to remove the tumour withoutjeopardizing the internal and common carotidvessels, do so.

4. If not, apply a temporary ligature to thecommon carotid, partially occluding it, and biopsythe tumour.

5. If the -biopsy shows the tumour to bemalignant, or if the symptoms warrant it, re-

explore three weeks later and excise the tumourtogether with the bifurcation of the carotid.

6. If possible, insert an arterial graft, but if notanastomose the distal cut ends of the internal andexternal carotids.

7. Carry out a stellate ganglion block with localanaesthetic.

8. Give anticoagulants post-operatively.9. Nurse in head-down position in an oxygen

tent for several days.

SummaryA case of carotid body tumour with marked

sinus syncope is described.The problem of treatment of these tumours is

discussed and a plan of treatment is given.The effects of various drugs on the syncopal

attacks are discussed.Our thanks are due to Dr. R. R. Hughes, under

whose care the patient was admitted, and toMr. J. Cosbie Ross, who performed the operation,for permission to publish this case.

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NEUROLOGICAL COMPLICATIONS IN HYPERSENSITIVITY · I1I NEUROLOGICAL COMPLICATIONS IN HYPERSENSITIVITY By S. FAZLULLAH, M.B.(Osmania), D.T.M. &H. Late MedicalRegistrar, Barrow-in-Furness