sarcoidosis ofthe central nervous system · sarcoidosis ofthe central nervous system case 1 d.h., a...

Journal of Neurology, Neurosurgery, and Psychiatry, 1973, 36, 1024-1033

Sarcoidosis of the central nervous system

A. C. DOUGLAS AND A. F. J. MALONEY

From the Departments of Respiratory Diseases and Neuropathology,University of Edinburgh, Edinburgh

SUMMARY Six patients with sarcoidosis of the central nervous system are described. Pathologicalconfirmation was obtained by brain biopsy in two patients and at necropsy in two; in two patientsthe diagnosis was presumptive and was made on the evidence of multisystem involvement. Thesymptomatology, methods of diagnosis, and results of treatment are discussed.

Involvement of the central nervous system insarcoidosis is relatively rare and in the Edin-burgh sarcoidosis register of more than 500cases there are only six examples. These sixcases illustrate the infinite variety of the clinicalexpressions of sarcoidosis of the nervous system,the difficulty in making the diagnosis in theabsence of evidence of sarcoidosis in othersystems, the chronicity of this form of the diseasein most instances, and its variable and usually

poor prognosis even when corticosteroid therapyis employed.

CASE REPORTS

The series consists of four female and two malepatients whose ages range from 16 to 55 years. Thediagnosis was established by brain biopsy in twocases, confirmed at necropsy in two cases, and pre-sumed in two cases in which multisystem involve-ment was proven (Table 1).

TABLE 1SARCOIDOSIS OF CENTRAL NERVOUS SYSTEM: SUMMARY OF FINDINGS IN SIX PATIENTS

Patient Age Sex Principal neurological features Other sarcoidfeatures Diagnosis Course(yr)

D.H. 44 F Mental deterioration, headache, Hilar and cervical Biopsy-lymph gland Alive 11 yr +. Responsevomiting, papilloedema, adenopathy, ? nasal to prednisolonediabetes insipidus granuloma

F.McI. 38 M Headache, paraesthesiae, right E.N. + hilar adeno- Biopsy-lymph gland, Progression despitefacial palsy, epilepsy, mental pathy, cervical nasal granuloma, prednisolone. Dieddeterioration, aphasia, nerve adenopathy, nasal brain 10 yrdeafness, optic atrophy granuloma, skin

sarcoid

E.F. 32 F Amenorrhoea, diabetes insipi- Nil Necropsy-CNS Died 2 yr +. Septi-dus, headache, epilepsy, caemiaataxia, meningeal irritation,coma

T.C. 46 F Right facial palsy, palatal weak- Lupus pernio Presumptive Fluctuating course, noness, right hemiparesis, treatment, permanentdiplopia, dysarthria, head- cerebral damage, aliveache 13 yr +

J.O. 55 F Rapid mental deterioration Nil Necropsy-CNS Died 2 mth, pulmonaryembolism

J.S. 16 M Somnolence, papilloedema, Nil Biopsy-brain Died 2 yr. Deteriorationright hemiparesis, aphasia, despite prednisoloneleft facial palsy

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CASE 1

D.H., a married woman aged 44 years presented in1961 with mental deterioration, headache, andvomiting and was found to have bilateral papill-oedema. A diagnosis of glioma was made andcerebral decompression was carried out using aSpitz-Holter valve. The expected deterioration didnot occur and over the next few months she developedenlarged cervical glands, biopsy of which showedfeatures compatible with sarcoidosis. A chest radio-graph showed bilateral hilar adenopathy and theMantoux test was negative to 1:100 O.T. Thecerebrospinal fluid (CSF) consistently showed araised serum protein of 200 to 300 mg/100 ml. butthe sugar level was normal and no cells were seen.A diagnosis of neurological sarcoidosis was madeand treatment was begun with prednisolone withmost gratifying results. On this treatment she becamefully conscious and well and the CSF returned tonormal. After a year an attempt was made to dis-continue the treatment but this was followed byrelapse within a month; the patient became drowsyand finally comatose and the CSF protein was againraised. Reintroduction of corticosteroids rapidlyrestored the status quo. On three occasions over thenext two years further attempts were made to with-draw treatment, with similar results each time. Atreview in 1965 she was also found to have diabetesinsipidus and to have gained an undue amount ofweight.The patient remains well with no discernible*}I j i. b X- ,", . .r .......... K

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neurological deficit and her mild diabetes insipidusis under satisfactory control. Treatment withprednisolone is being maintained in a dosage of10 mg daily.

In 1957 the patient had been found to have atrophicrhinitis which persisted until corticosteroid therapywas begun. Examination in 1965 showed completeabsence of the nasal septum and it was believed thatthe original nasal condition was probably due tosarcoidosis.

SUMMARY A case of CNS sarcoidosis, presumablypredominantly meningeal, which was initially mis-diagnosed as cerebral tumour. There has been a verysatisfactory and maintained response to cortico-steroid therapy during eleven years of observation.The CSF showed a raised protein only. There wasevidence of multisystem involvement in the form ofhilar and cervical adenopathy.

CASE 2

F.McI., a 38 year old male architect, came underobservation in June 1958 because of malaise,anorexia, erythema nodosum, and swelling of theankles and knees of two weeks' duration. TheMantoux test was negative to 1:100 O.T. He im-proved on treatment with salicylates but four monthslater again began to feel unwell and was then foundto have enlargement of liver and spleen and thechest radiograph now showed bilateral hilar adeno-pathy. In June 1959 the right posterior auricular

FIG. 1. Cerebral cortexshowing sarcoid granulomatain leptomeninges and greymatter. H and E, x SO.

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A. C. Douglas and A. F. J. Maloney

lymph nodes became enlarged and gland biopsyshowed the histological features of sarcoidosis.Corticosteroid therapy was begun and continued forone year, until June 1960. Three weeks after treat-ment was stopped he had his first indication ofneurological trouble in the form of a sudden attackof altered sensation in the right side of the face, stiff-ness and numbness of the right thumb and indexfinger, and some difficulty in finding words. Thesesymptoms were episodic at first, occurring every sixto eight weeks or so, lasting about 15 minutes, andfollowed by left-sided headache for a whole day.Neurological examination showed only brisk reflexeson the right side. The CSF protein was 160 mg/100 ml., the sugar level was normal and there wereno cells. He was also found to have a skin sarcoid onthe left side of the face. Corticosteroid therapy wasresumed and, although the frequency of the initialattacks was reduced, he had two grand mal attacks(in November and December 1961) for which treat-ment with phenobarbitone and phenytoin was given.Apart from one grand mal seizure in September 1962he remained fairly well until mid-1963 when hebegan to have episodes of awareness of a peculiarstrong smell, associated with nausea and lasting afew minutes at a time. Over the next few months hehad six such attacks and in January 1964 the olfac-tory aura was followed by major convulsions and astate of altered consciousness with confusion andagitation associated with repeated purposive move-ments involving rubbing the nose constantly. Overthe next few months there were repeated grand mal

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attacks and he remained confused. He also becamedisinterested in his person and would not wash him-self or change his clothes. His memory graduallydeteriorated. In April 1964 he complained of severenasal congestion and examination showed chronicatrophic rhinitis, biopsy of which showed thefeatures of sarcoidosis. After an episode of statusepilepticus in August 1964 he complained of noisesin both ears and became deaf so that communicationcould only be made in writing. Gradually even thisbecame difficult as he developed dysphasia whichsteadily worsened. In November 1964 he underwentfurther intensive neurological review. The CSFshowed a protein level of 900 ml./100 ml., a normalsugar content, and 4 cells/c. mm. There was now bi-lateral optic atrophy. No localizing information wasobtained by electroencephalography (EEG). On 4December 1964 pneumoventriculography showedsymmetrically dilated lateral ventricles. There waspersistent non-filling of the left temporal horn whichwas considered to be abnormal. After this he hadpersisting hiccups. Radiological screening of thechest showed no abnormality, the previous hilaradenopathy having resolved. On 22 December 1964left frontotemporal craniotomy and electrocortico-graphy were performed. Severe abnormality wasdemonstrated all over the exposed area. In additionthere were numerous minute (1 mm diameter) palenodules in the leptomeninges, mainly along thesulci. Subtotal excision of the temporal lobe wasperformed with partial removal of the middle andinferior part of the frontal lobe.

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Pathological examination of the resected speci-men showed numerous minute sarcoid nodules in theleptomeninges and along small penetrating corticalblood vessels (Fig. 1). The blood vessels in relation tothe nodules were in the main normal. Occasionallythey showed mild infiltration of their walls withchronic inflammatory cells (Fig. 2). The adjacentcortex showed severe focal gliosis. There was somegeneralized fibrosis of the leptomeninges. The post-operative course was stormy and included tracheos-tomy because of severe respiratory infection. Eventu-ally he recovered sufficiently to be allowed homewhere he remained until he died suddenly in 1968.After operation the epileptic attacks were much lessfrequent and the rate of mental deterioration wasslowed. Bilateral deafness remained and speech neverrecovered. Corticosteroid therapy was continueduntil death but did not appear to influence the clinicalstate. There was no necropsy.

SUMMARY A case of meningo-encephalitis due tosarcoidosis proved by cortical biopsy. Neurologicalfeatures included headache, paraesthesiae, rightfacial palsy, epilepsy, aphasia, nerve deafness, opticatrophy, and progressive mental deterioration.Multisystem involvement was shown by hilar andcervical adenopathy, nasal granuloma, and skinsarcoid. The course of the disease was apparentlyuninfluenced by corticosteroid therapy and deathoccurred eight years after the onset of neurologicalsymptoms. CSF studies showed raised protein withnormal sugar and few or no cells.

CASE 3

Details of E.F., a female aged 32 years, have pre-viously been recorded in detail elsewhere (Schonellet al., 1968). She presented with amenorrhoea andthe features of diabetes insipidus followed by head-ache, epilepsy, meningeal irritation, ataxia, andfinally coma and death two years after the onset ofneurological phenomena. Corticosteroid therapysupplemented by antituberculosis chemotherapygiven towards the end of the illness failed to influencethe clinical course, which was complicated terminallyby staphylococcal septicaemia. Necropsy showedextensive involvement of the meninges, brain,pituitary gland, and spinal cord with sarcoidosis.There was no evidence at necropsy of sarcoidosis inother systems.The CSF showed a protein content varying from

700 to 1,800 mg/100 ml., a glucose level which wasnormal on three occasions and low (26 mg/100 ml.)on one, and no cells.

SUMMARY A case of meningo-encephalomyelitis,with associated hypothalamic lesions, due to sar-coidosis apparently confined to the central nervoussystem. The CSF showed marked protein increase, anormal or low sugar and no cells. Despite the use ofcorticosteroids, death occurred two years after theonset of neurological features.

CASE 4

T.C., a female aged 46 years, had previously been

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FIG. 3. Cerebral cortex:diffuse and focal meningealfibrosis accompanied by scantyround cell infiltration. Theunderlying cortex shows milddiffuse gliosis. H and E, x 110.

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well until in 1959 she developed hypothyroidismwhich was treated successfully with thyroxine. Atthis time she first noticed a gradual onset of weaknessof the right hand which persisted and about a yearlater she developed right facial palsy and was alsofound to have palatal weakness. The CSF was undernormal pressure and showed a protein of 80 mg/100 ml., normal sugar, and no cells. The EEGshowed gross left-sided abnormality but angio-graphy and air studies did not demonstrate a spaceoccupying lesion. Diplopia, dysarthria, paraesthesiaein the right hand, frontal headache, and worseningof the right-sided weakness developed subsequentlyand in 1961 she was found to have lupus perniowhich was confirmed by skin biopsy. A diagnosis ofsarcoidosis having been established, the neurologicaldeficit was attributed to sarcoidosis of the centralnervous system. No treatment was given and thecondition has pursued a fluctuating course with slowdeterioration. The patient is dysphasic but under-stands spoken speech well, although there is fluctu-ating impairment of concentration. She is ambulantwith the use of a tripod. The EEG has continued toshow gross left-sided abnormality but the brainscan is normal.

SUMMARY A case of presumed sarcoidosis of thebrain resulting in headache, right facial palsy, palatalweakness, right hemiparesis, diplopia, dysarthria,and dysphasia. The illness has followed a fluctuatingcourse without treatment over 13 years. The CSFshowed increase in protein only.

CASE 5

J.O., a 55 year old married woman, had a 14 yearhistory of rheumatoid arthritis treated with tri-amcinolone 2 mg per day but was otherwise welluntil one month before admission to hospital inFebruary 1970 when she had two dizzy attacks, onewhile out walking when she fell down suddenly andlost consciousness for a few seconds, and the otherat home when she had to sit down but did not loseconsciousness. On admission she was disorientatedin time and place and laughed inappropriately. Thecranial nerves were intact and clinical examination ofthe nervous system was unrevealing. The CSF pro-tein was 67 mg/100 ml., the sugar level was normaland there were 53 lymphocytes/c. mm. There was noclinical or radiographic evidence of sarcoidosis in anyother system. There was rapid mental deteriorationover the next two weeks, the patient became febrileand developed a persistent sinus tachycardia. Shedied suddenly eight weeks after the onset of neuro-logical symptoms.Necropsy showed that the immediate cause of

death was pulmonary embolism. Apart from evi-dence of rheumatoid arthritis, the major pathologicalchanges were confined to the central nervous system,which showed a chronic granulomatous meningo-encephalitis histologically compatible with sarcoido-sis. There was no evidence macroscopically or micro-scopically of sarcoidosis in lymph nodes, lungs,heart, kidney, liver, spleen, or bone marrow.

Examination of the brain after fixation showedslight swelling and a mild meningitis, scanty collec-tions of pale yellow exudate being seen mainly overboth cerebral convexities. There was no atheroma.Section showed well-marked uniform dilatation ofthe entire ventricular system which appeared to beexcessive for the degree of atrophy which was un-doubtedly present. No focal lesions were seen andthere was no evidence of ventriculitis. The cerebellumwas normal.On microscopy there was evidence, in all sections

examined, of a chronic granulomatous meningitissuperficially resembling tuberculous meningitis. Pro-longed search of many sections stained by Ziehl-Neelsen's method, however, failed to reveal thepresence of any acid-fast bacilli (nor were anydemonstrated in the CSF during life). The amount ofexudate was variable and was composed of epi-thelioid cells, lymphocytes, Langhans type giantcells, and plasma cells. Small ill-defined tubercleswere present in many places and occasionally theseshowed some degree of central necrosis. Schaumannbodies and asteroids were not seen. Some of thesmaller blood vessels in the exudate showed slightintimal fibrosis.Mild to moderately severe inflammatory changes

were seen in the cortex. These were characterized byrod cell reaction, neuronophagia, and perivascularround cell cuffing. No granulomata were seen. Someparts of the cortex appeared normal. Striking changeswere also seen in many sections of the white matter,although some areas were normal. The abnormalitiesincluded cuffing of blood vessels with chronicinflammatory cells, mainly lymphocytes and a fewplasma cells, but also large mononuclear cells withstrongly eosinophilic cytoplasm and the presence ofsmall groups of mononuclear cells of like appear-ance forming tubercles. Giant cells were occasionallyseen in relation to these tubercles, but the tuberclesdid not show central necrosis and were unlike themiliary tubercles of tuberculosis. Where theseinflammatory changes were seen the white matterwas partially demyelinated.The alternative diagnoses of tuberculosis, syphilis,

fungal and protozoal infection, and malignancy wereconsidered but were ruled out by the combination ofclinical, microbiological, serological, and patho-logical evidence.

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SUMMARY A case of chronic meningo-encephalitismanifested by dizzy attacks and rapid mentaldeterioration due to sarcoidosis apparently confinedto the central nervous system. The CSF showedincrease in protein and cells, and a normal sugar.

CASE 6

J.S., a previously healthy 16 year old boy becamesuddenly unwell in January 1970 after what appearedto be a bout of influenza associated with a vagueabdominal discomfort. After this he became tiredand listless and showed a tendency to drag his feet.No obvious abnormality was found on clinicalexamination but the erythrocyte sedimentation rate(ESR) was 40 mm per hour. He improved spon-taneously and was apparently well until April 1970when there was a recurrence of abdominal symptomswith vomiting and associated epigastric tenderness.The ESR remained elevated at 60 mm per hour. Hewas found to be rather drowsy and to have a mildright hemiparesis and bilateral papilloedema. Ahistory of auditory hallucinations and thought diffi-culties was also elicited. EEG suggested a left frontallesion and a radioactive brain scan showed a large

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area of increased uptake in the left frontal lobe withsome diffuse increased activity on the right. Theclinical picture suggested a progressive lesion deep inthe left frontal region and possibly involving the rightside as well. The most likely diagnosis appeared to bea malignant tumour, infiltrating rather than dis-placing the brain.

In May 1970 brain biopsy was undertaken througha left frontal burrhole. Needle biopsies were ob-tained at about 5 cm depth. The lateral ventricle wascannulated and CSF under low pressure was obtain-ed. This showed a protein level of 64 mg/100 ml., anormal sugar level, and 31 nucleated cells per c. mm,mostly neutrophil polymorphs. Histological examina-tion of several specimens showed the features of agranulomatous meningo-encephalitis compatiblewith sarcoidosis (Fig. 3). A small area of infarctionwas seen in one section. Other forms of granuloma-tous disease were considered but so far as waspossible were excluded. Treatment was begun withprednisolone combined with antituberculosis chemo-therapy which coincided with initial substantialimprovement and for some weeks he was able to leada reasonably active life, although there was stillsome weakness in the right leg. In August 1970 there

FIG. 4. Scattered sarcoid granulomata innmeninges and cortex. Intervening tissue normal.Hand E, x SO.

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was sudden deterioration with marked right-sidedspasticity, dysphasia, and somnolence. There wasalso unexplained pyrexia. Although there was someimprovement over the next four months, a right-sided spastic hemiparesis and dysphasia persistedand six months later he suddenly developed left-sided hemiparesis and some evidence of pseudo-bulbar palsy. There was conjugate deviation of thehead and eyes to the right side. The patient becameincontinent and the pyrexia, which had previouslysubsided without specific treatment, recurred. On re-admission to hospital in July 1971 the patient wasalmost in a position of opisthotonos. The head wasmarkedly retracted and rotated to the right and theeyes were held in a fixed deviated position to theright side. He appeared to understand simple com-mands. He tried to speak, but could not. There wasvery little movement of the palate and pharyngealsensation was impaired, with a poor gag reflex. Theoptic fundi were now normal. There was a partialleft-sided upper motor neurone facial paresis. Theupper limbs were very spastic and were flexed atelbows and wrists. The abdominal muscles were alsoin marked spasm. The legs were held in an extendedspastic position with grossly exaggerated knee jerksand sustained ankle clonus. The plantar responseswere extensor. Because of the physical and psycho-logical state it was not possible to carry out fullsensory examination but certainly pin prick could bedistinguished anywhere over the skin.

Despite continuation of corticosteroid therapy thefurther progress was downhill and the patient died

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in October 1971. Permission for necropsy wasrefused.

SUMMARY A case of histologically proven sarcoid-osis of the central nervous system which, despitecorticosteroid therapy, followed an inexorable down-hill course to death within two years. Among theneurological features there was an upper motorneurone facial paralysis, which has been recordedonly rarely (Hb6k, 1954; Jefferson, 1957). Therewere no clinical or radiographic indications ofsarcoidosis elsewhere but there was no necropsy toprove that this was a case of isolated neurologicalsarcoidosis. The CSF showed a raised protein, mildpleocytosis and a normal sugar content.

DISCUSSION

Sarcoidosis affecting the nervous system mostcommonly results in cranial and peripheralneuropathies; rarely, it involves the centralnervous system (Colover, 1948; Pennel, 1951;Meyer et al., 1953; Hodk, 1954; Jefferson, 1957;Reske-Nielson and Harmsen, 1962; Robert,1962; Blain et al., 1965; Daum et a., 1965;Matthews, 1965; Silverstein et al., 1965;Wiederholt and Siekert, 1965; Scadding, 1967;Strickland and Moser, 1967). The neuropathiescharacteristically occur early in the course ofsarcoidosis (when lesions in other systems are

FIG. 5. Sarcoid granulomatainvolving wall of smallmeningeal vein. H and E,x100.

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usually obvious), are relatively transient andresolve completely as a rule. Lesions of thecentral nervous system, on the other hand, tendto develop later in the disease (when multi-system involvement may not be evident), usuallypursue a more chronic course, and recoverincompletely or even progress despite treatment(Silverstein et al., 1965). The neuropathies andsarcoidosis of the neuraxis are not clinicallydistinct, however, and central nervous systemsarcoidosis is frequently complicated by cranialneuropathies-particularly affecting the seventhnerve-due to involvement of the leptomeningesby sarcoid lesions at the base of the brain.

TABLE 2SARCOIDOSIS OF CENTRAL NERVOUS SYSTEM: CSF FINDINGS

IN SIX PATIENTS

Patient Protein Sugar Cells(,ng/I0O ml.) (N = normal)

D.H. 200-300 N 0

F.McT. 160 N 0900 N 4

E.F. 1,800 N 01,000 26 mg/ 100 ml. 0700 N 0760 N 0

T.C. 80 N 0

J.O. 67 N 53 (L)

I.S. 64 N 31 (P)

Any part of the central nervous system may beinvolved by sarcoidosis and any aspect of cere-

brospinal function can be affected. Thus neuro-

logical presentations may vary from impairmentof motor power in a limb to disturbance of thecentral control of respiration (Daum et al., 1965)or even mental deterioration or disorders ofpersonality. The possible combinations ofneurological manifestations are legion and thereis no constant association of signs or symptomswhich can be grouped together to describe a

syndrome for sarcoidosis of the central nervous

system. Nevertheless, certain combinations ofneurological involvement are suggestive-forexample, signs of chronic meningitis, diabetesinsipidus, facial palsy-and when these occur

examination of the CSF is mandatory and theusual investigations for sarcoidosis should beundertaken including a search for sarcoid lesionsin other systems and a Kveim test if the tempo ofthe neurological picture permits. When there isevidence of coexisting sarcoid involvement ofother organs, or a past history of this, thediagnosis of central nervous system sarcoidosispresents no great difficulties (Jefferson, 1957) andin this context the presumptive diagnosis ofcentral nervous system sarcoidosis usually provesto be correct. When, however, the neurologicalfeatures are the only indication of the site ofdisease the diagnosis becomes a formidableproblem. Random tissue biopsy (especially liverand scalene fat pad) may establish the diagnosisbut will not if sarcoidosis is confined to thecentral nervous system (Reske-Nielsen et al.,1962; cases E.F. and J.O.). The value of theKveim test in sarcoidosis of the central nervoussystem is limited because it takes four to sixweeks to read and is influenced by corticosteroidtherapy. Moreover, the positivity rate in sarcoid-osis clinically or pathologically confined to thecentral nervous system is not known. A positivetest would, however, be of inestimable value incases of sarcoidosis presenting only with symp-toms and signs of disease of the central nervoussystem.

Sometimes the diagnosis may be made afterhistological examination of tissue obtained atcraniotomy undertaken to exclude the presenceof tumour or for the relief of CSF block. Rarely,a tissue diagnosis is made after elective brainbiopsy (Robert, 1962) as in case J.S. reportedhere. Even the ultimate procedure of brainbiopsy may be unhelpful if needle biopsy is thetechnique used, since the granulomata are fre-quently widely dispersed (Fig. 4) and a singlebiopsy may not include pathological tissue.Also, the predominant site of involvement is thebase of the brain in most reported cases.CSF examination may be of great importance

in the diagnosis of central nervous systemsarcoidosis (Table 2). The most consistent find-ings are a normal pressure and appearance,raised protein, normal sugar, and a variablenumber of cells, mainly lymphocytes (Colover,1948; Pennell, 1951). A low sugar content hasbeen found occasionally (Ernsting and SillevisSmitt, 1944; Colover, 1948; Pennell, 195 1;

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Schonell et al., 1968). Patient E.F., previouslyreported on by this unit (Schonell et al., 1968),had a CSF protein of 1,800 mg/100 ml. at onestage, the highest value for protein ever recordedin sarcoidosis of the central nervous system.Absence of evidence of sarcoidosis in other

systems in some cases is not surprising in view ofthe fact that neuraxis sarcoidosis tends to occurlate in the timetable of the disease when co-existing multisystem involvement may be slightand not easily detectable. One would, howeverexpect that multisystem involvement would beproved at necropsy in such cases. In two patientsreported here (E.F. and J.O.) full necropsyshowed that the central nervous system was theonly definable histological site of the disease and'isolated' sarcoidosis of the central nervoussystem has also been reported by others (Reske-Nielsen et al., 1962). The alternative explana-tions would appear to be that 'isolated' sar-coidosis in this site is an entity or, as seems muchmore likely, that preexisting asymptomaticlesions in other systems have resolved withoutdemonstrable trace by the time the neurologicallesions become predominant and symptomatic.Obviously there must be great caution aboutacceptance of a diagnosis of 'isolated' centralnervous system sarcoidosis and all alternativediagnoses, including brain tumour, must bethoroughly excluded before applying this label.

Sarcoid lesions have been found in almostevery part of the central nervous system andvary from meningeal granulomata to actualtumour-like masses. The affinity of the sarcoidgranuloma for cerebral vessels has been stressedby many authors (Longcope and Freiman, 1952;Meyer et al., 1953; Reske-Nielson et al., 1962;Robert, 1962; Urich, 1967) and was striking inthe pathological material obtained from thecases reported here (Figs 2 and 5). This probablyoffers one explanation for the variable responseto corticosteroid therapy. Areas of cerebralischaemia and infarction have been described inrelation to granulomatous cerebral angiitis(Meyer et al., 1953) and were found in case J.S.in this series. There was, however, no evidence ofthrombosis in any of the involved vessels in ourcases. The development of meningeal fibrosis(Fig. 3) is another feature which may determineprogression of neurological phenomena andlimit response to corticosteroid drugs; it may

sometimes compel surgical treatment for reliefof hydrocephalus or of intractable epilepsy.The course of central nervous system sarcoid-

osis is unpredictable but it is generally agreedthat involvement of the central nervous systemindicates the use of corticosteroid therapy as theonly hope of influencing the disease and modify-ing its effects on function. To be maximallyeffective, treatment should be begun early.Sometimes corticosteroids have to be used on aprobability basis when there are life-threateningneurological manifestations which do not con-form to any clear disease pattern. No matter howlong the neurological features have been presentcorticosteroid therapy should be tried. In thepatient with the Guillain-Barre syndrome due tosarcoidosis reported by Strickland et al. (1967)an excellent result was obtained when treatmentwas begun two years after the onset of symptoms.Improvement does not always follow and theremay be deterioration despite corticosteroidtherapy (patients F.McI. and J.S.). If improve-ment does occur extreme caution must be ob-served when making reductions in dosage(patient D.H.); treatment may require to becontinued indefinitely.By analogy with asymptomatic and symptom-

atic skeletal muscle involvement in sarcoidosis,it is reasonable to postulate that in the commonforms of subacute, transient sarcoidosis theremay be involvement ofthe central nervous systemto a degree insufficient to disturb function andthat this resolves with no discernible residualdamage. Why it is that the diffuse granulomatousprocess should become dominant in one organ orsystem remains one of the many inexplicablefeatures of the disease.

We wish to thank Mr. Phillip Harris for permissionto publish case F.McI., Dr. J. B. McGuinness forpermission to publish case J.S., and Dr. D. C. Bouchfor the necropsy report on case J.O.

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Daum, J. J., Canter, H. G., and Katz, S. (1965). Centralnervous system sarcoidosis with alveolar hypoventilation.American Journal of Medicine, 38, 893-898.

Ernsting, W., and Sillevis Smitt, W. G. (1944). Neurologische

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Longcope, W. T., and Freiman, D. G. (1952). A study ofsarcoidosis. Medicine (Baltimore), 31, 1-132.

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