Whipple's disease confined to the CNS presentingwith multiple intracerebral mass lesions

S J Wroe, M Pires, B Harding, B D Youl, S Shorvon

AbstractA patient with isolated cerebralWhipple's disease presented with signs ofraised intracranial pressure and multi-ple ring enhancing intracerebral mass

lesions evident on CT and MRI imaging.Characteristic intracellular bacilliforminclusions were identified in a brainbiopsy. Clinical improvement followedtreatment with parenteral antibiotics fortwo weeks and long term sulphamethox-azole-trimethoprim. As CNS relapse ofWhipple's disease may occur afterseveral years, long term treatmentshould include antibiotics that are ableto cross the blood-brain barrier.

The National Hospital,LondonS J WroeS ShorvonDepartment ofNeuropathology andMultiple SclerosisNMR ResearchGroup,* Institute ofNeurology, LondonM PiresB HardingB D Youl*Correspondence to:Dr Wroe, The NationalHospital, Queen Square,London WC1N 3BG, UKReceived 6 December 1990and in revised form20 March 1991.Accepted 5 April 1991

In 1907 Whipple described a 36 year oldmedical missionary with a five year history offlitting arthritis, weight loss and productivecough who presented to the Johns HopkinsHospital with intermittent fever, abdominaldistension and steatorrhoea.' Anaemia, ery-

thema nodosum, severe wasting, dyspnoeaand peripheral oedema were noted and thepatient died two days after an exploratorylaparotomy. Pathological examination re-

vealed widespread deposition of neutral fatsand fatty acids, particularly in the small intes-tine and lymph nodes, with vacuolation andgiant foamy mononuclear cells containing rodshaped bacilli. Whipple concluded that the

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Figure 1 MRI scans (a) SE2,,,60. There are multiple large high signal mass lesio(b) After gadolinium-DTPA (0 1 mmol/kg) lesions show peripheral ring enhance?There is only slight surrounding oedema. The apparently homogeneous enhancementhe right lateralfrontal lesion is due to a tangential section.

disease was disorder of fat metabolism, andsuggested the term "intestinal lipodystro-phy". Subsequent studies with periodic acidSchiff (PAS) staining identified the phago-cytosed intracellular material as glycoprotein.'Although a bacterial cause remains unproven,the associated intracellular bacillus has beencharacterised in detail3 and probably plays an

aetiological role in Whipple's disease.Neurological symptoms frequently occur

during the course of the illness45 but progres-sive cognitive decline and hypothalamic dis-turbance leading to death are rare.67 Wereport a patient with Whipple's disease thatwas confirmed by biopsy and confined to theCNS illustrating the diagnostic difficulties inthese cases. CT and MRI scans showed multi-ple ring enhancing intracerebral mass lesions,a finding not previously described in thiscondition.

Case reportA 32 year old white heterosexual policemanwas admitted in December 1989 with a twoweek history of increasingly severe morningheadaches, vomiting and drowsiness. In thefew days before admission, his wife reportedthat he was less responsive, and more sleepythan usual. There had been no precedingfever, rashes, diarrhoea, or other systemicupset.

Examination showed him to be drowsy anddisorientated. He was apyrexial and had no

rash, lymphadenopathy or other abnormalityon general examination. Minimal bilateralpapilloedema was evident on fundoscopy; hehad a left upper motor neuron seventh nerve

palsy, slight left sided pyramidal weaknessand sensory inattention with symmetricalbrisk limb reflexes and flexor plantar re-

a sponses.

Routine investigations were all normal.CSF examination showed the presence ofoligoclonal bands (absent from paired serum)but was otherwise normal. Serum and CSFexamination for mycobacteria, viral and fun-gal antibodies including HIV, cryptococcus

j and toxoplasma were negative. A CT headscan showed multiple bilateral ring enhancingmass lesions. An MRI scan (Picker 0-5T)showed multiple high signal mass lesions withperipheral ring enhancement following theinjection of gadolinium-DTPA (fig 1). Psy-chometry showed a verbal IQ of 71 and per-

mls. formance IQ of 53 on the WAIS-R witht of. memory impairment, perceptual difficulties

and evidence of frontal lobe dysfunction.

Journal of Neurology, Neurosurgery, and Psychiatry 1991;54:989-992 989

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Figure 2 MRI scanshowing considerableenlargement of the leftfrontal mass which is nowcompressing the lateralventricle and causingmidline displacement. Theother lesions havedecreased in size.

* greatly improved. He was alert and able to* find his way to and from the hospital without

help. His conversation was appropriate andhis mood normal. Recall of the details of hisillness and subsequent events was poor, but he

l was aware of current events. MRI showedimprovement or resolution of all intracerebrallesions. Eleven months after onset of the ill-ness he had returned to work in a limitedcapacity.

Partial excision of the partly cystic rightfrontal lesion was performed at open crani-otomy. Post operatively the patient wastreated with intravenous penicillin and strep-tomycin together with oral tetracycline fortwo weeks and then continuous oral sulpha-inethoxazole-trimethoprim (co-trimoxazole).Gastroscopy and multiple duodenal andjejunal biopsies were all normal.One month later his condition was only

slightly improved. He was apathetic, docile,and did not initiate conversation. He showedsome intellectual improvement but had to beled to the table to eat. MRI showed most ofthe lesions to be smaller though there wasconsiderable enlargement of the left frontalmass (fig 2). Psychometry showed a verbal IQof 73 and performance IQ of 58.The patient was reviewed after a further

two months by which time his condition had

PATHOLOGICAL FINDINGSThe biopsy material was fixed and processedwith standard methods for both light andelectron-microscopy. Histologically the cortexand white matter were largely replaced bygliovascular tissue. Large numbers of swollengemistocytic astrocytes and smaller collectionsof foamy macrophages were present as well asperivascular cuffs of mononuclear cells. Manyof the macrophages contained irregular PASpositive, diastase resistant cytoplasmicmaterial (fig 3). Special stains for acid fastbacilli and fungi were negative.On electron-microscopy the macrophages

contained rod-shaped bacilli (fig 4), 0 2 by1-5-2-5 ,um. Although some appeared to bedegenerating, better preserved examples had awell defined trilaminar membrane.

DiscussionThis patient presented with symptoms ofrapidly evolving raised intracranial pressurewith multiple ring enhancing mass lesions onCT and MRI. Electron microscopy of materialobtained at open biopsy demonstrated intra-cellular bacterial inclusions similar to those

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Figure 3 A group offoamy macrophages containing PAS positive granular material,surrounded by large gemistocytic astrocytes. (PAS x 400).

Figure 4 (a) Bacilli within the cytoplasm of amacrophage x 26,000. (b) Detail of bacilli showing thetrilaminar plasma membrane x 132,000.

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Whipple's disease confined to the CNS presenting with multiple intracerebral mass lesions

Table Neurological complications of Whipple's disease

Progressive dementia689" 14 21 23 27Behavioural or emotional change4671'Memory loss6""2'Depression4'Psychosis23Headache4"9'Meningitis2'

Hypothalamic abnormalities:Disturbed sleep pattem810Somnolence7 8

Hypogonadotrophic hypogonadism6 23Increased appetite81'Polydipsia7 1

Hyponatraemia9Hypopituitarism"

Blurred vision8 "

Ocular abnormalities:Papilloedema'Uveitis" '229Retinitis'Vitreous opacities31Keratitis29Choroiditis"

Ophthalmoplegia4 21Supranuclear ophthalmoplegia8"' 421 32Nystagmus6 23

Ptosis'4 17 21Facial weakness'4Hemifacial spasm'4Absent gag reflex'4Dysarthria6 14 17 21Trigeminal neuralgia'3Hearing loss2' 2Vertigoll 21

Ataxia6 8 9 23 25

Oculomasticatory myorythmia'4Myoclonus2' 32Seizures9 l 12 23 27Pyramidal signs689" 23

Parkinsonism32Posterior column signs and spasticity33Peripheral neuropathy6 '7Proximal Myopathy"6

previously described from patients withWhipple's disease. Some immediate im-provement followed craniotomy and the startof antibiotic treatment, although cognitivedeficits and behavioural changes were not sig-nificantly improved until two to three monthslater.The majority of patients with Whipple's

disease present with arthralgia, gastro-intes-tinal symptoms or systemic upset, but 5 to 43%may have CNS involvement when first seen.45

The neurological picture is variable (table) andpresentation with an exclusively or predomin-antly neurological picture is uncommon.

Progressive cognitive decline, ataxia, hypotha-lamic disturbance or evidence of brainstemdysfunction with supranuclear ophthalmo-plegia have been described in such cases.'Jejunal biopsy may be normal""'2 and PASpositive cells in the CSF are an inconsistentfinding."" In these circumstances diagnosis isdifficult and, as in our patient, may only beestablished by brain biopsy.'2 An involuntarymovement disorder said to be specific forWhipple's disease has been termed oculomas-ticatory myorhythmia. 14 Rhythmic conver-

gence4 or verticle pendular'5 eye movements atone Hertz are accompanied by synchronousopening and closing of the jaw. Peripheralneuropathy and myopathy are reported, but theimportance of associated vitamin and nutri-tional deficiency in these cases remains uncer-

tain since PAS positive macrophages have beenidentified on muscle biopsy'6 but not in peri-pheral nerves."

Abnormalities on CT or MRI scans are notspecific for Whipple's disease. CT head scansare often normal'8 or show cortical atrophy,'4 17but areas of low density without mass effectwhich may show patchy contrast enhancementare described.6"2 MRI shows diffuse abnor-malities, especially increased signal on T2weighted images of the hypothalamus andadjacent medial temporal lobes8 but multiplemass lesions with ring enhancement aftergadolinium have not previously been describedin Whipple's disease.

DetailedEM and cytochemical studies of theWhipple's bacillus in jejunal biopsy specimensfrom untreated cases reveal a three layeredbacterial envelope surrounding free bacilli inthe lamina propria.' A 6 08 nm cytoplasmicmembrane is surrounded by a 20 nm cell wall.This contains peptidoglycan and polysac-charides whose PAS-positive remnants formthe characteristic intracellular inclusions. Anouter 4-7 nm surface membrane differs struc-turally from the outer membrane of Gramnegative bacteria.No immunological abnormalities were

evident in our patient and the role of alteredimmunity in the pathogenesis of Whipple'sdisease is uncertain. An association with HLAB27 has been suggested'9 and abnormalities ofT lymphocyte function have been reported.20The condition has been described in patientssuffering from AIDS and these patients mayhave cerebral involvement.2'

Before antibiotic treatment Whipple's dis-ease was uniformly fatal, usually withinmonths4 22 but rapid symptomatic and bio-chemical improvement of cases with no CNSinvolvement follows treatment with anti-biotics.42' Von Herbay reported 22 patientsfollowed up for one to 15 years with no CNSrelapses after initial treatment with tetracyclinecontinued for two years24, although CNSrelapse is reported after shorter courses oftetracycline.4 Progressive memory deficit andpersonality change may occur during otherwisesuccessful treatment and clearance of bacillaryorganisms from jejunal biopsy specimens.25Relapse is reported in up to 35% of patientsafter apparently successful treatment and maybe delayed.2' Keinath et al identified 88 patientsby literature review and correspondence whohad been followed up for at least two years afterdiagnosis or one year after completingtherapy.2' Relapse occurred in 31 patients at amean of 4-2 years after diagnosis and relativelymore frequently after initial treatment withtetracycline or penicillin alone than after com-bined penicillin, streptomycin, tetracycline ortrimethoprim-sulphamethoxazole. CNS re-lapse was most common, occurring in 11 (13%)of patients, all more than two years afterdiagnosis. Six of these patients died and fourothers responded poorly to further treatment.Similarly presentation with neurological symp-toms usually indicates a bad prognosis, mostcases responding poorly to treatment and dyingwithin months or a few years of diagnosis.689

Since late CNS involvement may followinitial therapy with tetracycline it has beensuggested that patients should be treated with

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drugs that are better able to cross the blood-brain barrier and a single case report existswhich describes reversal ofprogressive demen-tia in a patient with Whipple's disease treatedwith trimethoprim-sulphamethoxazole.'8 Forthis reason our patient was treated with paren-

teral penicillin and streptomycin for 14 daysfollowed by long term oral trimethoprim-sul-phamethoxazole.23Macrophage bacterial inclusion associated

CNS disease appears to have a poor prognosiswhether or not associated with systemicWhipple's disease. Efforts in such cases shouldbe directed towards identifying specificcausative organisms and long term treatmentwith antibiotics known to cross the blood-brainbarrier.26 Further information is required todetermine whether CNS involvement occurs inother cases of Whipple's disease with a goodoutcome, and to determine the relative impor-tance ofimmune deficiency and direct bacterialinvasion in the pathogenesis of the condition.Long term follow up studies would help iden-tify the optimum antibiotic regime and dura-tion of treatment.

The Multiple Sclerosis NMR Research Group is supported bythe Multiple Sclerosis Society of Great Britain and NorthernIreland.

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