Whipple's Disease Diagnosed by Stereotactic Biopsy Intracerebral Whipple's Disease Diagnosed by Stereotactic Biopsy: A Case Report and Review of the Literature Ehud Mendel, M.D., Larry T. Khoo, M .D., John L. Go, M.D., David Hinton, M.D., Chi-Shing Zee, M.D., Michael L.J. Apuzzo, M.D. Departments of Neurological Surgery (EM, LTK, MLJA), Radiology (JLG, C-SZ), and Pathology (DH), University of Southern California School of Medicine, Los Angeles, California b y w o r d s : Brain biopsy, Dementia, Hypogonadism, Stereotaxy, Whipple s disease lA /bipple's disease is characterized by a widespread chronic granulomat°us infiltration of the gastrointesti' cardiac, pulmonary, and nervous systems. Originally described in 1907 as "intestinal lipodystrophy," this entity is now recognized as an infectious disor­ der caused by the rod-shaped bacillus Neurosurgery , Vol. 44, No. 1, January 1999 Tropheryma whippelii. Central nervous system (CNS) involvement is well de­ scribed in systemic W hipple's patients and occurs in 10 to 20% of cases (8). On rare occasions, neurological manifesta­ tions may be the first and only herald of the disease process. The nonspecific symptomatology combined with the rar­ ity of this entity often leads to difficulties and delays in the management of these patients. We present a rare case of isolated intracerebral Whipple's disease that ulti­ mately required stereotaxy-guided brain biopsy before definitive diagnosis and treatment could be rendered. CASE REPORT A 36-year-old right-handed Greek man presented with a 4-month history of gen­ eralized lethargy, behavioral changes, and brief sporadic periods of hypersom­ nia. These were described as episodes of spontaneous sleep onset with speech ar­ rest and unarousability. His family re­ ported that the patient also had become increasingly w ithdraw n, unm otivated, and listless during the previous 3 months. No history of nausea, vomiting, bowel or bladder incontinence, fever, chills, or trauma was reported. There were no episodes of rhythmic or stereo­ typed movements noted. He denied any significant previous medical problems and was in a state of good health before the onset of symptoms. He was receiv­ ing no medications and denied any rec­ reational drug or alcohol consumption. He did report a weight gain of 20 to 30 pounds during a period of 2 months as well as a 2-month history of impotence and decreased libido. At admission, the patient was afebrile and normotensive. A neurological ex­ amination revealed Cranial Nerves II through XII to be intact. The results of a fundoscopic examination were unre­ markable, without evidence of papil­ ledema. Although the patient was drowsy and had a blunted affect, he was able to fully cooperate with the examination. No sensory or motor deficits were discov­ ered. All reflexes were brisk. The patient's gait was steady, and the results of his Downloaded from https://academic.oup.com/neurosurgery/article-abstract/44/1/203/2849554 by University of Cambridge user on 17 March 2019 OBJECTIVE AND IM PO RTAN CE: This case demonstrates the rare occur­ rence of intracerebral Whipple's disease in a patient lacking classic systemic manifestations of the disease. Because of the nonspecific pre­ sentation and the typically deep-seated location of cerebral lesions in these patients, definitive diagnosis is frequently problematic. We present the first reported use of stereotaxy-guided brain biopsy to confirm the diagnosis of isolated intracranial Whipple's disease. CLINICAL PRESENTATION: The patient was a 36-year-old man who presented with a 4-month history of progressive lethargy, hypersomnia, behavioral changes, and weight gain. The results of the physical examination were remarkable only for findings of hypogonadism. Subsequent laboratory eval­ uation confirmed the diagnosis of hypogonadotrophic hypogonadism, with low levels of testosterone, luteinizing hormone, cortisol, and prolactin. INTERVENTION: A magnetic resonance image of the brain demonstrated hyperintense lesions on T2-weighted images in the regions of the right fornix, hypothalamus, and putamen that subsequently enhanced with intravenously administered contrast medium. A biopsy was then obtained from the right putaminal lesion under stereotactic guidance. Histopathological analysis of the tissue revealed findings consistent with intracere­ bral Whipple's disease that were subsequently confirmed using electron microscopy. CONCLUSION: Intracerebral Whipple's disease should be included in the differential diagnosis of patients presenting with progressive dementia and cognitive decline. In these patients, lesions have typically been observed in the hypothalamus, cingulate gyrus, basal ganglia, insular cortex, and cerebellum. As evidenced by our case, stereotaxy affords clinicians the attractive option of a minimally invasive technique by which to obtain tissue from such deep-seated areas. A review of this rare neurosurgical entity is presented. (N e u ro su rg e ry 4 4 :2 0 3 - 2 0 9 , 1 9 9 9 ) 203 204 Mendel et al F IG U R E 1. T2 -w e ig h ted a x ia l im age, F IG U R E 3. P o stco n tra st Tl-w eig hted co ro n a l m a g n e tiza tio n tra n sfe r image o b tained at the level o f the a n te rio r co m m issu re , d e m o n stratin g a b n o rm a l d e m o n stra tin g a b n o rm a l enhancement h yp e rin te n se signal w ith in the co lu m n s o f the right p u ta m e n , right colum n of o f the fo rn ix and h yp o th a la m u s w ith o u t the fo rn ix , and an e n h a n c in g mass m ass e ffe ct. w ith in the h y p o th a la m ic reg io n . F IG U R E 4. P o stco n tra st C T scan dem­ o n stra tin g a b n o rm a l en h an cem e n t w ith in the right p u tam e n . T h is was taken as the target point fo r stereotac­ tic b iop sy (a rro w ). F IG U R E 2. P o stco n trast T1 -w eig h ted a x ia l m ag n e tiza tio n tra n sfe r im age d e m o n stratin g a b n o rm al e n h a n ce m e n t w ith in the right p u tam en , h y p o th a la m ic region w ith o u t m ass e ffe ct. routine processing after formalin fixa­ tion. The permanent sections revealed reactive glial tissue widely infiltrated by macrophages and perivascular lym pho­ cytes (Fig. 5A ). 1 here was no evidence of a neoplastic process. Periodic acid-Schift (PAS) stain revealed that the macro­ phages were intensely positive and con­ tained irregular PAS-positive/diastaseresistant cytoplasmic material. After Ncurosurgcry, Vol. 44, No. I January 1444 PAS staining, the large number of PASpositive m acrophages infiltrating the tissue became apparent, especially in the perivascular regions (Fig. 3B). Special stains for acid-fast bacilli and fungi were negative. Electron microscopy ^' vealed that the m acrophages contained num erous rod-shaped bacilli measuring 1.5 to 2.0 x 0.2 pan (Fig. 6 A). Many of the bacilli showed a w ell-defined trilaminar membrane inclusion as well (Fig. 66)The diagnosis ot intracerebral Whip’ pie's disease was thereby rendered. After histopathological confirmation, a regimen of high-dose parenteral pcn- Downloaded from https://academic.oup.com/neurosurgery/article-abstract/44/1/203/2849554 by University of Cambridge user on 17 March 2019 Romberg test were negative. No evidence of cerebellar dysfunction was elicited. The results of the physical examination were significant only for features of hypogo­ nadism (decreased size of testes, loss of muscle mass). An endocrinological consultation was thus obtained. Hormonal assay dem on­ strated an abnormally low serum testos­ terone level of 42 ng/ml (normal range, 270-1070 ng/ml). Cortisol, prolactin, and luteinizing hormone levels were similarly depressed (0.8-1.8 ng/dl). The remainder of the laboratory examination showed a mild anemia, a negative dementia panel (B12, folate, thyroid panel, heavy metals), normal liver functions tests, negative hep­ atitis and human immunodeficiency virus panels, and a mildly elevated erythrocyte sedimentation rate of 30. Analysis of the cerebrospinal fluid (CSF) revealed a mild pleocytosis, with negative results of the Venereal Disease Research Laboratory test and cryptococcus, toxoplasmosis, coccidiomycosis, India ink, fungal, and bacterial cultures. An electroencephalo­ gram revealed only mild diffuse slow ­ ing, without focal ictal activity. Magnetic resonance imaging (MRI) of the brain demonstrated abnormal hy­ perintense signal in the columns of the fornix and hypothalamic region, with­ out mass effect on the T2-weighted im­ ages. Postcontrast Tl-w eighted m agne­ tization transfer images demonstrated abnormal enhancement of the right putamen and right column of the fornix and an enhancing mass within the hy­ pothalamic region (Fig. 1-3). A postcon­ trast computed tomographic (CT) scan of the brain demonstrated similar re­ sults. A contrast-enhanced computed tomography-guided stereotactic biopsy of the lesion in the right putamen was performed with the patient under local anesthesia (Fig. 4). The patient tolerated the procedure well, without any new neurological deficits. At stereotactic biopsy, two pieces of tissue were obtained. One-half of the first piece was used for smear prepara­ tion and showed reactive gliosis with macrophage and lymphocytic infiltra­ tion. Because of a pathological suspicion of Whipple's disease, the remaining half of the first piece was submitted in glutaraldehyde for electron microscopy and the second piece was submitted for Whipple's Disease Diagnosed by Stereotactic Biopsy W • -4 , # * *« A * . v \ * . • » FIGURE 5. A, hematoxylin and eosin-stained section showing reactive . A # * *f f - * % 4 » v | , • • * gemistocytic glial tissue (arrowheads) infiltrated by * • f f < '• » / ;w ‘ * "• # •! ^ T % s •- * I v « 4 V : * A. •¥ | V '* 1 macrophages (straight arrows) and perivascular lymphocytes (curved arrows) (original magnification, x 4 4 0 ). B, PAS stain of a complete section of one of the stereotactic biopsies, showing the heavy infiltration of (arrows) (original magnification, X110). icillin, streptomycin, and oral trimethoprimsulfametoxazole (TMP-SMZ) was begun and was continued for a 2-week period. The patient became less lethargic and experi­ enced a decremental number of hypersomnic periods. His affect and behav ior remained unchanged. Hormonal assays obtained before discharge were similarly unimproved. The patient was discharged and was to receive a prolonged course of oral TMP-SMZ in the hope that it would arrest intracerebral disease progression and prevent future relapses. d is c u s s io n Pathological findings In 1907, George H. W hipple elo­ quently described an unusual case of a 56-year-old medical missionary who presented to the Johns Hopkins H ospi­ tal with a 5-year history of intermittent arthritic pain and fever, weight loss, ab­ dominal distention, steatorrhoea, and productive cough (29). An examination rovealed anemia, erythema nodosum , dyspnea, peripheral edema, ascites, and severe cachexia. A postmortem exami­ nation revealed the salient finding of neutral fats and fatty acids that were widely distributed in the body, particu­ larly in the small intestine and lymph nodes. A histological analysis demonstrated vacuolation and giant foamy mononuclear cells. From these observations, Whipple postulated an inherent deficiency of fat metabolism and thus termed the entity "intestinal lipodystrophy." PAS staining was subsequently used by Black-Schaffer in 1949 and led to the observation that the foamy macrophages were filled with mucopolysaccharide or glycoprotein and not lipid as Whipple had thought (8). Most commonly, the di­ agnosis of systemic Whipple's disease is obtained via histological examination of small bowel biopsy specimens. Findings include macrophages containing PAS granules (resistant to diastase) in the lamina propria, free rod-shaped bacilli in the lamina propria, distortion of the villous architecture, and dilated lym­ phatic channels (7). Granulomatous infil­ trations filled with PAS-staining macro­ Neurosurgery, Vol. phages have since been identified in a diverse number of tissues: small bowel, lymph nodes, CSF, brain, pericardium, endocardium, lung, liver, synovial mem­ branes, spleen, pancreas, esophagus, stom­ ach, colon, muscle, brain, and adrenal glands (8). Accordingly, Whipple's dis­ ease is often referred to by the descriptive title of multisystem chronic granuloma­ tous disease (3). Recent work suggests that granuloma formation is a direct and specific reaction to the T. whippelii bacil­ lus, with delayed hypersensitivity as the underlying mechanism (30). Although no consistent immunological deficit has been described in Whipple's patients, an asso­ ciation with HLA B27 and abnormalities of T lymphocyte function has been re­ ported (11, 31). In 1961, the classic electron micro­ scopic findings of W hipple's disease were simultaneously reported by two separate investigators (4, 32). Rod­ shaped bacillary bodies measuring 1.5 to 2.5 ixm long and 0.25 i±m wide with a homogenous cell wall and a bacterial trilaminar plasma membrane are typi­ cally seen within the PAS-positive gran­ ules of macrophages. A 6.08-nm cyto­ plasmic membrane is surrounded by a 20-nm cell wall. The core of the bacteria contains a pale, amorphous nucleoid and delicate tubular structures. The PAS-granules have since been defined as lysosomes containing bacilliform bodies in varying stages of degeneration (28). Through molecular techniques, these "W hipple's bacilli" were phylogenetically determined to be in the bacte­ rial subdivision of the order of Actinomycetales and were named Tropheri/ma whippelii (23). Some researchers have theorized that the continued inability to culture the bacillus is because of the outer membrane external to the cell wall of T. whippelii (9). In 1959, Sieracki et al. (27) described pathological changes in the brains of two patients who had succumbed to the disease but had not demonstrated any neurological symptoms. Lampert et al. (18) went on to provide the first post­ mortem diagnosis of intracerebral W hipple's disease in the case of a pa­ tient with neurological deterioration in 1962. Since that time, PAS-positive in­ clusions of characteristic histiocytes have been a well-described postmortem 44 ,No. , lanuary 1999 Downloaded from https://academic.oup.com/neurosurgery/article-abstract/44/1/203/2849554 by University of Cambridge user on 17 March 2019 PAS-positive macrophages, particularly in a perivascular location -Ml ’ 206 Mendel et al. 0 y - T*•* ' *•,>•%^♦•>• \« . *V » 0 * 4* A •*V «'C_*•»«V ' m3 t> V \. • t *i n V . **-Q F IG U R E 6. # •v •* .vX*' • «; > " * _ . .* containing numerous bacilli measuring 1.5 to 2.0 x 0.2 /mm (original magnification, X 5 5 0 0 ). B, bacilli t shown in cross and longitudinal section at higher magnification. The m typical trilaminar M appearance of the membrane is appreciated (arrows) (original magnification, x 2 6 ,9 5 0 ). abnormalities seen include (in order) low serum carotene, hypoalbuminemia, steatorrhoea, low serum iron, anemia, ele­ vated erythrocyte sedimentation rate, low protein, proteinuria, pyuria, hematuria, elevated prothrombin time, abnormal chest radiograph, low cholesterol, ele­ vated liver function indices, hypokalemia, electrocardiographic abnormalities, low folate, and hypocalcemia. , Involvem ent of the CN S is observed | in 10 to 20% of all cases and can occur at varying stages of the disease process (8). It may remain clinically silent only to be incidentally diagnosed by radiographic . or postm ortem exam ination (27). As with our patient, sym ptom atic CNS in- ' volvem ent can occur as an isolated find­ ing without any peripheral hallmarks of ' systemic disease. Instances of Whipple's ’ disease confined to the CN S are rare, 1 with fewer than 10 patients reported to : date and com prising less than 5% of all cases (1, 3, 14, 17, 22, 24, 28, 31). Neuro­ logical manifestations may also be en­ countered as a late form of relapse . after antibiotic therapy for intestinal disease with oth erw ise minimal evi­ dence of system ic relapse. The inci­ dence of such isolated C N S relapses ch aracteristically peaks 1 to 4 years after initial treatm ent and most com­ m only occurs in p atients treated with antibiotics that do not cross the blood- „■ brain barrier (16). The neurological hallmarks of intrace­ rebral W hipple's disease are p rotean in nature but may include a slowly pro- gressive dementia, headache, memory and cognitive deterioration, hypotha- _ lamic dysfunction, seizures, meningitis, supranuclear opthalmoplegia, myoclo­ nus, ataxia, nystagm us, uveitis, papill- . edema, hemiparesis, peripheral neurop­ athy, myopathy, hyperactive reflexes, and gaze palsies (1, 5, 11, 12, 14, 16,20, 22). An unusual involuntary movement ^ disorder characterized by a slow (1 Hz) convergent-divergent pendular nystag­ mus that is associated with a synchrom % nous opening and closing of the masti­ cation muscles, mouth, and other body parts has been observed in some pa' tients. Several clinician s consider this o cu lo m asticato ry m yorhythm ia to ho virtu ally p ath o g n o m o n ic for CNS W h ip p le's disease (2, 26). The triad of _ p rogressive d em entia, m yoclonus, and Whipple's Disease Diagnosed by Stereotactic Biopsy external opthalmoplegia (with pupillary sparing) is similarly thought to be highly C l and MRI findings are not specific for W hipple's disease. Cranial CT scans are often normal or demonstrate only cortical atrophy (31). When present, classic CT abnormalities include nodu­ lar abnormalities in the cortical and sub­ cortical gray and white matter (especial­ ly in the hypothalamus, cingulate gyrus, basal ganglia, insular cortex, and cere­ bellum), hydrocephalus, and white mat­ ter alterations (14, 19, 22, 31). A review of the literature dem onstrates eight previously described case reports of Whipple's disease for which magnetic resonance images were obtained (Table 1) (1-3, 6,10 , 25, 28, 31). The lesions were all hyperintense on T2-weighted images, with predominantly homogeneous en­ hancement after the administration of gadolinium (2, 9, 25, 28). However, one case demonstrated ring-like enhance­ ment on the postcontrast scan (31). The locations of these lesions on the m ag­ netic resonance images paralleled those seen on the CT scans and correlated with previously described histopathological findings at autopsy (24). Of the cases presented in Table 2, the diagnosis of W hipple's disease was made by lymph node biopsy in two cases (2, 25), at autopsy in one case (1), by duodenal or jejunal biopsy in two cases (2, 10), by open laparatomy and sampling of mesenteric lymph nodes in one case (6), and by open craniotomy with brain biopsy in three cases (3, 28, 31). Brain biopsy has been recom ­ mended for patients in whom the CNS lesion is easily accessible and there is a high degree of suspicion (3, 15). H ow ­ ever, the frequent inaccessibility of deep gray matter lesions and the focal nature of the disease has led to a moderately TABLE 1. Case Reports of Central Nervous System Whipple's Disease Adler and G a le tta , 1 9 9 0 ( 2 ) Jejunal biopsy; intracranial lesions em pirically treated for W hipple's disease Retroperitoneal lymph node biopsy Brown et al., 1 9 9 0 ( 3 ) Open right temporal and leptomeningea Adams et al., 1 9 8 7 ( 1 ) MRI Findings Diagnostic Method Study biopsy Davion et al., 1 9 9 0 ( 6 ) Hepatic and mesenteric lymph node Erdem et al., 1 9 9 3 ( 1 0 ) biopsy Duodenal biopsy Schnider et al., 1 9 9 5 ( 2 5 ) Inguinal lymph node biopsy Tan et al., 1 9 9 5 ( 2 8 ) Open brain biopsy W ro e e t a l., 1991 ( 3 1 ) Open excision of right frontal lesion T2-weighted image with low signal in the hypothalamus, uncus, medial temporal lobes, with gadolinium enhancement T2-weighted image with increased signal in the medial temporal lobes bilaterally, with enhancement T2-weighted image showing diffuse cerebral atrophy, increased signal in pons, brachium pontis; later increased signal in right temporal lobe and ventriculomegaly T2-weighted image with increased signal intensity in left frontal lobe and caudate nucleus T2-weighted image with increased signal in both frontal, left temporal, and occipital lobes, with enhancement T2-weighted image with increased signal showing mediobasal temporal lobes, hypothalamus, amygdala, hippocampal gyrus, mammillary bodies, and optic tracts, with enhancement T2-weighted image with increased signal in subthalamic and anterior thalamic regions and pons; also showed nodular abnormalities in cortical and subcortical gray matter and cerebellum T2-weighted image showing multiple high-signa lesions with mass effect throughout gray and white matter of varying sizes; gadoliniumenhanced study showed areas of periphera enhancement MRI, magnetic resonance imaging. Neurosurgery/ Vol. 44, No. i, lanuary I J 9 J Downloaded from https://academic.oup.com/neurosurgery/article-abstract/44/1/203/2849554 by University of Cambridge user on 17 March 2019 suggestive of the diagnosis (8). Halperin et al. (14) reported the first antemortem case of isolated CNS Whipple's disease diagnosed via temporal lobe bi­ opsy. Like his patient, our gentleman also presented with a history of behavioral changes, dementia, and impotence. In both cases, endocrinological evaluation revealed a picture of hypogonadotrophic h y p o ­ gonadism. Such h yp othalam op itu itary involvement is com m on am o n g p a­ tients with systemic W h ip p le's disease and includes sym ptom s of insom nia/ hypersomnia, hyperphagia, weight gain, and polydipsia (3, 8). As with most cases, our patient demonstrated a mild pleocytosis in his CSF analysis. Pleocytosis, an elevated protein level, and PAS-staining cells (Sieracki cells) are com m only de­ scribed CSF findings (13). Imaging and intervention 207 208 Mendel et al. Treatment and outcome Historically, cases of untreated CNS Whipple's disease invariably carried a poor prognosis with certain eventual fa­ tality. In 1952, Paulley (21) first reported the successful use of antibiotics in a pa­ tient with systemic W hipple's disease. Because the optimal type and duration of antibiotic regimen remain undefined, therapy has primarily been empiric (13). Treatment of systemic W hipple's has in­ cluded combinations of chloramphenicol, penicillin, streptomycin, tetracycline, arnpicillin, sulfonamides, TMP-SMZ, isoniazid, and para-aminosalicylic acid for vari­ able durations (5 ,7 ,8 ,1 3 ,1 6 ,2 2 ). For cases of CNS Whipple's disease, the mainstay of treatment is the use of antibiotics that effectively cross the blood-brain barrier (i.e., penicillin, TMP-SMZ, chlorampheni­ col). The typical regimen for intracerebral disease consists of 1.2 million units of par­ enteral penicillin G and 1 g of streptomy­ cin for 2 weeks for the intestinal disease, combined with one double-strength tablet of TMP-SMZ for 1 year (8, 28). Patients allergic to sulfonamides may be treated with oral penicillin (250 mg administered four times/d for 1 yr) in place of TMPSMZ. Oral chloramphenicol administered for 6 to 12 months may be used for ad­ junct therapy in unresponsive cases (28). Assessment of therapy is difficult, be­ cause symptoms may fluctuate in severity with bland manifestations that do not rep­ resent the extent of the disease. Gaze pal­ sies, nystagmus, and focal deficits have been reported to be the signs most re­ sponsive to treatment (1, 22). Personality and affect changes are typically much slower to improve after therapy (31). Al­ though our patient's lethargy and hyper­ somnia responded early on to medication, his apathy and personality changes may thereby require prolonged therapy before improvement is seen. Despite antimicrobial therapy, relapse of Whipple's disease is well recognized and should be cautiously anticipated in all cases (8, 13). Keinath et al. (16) re­ viewed 88 treated patients and found symptomatic relapse in 31 (35%) at a mean of 4.2 years after diagnosis. Of these 31 patients, 21 had been treated with tetracycline or penicillin alone and 10 had received combined penicillin, streptom ycin, tetracycline, or TM PSMZ. The CNS is considered the most common and serious site for recurrence. Recurrence occurs in approximately 13% of patients 2 years after treatment. Such symptomatic relapse with neurological manifestations usually indicates a poor prognosis; most patients respond poorly to additional therapy and die within months or a few years (1, 14, 24, 31). C O N C L U S IO N Intracerebral involvement is a com ­ mon finding in patients with known systemic W hipple's disease. Difficulties arise when neurological findings are the initial manifestation of the disease be­ cause the symptoms are often vague and nonspecific. For patients presenting with dementia, cognitive decline, hypothalamopituitary dysfunction, and opthamological disorders, the diagnosis of CNS Whipple's disease should he considered early on. J Appropriate MRI of the brain is then es­ sential to visualize the characteristic deepseated nodular gray and white matter le­ sions. Brain biopsy under stereotaxy allows for a relatively safe, minimally invasive, and rapid confirmation of the tissue di­ agnosis so that appropriate antibiotic therapy can instituted in a timely fash­ Neurosurgery, Vol. 44, No. /, /anuar) 1999 ion to prevent further neurological de­ terioration. The possibility that earh diagnosis, rapid intervention, new anti­ microbial agents, and novel routes of drug delivery may improve the natural course of CN S W hipple's disease re­ quires continued investigation. Received, May 29, 1998. ^ Accepted, September 3, 1998. Reprint requests: John L. Go, M.D., Depart­ ment of Radiology, Los Angeles CountyUniversity of Southern California Medical Center, 1200 N. State Street, Suite 3750-D,Los Angeles CA, 90033. REFERENCES 1 . Adams M, Rhvner PA, Day J, DeArmond S, Smucker EA: W hipple's disease confined to the central nervous system. A n n Neurol 21:104108, 1987. 2. Adler CH, Galetta SL: Oculo-facial-skeletal myorhythmia in W hipple's disease: Treatment with ceftriaxone. A nn In tern M ed 112:467469, 1990. 3. Brown AP, Lane JC, Murayama S, VollmerDG: W hipple's disease presenting with isolated neu­ rological symptoms. ] N eu ro su rg 73:623-627, 1990. 4. Chears WC Jr, Ashworth CT: Electron micro­ scopic study of the intestinal mucosa in Whipple's disease: Demonstration of encapsulated badlliform bodies in the lesion. Gastroenterology 41: 129-138, 1961. 5. Com er G M , Brandt LF, Abissi CJ: Whipple’s disease: A review. Am J G astro en tero l 78:107114, 1983. H 6. Davion T, Rosat P, Sevestre H, Desablens B, Debussche C, Delamarre J, Capron J-P: MR im­ aging of CN S relapse of Whipple disease J C o m p u t A ssist T o m o g r 14:815-817, 1990. 7. Dobbins W D III: W hipple's disease: An histor­ ical perspective. Q J M ed 5 6 :5 2 3 -5 3 1 , 1985. 8. Dobbins W D III: W hipple's disease. Mavo Clin Proc 6 3 :6 2 3 -6 2 4 , 1988. 9. Dobbins WD, Kawanishi H: Bacillarv character­ istics in W hipple's disease: An electron micro­ scopic study. G a s tro e n te ro lo g y 8:1468-14, 1981. 10. Erdem E, Carlier R, Delvalle A, Caquet R. Etienne JP, Doyon D: Gadolinium-enhanced MRI in cerebral W hipple's disease. Neuroradi­ Downloaded from https://academic.oup.com/neurosurgery/article-abstract/44/1/203/2849554 by University of Cambridge user on 17 March 2019 high rate of inconclusive open biopsies in the past (1). To our knowledge, this is the first case in which the diagnosis of the intracranial lesions was made by ste­ reotactic brain biopsy instead of either by open brain biopsy or empirically from a systemic diagnosis of W hipple's disease. Stereotaxy provides a relatively safe, minimally invasive means of obtain­ ing tissue from deep-seated targets that are otherwise inaccessible to open meth­ ods. Because patients with W hipple's disease are often elderly or m edically tenuous, stereotaxy-guided biopsy is additionally attractive in its rapidity and ability to be perform ed with the patient under local anesthesia. Recent work suggests that contrast-enhanced MRI may be particularly useful in iden­ tifying lesions in cases in which there is an active breakdown of the blood-brain barrier for optimal brain biopsy. High T2-signal intensity lesions that fail to enhance are thought to be chronic in nature and may lead to indeterminate tissue diagnosis (10, 28). W M o lo g y 3 5 :5 8 1 -5 8 3 , 1993. 11. Feurle GE, Volk B, Waldherr R: Cerebral Whipples disease with negative jejunal histology. N Engl J Med 300:907-908, 1979. H 12. Finelli P, McEntee WJ, Lessell S, Morgan TF, Copetto J: W hipple's disease with predom i­ nantly neuroophthalmic manifestations. Ann N eurol 1:1247-1252, 1977. 13. Fleming JL, Wiesner RH, Shorter RG: Whippys disease: Clinical, biochemical, and histopatho­ logic features and assessment of treatm ent in 2° patients. M a y o C lin Proc 6 3 :5 3 9 -5 5 1 , 1988. 14. I lalperin JJ, Landis DM, Kleinman GM: Whippy disease of the central nerv ous system. Neurolog) 32:612-617,1982. 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Pallis CA, Lewis PD: Neurology of g astro in tes­ tinal disease, in Vinken PJ, Bruyn SW (eds): The HandbookofNeurology. A m sterdam , N orth H o l­ land, 1980, vol 39, pp 449-468. 21. Paulley JW: A case of W hipple's disease (intes­ tinal lipodystrophy). G a stro en te ro lo g y 2 2 :1 2 8 133,1952. 22. Pollock S, Lewis PD, Kendall B: W h ip p le's d is­ ease confined to the nervous system . J N eurol Neurosurg Psychiatry 4 4 :1 104 -110 9, 1981. 23. Reiman DA, Schmidt TM , M acD erm o tt RP, lus of Whipple's disease. N Engl J M ed 327: 293-301, 1992. 24. Romanul FCA, Radvany J, Rosales RK: W hipple's disease confined to the brain: A case studied clin­ ically and pathologically. J Neurol Neurosurg Psychiatry 40:901-909, 1977. 25. Schnider P, Trattnig S, K ollegger H, A u ff E: MR of cerebral Whipple disease. A JN R Am J Neuroradiol 16:1328-1329, 1995. 26. Schwartz MA, Harris JK, Campbell W W , Ochs AL, Waters B, Selhorst JB: Oculomasticatory m yo­ rhythmia: A sign of Whipple's disease. Ann Neurol 18:135-136,1985 (abstr). 27. Sieracki JC, Fine G, Horn RC, Bebin J: Central nervous system involvement in W h ip p le's d is­ ease. J Neuropathol Exp N eurol 1 9 :7 0-75, 1960. 28. Tan TQ, Vogel H, Tharp BR, Carrol C L, K aplan SL: Presumed central nervous system W hipple's disease in a child: Case report. C lin Infect Dis 20:883-889,1995. 29. Whipple GH: A hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal and m esenteric lymphatic tissues. Jo h n H o p k in s M ed B ull 198: 382-391,1907. Harel Deutsch Martin B. Camins New York , New York 30. Wilcox GM, Tronic BS, Schecter DJ, A rron MJ, Righi DF, Weiner NJ: Periodic acid-Schiff- negative granulomatous ly m p h ad en o p a th y in patient with Whipple's disease: Localization of the Whipple bacillus to noncaseating g ran u lo ­ mas by electron microscopy. Am J M ed 8 3 :1 6 5 170,1987. ™ 1 Wroe SJ, Pires M, Harding B, Youl BD, Shorvon •Whipple s disease confined to the C N S present- 1 . D obbins W O III: The diagnosis of W hipple's disease. N Engl J M ed 332:390-392, 1995. 2. R eim an DA, Schm idt TM , M cDerm ott RP, Falkow S: Identification of the uncultured bacil­ lng with multiple intracerebral mass lesions. lus of W hip p le's disease. N Engl J Med 327: J Neurol Neurosurg Psychiatry 54:989-992, 1991. 2 9 3 -3 0 1 , 1992. Neurosurgery , Vol. 44, No. 7, January 1999 The authors present a case in which the precise diagnosis of W hipple's dis­ ease was made using standard stereo­ tactic biopsy. The key to reaching this critical conclusion was the careful and thoughtful handling of the biopsy m ate­ rial. A significant suspicion based on the frozen section led to the preparation of ma­ terial for electromicroscopic evaluation. William F. Chandler Ann Arbor, Michigan This is a case report of clinically un­ suspected central nervous system W hip­ ple's disease that was diagnosed by electron microscopy of the material ob­ tained by performing stereotactic bi­ opsy. This report emphasizes what has been repeatedly demonstrated in recent years as experience with stereotactic bi­ opsy specimens has increased exponen­ tially, i.e., that exact diagnoses can sometimes be made on very small spec­ imens. It is still essential that the pathol­ ogist make the correct inferences on the basis of the light microscopic picture and then perform the proper special strains or additional procedures. In this instance, the suspicion was aroused with the initial routine stains that led to the performance of PAS stains and elec­ tron microscopy, identifying the pecu­ liar bacteria that cause this still enig­ matic condition. With this said, it needs to be em pha­ sized that this is not always so and that greater care is still needed to recognize when we do not know the diagnosis and must persist in our diagnostic efforts. Further, it must be remembered that sampling error remains a major prob­ lem, amplified by the small size of avail­ able specimens; this is particularly true for brain tumors, in which so much his­ tological variability can be present. Good fortune should be accepted and appreciated but not expected. Richard L. Davis Neuropathologist San Francisco, California Downloaded from https://academic.oup.com/neurosurgery/article-abstract/44/1/203/2849554 by University of Cambridge user on 17 March 2019 Falkow S: Identification of the uncultured b acil­ W hipple's disease is a rare disease, with fewer than 10 cases reported in the w orld's literature every year. The most com m on manifestation is a malabsorp­ tion syndrome and arthralgias, although cardiac and central nervous system in­ volvement is also common (1). The article describes a case report involving a patient presenting with neurological symptoms who was found, by brain biopsy, to have macrophages that stained positive for the periodic acid-Schiff (PAS) stain. Evalua­ tion by electron microscopy revealed the characteristic gram-positive intracellular Tropheryma zvhippelii. Strongly PAS-positive intestinal biopsies are very suggestive of Whipple's disease if Mycobacterium avium is excluded with an acid-fast staining. In other tissues, PAS-positive staining can occur with a variety of diseases and elec­ tron microscopy is required to demon­ strate the characteristic bacilli. PAS stain­ ing can be negative, but the bacilli can still be present and be detectable only by elec­ tron microscopy. Newly developed poly­ merase chain reaction testing involving the amplification of the bacterial 16 S ribosomal ribonucleic acid has recently been developed and promises to be a more sensitive and convenient test (2). Al­ though Whipple's disease is rare, it should be considered in patients with hypotha­ lamic symptoms and ophthalmoplegia be­ cause it is a potentially treatable disease. 209