whipple's disease confined to the central nervous system

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  • There have been previous isolated case reports of subacute and relapsing neuropathy occurring in preg- nancy, frequently during its later stages. Castaigne and colleagues [ 3 ] referred briefly to 2 patients who had relapses during pregnancy at 3 and 6 months, respec- tively. Calderon-Gonzalez and associates 121 described a patient in whom relapses of a symmetrical poly- neuropathy occurred during the second and third trimesters in three successive pregnancies, and subse- quently while taking oral contraceptives. Novak and Johnson [ll] reported a patient who had a subacute onset of peripheral neuropathy in the third trimester of her first pregnancy and in the second trimester of her second pregnancy. Jones and Berry IS] descrihed a patient who had the onset of CIDP in her first preg- nancy and relapses in the subsequent two pregnancies. Dalakas and Engel 141 studied one patient in whom the onset occurred in the later months of pregnancy. DAmbrosio and de Angelis 153 described a patient who had the onset of relapsing polyneuritis during the third trimester of her first pregnancy, a relapse late in the third trimester of the second pregnancy, and a further relapse six months after commencement of an oral contraceptive.

    Guillain-Bar& syndrome may occur in pregnancy but it does not appear to be more commcm in pregnant women than in the general population, and pregnancy does not seem to influence the course or severity of the disease [I, 5 , 10, 131.

    The mechanism of relapses of CIDP in pregnancy is uncertain. Studies of the immune system in pregnancy have been directed mainly toward the mechanism of protection of the fetus from rejection by the mother [71. It is not known how immunological responses in pregnancy could cause or exacerbate CIDP. PossibIe mechanisms may be the existence of a cross-reactivity between fetal and maternal neural antigens or an im- mune response in pregnancy that provokes an anam- nestic response to neural antigen.

    - P. A. McCombe was a National Health and Medical Research Coun- cil Postgraduate Medical Scholar and P. G. McManis was a Bushell Research Fellow. The statistical advice of Professor G. Berry, School of Public Health and Tropical Medicine, and Dr J . Simes, Royal Prince Alfred Hospital, and the skilled technical assistance of Miss P. Martin are gratefully acknowledged. -

    References 1. Ahlberg G, Ahlmark G. The Landry-Guillain-Barre syndrome

    and pregnancy. Acta Obstet Gynecol Scand 57:377-380, 19.78 2. Calderon-Gonzalez R, Gonzalez-Cantu N, Rizzi-Hernandez H:

    Recurrent polyneuropathy with pregnancy and oral contracep- tives. N Engl J Med 282:1307-1308, 1970

    3. Castaigne P, Brunet P, Nouailhat F: Enquete cilinique sur les polyradiculonCvrites inflammatoires en France. Rev Neurol (Paris) 115:849-872, 1966

    4. Dalakas MC, Engel W K Chronic relapsing (dysimmune) poly-










    neuropathy: pathogenesis and treatment. Ann Neurol

    DAmbrosio G, de Angelis G: Syndrome de Guillain-Barre au cours de la grossesse. Rev Neurol (Paris) 141:33-36, 1985 Dyck PJ, Lais AC, Ohta M, et al: Chronic inflammatory poly- radiculoneuropathy. Mayo Clin Proc 50:62 1-637, 1975 Jacoby DR, Olding LB, Oldstone MBA: Immunological regula- tion of fetal-maternal balance. Adv Immunol35:157-208, 1984 Jones MW, Berry K Chronic relapsing polyneuritis associated with pregnancy. Ann Neucol9:413, 1981 Korn-Lubetzki I, Kahana E, Cooper G, Abramsky 0: Activity of multiple sclerosis during pregnancy and puerperium. Ann Neurol 16229-231, 1984; (reply to letter) 18:101, 1985 McFarland HR, Heller G L Guillain-Barr6 disease complex: a statement of diagnostic criteria and analysis of 100 cases. Arch Neurol 14:196-201, 1966 Novak DJ, Johnson KF: Relapsing idiopathic polyneuritis dur- ing pregnancy. Arch Neurol 28:219-223, 1977 Prineas JW, McLeod JG: Chronic relapsing polyneuritis. J Neurol Sci 27:427-458, 1976 Ravn H: The Landry-Guillain-Barre syndrome. Acta Neurol

    ~ ( suPP~) : 134- 135, 1981

    Stand 43:l-64, 1967

    Whipples Disease Confined to the Central Nervous System Melanie Adams, MD, Patricia A. Rhyner, MD,t John Day, MD,S Stephen DeArmond, MD, PhD,+ and Edward A. Smuckler, MD, PhD

    Progressive hypersomnia, memory disturbance, and vertical ophthalmoplegia developed in a 63-year-old woman. The diagnosis of Whipples disease of the cen- tral nervous system was suggested by her presentation and results of studies using magnetic resonance imag- ing. Despite a one-month course of antibiotics, active Whipples disease, localized to the central nervous sys- tem, was found at autopsy.

    Adams M, Rhyner PA, Day J, DeArmond S, Smuckler EA: Whipples disease confined

    to the central nervous system. Ann Neurol 21:104-108, 1987

    Whipples disease is a rare multisystem disorder pre- senting most often with symptoms of gastrointestinal malabsorption, fevers, arthralgias, and lymphadenopa-

    From the Departments of Pathology, t Radiology, and $Neurology, School of Medicine, University of California, San Francisco, San Francisco, CA 94143. Received Feb 18, 1986, and in revised form June 9, 1986. Accepted for publication June 9, 1986. Address reprint requests to Dr Adams, Department of Pathology, HSW-501, School of Medicine, University of California, San Fran- cisco, CA 94143.


  • thy. Demonstration of Whipples bacilli, the bacil- liform bodies visible by electron microscopy, estab- lishes the diagnosis E2). It is suggested that these are microorganisms, based on their morphological features and antibiotic sensitivity, but serological definition and culture of the bacilli have not yet been accomplished. The mechanism of dissemination of the bacillus is also unclear. The central nervous system (CNS), liver, spleen, and heart are vulnerable. While it has been thought that the gastrointestinal tract is primarily in- volved, it has been reported that Whipples disease may present solely with CNS involvement IS, 7-91. A case of fulminant primary CNS Whipples disease is reported in which the diagnosis was made on clinical presentation and the magnetic resonance image.

    Case Report A 63-year-old woman was admitted to the University of California, San Francisco, for evaluation of hypersomnia, memory disturbance, and ataxia. She had been in excellent health until approximately 6 months prior to admission, when she noted increased appetite and somnolence. Review of systems revealed the recent development of mild blurred vision and bilateral shoulder pain. She had no gastrointestinal complaints or history of fever. Two months prior to admis- sion, the patient was evaluated with two computerized axial tomography (CT) scans of the head, which were described as normal. She was admitted to the hospital because of progres- sion of her symptoms.

    Physical examination was within normal limits, with the exception of the neurological findings. She was awake and alert, but disoriented to time and unable to name the hospi- tal. Long-term memory was impaired. Pupils were equal, round, and reactive to light. Extraocular movements were abnormal, with limitation of volitional upward gaze but pre- served ability to track upwardly, suggesting a supranuclear gaze palsy. She had limb and trunk ataxia and bilateral Babin- ski signs. There was no evidence of peripheral neuropathy.

    Laboratory values on admission revealed hyponatremia with a sodium level of 119 mEqL and chloride content of 85 mEq/L. Cerebrospinal fluid showed 7 neutrophils, with other values within normal limits. No macrophages were seen.

    In the hospital, she had increasingly abnormal eye move- ments, marked hypersomnia, and disorientation. Paralysis of upward gaze developed, with episodic limitation of left eye abduction. Her pupillary reflexes remained normal. Dolls eyes and caloric reflexes were absent. An electroencepha- logram showed diffuse slowing. Follow-up CT scan (General Electric 8800) revealed contrast enhancement in the region of the hypothalamus. The magnetic resonance images were obtained on a 0.35-Tesla (Diasonics MT15) system. TZ- weighted images (TR, 1.5 sec; TE, 56 msec) showed abnor- mal high-signal intensity in the hypothalamus, uncus, and medial temporal lobes (Fig 1). A jejunal biopsy was per- formed that showed onIy nonspecific Iymphangiectasia with few macrophages, which did not contain periodic acid-Schiff (PAS)-positive bacilli; a diagnosis of gastrointestinal Whip- ples disease could not be made.

    It was decided to treat empirically for primary CNS Whip-

    Fig 1 . Direct coronal T,weighted magnetic resonance image {TR, 1.5 sec; TE, 56 msec), showing abnormal higb-signal in- tensity about the hypothalamus, uncus, and medial temporal lobes.

    ples disease. She was initially treated with high-dose peni- cillin without improvement, then with trimethoprim- sulfamethoxazole, which was discontinued because of granulocytopenia. With return of her white cell count to normal, rifampin and chloramphenicol were started followed by marked clinical improvement. Her sleep pattern nor- malized as did her extraocular movements, although there were continued transient episodes of mild ocular paresis and ataxia. The hyponatremia reversed with demeclocycline treatment, and the patient was discharged one month after admission. Four days after discharge she developed hiccup- ping and pain in the back of the head. Laboratory studies revealed a serum sodium concentration of 153 mglL and he- matocrit of 50%. Demeclocycline was discontinued. The fol- lowing morning she could not be roused from sleep and died en route to the hospital.

    Gross findings at autopsy showed the viscera were normal. Histological examination revealed only a healed granuloma in the apex of the left upper lobe of the lung. Examination of multiple sections of bowel with special stains and electron microscopy failed to reveal evidence of Whipples disease.

    Her brain weighed 1,250 gm. On coronal sections, the septal nuclei, hypothalamus, and mamillary bodies had a uni- form yellow granular discoloration with indistinct borders bilaterally. No further lesions were identified grossly. Micro- scopically, the hypothalamus, thalamus, and mamillary bodies were the focus of extensive inflammation. Mac- rophages containing PAS-positive bacillary structures were seen perivascularly and were scattered both individually and in small microglial nodules within the parenchyma (Fig 2). Free PAS-positive baciliiform structures were clustered

    Brief Communication: Adams et al: Whipples Disease in CNS 105

  • A A


    Fig 3. (A) Hypothalamus: electron micrograph of macrophages, showing lysosomes containing tightly packed membranous strgc- tures and bacillary shaped shells. ( x 18,500 before 13% reduc- tion.) (B) Bacilli diagnostic of Whipples disease, with organelles apparent. ( x 3 1,500 before 5% reduction.)


    Fig 2. (A) Hypothalamus: large periodic acid-Schiff (PAS) = positive macrophages cluster perivascularly and ikdividually within brain parenchyma. Reactive astrocytes filC the area. ( x 40 before 13% reduction.) (Bi Macrophages packed with PAS- positive granules. ( x 80.)

    within neuropil, adjacent to macrophages. [dentical PAS- positive bacilli were seen in the macrophages. Reactive astro- cytes surrounded these rnicroglial nodules ,and occasional PAS-positive giant cells were present. Intense reactive astro- cytic gliosis was most extensive in the hypothalamus, includ- ing the marnillary bodies. Infiltration of PAS-positive niac- rophages and nerve cell loss was correspondingly greatest in these two regions. Microglial nodules containing many P,4S- positive macrophages were found bilaterally in the substantia innominata, amygdala, and cingulate gyrus. The inflammation

    extended caudally into the midbrain, primarily involving the colliculi and periaqueductal gray matter of the pons. Addi- tionally, occasional microglial nodules with PAS-positive macrophages were scattered throughout the pontine and medullary tegmentum. The cerebellum contained a focus of PAS-positive macrophages infiltrating the molecular layer and within the subarachnoid space. The spinal cord was nor- mal.

    Electron microscopic examination of periventricular tissue of the hypothalamus revealed bacilliform structures diag- nostic for Whipples disease within the cytoplasm of the mac- rophages Ell). Empty bacillary forms were seen, as well as degraded structures appearing as wavy, closely packed mem- branes within phagosomes (Fig 3) . No bacillary forms were noted in neurons or astrocytes.

    Discussion CNS involvement in Whipples disease is an infre- quent complication of a rare disorder. There are only

    106 Annals of Neurology Vol 21 N o 1 January 1387

  • Summary of Cases of Wh$ples Disease in the Central Neruous System

    Neuropathological Case Clinical Summary Treatment Course Findingsqb

    40-yo male et al C91)

    (Romanul Headaches, seizures, Antibiotics + (for up Steady neurological gait ataxia, short- to 1 mo), methyl- deterioration over term memory loss, prednisone, phe- 4 yr; death 4 yr af- incontinence, nys- nytoin ter presentation, 2 tagmus yr after treatment

    58-yo male (Halperin et al I511

    22-yo male (Kitamura tm

    63-yo female (present case)

    36-yo female (Pollock et al 183)

    Arthralgias (impo- tence, low testos- terone, luteinizing hormone, and folli- cle-stimulating hor- mone levels), per- sonality change, sensory & motor peripheral neuropathies, ataxia, nystagmus

    Motor excitation fol- lowed by somno- lence, fever

    Hypersomnia, hyper- phagia, memory disturbance, ataxia, ophthalmoplegia

    Seizures, memory loss, dementia

    Antibiotics + + Steady neurological deterioration over 6 yr; rapid neuro- logical deteriora- tion over 6 mo while on antibiotics

    Antibiotics + + + Multisystem failure 3 wk after presenta- tion

    Antibiotics + + + + Steady neurological deterioration over 6 mo; marked im- provement after antibiotic therapy; sudden death 1 wk after hospital dis- charge

    Antibiotics Dementia, memory + + + + +, pred- loss; stabilized on nisolone, anticon- long-term anti- vulsants biotics

    Antemortem: Tempo- ral lobe biopsy: granulomatous en- cephalitis (no EM studies performed)

    Postmortem: Lesions found in cortical gray matter, cau- date nucleus, puta- men, thalamus, cerebellar cortex, leptomeninges

    Antemortem: Tempo- ral lobe biopsy: le- sions found in cerebellar cortex and underlying white matter

    Postmortem: No au- topsy

    Postmortem: Lesions found in anterior thalamus, hypothal- amus, caudate nu- cleus, globus pal- lidus, putamen

    Postmortem: Lesions found in thalamus, hypothalamus, mamillary bodies, substantia in- nominata, amyg- dala, hippocampus, cingulate gyrus, medulla, cere- bellum

    Antemortem: Tempo- ral lobe biopsy: le- sions found in ce- rebral cortex and underlying white matter

    Lesions in all four cases consisted of aggregates of periodic acid-Schiff-positive macrophages that were positive for bacillus on electron microscopy. bAll other organs sampled ante- and postmorrem were free of Whipples disease. + = tetracycline, gentamicin, ampicillin, cephalexin; + + = tetracycline, chloramphenicol; + + + = not specified; + + + + = penicillin, trimethoprim-sulfamethoxazole, rifampin, chloramphenicol; + + + + + = minocycline, tetracycline; yo = years old; EM = electron micro- scopy.

    four cases with CNS involvement documented in the literature, but with no systemic involvement through- out the course of the disease (see TEbce) {S, 7-91. The earliest manifestation of Whipples disease in our case was hypothalamic disturbance. However, it was the development of supranuclear ophthalmoplegia that was most useful in making the clinical diagnosis, as in

    other cases of CNS Whipples disease {4]. Our patient had an unusually fulminant course of Whipples disease that remained restricted to the CNS. Despite three weeks of therapy and abatement of symptoms, active encephalitis was seen at autopsy.

    The inflammatory reaction has a predilection for the gray matter of the hypothalamus, cingulate gyrus, basal

    Brief Communication: Adams et al: Whipples Disease in CNS 107

  • ganglia, insular cortex, and cerebellum. Why these tis- sues are preferentially involved in Whipples disease, and why they appear to be resistant to therapy de- signed to cross both disrupted and intact blood-brain barrier, is unknown. Ultrastructural analysis of in- volved tissue reveals a distinctive bacillary inclusion that is diagnostic for Whipples disease 1111. Studies of involved bowel characteristically demonstrate free bacillary forms in the extracellular spaces of the lamina propria as well as within macrophages 131. There is no invasion of the overlying epithelium imd there are no free organisms within vascular channels. Neutrophils with intracellular bacillary forms can be seen circulat- ing in vascular compartments, and Dvorak and Mona- han 131 speculate that this provides a mechanism for spread. Free bacillary structures have also been re- ported infiltrating glial substances around macrophages and within neural perikarya, with bacillary wall mate- rial noted in pericytes and astrocytes (61. Cerehrospi- nal fluid of patients with CNS Whipples disease can sometimes contain PAS-positive macrophages, and the possibility exists that there is seeding of the periven- tricular tissue through the cerebrospinal fluid. Individ- ual immunological responses may vary in their ability to contain and eradicate this bacillus; disseminated Whipples disease in a patient with acquired immune deficiency syndrome has recently been reported C 11.

    Chloramphenicol and trimethoprhsulfamethox- azole may arrest the course of CNS disease. It is sug- gested that the delayed onset of CNS involvement may be more frequent in patients treated with tetracy- cline for their gastrointestinal diseases { 101. Assess- ment of therapy is difficult, as symptoms may fluctuate in severity with bland manifestations that do not repre- sent the extent of the disease. It appears that gaze palsies and nystagmus are the signs most responsive to treatment 181. Our patient showed almost complete resolution of her hypersomnia, confusion, and gaze disturbance while on chloramphenicol, although active disease was present at autopsy.

    In this patient, Whipples disease was suggested by the clinical presentation and the radiographic findings. Early recognition can be critical in a disease that can lead to irreversible sequelae and that can potentially be treated. Brain biopsy has been suggested as a diag- nostic method in cases of high suspicion {GI; however,

    the lesions are frequently inaccessible and the focal nature of the disease leads to a moderately high rate of false negatives. As imaging techniques improve, the yield with this method may increase, as the biopsy may be more accurately directed. Sensitive imaging tech- niques may also be valuable in assessing therapeutic response. In those cases of high clinical suspicion, in which Whipples disease cannot be diagnosed with pro- cedures such as jejunal biopsy, a trial of antibiotic ther- apy is recommended.

    We would like to thank David Geller for his invaluable editorial assistance, Glenda Reifenrath for her skillful electron microscopic work, and the UCSF Department of Pathology histotechnicians for their patience and excellence in preparing the multiple histological specimens involved in this study.

    References 1. Autran B, Geran I, Leibowitch M, et al: AIDS in a Haitian

    woman with cardiac Kaposis sarcoma and Whipples disease (letter). Lancet 1:767-768, 1983

    2. Chears WC Jr, Aschworth CT: Electron microscopic study of the intestinal mucosa in Whipples disease. Demonstration of encapsulated bacilliform bodies in the lesion. Gastroenterology

    3. Dvorak A, Monahan R Weight loss, fatigue, diarrhea, fever, and lymphadenopathy in a 48-year-old male industrial engineer. Electron Optics Report 3 1 : 10-2 1, 1984

    4. Finelli PF, McEntee WJ, Lessell S, et al: Whipples disease with predominantly neuroophthalmic manifestations. Ann Neurol

    5. Halperin J, Landis DMD, Kleinman GM: Whipples disease of the nervous system. Neurology 32:612-617, 1982

    6. Johnson L, Diamond I: Cerebral Whipples disease. Diagnosis by brain biopsy. Am J Clin Pathol 74:486-490, 1980

    7. Kitamura T: Brain involvement in Whipples disease: a case report. Acta Neuropathol 33:275-278, 1975

    8. Pollock S, Lewis PD, Kendall B: Whipples disease confined to the nervous system. J Neurol Neurosurg Psychiatry 44:1104- 1109, 1981

    9. Romanul FC, Radvany J, Rosales RK. Whipples disease confined to the brain: a case studied clinically and pathologically. J Neurol Neurosurg Psychiatry 40:901-909, 1977

    41~129-138, 1961

    1~247-252, 1977



    Ryser RJ, Locksley RM, Eng SC, et al: Reversible dementia associated with Whipples disease by trimethoprim-sufamethox- azole, drugs that penetrate the blood-brain barrier. Gastroen- terology 86:745-75 1, 1984 Schochet SS Jr, Lampert PW: Granulomatous encephalitis in Whipples disease. Electron microscopic observations. Acta Neuropathol (Berl) 13:l-11, 1969

    108 Annals of Neurology Vol 21 No 1 January 1987