Neurologic Presentation of Whipple Disease: Report of 12 Cases and Review of the Literature
Whipple disease is a rare multisystemic infectious disease caused by Tropheryma whippelii. This bacteria is probably a commensal organism of the gastrointestinal tract but may cause infection if underlying immunologic abnormalities are present, especially of macrophages (6,30,34). The disease is multifocal but usually affects the gastrointestinal tract, and duodenal biopsy remains the standard diagnostic procedure. T. whippelii cannot be cultured by traditional methods (38,39,46), so the diagnosis is based on typical histologic lesions and identification of the causative organism by polymerase chain reaction (PCR). The disease can be cured with prolonged antibiotic treatment.
Involvement of the central nervous system is a classical feature of Whipple disease (20%–40%) (17,31,52) but clinical symptoms usually develop in the later stage of the disease. Neurologic involvement has been reported particularly in patients who previously received antibiotic treatments that could not cross the blood-brain barrier. We conducted the present study to describe neurologic aspects of Whipple disease, based on the analysis of 12 original cases and a review of the published literature.
Case 1
Mrs. M. was born in 1955. Her medical history began in 1975, with the sudden onset of left hemiparesis sparing the face. Neither sensitivity disorders nor Babinski sign was noticed. Examination of the ocular fundus was normal. The erythrocyte sedimentation rate (ESR) was 11 mm/h. Cerebrospinal fluid (CSF) was normal. Computed tomography (CT) of the brain showed an expansive lesion in the posterior part of the right frontal lobe. A neurosurgical resection of the tumor was performed. The histologic analysis showed a necrotic lesion with no evidence of malignancy but with inflammatory granulomatous tissue infiltrated by numerous cells. The macrophages presented only a few periodic acid Schiff (PAS)- positive granules. In August 1998, the patient presented with agitation, behavior disorders, and confusion associated with clonic movements on the right side and decreased bilateral visual acuity. Physical examination revealed bilateral upper motor neuron disorder. Biologic investigations showed a hemoglobin of 107 g/L and an ESR of 25 mm/h. The brain CT scan revealed prominent edema of the left hemisphere associated with a hypodense lesion in the left occipital lobe with a mass effect (Figure 1). The patient was transferred to the neurosurgery department in September 1998 with total dementia with mutism. Stereotactic biopsy of the left occipital lobe was performed. The histology was similar to that observed in 1975. The lesions involved both white and gray matter, mimicking encephalitis. There were also associated perivascular and intraparenchymatous macrophages exhibiting PAS-positive inclusions suggestive of Whipple disease (Figure 2). Analysis of the CSF did not show any cell with PAS-positive cytoplasm. The specific search for T. whippelii with DNA extraction and specific PCR controlled with hybridization in the CSF was negative. At the end of October 1998, because of delirium, a gastroscopy was performed. The gastroscopy did not reveal any macroscopic abnormality. Duodenal and jejunal biopsies were normal. Treatment with trimethoprim-sulfamethoxazole (TMP-SMX) 320 + 1,600 mg/d was introduced and significant neurologic improvement was noticed. The deficit in the right part of the body decreased, delirium disappeared, and the patient was able to talk and perform daily activities again. A CT scan of the brain was performed for follow-up in December 1998: the hypodense edematous lesions had clearly shrunk, especially in the left part of the brain
Fig. 1. Cerebral CT scan with contrast medium (Case 1, September 1998). Prominent edema in the left hemisphere without deep Sylvian tumorous lesion; left Sylvian fissure heterogeneous in appearance, associated with hypodense lesion in the left occipital lobe with a mass effect but without specific contrast enhancement.
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Whipple's disease causes weight loss, incomplete breakdown of carbohydrates or fats, and malfunctions of the immune system. When recognized and treated, Whipple's disease can usually be cured. Untreated, the disease may be fatal. ...
A 68-year-old man was admitted for walking difficulties, memory loss, and incontinence that had been progressing for 5 months. For 12 years, he had complained of arthralgias of the hands and wrists. The diagnosis of rheumatoid polyarthritis had been made.
A neurologic examination revealed a tetrapyramidal syndrome associated with apathy and memory loss. Blood tests indicated an inflammatory syndrome with an elevation of the erythrocyte sedimentation rate (80 mm at the first hour) and an increase of proteins. The results of antinuclear antibody, HIV, B and C hepatitis, latex, and Waler Rose tests were negative. The CSF test showed an increase in the protein rate (1.95 g/L) with an absolute increase of immunoglobulin G (205 mg/L), but the cell count and glucose level were normal. Polymerase chain reaction for Tropheryma whippelii was negative.
MR images of the brain (Fig 1A–D and F) had areas of T2 hyperintensity in the right and left mediobasal temporal lobe, anterior commissure, right and left mamillary bodies, left cerebral peduncle, right middle cerebellar peduncle, bulb, right lobe of the cerebellum, and optic chiasm. These lesions showed no mass effect. After IV infusion of a contrast agent, mild enhancement of the right temporal lesion could be seen. MR imaging of the spinal cord was also performed, showing T2 panmedullary central hyperintensity.
FIG 1. Images from the case of a 68-year-old man who was admitted for walking difficulties, memory loss, and incontinence that had been progressing for 5 months.
A, Axial T2-weighted MR image (4347/100/4) of the brain shows hyperintensity in the mediobasal part of the right and left temporal lobes (arrows), in the mamillary bodies (star), and in the optic chiasm (arrowhead).
B, Axial T2-weighted fluid-attenuated inversion recovery MR image (11000/140/2 [TR/TE/excitaitons]) of the brain shows diffuse hyperintensity involving the right mediobasal and left mediotemporal lobes (arrows), as well as involvement of the left cerebral peduncle (arrowhead). Note the lack of mass effect despite the size of the lesion.
C, Coronal fluid-attenuated inversion recovery MR image (11000/140/2) of the brain shows hyperintensity in the mediobasal part of right and left temporal lobes (arrows), brain stem (star), and right middle cerebellar peduncle (arrowhead).
D, Coronal T1-weighted MR image (535/14/2) of the brain shows mild enhancement of the right temporal lesions after the IV administration of a contrast agent (arrow).
E, Sagittal T2-weighted MR image (2745/120/6) of the spine shows hyperintensity in the central part of the spinal cord (arrow).
F, Coronal T2- weighted fluid-attenuated inversion recovery MR image (11000/140/2) of the brain, obtained after 1 year of treatment, shows nearly complete resolution of the right temporal lesion (arrow).
The patient underwent a duodenal biopsy, which showed macrophages that stained positively with periodic acid-Schiff stain (Fig 2). Polymerase chain reaction for Tropheryma whippelii was positive on the duodenal biopsy.
However, Dobbins (1) postulates that all patients suffering from Whipple disease have anatomic-pathologic CNS involvement (13). It consists of multiple small circular or oval lesions, measuring an average of 2 mm in diameter, disseminated throughout the gray matter and characterized by the accumulation of macrophages, staining very intensely with periodic acid-Schiff stain, as shown in postmortem studies . Electron microscopy shows that the macrophages contain a bacilliform organism, named Tropheryma whippelii by Relman et al (3), revealing the bacterial cause of the disease (2, 6). The same lesions are found in other organs when they are affected by the disease (2, 6). Recently, molecular biology allowed the detection of the presence of Tropheryma whippelii in the affected organs by using polymerase chain reaction (3). Previous studies have shown a good correlation between preferential sites of anatomic-pathologic lesions and the lesions revealed by MR imaging and CT (5, 8, 9, 14).
The first neuroradiologic descriptions of CNS involvement were reported as seen on CT scans (8, 14), and they presented no specific characteristics (2). The CT scan can be normal, regardless of the clinical features, or can reveal focalized lesions, which can be hypo- or hyperdense, contrast enhanced or not, and with or without mass effect (2). However, MR imaging has proved its superiority for the detection of small lesions (3). In a review of the literature presented by Louis et al (4), 43 patients had undergone CT or MR imaging and three patients with normal CT findings had focal abnormalities on their MR images (4).
These lesions, which occur in 53% of the cases (4), often consist of T1 hypointensity and T2 hyperintensity, show no mass effect, and are located in the medial part of the temporal lobes, in the hypothalamic region, or in the pons (9, 10). These lesions are sometimes enhanced after infusion of contrast media (4, 8, 9, 14). Moreover, associated moderate atrophy occurs in 42% of the cases (4).
Multiple mass lesions have rarely been described. They usually appear hypointense on T1-weighted images and hyperintense on T2-weighted images and enhance after infusion of contrast media (12). However, a small number of patients have normal-appearing MR images (4).
The involvement of the spinal cord has rarely been reported. We found only one report of myelopathy secondary to Whipple disease, diagnosed by using MR imaging (11). It was located in the cervical region, and it appeared hyperintense on T2-weighted images after IV injection of gadolinium.
Involvement of the optic chiasm has also rarely been revealed by neuroradiologic examination, although it is more often discovered during postmortem studies (9). We found only one report with an increased T2 signal intensity located in the optic tracts (9). However, clinical optical manifestations are common in cases of Whipple disease (4, 5).
Early treatment of Whipple disease leads to improvement of the lesions revealed by neuroradiologic examination (4, 9, 12), as shown in our case, but diagnosis is often difficult. Diagnosis is often difficult to determine on the basis of polymerase chain reaction or histologic findings (98%); more precisely, 63% of patients underwent biopsy (88% of which were obtained from the small bowel (4). More rarely, the diagnosis is made based on lymph node biopsy or cerebral biopsy. However, polymerase chain reaction has shown sensitivity and specificity to confirm a diagnosis of Whipple disease (15), and recent studies have revealed genetic material of Tropheryma whippelii in peripheral blood mononuclear cells and in cells of pleural effusion (16), suggesting that the diagnosis can sometimes be made on the basis of polymerase chain reaction of peripheral blood (17). The diagnosis can also be obtained by conducting an analysis of the CSF for periodic acid-Schiff stain-positive cells (2), but the value of polymerase chain reaction in CSF has not yet been evaluated because of the rarity of the disease.
Treatment is often delayed, however, resulting in death or irreversible cerebral lesions, such as atrophy (9, 13). Moreover, relapse of the disease is frequent, leading to the reappearance of the CNS lesions on MR images (4).
In conclusion, this case report shows the importance of neuroradiologic examinations, particularly MR imaging, for the detection of CNS lesions in the initial evaluation of patients suspected of having Whipple disease and for the long-term follow-up of these patients. It is necessary to perform MR imaging of the brain and spinal cord to ascertain the different locations of these lesions
In August 1994, a 65-year-old woman presented with a 2-month history of upper and lower limb paresthesias and 1-week paraparesis and sphincter dysfunction. On clinical examination, sensory motor myelopathy with an upper cervical level was confirmed.
FIG 1. August 1994. Sagittal fast spin-echo T2-weighted (5000/112/2) (TR/TE/excitations) image shows enlarged and inhomogeneously hyperintense spinal cord from the cervico-occipital junction to the upper dorsal region (A). Sagittal spin-echo T1-weighted (460/17/2) images with gadopentate dimeglumine show peripherical enhancement (. After seven days of corticosteroid therapy, spinal cord enlargement has decreased (C). Eight months later (April 1995), the cord is normal (D)
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