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Show ORIGINAL CONTRIBUTION Whipple Disease with Supranuclear Ophthalmoplegia Diagnosed by Polymerase Chain Reaction of Cerebrospinal Fluid Andrew G. Lee, MD An elderly man developed acute progressive supranuclear ophthalmoplegia and other central nervous system manifestations that suggested Whipple disease. Results of small intestinal biopsy were negative but polymerase chain reaction testing of the cerebrospinal fluid confirmed the diagnosis. ( JNeuro- Ophthalmol 2002; 22: 18- 21) hippie disease is an uncommon multisystem infectious disease characterized by weight loss ( 95% of cases), generalized wasting, abdominal pain ( 60%), diarrhea ( 78%), gastrointestinal bleeding, and steatorrhea ( 93%) ( 1). Central nervous system and ocular involvement are uncommon ( 1- 5). The diagnosis can be challenging because the organism has proved difficult to culture. Whipple disease can now be accurately diagnosed using the polymerase chain reaction ( PCR) for the bacterial ribosomal RNA ( 5- 14). This report describes an unusual patient with Whipple disease presenting with an acute progressive supranuclear ophthalmoplegia in whom the results of the small intestinal biopsy were negative and the diagnosis was confirmed by PCR in the cerebrospinal fluid. CASE REPORT A 72- year- old white man presented with binocular horizontal diplopia. He was well until December 2000, when he developed slowly progressive generalized weakness, difficulty swallowing, a 60- pound weight loss, difficulty walking, and imbalance. He had no steatorrhea or diarrhea. He was afebrile and had no arthralgias or From the Departments of Ophthalmology, Neurology, and Neurosurgery, The University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA. Address correspondence to Andrew G. Lee, MD, 200 Hawkins Drive, PFP, Department of Ophthalmology, The University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA This work was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc., New York, NY, USA. myoclonus. Over the next several months, he developed worsening anorexia, mild abdominal pain with reflux symptoms, and rare rectal bleeding. By February 2001, he had severe generalized weakness, fatigue, and incoherent speech. He was evaluated at an outside hospital and underwent an extensive evaluation for weight loss and the gastrointestinal symptoms. Colonoscopy showed a colonic polyp and nonspecific acute and chronic inflammatory cells. Upper endoscopy showed increased lymphoid inflammation and germinal centers in the lamina propria of the duodenum. Duodenal and transverse colon biopsies showed mildly active colitis with focal cryptitis, and a gastric biopsy showed acute and chronic inflammation. The patient was transferred to the University of Iowa Hospital on May 27,2001. Because of his complaint of binocular diplopia, he was referred to the neuro- ophthalmol-ogy service. He had complete volitional upgaze palsy bilaterally, a 30% to 40% reduction in depression OU and a 50% to 60% reduction in horizontal gaze in both directions for both sac cades and pursuit. In primary position, he had a small esophoria, and in right and left gaze a 5- prism diopter esotropia. Pursuit was slow and saccadic and saccades were slow and dysmetric in all directions. The doll's head maneuver overcame the vertical gaze paresis and mildly improved the horizontal eye movements. There was no ptosis, nystagmus, oculomasticatory myorhythmia, or myoclonus. The neuro- ophthalmic findings were considered consistent with a diagnosis of supranuclear ophthalmoplegia. The neurologic examination otherwise showed normal cranial nerve function. The patient had mild cerebellar dysmetria on fmger- to- nose testing and a score of 4 out of 5 on extremity weakness, worse proximally. There was some gait imbalance, but he could walk without assistance. Deep tendon reflexes were normal. Sensory examination was intact to light touch and temperature, but vibration sense was slightly diminished on the left side. T2- weighted and fluid attenuation inversion recovery ( FLAIR) magnetic resonance imaging scans of the brain showed hyperintense signal involving the middle cerebellar peduncles and the vermis. There was homogeneous 18 J Neuro- Ophthalmol, Vol. 22, No. 1, 2002 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. WHIPPLE DISEASE DIAGNOSED BYPCR OF CEREBROSPINAL FLUID JNeuro- Ophthalmol, Vol. 22, No. 1, 2002 enhancement of these signal abnormalities on the Tl- weighted cranial magnetic resonance imaging scans ( Fig. 1). There was no radiologic abnormality in the midbrain or in the diencephalon. There were a few nonspecific FLAIR and T2- weighted focal signal abnormalities in the white matter of the cerebral hemispheres bilaterally. Computed tomographic scans of the abdomen and chest showed mild mesenteric lymphadenopathy but no evidence of mass or malignancy. Lumbar puncture showed a normal opening pressure, 6 white blood cells/ mm3, protein 32 mg/ dL, and glucose 88 mg/ dL. Cerebrospinal fluid cytologic findings were negative. Periodic acid- Schiff stains of the cerebrospinal fluid were not performed. On June 7,2001, the patient aspirated, developed respiratory distress, and was transferred to the intensive care unit. The motility disturbance progressed to an almost complete external ophthalmoplegia OU ( Fig. 2). Vertical and horizontal doll's head maneuver could still overcome the ophthalmoplegia. The patient's worsening FIG. 1. Cranial magnetic resonance imaging demonstrates ally on T2- weighted sequence ( A), and on fluid attenuated mental status, progressive course, and increasing ophthalmoplegia were so suggestive of Whipple disease that they prompted cerebrospinal fluid PCR testing for Tropher-myma whippleii. The result proved to be positive. After the positive cerebrospinal fluid PCR for Whipple disease, pe-riodic- acid- Schiff stain and diastase were performed on the previous duodenal biopsy sample and had negative results. There were no increased histiocytes, and the villous architecture of the duodenum was normal. No electron microscopy was performed. Intravenous ceftriaxone and streptomycin therapy was initiated. After 3 days of intravenous antibiotics, the treatment regimen was converted to oral trimethoprim-sulfamethoxazole, but the neurologic symptoms worsened and the patient was re- started on a 2- week course of intravenous antibiotics with ceftriaxone and streptomycin. In spite of treatment, the patient developed progressive neurocognitive deficit, memory loss, hypersomnia, and incoherent speech. The supranuclear ophthalmoplegia hyperintense signal in the middle cerebellar peduncles bilater-inversion recovery ( FLAIR) sequence ( B, arrows). 19 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. JNeuro- Ophthalmol, Vol. 22, No. 1, 2002 Lee FIG. 2. Decreased volitional eye movements in all directions. persisted. He was discharged from the hospital to a skilled care nursing facility on long- term oral trimethoprim-sulfamethoxazole and subsequently died. DISCUSSION Central nervous system involvement by Whipple disease is rare but may be the presenting or predominant feature of Whipple disease in up to 5% of cases. The most common central nervous system presentations are neu-rocognitive symptoms ( progressive somnolence, depression, cognitive decline, confusion, personality change, and memory loss) ( 11- 14). Ocular motor abnormalities, including supranuclear gaze palsies ( usually vertical rather than horizontal), internuclear ophthalmoplegia, and, rarely, ocular motor palsies, are the next most frequently reported neurologic manifestations ( 10- 13). Louis et al. ( 11) reported that 81% of patients had either cognitive change or supranuclear gaze palsy and that 42% had both. The classic triad of dementia, ophthalmoplegia, and myoclonus is highly suggestive of Whipple disease and occurs in about 10% of cases. In our patient, progressive mental status changes, incoherent speech, and supranuclear ophthalmoplegia were the prominent features. In the series of Louis et al. ( 11), oculomasticatory or ocular- facial- skeletal myorhythmia was found in 20% of cases but was always associated with supranuclear vertical gaze palsy. The typical pathologic finding of Whipple disease in small intestinal biopsies is disruption of normal villous architecture by an infiltrate of periodic acid- Schiff- positive " foamy" macrophages in the intestinal lamina propria. Electron microscopy may show the rod- shaped bacilli. Our patient underwent a biopsy of the duodenum as part of a nonspecific evaluation of gastrointestinal complaints rather than for Whipple disease. Whipple disease preferentially involves the jejunum but is known to involve the duodenum as well. We cannot exclude the possibility that a directed jejunal biopsy in our case would have been diagnostic of Whipple disease. Although intestinal pathologic examination has been the classic diagnostic test for Whipple disease, PCR in intestinal and extraintestinal sites has emerged as a highly sensitive and specific test for Whipple disease, especially in cases with inconclusive or nondiagnostic biopsies. The PCR assay for the 16S ribosomal RNA gene ( rDNA) of T. whippleii has shown positive results from both duodenal biopsies and extraintestinal tissues ( lymph nodes and cerebrospinal fluid). PCR has shown high specificity and sensitivity for Whipple disease in biopsy proven cases ( 5- 9,14). Ramzan et al. ( 9) reported PCR positivity in 29 ( 97%) of 30 histologically confirmed specimens. Forty- two control subjects tested in a blinded fashion had negative PCR results. Nucleic acids identified by PCR were also found in seven additional intestinal and extraintestinal samples from patients with strong clinical evidence of Whipple disease but negative histology. This suggests that the PCR test may be a more sensitive test than tissue biopsy in some cases. Pron et al. ( 8) performed PCR on eight patients with proven Whipple disease and on 34 control subjects. PCR was positive in 13 ( 87%) of 15 tissue samples from patients with biopsy- positive Whipple disease ( gut, 8 of 8; lymph nodes, 2 of 2; bone marrow, 1 of 2; peripheral blood, 2 of 3) but in none of the 54 tissue controls. Because PCR test results converted from positive to negative within 4 to 6 months in six of eight patients treated for Whipple disease, PCR was proposed as a means of monitoring the results of therapy ( 8). 20 © 2002 Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. WHIPPLE DISEASE DIAGNOSED BYPCR OF CEREBROSPINAL FLUID JNeuro- Ophthalmol, Vol. 22, No. 1, 2002 Polymerase chain reaction testing of cerebrospinal fluid or blood may also be positive in patients who clinically have central nervous system Whipple disease and negative intestinal biopsies. Coria etal. ( 10) reported a case of a patient who presented with ataxia, ophthalmoplegia, hypersomnia, hemiparesis, and generalized myorhythmia. The diagnosis was made by PCR of peripheral blood despite a negative jejunal biopsy. Cohen et al. ( 14) reported a positive cerebrospinal fluid PCR in a case of a patient with gait and oculomotor disturbances and a negative jejunal biopsy. Louis et al. ( 11) reported that PCR testing of intestinal or extraintestinal sites confirmed the diagnosis in 10 patients and that cerebrospinal fluid PCR was confirmatory in two additional patients with central nervous system Whipple disease. One of these patients had a nondiagnostic biopsy finding and required confirmation of central nervous system Whipple disease by cerebrospinal fluid PCR ( 11). Thus, definite central nervous system Whipple disease is now defined by the presence of one the following three features: ( 1) oculomasticatory myorhythmia or ocular- facial- skeletal myorhythmia, ( 2) positive tissue biopsy result, or ( 3) positive PCR analysis result. Our patient had a negative small intestinal biopsy result, and the diagnosis required cerebrospinal fluid PCR confirmation. The prognosis in central nervous system Whipple disease is quite variable, despite antibiotic therapy. Central nervous system involvement is associated with a high rate of relapse and is difficult to treat. Suzer et al. ( 4) reported only variable improvement in the nine cases of treated central nervous system Whipple disease. Our patient did not improve significantly, despite antibiotic therapy, and died. Clinicians should be aware that an acute and progressive supranuclear ophthalmoplegia may be the prominent or presenting feature of central nervous system Whipple disease. The diagnosis should be considered in patients with changes in mental status, ophthalmoplegia, and myoclonus, and central nervous system Whipple disease should be considered even in the absence of prominent malabsorption signs or symptoms. PCR testing has proved to have high specificity and sensitivity for Whipple disease in biopsy- proven cases, and results of PCR testing of cerebrospinal fluid in central nervous system Whipple disease may be positive even when the intestinal biopsy finding is negative. REFERENCES 1. Maizel H, Ruffin JM, Dobbins WO. Whipple's disease: a review of 19 patients from one hospital and a review of the literature since 1950. Medicine 1970; 49: 175- 205. 2. Kremer S, Besson G, Bonaz B, et al. Diffuse lesions of the CNS revealed by MR imaging in a case of Whipple disease. 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