Pearls & Oy-sters: A rare presentation of Whipple disease

Pearls

• Neurologic manifestations occur in 20%–40% of patients with Whipple disease, a rare infectious disorder caused by the bacterium Tropheryma whipplei.

• Neuro-Whipple should be considered in patients with diverse unexplained neurologic and psychiatric symptoms with concurrent arthritis and gastrointestinal symptoms.

• The most common—though nonspecific—symptoms in neuro-Whipple are cognitive dysfunction (dementia or memory impairment) and psychiatric signs, such as personality changes and depression.

Oy-sters

• A diagnostic delay occurs often, due to the nonspecific symptoms and the rarity of Whipple disease. However, timely diagnosis and treatment will improve prognosis, stressing the importance of early recognition.

• Periodic acid–Schiff (PAS) staining, PCR, or immunohistochemistry on biopsy specimens of the involved organs can be negative despite presence of Whipple disease. In any suspected patient, a combination of all these diagnostics should be considered in the diagnostic workup.

Case report

A 70-year-old man was referred to the neurology outpatient clinic with an abnormal MRI scan of the brain, which was performed by the ear, nose, and throat specialist because of complaints of subacute tinnitus. MRI brain showed hyperintensities in the parahippocampal gyrus on both sides (figure 1). His medical history consisted of a radical removal of a thymoma, TIAs, atrial fibrillation on anticoagulative therapy, hypertension, benign prostatic hyperplasia, and coxarthrosis.

• Download figure
• Open in new tab
• Download powerpoint

Figure 1 MRI brain

(A–C) Axial T2 fluid-attenuated inversion recovery without gadolinium shows bilateral hyperintensities in the parahippocampal gyrus, more pronounced on the right side.

Except for tinnitus, the patient reported no neurologic complaints, and neurologic examination was unremarkable. However, a few weeks later, his partner reported that the patient had sleeping disturbances, with reversal of his day–night cycle, and fluctuating disorientation manifesting as getting lost in his own house. On other days, he behaved normally. Gradually he became more passive, sitting on the couch most of the day. He had memory problems like forgetting the latest news items.

The patient was admitted to the neurology ward. Our differential diagnosis was limbic encephalitis due to an autoimmune or infectious cause, systemic disease such as sarcoidosis, or CNS localization of a malignancy. Due to progression of symptoms, MRI scan of the brain was repeated, showing no progression or new abnormalities. Laboratory investigation—aiming to investigate infectious, malignant, and systemic diseases—showed slightly increased C-reactive protein and erythrocyte sedimentation rate but no other abnormalities. Serum antineuronal antibodies (Hu, Yo, Ri, Tr, amphiphysin, CV2, Ma1, Ma2, AMPA-R, and VGKC-R) were negative. EEG showed no signs of encephalitis or epilepsy. A lumbar puncture was performed and showed a pleiocytosis of 17 cells/μL (85% mononuclear) and a normal protein and glucose level. Antineuronal antibodies (Hu, Yo, Ri, Tr, amphiphysin, CV2, Ma1, Ma2, Caspr2) in CSF were negative. Borrelia, Lues, and Coxiella burnetii diagnostics in blood and CSF were negative as well. A CT scan of the thorax and abdomen was performed with the aim of investigating the presence of malignancy associated with paraneoplastic encephalitis and there were no signs of recurrence of the thymoma. FDG PET CT showed no pathologic uptake elsewhere besides the brain. After all the investigations had negative results, the patient withdrew himself from further testing and admission in the hospital.

Over a few months, the clinical situation of the patient gradually deteriorated, and he returned to the hospital. He slept during most of the day, he was incontinent for urine, his memory problems worsened, and his defecation pattern had changed into watery diarrhea. On neurologic examination, the patient had a fluctuating consciousness, was bradyphrenic, was disorientated in time and place, and had visual hallucinations. He had an expressive aphasia and was not able to speak fluently. He had double-sided ptosis and pathologic plantar reflexes. His walking pattern was unstable. The clinical diagnosis was limbic encephalitis, either autoimmune mediated or based on an infectious cause. Repeated lumbar puncture showed a pleiocytosis of 33 cells/μL and no other abnormalities. Immunophenotyping showed no abnormalities. Repeated antineuronal antibodies testing and PCRs on viruses were all negative.

Because the patient was deteriorating and a diagnosis was lacking, a brain biopsy was performed. No corticosteroids were started pending the results of the brain biopsy. On pathologic examination, periodic acid–Schiff (PAS) staining was positive, showing macrophage infiltration containing bacilli, fitting Whipple disease (figure 2). The diagnosis was confirmed with a PCR showing Tropheryma whipplei DNA in the brain tissue.

• Download figure
• Open in new tab
• Download powerpoint

Figure 2 Histology of the brain biopsy specimen (magnification ×10)

(A) Hematoxylin & eosin staining shows macrophage infiltration. (B) Periodic acid–Schiff staining shows macrophages containing bacilli.

Follow-up of the case

There was a delay of 15 months between the first MRI and diagnosis, despite extensive investigations and testing. Treatment with IV ceftriaxone was started immediately after diagnosis. After finishing 2 weeks of IV therapy, antibiotics were switched to oral cotrimoxazole. At that time, the patient's clinical condition was poor; he was bedridden, only awake after verbal stimuli, but did not respond adequately to questions or simple commands. He was discharged to a nursing home and after 2 months transferred to a rehabilitation center, where he stayed for several months before returning home. During this time, his clinical condition was improving slowly. At the time of writing this case report, he could walk with assistance of a walking aid and was able to have simple conversations, but still needed help for most daily activities.

Speculating about the source of infection, the patient's partner reported that the patient lived in a house containing an old draw-well, from which he frequently drank water. The patient had multiple episodes of diarrhea and joint pains over recent years. The water quality of the draw-well was investigated and appeared to be heavily polluted by a nearby cemetery, possibly explaining the route of infection.