CNS Whipple Disease Treatment & Management

Updated: Dec 10, 2019
  • Author: George C Bobustuc, MD; Chief Editor: Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM  more...
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Medical Care

Treatment of Whipple disease is less challenging than its diagnosis. Antibiotics are the mainstay of therapy. A good outcome relies on a timely diagnosis and initiation and completion of a long-term antibiotic course. The literature comprises a consensus about the need for completion of a lengthy antibiotic course of 1–2 years. Treatments of shorter duration have been associated with a high rate of relapse. The use of specific diagnostic techniques (eg, PCR) is important in establishing a diagnosis [23] and in evaluating response and adjusting the antibiotic therapy.

The following guidelines have been proposed for diagnostic screening, biopsy, and treatment of CNS-WD:

  • Definite CNS-WD must have any 1 of the following 3 criteria:

    • OMM or OFSM

    • Positive tissue biopsy

    • Positive PCR analysis

    • If histologic or PCR analysis was not performed on CNS tissue, then the patient also must demonstrate neurological signs. If histologic or PCR analysis was performed on CNS tissue, then the patient need not demonstrate neurological signs (ie, asymptomatic CNS infection).

  • Possible CNS-WD should include 1 of 4 systemic symptoms and 1 of 4 neurologic signs and/or symptoms.

    • Any 1 of the 4 systemic symptoms, not due to another known etiology, as follows:

      • Fever of unknown origin

      • GI symptoms (ie, steatorrhea, chronic diarrhea, abdominal pain)

      • Chronic migratory arthralgias or polyarthralgias

      • Unexplained lymphadenopathy, night sweats, or malaise

    • Any 1 of 4 neurological signs, not due to another known etiology, as follows:

      • Supranuclear vertical palsy

      • Rhythmic myoclonus

      • Dementia with psychiatric symptoms

      • Hypothalamic manifestations (dysautonomia, vigilance problems)

  • In a review of the literature, which represents the basis for these guidelines, 20% of patients with CNS-WD had no systemic symptoms or signs. Another 11% had only "soft" neurological features such as subtle cognitive changes or altered level of consciousness. Thus, even when these guidelines are followed, the diagnosis of some cases of CNS-WD may not be reached premortem.

A combination of antibiotics is preferable, particularly at the initiation of treatment. Antibiotics usually provide rapid resolution of extraneuraxial symptoms. Arthralgias and fever usually resolve within a few days. Diarrhea and malabsorption disappear within 2-4 weeks.

  • CNS symptoms can be limited by initiation of antibiotic treatment but remain difficult to reverse completely. This is especially true for focal deficits accompanied by positive corresponding imaging with obvious structural changes such as granulomas, infarcts, and atrophic changes. The cognitive abnormalities reverse more than other CNS symptoms and signs.

  • In some patients, worsening neurological symptoms have been noted even after onset of antibiotic therapy; this usually requires changing the antibiotic regimen.

Relapse is quite common in Whipple disease; the disease relapses in approximately one third of patients in whom cessation of treatment was made based on negative serial duodenal biopsies alone.

  • Symptoms at relapse usually take place several weeks to several years after treatment was discontinued.

  • Neurologic complications are usually more prominent in patients with relapsed Whipple disease.

  • Relapse commonly involves the CNS in almost all patients with Whipple disease. Patients with previously known CNS involvement have the highest relapse rate.

  • Relapse is usually more difficult to treat than the initial episode. Acquired resistance to previously known efficacious antibiotics has been reported at relapse. A higher rate of relapse occurs in patients treated with a single antibiotic, with antibiotics with very low BBB penetrance, and/or for an inadequate amount of time.

Monitor clinical response to treatment and complement it with other data obtained with biopsy and imaging studies.

  • PCR analysis is a great tool for documenting response. It should target various tissues obtained at biopsy of significant organs and CSF.

  • In all patients with Whipple disease, consider CSF PCR analysis prior to onset of treatment together with follow-up serial studies for monitoring response, for deciding when treatment should be stopped, and even after cessation of treatment for early detection of relapse based on the clinical progress of the patient and physician index of suspicion.

  • No mention is found in the literature as to when to stop antibiotic therapy after the first negative CSF PCR analysis. Most investigators recommend first confirming this result within 2-3 months and continuing the antibiotic therapy for an additional 8–12 months.


Surgical Care

Neurosurgical care is relevant for both obtaining diagnostic biopsy specimens in selected patients and placement of ventriculoperitoneal shunt (VPS) in patients with hydrocephalus.

Both communicating and noncommunicating hydrocephalus has been reported in patients with CNS-WD. The role of shunting has to be assessed thoroughly.

WD bacillus has a predilection for the periaqueductal gray matter, making noncommunicating hydrocephalus (secondary to aqueductal stenosis) more likely in patients with advanced CNS-WD. Patients with aqueductal stenosis represent a neurosurgical emergency and VPS should be placed urgently.

In progressive CNS-WD with progressive, communicating hydrocephalus, some of the cognitive and motor deficits noted in these patients potentially could be limited rapidly and sometimes reversed by shunting. This is especially important as the reported reversal of other CNS symptoms and signs remains limited and requires several weeks to months despite otherwise efficient antibiotic treatment.

Rapid initiation of efficacious antibiotic treatment prior to, or at the time of, shunting is most important as placement of VPS without concomitant antibiotic treatment potentially could initiate dissemination of disease in the peritoneal cavity. No such cases have been reported in the literature.

Placement of a VPS (with Ommaya reservoir) raises an interesting question about a great therapeutic opportunity, intrathecal/intraventricular antibiotic therapy concomitant with systemic treatment. No reports of attempted intraventricular antibiotic treatment have been published. This is especially important as some reports emphasized the meningoependymitis (ventriculitis) pattern seen in patients with CNS-WD.

No attempts at concomitant systemic antibiotic treatment together with intrathecal antibiotic treatment through lumbar puncture have been reported.