Chapter 14 - Whipple's disease of the central nervous system

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This chapter discusses the epidemiology, etiology, pathogenesis, clinical features, diagnosis, and management of the Whipple's disease of the central nervous system (CNS). CNS involvement in Whipple's disease occurs in three circumstances: (1) neurological involvement with systemic disease, (2) neurological relapse in patients treated for systemic disease, and (3) neurological disease without systemic disease. The most characteristic primary presentation associated with CNS Whipple's disease is the triad of cognitive changes, ophthalmoplegia, and myoclonus. The dementia of Whipple's disease usually occurs subacutely to chronically. It may or may not be associated with systemic symptoms of weight loss, diarrhea, arthralgias, and other overt manifestations of systemic disease. Neuroimaging abnormalities are thought to occur in at least half of the patients with CNS Whipple's disease. Magnetic resonance imaging (MRI) of the brain is the most sensitive neuroimaging study and has most commonly shown focal increased T2 or fluid-attenuated inversion recovery (FLAIR) signal involving the hypothalamus, uncus, and medial temporal lobes. After neuroimaging, cerebrospinal fluid (CSF) analysis is the most specific means of investigating patients for involvement of the CNS by Whipple's disease.

Introduction

George Whipple initially reported the disease bearing his name in 1907, in which he described a 36-year-old male medical missionary with an illness characterized by weight loss and intractable diarrhea (Whipple, 1907). However, extragastrointestinal manifestations were recognized from the first descriptions of this illness as well as in subsequent reports. Whipple's initial observations included all of the essential bowel manifestations of the disease, with pathological features of lipid degeneration involving the intestinal mucosa, and involvement of the mesenteric lymph nodes with argyrophilic rod-shaped microorganisms; this initial description included the name “intestinal lipodystrophy.” Whipple also recognized the systemic features of the disease such as polyarthritis, polyserositis, endocarditis, and lymphadenopathy. It was later established that the macrophages involved by this disease contained periodic acid–Schiff (PAS)-positive material, indicative of the presence of glycoprotein. Later, electron microscopic investigations showed that the PAS-positive material consisted of curvilinear-shaped bacilli (Chears and Ashworth, 1961, Yardley and Hendrix, 1961).

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Etiology and Epidemiology

Identification and characterization of the Whipple's disease agent were performed by molecular techniques using ribosomal RNA sequences amplified from the duodenal tissue of a patient with Whipple's disease (Relman et al., 1992). This sequence was subsequently detected in tissues from patients identified with Whipple's disease, but in none of the patients without the disorder (Relman et al., 1992). The bacterium was discovered to be a gram-positive actinomycete which, at the time, was not

General features

Whipple's disease remains a rare disorder. Although no incidence data are available, at least 1000 cases have been reported (Fenollar et al., 2007). It can occur in all ages and races, but white middle-aged men have been the predominant group affected. The primary systemic symptoms are weight loss, diarrhea, and abdominal pain. Other systemic symptoms, including serositis, arthritis, lymphadenopathy, and fever, have been identified; cardiac involvement is also well recognized (Enzinger and

Neuroimaging

Neuroimaging abnormalities are thought to occur in at least half of the patients with CNS Whipple's disease (Louis et al., 1996). Magnetic resonance imaging (MRI) of the brain is the most sensitive neuroimaging study and has most commonly shown focal increased T2 or fluid-attenuated inversion recovery (FLAIR) signal involving the hypothalamus, uncus, and medial temporal lobes (Fig. 14.1A) (Adams et al., 1987). Bright T2 and FLAIR signal abnormalities may also be prominent in the cerebellar

Neuropathology

The first descriptions of pathological changes in the brains of patients with Whipple's disease date back to 1960, when descriptions of presumed neurologically asymptomatic individuals with granular ependymitis were published (Sieracki et al., 1960). Pathological studies were subsequently published, emphasizing the involvement of brainstem and basal brain structures which paralleled the clinical symptomatology (Lampert et al., 1962, Halperin et al., 1982); the neuropathology of a nodular

Treatment

Intravenous penicillin, followed by a prolonged course of oral trimethoprim-sulfamethoxazole, had been the regimen of choice in the treatment of CNS Whipple's disease. Tetracycline has also been utilized, but is associated with a high incidence of relapse of disease (Marth and Raoult, 2003). The current treatment recommendation for CNS disease is ceftriaxone 2 grams intravenously every 12 hours for 2 weeks followed by oral trimethoprim-sulfamethoxazole (one tablet double strength twice daily)

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