Whipple disease …

Peter K Panegyres MD PhD PhD FRACP

Infectious Disorders

Updated 07.12.2023
Released 12.09.2003
Expires For CME 07.12.2026

Whipple disease

Author: Peter K Panegyres MD PhD PhD FRACP

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Editor: John E Greenlee MD

Whipple disease

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Introduction

Overview

Whipple disease is a treatable, multisystem disease caused by infection with Tropheryma whipplei. Primarily considered a gastrointestinal disorder, the organism also invades joints, heart, skin, eyes, endocrine, and nervous system. Rarely, Whipple disease of the brain may occur as a primary neurologic disorder without multisystem involvement. Cognitive changes, supranuclear gaze palsy, altered consciousness, myoclonus, seizures, and ataxia occur. Oculomasticatory myorhythmia and oculofacioskeletal myorhythmia are pathognomonic signs. Isolated Whipple disease also mimics glioma. PET studies are useful in evaluating atypical MRI; diffusion restriction might also be a useful marker of progression and response to treatment. The author of this article emphasizes the importance of molecular techniques, particularly polymerase chain reaction, to identify and confirm the diagnosis and evaluate therapy. Antibiotic treatment results in improvement with a sustained remission in the majority of patients.

Key points

	• Whipple disease of the central nervous system may be primary (ie, without evidence of disease outside of the brain) or secondary, occurring in the context of a multi-system condition.
	• The neurologic features of primary and secondary Whipple disease of the brain are diverse and overlap.
	• Molecular techniques, in particular, PCR on CSF and blood are essential to the diagnosis.
	• Antibiotics can successfully treat Whipple disease of the brain and prevent fatal infection.

Historical note and terminology

Whipple disease is caused by Tropheryma whipplei (T whipplei) and was first described in 1907.

Clinical manifestations

Presentation and course

Neurologic features may be found in about one third of patients with systemic Whipple disease, but they are very diverse. Cognitive changes, supranuclear ophthalmoplegia, and altered levels of consciousness are the most common (Table 1) (36).

Table 1. Neurologic Features of Systemic Whipple Disease

Cognitive change	71%
Supranuclear ophthalmoplegia	51%
Altered consciousness	50%
Psychiatric signs (such as depression, hypomania, anxiety, psychosis, change in personality)	44%
Upper motor neuron signs	37%
Hypothalamic manifestations (such as polydipsia, hyperphagia, decreased libido, amenorrhoea, change in sleep-wake cycle with insomnia, hypopituitarism)	31%
Cranial nerve abnormalities	25%
Myoclonus	25%
Seizures	23%
Oculomasticatory or oculofacial-skeletal myorhythmia	20%
Ataxia	20%
Sensory deficits	12%
(36)

The neurologic features of primary Whipple disease of the brain include hemiparesis, cognitive dysfunction, seizures, eye movement abnormalities, and other conditions (Table 2).

Table 2. Neurologic Phenomenology in Patients with Primary Whipple Disease of the Brain

Symptoms/Signs		Number of patients*	% Frequency
Hemiparesis		8	17.02%
Cognitive dysfunction		7	14.89%
	Amnesic syndrome/memory loss Behavioral change Dementia	5 1 1
Seizures		6	12.77%
	Generalized tonic-clonic seizures Limbic seizures Simple partial seizures	3 2 1
Eye movement abnormalities		5	10.64%
	Supranuclear ophthalmoplegia Vertical gaze paresis Horizontal diplopia	3 1 1
Sleep disorders		4	8.51%
	Hypersomnolence Insomnia Obstructive sleep apnea	2 1 1
Headache		4	8.51%
Language difficulties		3	6.38%
	Speech disturbance Global aphasia Dysarthria	1 1 1
	Ataxia	3	6.38%
	Meningoencephalitis	2	4.26%
	SIADH	1	2.13%
	Facial palsy	1	2.13%
	Oculomasticatory myorhythmia	1	2.13%
	Ocular, facial & limb myoclonic jerks	1	2.13%
	Bilateral papilledema	1	2.13%
		47	100%
*N=17 confirmed patients with primary Whipple disease of the brain. Patients may have more than one symptom/sign.

Following the studies of Panegyres, there has been an elaboration of the clinical phenomenology, diagnosis, and treatment of Whipple disease of the brain (81; 80). Primary cerebral Whipple disease has been reported as presenting as a Klüver-Bucy syndrome: a 55-year-old Hispanic woman developed sexually inappropriate behavior in which she explored objects orally with compulsive fasting/eating (63). After 12 years of successful treatment for systemic Whipple disease, solitary brain lesions of Whipple disease that resembled brain tumors occurred, emphasizing the need for ongoing surveillance of patients with Whipple disease (39). A patient newly diagnosed with AIDS developed an intracranial lesion proven by stereotactic brain biopsy to be Whipple disease (45). A 68-year-old Turkish man developed fever, neck stiffness, dysarthria, paraplegia, and generalized tonic/clonic seizures (30). His MRI scan revealed diffuse bilateral hyperintensities in the frontal and parietal regions and in the left temporal lobe, and diffusion weighted imaging revealed several areas of restricted diffusion. Whipple disease was confirmed on brain biopsy with PAS positivity, but PCR for the Whipple organism was negative. The patient had an excellent response to ceftriaxone and cotrimoxazole.

Mayo Clinic studies demonstrated that a range of MRI findings may be found, which may include no abnormalities; symmetrical midline T2 signal hyperintensities in hypothalamus, midbrain, or mesial temporal lobe with minimal enhancement and normal restricted diffusion; lesions showing mild mass effect; FLAIR sequence abnormalities; mesial temporal lobe lesions resembling encephalitis; high signal intensity of the corticospinal tracts; areas of restricted diffusion; or diffuse meningeal contrast enhancement (the severity and degree of the MRI abnormalities did not correlate with prognosis); the duration from symptoms to treatment influencing outcome (09).

Neurologic involvement may complicate Whipple endocarditis. Three patients developed cognitive disorder and one developed ataxia; MR displayed multiple or solitary contrast enhancing lesions (07). MRI should be performed in Whipple disease endocarditis as brain involvement may be difficult to recognize. Diagnosis of Whipple disease may require brain biopsy because MRI, CSF, and endoscopy may be unhelpful (26).

The phenomenology has been extended to progressive dementia with ataxia or obesity and limbic encephalitis (36; 10; 73). Whipple disease of the brain should be included in the differential diagnosis of potentially treatable and reversible dementia (72). Some patients may have persisting amnesic syndrome years after ongoing treatment (82). Whipple disease of the brain should always be considered in patients presenting with unusual neurology, even in the presence of normal MRI scans (03). Early recognition and treatment decreases serious disability and even mortality.

Undiagnosed Whipple disease has again been validated as a cause of death (35). Surprisingly, isolated central nervous system Whipple disease has been associated with a normal MRI scan and false positive CSF 14-3-3 protein, which is typically considered suggestive of prion disease. It is possible that patients with Whipple disease may be misdiagnosed as prion disease on account of a picture reminiscent of rapidly progressive dementia; therefore, the finding of positive CSF protein 14-3-3 may not be relevant to the underlying diagnosis, and Whipple disease might be missed (103). Furthermore, Whipple disease may be found with a unique positive anti-neutrophil cytoplasmic antibody (01).

A 53-year-old man without gastrointestinal symptoms developed a 2-year history of progressive gait and balance disturbance, supranuclear ophthalmoparesis, and mild cerebellar dysmetria, with axonal sensory motor neuropathy (85). He had a small focal lesion in the right frontal lobe with diffuse hyperintensity of the periventricular white matter and diffuse brain atrophy. Magnetic resonance spectroscopy showed an N-acetyl-aspartate peak with an increase in the choline peak. The diagnosis of Whipple disease was made by PCR in the CSF. This report emphasizes that, in the absence of gastrointestinal involvement, in all complex and atypical neurologic patients one should suspect Whipple disease, even in the presence of peripheral nerve involvement.

A 30-year-old woman presented with headache associated with tingling and clumsiness of the left arm (64). A CT showed hypo-dense areas in the caudate and globus pallidus, T1 weighted MRI sequences revealed multiple hyperintensities, and gadolinium showed multiple areas of peripheral enhancement in the brain. Her condition worsened with abulia, hypersomnia, urinary incontinence, and corticospinal tract signs. A brain biopsy displayed numerous macrophages with clear cytoplasm showing granular PAS+ structures supportive of the diagnosis of Whipple disease. Tissue and serum PCR reactions were negative, as were gastrointestinal biopsies. She was treated with ceftriaxone with resolution of the MR abnormalities. The patient improved, and the abulia and other neurologic phenomena disappeared. This patient was reported from Spain, highlighting the international nature of the concern regarding Whipple disease of the brain and its challenging diagnosis.

Out of a series of 144 individuals, Chandra and colleagues described one patient with rapidly progressive cognitive decline with Whipple disease; other causes included autoimmune encephalopathy, Creutzfeldt-Jakob disease, neurocysticercosis, subacute sclerosing panencephalitis, and others (19).

Pessa and colleagues described a 72-year-old woman who presented with confusion, aphasia, ataxia, urinary incontinence, and with mood disturbance over about 5 months (87). The patient was notable in that she was diagnosed with gastrointestinal Whipple disease in 1985, and 30 years later presented with a progressive neurologic syndrome diagnosed as Whipple disease of the brain. She showed some response to ceftriaxone and trimethoprim-sulfamethoxazole.

A 63-year-old man who was diagnosed with Whipple disease presented with abdominal pain, weight loss, dementia, ataxia, extrapyramidal features, falls, up-gaze palsy, oculomasticatory skeletal myorhythmia, and with unusual lesions of the skin and face (18). However, this patient, described by Chandra and colleagues, was unconfirmed as PCR was not performed, and the patient had unusual skin lesions that were not previously described in Whipple disease. This is, therefore, an unconfirmed case of Whipple disease of the brain.

Limbic encephalitis has been seen as a complication of secondary Whipple disease with malabsorption, spondyloarthritis, epilepsy, and confusion in a 47-year-old man. A brain biopsy was essential to establish the diagnosis (13). A unique presentation of primary Whipple disease with rhombencephalitis has also been recorded (05). A 70-year-old male developed subacute tinnitus with an MRI revealing hyperintensities in the parahippocampal gyrus. After a few weeks, there was a reversal of diurnal variation, fluctuating disorientation, aphasia, and ptosis. A brain biopsy confirmed Whipple disease on histology with periodic acid-Schiff (PAS)-positive macrophages and PCR positivity in CSF (61). This patient was a rural waste water worker. These authors emphasized that to avoid delay in diagnosis, consider Whipple disease when there are unusual neurology and unexplained systemic symptoms. Chorea and dystonia have also been observed (79).

A retrospective analysis of 36 patients from a German institution discovered that neurologic involvement is common in Whipple disease and that direct T whipplei only partly explains the neurologic symptoms (71). These authors identified about 28% of Whipple disease patients had unrecognized stroke and postulated that mechanisms beyond central nervous system (CNS) infection contribute to the spectrum of CNS involvement in Whipple disease and raise the possibility of cardioembolic phenomenon from undetected T whipplei endocarditis.

Recent publications emphasize the association of Whipple disease with movement disorders like oculomasticatory myorhythmia chorea, myoclonus, and dystonia (105). These authors described oculopalatal myoclonus with supranuclear gaze palsy and hyperkinetic movement disorder with myoclonus, chorea, and dystonia (58; 105). Whipple disease needs to be part of the differential diagnosis of progressive supranuclear palsy (PSP) and assessment of the gastrointestinal system and joints should be performed in patients with a presentation like progressive supranuclear palsy and PCR for T whipplei should be searched (62).

It has been emphasized that Whipple disease should be considered as part of a differential diagnosis of rapidly progressive dementia (50). Research presented by Manini and colleagues showed a patient with rapidly progressive dementia; intractable diarrhea, with fluctuating arousal disturbances; supranuclear ophthalmoparesis; and fever spikes that led to cognitive decline with psychiatric manifestations, hypothalamic involvement, and fever. Whipple disease needed to be considered (66). Patients with mass lesions have been reported in two cases of women of average age 43.5 years, emphasizing the importance of considering Whipple disease in mass lesions of the CNS (06). A patient with previously diagnosed classic Whipple disease with gastroenteritis developed functional decline and extreme somnolence years after initial diagnosis, with recurrent admissions for hydrocephalus, emphasizing to consider relapse in the CNS in traditional gastrointestinal Whipple disease (96). The association of infective endocarditis and CNS has been emphasized with a 49-year-old female developing weight loss and diarrhea with anemia who had cerebral demyelination with endocarditis in three valves who was treated with intravenous ceftriaxone and then oral trimethoprim-sulfamethoxazole with a good response (24). Other authors have emphasized that large numbers of T whipplei can be demonstrated by electromicroscopy in valvular tissue indicating that T whipplei may live in biological tissue for many years in vegetations in valvular tissue and may lead to neurologic disease and stroke, as emphasized by Mecklenberg (71). Practitioners should also be wary of systemic embolization to brain and other organs from culture negative endocarditis (48).

Another patient, 60-year-old male, who developed movement disorders including head tremor, was diagnosed with rhombencephalitis due to T whipplei with a proceeding cerebellar syndrome and rapid progression, developing supranuclear gaze palsy, polyarthralgia, and weight loss (28). Unexplained weight loss, lower leg oedema, low albumin, in the absence of obvious malabsorptive symptoms in the context of neurologic disease, raises the possibility of Whipple disease (49).

It needs to be emphasized that Whipple disease of the brain can present as an ophthalmic condition with keratitis, uveitis, retinal vasculitis, cranial nerve palsies, nystagmus, ptosis, ophthalmoplegia, optic neuritis, optic disc oedema, optic atrophy, and orbital involvement (56). Bilateral ocular myositis has been identified in a 38-year-old female presenting with diplopia; immunohistochemistry with antibodies to T whipplei prove the diagnosis on a biopsy of extraocular muscle (84). Eye movement disorders have been seen in Whipple disease, such as staircase horizontal saccades, gaze-evoked nystagmus, and esotropia (100).

Prognosis and complications

Whipple disease of the brain may be fatal; patients may be left with residual amnesia, sleep orders, and eye movement abnormalities.

Clinical vignette

Patient 1: Primary Whipple disease of the brain. A 46-year-old woman presented in November 2003 with generalized tonic-clonic seizures. She subsequently developed diplopia and ataxia. Four months later, she developed tremor, a fluctuating left VI nerve palsy, eye movement abnormality with impaired saccadic pursuit functions, and hyponatremia secondary to the syndrome of inappropriate antidiuretic hormone secretion. Later blepharospasm, complete paralysis of upgaze, worsening ataxia, and a positive Romberg sign appeared. She had a severe amnesic syndrome, including impaired verbal and visual spatial memory.

Five months after presentation, she had a rapid deterioration with a fluctuating consciousness and a Glasgow Coma Score ranging from 2 to 14. She experienced hallucinations and confusion. Vertical gaze was absent. Initial MRI scanning of the brain revealed atrophy and gliosis of the right hippocampal formation. Concomitant with her deterioration was the development of multiple nodular enhancing lesions on MRI scanning involving the right temporal lobe, caudate nucleus, anterior commissure, right globus pallidus, left insula cortex, left hippocampal formation, lenticular striate territory, mesencephalon, and perivascular spaces. At the time of her deterioration, a lumbar puncture showed an opening pressure of 17 cm of water with 464 WC/μL (90% polymorphs, 10% lymphocytes). There were 30 red cells/μl. Cytology showed polymorphs and lymphocytes without malignant cells. The protein was 0.03 g/L (0.15-0.45); glucose was 1.6 g/L (concurrent blood glucose 3.1). Gram stain, India ink preparation, and cultures for Mycobacteria were negative.

She was treated with methylprednisolone, trimethoprim/sulfamethoxazole, meropenem, furosemide, salt tablets, and fluid restriction. She responded successfully to this treatment, and after 5 days, her conscious level returned to normal. The PCR for Whipple disease on the CSF was positive on two occasions and confirmed by an independent laboratory. The PCR was also positive on the blood. The duodenal biopsy was negative. Her eye movements gradually improved. Examination showed no evidence of lymphadenopathy or arthritis. The CT of the abdomen showed no lymphadenopathy. She responded well to therapy and was eventually able to sit out of bed, walk, and manage herself independently. She was discharged home with only a mild eye movement abnormality and difficulties with episodic memory. She experienced hypersomnolence and snoring, and was shown to have obstructive sleep apnea on overnight polysomnography and required a CPAP device. She was also shown to have reduced sleep efficiency and fragmentation. She was able to live independently with her amnesic syndrome, was able to drive, and eventually returned to work as a child caretaker on a supervised basis. She had a persistent eye movement abnormality. Repeat MRI scan about 6 months after discharge showed complete resolution of the nodular enhancing lesions with residual gliosis and atrophic change in the right hippocampal formation. Twelve months after her deterioration the MRI was stable, with normal CSF apart from persistent oligoclonal bands. Her sodium level normalized. She continues to live independently.

Patient 2: Secondary Whipple disease of the brain. A 41-year-old male metallurgist presented with the abrupt onset of continuous and involuntary twitching of the muscles of the left side of the face, which prevented him from sleeping. He also had difficulty using his eyes. His eyes were “blurry,” with difficulty “focusing” and inability to “track an object.” He also had difficulty looking down. He had problems driving, impaired balance, and was hypersomnolent and experienced difficulty working.

There was no past neurologic history. He had been treated briefly with fluoxetine, clonazepam, and ropinirole prior to neurologic presentation, all without benefit. He was a non-smoker and took no alcohol. There was no family history of neurologic disease. He had been of poor energy for some months. He had no abdominal pain, change in bowel habit, nor evidence of malabsorption or arthritis.

Examination showed a man 197 cm in height and 99 kg in weight. He looked chronically ill. Throughout the examination, he had involuntary twitching in the muscles of the left side of the face, involving left masseter and zygomaticus. Twitching also extended to the left orbicularis oris, platysma, stylohyoid, and digastric muscles. There was no twitching of the muscles of the right cheek. He had occasional twitching of both frontalis muscles. He had 20 degrees of vertical upgaze and 15 degrees of vertical downgaze from the horizontal meridian. Lateral gaze was normal and pursuit function intermittent. There were no saccadic movements in the vertical plane and very reduced saccades in the horizontal plane within insuppressible blinks. Vertical gaze paresis was overcome completely by head position, indicating a supranuclear component. Accommodation reflex revealed reduced ocular fixation, with reduced mesial movements of both eyes with absent pupillary responses. Light reflexes and fundi were normal. The remainder of the cranial nerve examination was normal. Peripheral motor system was normal. Walking was normal. No ataxia and no truncal ataxia were noted. Romberg sign and enhanced Romberg sign were negative. Abdominal examination was normal. There was no evidence of arthritis.

He had two MRI scans of the brain (1.5 Tesla and 3 Tesla), with and without gadolinium, both of which were normal.

His blood count showed hemoglobin of 130 g/L (135-70), microcytosis of 81 fL (82-98), ESR 68 mm/h (1-20), and platelets 428 x 189/L (140-370). White cell count was 9.6 x 10/L, with a normal differential count (4.0-11.0). Serum albumin was 35 g/L (38-50). C-reactive protein was 56 mg/L (< 10). Liver function tests were normal. Urea, creatinine, and electrolytes were normal. CSF examination showed an opening pressure of 21.5 cm of water. No leukocytes and 10 red cells per mL. No bacteria were seen. Culture was negative. Protein was 0.41 g/L, glucose was 3.2 mml/L, and concurrent blood glucose was 5.2 mml/L. Cytology showed a mild CSF lymphocytosis without malignant cells. Oligoclonal bands were not detected. PCR on CSF was positive for T whipplei on two occasions. Blood PCR was positive. T whipplei was also confirmed by DNA sequencing. Paraprotein estimation in blood revealed a polyclonal increase in gamma globulins. Immunofixation electrophoresis excluded an underlying paraprotein. Blood flow cytometry showed an abnormal population of B-lymphocytes suggestive of a B-cell lymphoproliferative disorder. CT of the abdomen showed pathological multiple paraaortic, paracaval, and mesenteric lymphadenopathy with the largest mesenteric lymph node measuring 27 x 13 mm. A fine needle aspiration of the abdominal lymph nodes was nondiagnostic. Lymph node biopsy at laparotomy showed multiple collections of epithelioid histiocytes, with focal multinucleated cells and large numbers of foamy and granular histiocytes in sheet-like arrangements. The cytoplasm of many of the cells had a granular appearance. Large numbers of PAS-positive bacilliform organisms within the histiocytes were found diagnostic of Whipple disease. Gram and Ziehl-Neelsen stains were negative.

He was commenced on 1 gram of meropenem intravenously three times a day and oral trimethoprim-sulfamethoxazole tablets twice a day. After one week, the meropenem was changed to 2 grams of ceftriaxone intravenously per day. After the first week he developed drug sensitivity to the trimethoprim-sulfamethoxazole tablets and was changed to oral doxycycline (100 mg twice a day). He was treated with ceftriaxone for 14 days. He has been maintained on doxycycline 100 mg twice a day.

His facial twitching and eye movement abnormalities did not respond to valproate, carbamazepine, clonazepam, or levetiracetam. Botox injections were required to control his facial twitching. He gained weight and was able to return to full-time work; however, he remained lethargic. His weight on 10 November 2007 was 113 kg (99 kg at diagnosis in April 2007).

Biological basis

Etiology and pathogenesis

Whipple disease is a rare condition caused by a soil-borne gram-positive bacillus T whipplei (69). Whipple disease of the brain is rare. It may occur in the context of a systemic illness with gastrointestinal or rheumatological features, or as a primary central nervous system infection (81).

The first isolation of T whipplei from the CSF of two patients in 2003 showed that viable bacteria may survive in the central nervous system after prolonged antibiotic therapy (65). The two patients did not have neurologic symptoms or signs. One specimen was obtained before treatment; the other at relapse 12 months after cessation of therapy. These observations suggest that the organism may be isolated from the central nervous system in the absence of obvious infection, that all patients with Whipple disease should be regarded as having subclinical brain involvement and should be treated as such, and that patients may have evidence of central nervous system infection even after prolonged treatment and relapse (65).

Trotta and colleagues observed that patients with Whipple disease lacked peripheral heat shock protein 70 and its cofactor GrpE, showing that people with Whipple disease do not elicit an effective response to T whipplei to control bacterial spread (106). This might be a selective immunological defect that can contribute to the pathogenesis of Whipple disease.

Rollin and colleagues found in a genotypic analysis of T whipplei in the Americas showed that there is diversity in the highly variable genomic sequences of T whipplei (94). Seventy genotypes have been determined. These authors describe genetic analysis of DNA from tissue samples from 30 patients with Whipple disease. They observed 14 newly-reported genotypes and four that were previously identified, showing that there is genetic diversity without a single genotype correlating with the development of Whipple disease.

Guérin and associates observed that Whipple disease only affects a small number of individuals infected with T whipplei (< 0.01%) and found a large frequency of asymptomatic carriage (43). These authors studied a kindred with four diseased patients and five healthy T whipplei chronic carriers. They hypothesized that Whipple disease was an inheritance with incomplete penetrance. It was found that a single very rare nonsynonymous mutation in four patients, the private R98W variant of IRF4, a transcription factor involved in immunity, resulted in haploinsufficiency and loss of function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. They also observed that six of the other 153 known nonsynonymous IRF4 variants experienced loss of function. These authors found that IRF4 evolved under purifying selection. It was hypothesized that autosomal IRF4 deficiency can cause Whipple disease by haploinsufficiency with age-dependent incomplete penetrance.

An idiosyncratic immune defect has been postulated as predisposing individuals to Whipple disease, possibly involving HLA-DRBI*13 and HLA-DQBI*06 (33). The infection with T whipplei resulted in asymptomatic seroconversion, self-limited primary acute infections, chronic asymptomatic carriage, classic Whipple disease, chronic localized infection, and isolated neurologic disease.

Differential diagnosis

The following should be considered in the differential diagnosis of Whipple disease:

• AIDS dementia complex
• Alzheimer disease
• Autoimmune encephalitis, such as those associated with anti-N-methyl D aspartate receptor (NMDAR) antibodies or antibodies to the voltage-gated potassium complex
• glioblastoma multiforme
• HIV-1-associated CNS complications
• HIV-1 encephalopathy
• Lyme disease
• multiple system atrophy
• neurosarcoidosis
• neurosyphilis
• olivopontocerebellar atrophy
• prion-related diseases
• vitamin B12-associated neurologic diseases
• Wegener granulomatosis

Whipple disease should be considered in the differential diagnosis of rapidly progressive dementia (50; 66), in the differential diagnosis of progressive supranuclear palsy (62), in isolated CNS lesions (06), and in the differential diagnosis of unusual eye movement disorders (56; 100; 58). Whipple disease should also be considered in the differential diagnosis of treatable ataxia (102).

Anti-Ma2-associated encephalitis myelitis can also mimic as a Whipple-like disease with an unusual eye movement disorder, an extrapyramidal syndrome, and has been referred to as pseudo-Whipple disease (16).

Confusing conditions

Alexander disease, a rare leukodystrophy characterized by the deposition of Rosenthal fibers in the brain and glial fibrillary acidic protein mutations, may present with spastic paraparesis, bulbar or pseudobulbar palsy, palatal myoclonus, and atrophy of medulla and cervical spinal cord can masquerade as Whipple disease (55). NMDA receptor encephalitis may present with enhancing CNS lesions and may be confused with Whipple disease (95). Langerhans cell histiocytosis is a rare disease of the dendritic cell system that can involve every organ including the CNS with granuloma formation. Hypothalamic pituitary dysfunction, cerebellar and basal ganglia pathology, and involvement of the meninges can easily be mistaken for Whipple disease (70). Mitochondrial neurogastrointestinal encephalomyopathy can also resemble Whipple disease of the brain (78). Tauopathies, such as progressive supranuclear palsy, also enter the differential diagnosis (41). Wernicke encephalopathy can mimic Whipple disease and complicate Whipple disease of the gastrointestinal tract from malabsorption resulting in thiamine deficiency (107). Whipple disease is part of the differential diagnosis of myoclonus (17).

Associated or underlying disorders

A culture negative endocarditis with systemic embolization causing neurologic disease led to the diagnosis of Whipple disease (54). This supports the findings of Mecklenberg that a high frequency of unexplained stroke might relate to clinically occult T whipplei endocarditis and result in embolization of the CNS (71).

Diagnostic workup

The diagnosis of Whipple disease of the brain depends on a low threshold for investigation, and PCR for T whipplei on CSF and blood should be considered in the workup of complex symptomatology, including cognitive change, hemiparesis, seizures, and eye movement abnormality, which may or may not be associated with oculomasticatory myorhythmia. In the context of such neurologic features, MR brain scanning should, of course, be performed, but it may be normal as in Patient 2. Further, even if abnormal, the findings are non-specific with multiple nodular enhancing lesions, as found in Patient 1, or may be solitary space-occupying lesions (81).

The diagnosis of secondary Whipple disease of the brain might be confirmed on tissue biopsy, such as of an abdominal lymph node, and in both primary and secondary cases by the application of molecular biological techniques to confirm active infection in the central nervous system. In the presence of the clinical suspicion of Whipple disease of the brain and armed with imaging consistent with the diagnosis, PCR should be performed on the CSF and blood, even if the MRI is normal. Sometimes brain biopsy may be necessary if the diagnosis is suspected and the PCR is negative. The sequencing of T whipplei should be attempted on blood and CSF only if the PCR is positive in a laboratory in which these tests have high sensitivity and specificity. Molecular biology techniques are especially important in certain situations in which tissue is not available for biopsy. The authors believe that patients with Whipple disease of the brain are likely to be overlooked if this diagnostic approach is not used and, further, that this disease may be more common than realized (Table 3).

Table 3. The Diagnosis of Whipple Disease of the Brain

Clinical question	Complex neurologic symptoms and signs: could it be Whipple? Lymphadenopathy? Arthritis? Gastrointestinal involvement?
MRI brain	Space-occupying lesion Multifocal nodular gadolinium-enhancing lesions Normal
Inflammatory markers – evidence of systemic disease	ESR, CRP, immunoglobulins CT thorax and abdomen – biopsy pathological Lymph nodes or duodenal biopsy
Molecular biology	CSF PCR: T whipplei CSF DNA sequence: T whipplei Blood PCR: T whipplei Blood DNA sequence: T whipplei

The PCR on CSF and blood can also be used to monitor the response to treatment. It is proposed that even with the slightest suspicion of Whipple disease of the brain, with strange neurologic phenomena, PCR on CSF and blood should be performed. The test is relatively cheap and relatively easy to perform, and available in most university teaching hospital laboratories.

Therefore, the diagnosis of Whipple disease of the brain depends on the following:

1. Asking the question: could it be Whipple?
2. Looking for evidence of systemic involvement.
3. PCR and DNA sequencing for T whipplei in CSF and blood.

Dolmans and colleagues emphasized the importance of molecular techniques in the diagnosis of Whipple disease, as periodic acid-Schiff (PAS) staining may have poor specificity and sensitivity (27).

Boban and colleagues emphasized that cytology of cerebrospinal fluid might be useful by demonstrating PAS+ in cytoplasmic granules (11).

Hujoel and others emphasized that Whipple disease can be intestinal or localized (52). They believe that a negative small bowel biopsy looking for PAS+ cells does not exclude T whipplei infection. These authors also believe that blood PCR is insensitive for active infection. This study highlights that careful history and examination is required and diagnostic testing, such as histopathology and PCR, appreciating that blood PCR may be insensitive. A negative PAS does not rule out classic or localized Whipple disease, and a high degree of suspicion, targeted testing, and multiple upper endoscopies are required.

Management

Whipple disease of the brain can be fatal if untreated and neurologic symptomatology, especially eye movement disorder, may persist after MRI and even after molecular evidence of eradication of infection. Unfortunately, the treatment is as difficult as the diagnosis. Therapeutic advice is limited by the lack of randomized controlled trials, unsurprising given the small numbers of patients. A generally accepted regime is provided in Table 4.

Table 4. Antibiotic Guidelines to Treat Whipple Disease of the Brain

A.	(i) Ceftriaxone (2 g intravenously daily) or meropenem (1 g intravenously three times daily) for 2 weeks
	(ii) Trimethoprim-sulfamethoxazole (trimethoprim 160 mg + sulfamethoxazole 800 mg) two tablets orally twice daily [indefinite]
	(iii) Folinic acid (15 mg orally daily) [indefinite to combat the antifolate effect of (ii)
B.	If allergic or lack of response:
	(i) Streptomycin (2 g intravenously daily) + penicillin G (1.2 x 106 units intravenously daily) for 2 weeks, then
	(ii) Doxycycline (100 mg orally twice daily) [indefinite] or
	(iii) Hydroxychloroquine (200mg orally twice daily) [indefinite]
C.	If allergic or lack of response:
	Consider chloramphenicol or cefepime intravenously
	[C only recommended if B unsuccessful or allergic]

Retrospective analyses on small series of patients have suggested that co-trimoxazole (trimethoprim-sulfamethoxazole) is one of the best oral treatments, and in tissue culture, this is more related to the sulfamethoxazole than the trimethoprim (15). Doxycycline and hydroxychloroquine are bactericidal against Coxiella burnetii, a bacterium also found in intracellular acidic vacuoles like T whipplei (12). However, doxycycline and other tetracyclines do not cross the blood-brain barrier, and hydroxychloroquine accumulates in the CNS to a lesser extent than in other organs. Although these drugs might be useful in systemic Whipple disease without neurologic involvement, the reduced penetration of the central nervous system might be responsible for reported relapses in brain Whipple disease from 2% to 33% over 5 years (59; 97).

Schnider and colleagues, in a study of 15 patients with Whipple disease, have shown that third-generation cephalosporins are effective in Whipple disease of the brain and recommend that ceftriaxone be combined with streptomycin (97). There was lack of response in 40% of patients treated with trimethoprim-sulfamethoxazole. These authors recommend that if neurologic relapse occurs during treatment with trimethoprim-sulfamethoxazole, an oral third-generation cephalosporin might be useful. Unfortunately, seven of the 15 patients evaluated in this study died, confirming the grave nature of Whipple disease of the brain.

The European Network on T whipplei Infection completed the first prospective nonrandomized trial comparing parenteral meropenem (3 g daily) with ceftriaxone (2 g daily) for the first 2 weeks of therapy, followed by maintenance with oral trimethoprim-sulfamethoxazole for the first year, in 40 patients (published results not yet available). These antimicrobials penetrate the central nervous system and are generally desirable in the context of Whipple disease of the brain and should be recommended (Table 4). The required duration of therapy is unknown, and patients require assiduous follow-up.

For patients who are allergic or do not respond to ceftriaxone or meropenem, chloramphenicol or cefepime can be used (31). If meropenem and ceftriaxone are not possible, then streptomycin with penicillin G (2 g and 1.2 million units daily, respectively) should be considered for 2 weeks. Interferon-γ has been successfully used in one patient with relapses despite appropriate antibiotic therapy (98).

Central European patients were randomized to intravenous ceftriaxone or meropenem for 14 days and followed by oral trimethoprim and sulfamethoxazole for 12 months (38). At 3 years, remission was achieved in 95% of patients. A patient developed antibiotic resistance, which correlated with advancing diffusion restriction and not lesion enhancement (92). The lesion demonstrated with hypoperfusion, increased choline, and decreased N-acetyl-aspartate on MR perfusion and spectroscopy. These findings indicate that diffusion restriction might be a useful marker of progression and therapeutic response. Sixteen percent of 91 Spanish patients were reported with neurologic manifestations; four of nine relapses were neurologic prior to the introduction of cotrimoxazole (77).

In 2013, Compain and colleagues (22) studied 18 patients with central nervous system Whipple disease and were able to classify involvement as: (1) CNS involvement in classic Whipple disease; (2) CNS relapse in previously treated Whipple disease; and (3) isolated CNS infection.

These authors retrospectively analyzed clinical features, diagnostic workup, brain imaging, and other features, including the effects of treatment in 10 men and eight women. As other authors have emphasized (81; 36), the neurologic symptoms were various, and brain magnetic resonance imaging showed a unique focal lesion in 35% that looked like a tumor, or multifocal lesions in 23%; a periventricular diffuse leukoencephalopathy, diffuse cortical atrophy, and pachymeningitis were also observed. Of note, the spinal cord was involved in two patients in their series. The CSF cytology was normal in 62% and the T whipplei polymerase chain reaction was positive in 92% of cases. PAS-positive cells were found in cerebral biopsies of four patients. All patients were treated with antimicrobial therapy for a mean duration of 2 years with either oral monotherapy trimethoprim sulfamethoxazole (TMP/SMX), doxycycline, third generation cephalosporins, or a combination of antibiotics including a beta-lactam antibiotic and aminoglycosides. Eight patients also received hydroxychloroquine. At the end of follow up, the clinical outcome was favorable in 14 patients (78%), with mild to moderate sequelae in 9. Seventy-two percent of patients stopped treatment at an average of 4 years. Four patients had clinical worsening despite antimicrobial therapy and two died with diffuse encephalitis and lung infection. These authors highlighted the diverse neurologic manifestation of Whipple disease, and that Whipple disease may mimic almost any neurologic condition. They also pointed out that brain involvement may occur during or after TMP/SMX treatment and that CSFT whipplei PCR is a major tool for diagnosis and may be positive in the absence of meningitis. They stressed that immune reconstitution syndrome may occur in the early months of treatment. The prognosis may be better than previously described as a consequence of early diagnosis and better use of antimicrobial therapy including hydroxychloroquine and doxycycline combination (22). An impaired TH1 immune response is seen in relation to Whipple disease infection, and T whipplei replication in vitro is dependent on interleukin 16 and is accompanied by apoptosis of host cells, facilitating dissemination of the bacterium; immune reconstitution syndrome and recurrence remain possible (90).

Whipple disease with multiple systemic and neurologic features was emphasized in Spanish (29) and Greek patients (21). The latter patient, a 48-year-old male, is notable in that he had a dementia syndrome with neurocognitive deficits identified even after treatment. Whipple disease has even masqueraded as dementia with Lewy bodies (53). The neurologic manifestations of malabsorptive syndromes, irrespective of direct central nervous system invasion by an infectious agent, include demyelinating disorders and movement disorders as found in Whipple disease; malabsorption of copper, thiamine, niacin, and vitamin E might complicate the neurology of Whipple disease (37; 88). A 46-year-old man was reported with an encephalopathy after 6 years of weight loss, diarrhea, and arthralgias (101). The MRI showed hydrocephalus secondary to obstruction at the aqueduct of Sylvius as a result of inflammation, with extensive periventricular medial temporal hyperintensities in T2 signal; in this patient a temporal craniotomy biopsy showed perivascular macrophages with immunohistochemical staining of T whipplei. Neuropathological studies in three patients with pre- or postmortem PCR confirming central nervous system Whipple disease revealed: one patient had an acute onset with spine and brain involvement and died after 14 weeks, with neuropathology showing extensive inflammatory and necrotizing lesion with abundant foamy PAS positive macrophages; the second patient had a subacute evolution of CNS Whipple disease with death occurring 18 months after onset despite antibiotic treatment – the brain showed an inflammatory lesion of the brainstem, thalamus, and cerebellum with abundant foamy PAS positive macrophages; the third patient was diagnosed 4 weeks after onset and treated with an excellent response and died after a disease-free interval of 24 months from unrelated causes, with neuropathology showing cystic residual lesions devoid of microorganisms and without an inflammatory reaction. The authors concluded that CNS Whipple disease may have an acute or subacute course with variable response to treatment. Some lesions may be a severe acute necrotizing encephalopathic process or a subacute inflammatory pathophysiology involving the diencephalon, brain stem, cerebellum, and spinal cord. Chronic cavitary brain lesions may be the outcome of successful treatment (04).

The importance of the diagnosis of Whipple disease in rheumatological and infectious diseases practice has been stressed (99; 91).

Whipple disease can involve the eye, and a 63-year-old male had T whipplei PCR positivity in a vitrectomy specimen, after fundoscopy showed opacities that looked like white mulberries (40). This patient subsequently developed malaise, weight loss, joint symptoms, and neurologic phenomena with paralysis of his legs and paraesthesia of his mouth, tongue, and fingers with a normal CSF and MRI. Transesophageal echocardiography revealed a cardiac vegetation and gastroscopy, with duodenal biopsy, and showed PAS-positive macrophages with a PCR test positive for T whipplei. The patient’s symptoms improved with antibiotic therapy; his uveitis and vitritis disappeared. This study spotlighted that uveitis may complicate intraocular operations in patients with Whipple disease; furthermore, another description of isolated Whipple endocarditis has been presented in which the patient required mitral valve replacement (51).

In 2014, the sleep disorders of Whipple disease were described in two patients with primary and secondary Whipple disease of the brain, disclosing that Whipple disease may affect sleep biology, leading to hypersomnolence from obstructive sleep apnea, sleep fragmentation, reduced sleep efficiency, sleep initiation insomnia, and intrusive oculomasticatory myorhythmia (83). The patient with primary Whipple disease had hypersomnolence with severe obstructive sleep apnea, reduced sleep efficiency, frequent waking, and sleep fragmentation. The patient with secondary Whipple disease was also hypersomnolent with oculomasticatory myorhythmia. He was shown to have severe sleep initiation insomnia with poor sleep efficiency, severe obstructive sleep apnea/hypopnea, and oculomasticatory myorhythmia at sleep-wake transitions. This experience highlights the importance of the disruption of sleep biology by Whipple disease.

Peregrin and Malikova studied a 33-year-old female with a mass lesion and multiple neurologic symptoms and signs, as well as multiple modular enhancing lesions in the brain on MRI scanning (86). She was followed for 12 years. Initially she had no neurologic phenomena, but, with time, developed a tumor-like lesion and hypothalamic infiltration with development of cognitive impairment 10 years later. This experience with primary Whipple disease again highlights and confirms the complexities of Whipple disease involving the brain.

Poureisa and colleagues studied a patient with neurologic phenomena and MRI lesions with marked mass effect similar to infiltrative tumors (89). These were located in several areas of the brain associated with gliosis and atrophic changes, with the development of active infiltrative-like lesions elsewhere. The MRI findings were confirmed by stereotactic brain biopsy, and PAS positivity led to the diagnosis of Whipple disease.

Hurth and colleagues studied a 49-year-old Caucasian male who had a 4-year history of progressive cognitive and behavioral impairment, parkinsonism, cognitive fluctuation, altered sleep-wake cycles, myoclonus, and visual hallucinations who died without diagnosis (53). The neuropathology suggested the diagnosis of Whipple disease, which was confirmed by immunocytochemical techniques. This experience highlights why it is important to consider Whipple disease as it can masquerade as a neurodegenerative disorder.

Vural and colleagues described two patients with Whipple disease of the nervous system (109). The first patient was a 56-year-old male who presented with headache, gait difficulty, and rapidly progressive cognitive impairment. MRI showed multiple T2-signal hyperintensities with enhancement. Neuropsychological evaluation revealed severe impairment in all cognitive domains with negative duodenal biopsy. The brain biopsy revealed findings consistent with Whipple disease. The second patient was a 22-year-old male who presented with left-sided hypoesthesia, polydipsia, and polyuria. MRI showed infundibular thickening. He was initially diagnosed with lymphocytic hypophysitis, but then developed progressive ataxia. MRI showed multiple T2A hyperintense nodular lesions in the middle cerebellar peduncles, brainstem, cerebrum, cerebellum, basal ganglia, optic chiasm, and hypothalamus. He eventually became bedridden and developed eye movement abnormalities and truncal ataxia. MRI showed multiple contrast-enhancing lesions. Brain biopsy showed PAS-positive abnormalities, and he was treated with ceftriaxone. Unfortunately, he died. Both cases illustrate the complexities of isolated cerebral Whipple disease as a diagnosis.

Derrick and colleagues reported the successful treatment of gastrointestinal Whipple disease with ceftriaxone and minocycline maintenance (25). Delayed recognition or treatment may lead to serious cognitive complications and progress to death after central nervous system involvement. Therefore, it is imperative that Whipple disease, especially gastrointestinal in origin, be recognized as this may prevent central nervous system complications.

Gűnther and colleagues described their experience with gastrointestinal diagnosis of classic Whipple disease in 191 patients (44). They reported that classical Whipple disease presents with gastrointestinal manifestations in most patients. The small bowel is macroscopically affected in 27%, with 91% of patients having characteristic histological changes and some patients having normal bowel histology. In nine patients other tests were positive from duodenal specimens, including positive T whipplei–specific PCR. They found that in 95% of patients there is a diagnostic hint toward classical Whipple disease from small bowel biopsies, and only a small number were diagnosed with T whipplei–specific PCR in extraintestinal fluids, including cerebrospinal fluid. These authors believe that gastroscopy with duodenal biopsy and histological and molecular biological examination are the most reliable diagnostic method for classical Whipple disease and emphasize that Whipple disease with atypical features may be a complex diagnosis, especially if it presents in the central nervous system. The authors emphasize that T whipplei–specific PCR and immunohistochemistry are particularly important in patients with central nervous system involvement.

Zalonis and colleagues described a 48-year-old male with a brief history of arthritis who developed myoclonic-like movements in his limbs, gait ataxia, oculomotor abnormalities, sleep difficulties, and cognitive impairment (110). On examination he was ataxic with impaired vertical gaze, dysarthria, and myoclonic movements. His MRI showed nonspecific white matter hyperintensities with gadolinium enhancement in the right frontal lobe. The duodenal biopsy did not show PAS positivity, and PCR for T whipplei in cerebrospinal fluid, stools, and blood were positive, suggesting the diagnosis of Whipple disease of the central nervous system. He was given intravenous ceftriaxone followed by oral trimethoprim/sulfamethoxazole with good effect. In particular, oculomotor function and myoclonus improved after 2 weeks, with further progress over the following 6 months. He was able to return to everyday activities, but unable to work in a professional capacity. His MRI showed resolution of the white matter lesions. This case, again, confirms the complexities of diagnosis and treatment of Whipple disease.

Marth has emphasized that Whipple disease should be excluded before therapy with tumor necrosis factor inhibitor substances as it is believed that the immunosuppression contributes to the progression of T whipplei (67). The author described Whipple disease as an acute self-limiting disease in children, and localized forms affecting cardiac valves or the central nervous system without intestinal symptoms and asymptomatic carriage of T whipplei is present in around 4% of Europeans. Genomic analysis has suggested that T whipplei represents a host-dependent bacterium, and it is believed that the clinical cause of T whipplei can be influenced by medical immunosuppressants.

Marth studied 19 reports on immunosuppression, including tumor necrosis factor inhibitors (TNFIs), and found 41 patients developed Whipple disease (67). Arthritis may precede the diagnosis of Whipple disease by many years, and, in about 50% of the reports, patients were treated with immunomodulating drugs or TNFIs. He emphasized the complicated natural history of Whipple disease when medical immunosuppression is used, especially TNFIs. Standard diagnostic tests like PAS staining might be negative if patients are given immunosuppression, making the diagnosis difficult. Therefore, Marth concluded that Whipple disease should be excluded before therapy with TNFIs is prescribed as immunosuppressants can affect the progression of T whipplei infection.

Marth and colleagues summarized advances in the medical microbiology, epidemiology, cytobiology, and the availability of diagnostic tools including histopathology, immunocytochemistry, PCR bacterial culture, and understanding infections caused by T Whipplei (68). These authors emphasized the development of immune reconstitution inflammatory syndrome (IRIS) that occurs in patients having immunosuppressive treatment in the context of Whipple disease. Immune reconstitution inflammatory syndrome is characterized by recurrence of inflammatory signs and symptoms after initial clinical improvement, followed by recurrence of local and systemic clinical signs in the absence of other causes; immune reconstitution inflammatory syndrome may be present in up to 10% of treated patients and is thought the most frequent complication during Whipple disease therapy. Immune reconstitution inflammatory syndrome seems to occur in patients who are treated over the years, if not decades, with immunosuppressants because of an assumed diagnosis of rheumatic disease. Immune reconstitution inflammatory syndrome is strongly seen with the use of immunosuppressive therapy before the diagnosis of Whipple disease and can be seen even after a long interval (ie, several years). Common signs of immune reconstitution inflammatory syndrome are frequently fever and arthritis. Immune reconstitution inflammatory syndrome can be fatal; oral corticosteroids can be effective and might be life-saving.

Two patients were reported from Spain with Whipple disease following treatment with antitumor necrosis factor treatment alpha, and they cautioned that patients with inflammatory arthritis who failed antitumor necrosis factor treatment might in fact have Whipple disease. Such patients’ condition might worsen with treatment, which is the treatment of longstanding joint disease, due to Whipple disease, with progression in several organs from Whipple disease; antitumor necrosis factor alpha has an immunosuppressive effect, encouraging the growth of T Whipplei throughout all organs of the body including into the central nervous system (93).

T Whipplei infection has for the first time been described in a patient following liver transplantation in the context of graft versus host disease (108). These authors emphasized that Whipple disease may be undiagnosed in immunosuppressed transplant patients because of the unusual nature by which Whipple disease can present. Whipple disease should be considered in patients following transplantation in the context of a high level of immunosuppression, with certain HLA types (DRB1*13 and DQB1*06) and in the absence of trimethoprim sulfamethoxazole. It is possible that Whipple disease may be underdiagnosed in a transplant setting. The presence of graft versus host disease suggests a relationship between a compromised immune system and the development of Whipple disease.

Campagnolo and colleagues described a 63-year-old man with an 8-year history of uveitis and seronegative arthritis, without gastrointestinal symptoms, who developed cerebral and cerebellar atrophy with worsening gait and dysarthria (14). He developed difficulties with attention and short-term memory. He had impaired vertical gaze. A right vitrectomy returned a positive PCR for T Whipplei, and the T Whipplei on the CSF eventually became positive. He was diagnosed with Whipple disease of the brain and commenced on sulfamethoxazole; his condition gradually improved, especially the ocular inflammation. His dysarthria, gait impairment, and cognitive difficulties only slightly improved. The PCR eventually became negative. This patient is notable in that the Whipple disease diagnosis was achieved 8 years after the onset of symptoms and suspected on the combination of CNS signs, uveitis, and arthritis, even though he did not have gastrointestinal symptoms. These authors emphasize the importance of considering Whipple disease in the history of long-term ocular and joint disease without gastrointestinal involvement. Other PCR for T Whipplei should be performed in multiple tissues (14).

Tábuas-Pereira and colleagues from Portugal described prosopagnosia as a presenting symptom of Whipple disease in a 54-year-old female (104). She had experienced abdominal pain and arthralgia. A duodenal biopsy was negative. Central nervous system Whipple disease was confirmed by a PCR from a brain biopsy. She was treated with ceftriaxone and then cotrimoxazole for 2 years; at the 8-year follow up, the prosopagnosia persisted. This is the first patient to be described with prosopagnosia in primary central nervous system Whipple disease.

Kilani and colleagues described a 68-year-old man who developed partial epileptic seizures, difficulties with concentration, and irritability without headache (60). A MRI scan revealed a right frontal lobe cyst, which showed gadolinium enhancement with surrounding edema and midline shift. The biopsy demonstrated reactive gliosis and infiltration with perivascular foamy histiocytes, which were periodic acid-Schiff positive, with intense staining in macrophage histiocytes. Acid-fast bacilli and fungal stains were negative. The CR for T Whipplei was positive in the CSF. He was given ceftriaxone and then trimethoprim-sulfamethoxazole for 12 months, and his concentration improved. He has had no recurrence of seizures and continues to take trimethoprim and sulfamethoxazole. This report emphasizes that Whipple disease can present as a solitary tumor-like lesion (60). This is in contrast to the patient of Tábuas-Pereira and colleagues with prosopagnosia whose MRI showed extensive cortical and subcortical edema in both temporal lobes and, in the right, reflecting involvement of the inferior temporal lobe facial recognition centers.

A 52-year-old man developed hypersomnolence with myoclonic jerks and was found to have MRI FLAIR abnormalities in the cortical and subcortical regions of the frontal regions and anterior parietal areas (42). His condition deteriorated with myoclonic jerks and weakness; the MRI findings became more dramatic. His condition further deteriorated with an inability to walk and his conscious level deteriorated with tetraparesis and areflexia. A brain biopsy showed severe neuronal loss in the right temporal lobe with vacuolation, gliosis, and numerous reactive astrocytes by GFAP with microglial activation. There was mild lymphocytic perivascular infiltration in subcortical white matter and leptomeninges with infiltrates of CD45 for T Whipplei and CD68 positive cells. Macrophages had periodic acid-Schiff positive diastase resistant material, and the PCR was shown to be positive, which was confirmed on PCR tissue taken from the frozen specimen. Unfortunately, he died a month after biopsy, and an autopsy was not performed. He was given intravenous antibiotics.

A 63-year-old man with rapidly progressive dementia was shown to have PAS positive material on brain biopsy and PCR positive brain tissue for T Whipplei. He was given ceftriaxone and doxycycline with hydroxychloroquine, and his condition improved. Hale and colleagues emphasize the importance of central nervous system Whipple disease in patients presenting with rapidly progressing dementia, neurologic signs, and abnormal MRI (46).

Biagi and colleagues raise the question of what is the best therapy for Whipple disease (08). These authors emphasized that the optimum choice of antibiotics and duration of treatment have not been finalized. They posit that ceftriaxone and trimethoprim-sulfamethoxazole are effective in the vast majority of patients in the first few years; however, because reinfections and reactivations occur, lifelong prophylaxis is necessary, and they proffer doxycycline as the best option. They proposed merging the ceftriaxone and trimethoprim-sulfamethoxazole for the first few years with lifelong prophylaxis using doxycycline.

Three reports emphasized ocular involvement in Whipple disease. Bilateral optic disc swelling was observed by Chiu and Moore in a 57-year-old male with a gastrointestinal and arthritic illness, in which Whipple disease was diagnosed on PAS staining, PCR testing, and electron microscopy (20).

Ocular myositis was found in a 38-year-old female in the context of biopsy-proven gastrointestinal Whipple disease on a stable medication regime (84). In this patient, imaging of her orbits showed diffuse enhancement of the extraocular muscles. Biopsy of the extraocular muscles showed that PAS+ macrophages, and immunohistochemistry to T whipplei was positive. Electron microscopy confirmed T whipplei in cell membranes of lysosomes.

In a study of classical and localized Whipple disease, it was observed that small bowel biopsy PAS stain/PCR is helpful in classical Whipple disease but may be less useful in localized Whipple disease or CNS Whipple disease without gastrointestinal symptoms (23). Therefore, synovial fluid or PCR should be performed in both classical and localized Whipple disease to help confirm the diagnosis.

Immune reconstitution inflammatory syndrome (IRIS) may complicate the treatment of Whipple disease. IRIS can be a serious complication and may result in death (57).

Ocular myorrhythmia, a progressive dementia and myoclonus, may complicate Whipple disease of the brain (32).

Anti-IgLON5 disease is a rare neurodegenerative disorder with an unusual tauopathy, neuronal loss, and gliosis in the tegmentum of the brain stem and hypothalamus, which can mimic Whipple disease with limb jerks, sleep disturbance, cognitive changes, dysphasia, and obstructive sleep apnea (74; 76).

Outcomes

Whipple disease of the brain may be fatal; patients may be left with residual amnesia, sleep orders, and eye movement abnormalities.

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Peter K Panegyres MD PhD PhD FRACP

Dr. Panegyres, Director of Neurodegenerative Disorders Research, has no relevant financial relationships to disclose.
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John E Greenlee MD

Dr. Greenlee of the University of Utah School of Medicine has no relevant financial relationships to disclose.
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Ajitesh Rai MD and John B Selhorst MD

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Whipple disease

Associated Disorders

Peripheral oedema
Culture-negative endocarditis

Differential Diagnosis

AIDS dementia complex
Alzheimer disease
Autoimmune encephalitis
glioblastoma multiforme
HIV-1–associated CNS complications
- HIV-1 encephalopathy
- Lyme disease
- multiple system atrophy
- neurosarcoidosis
- neurosyphilis
- olivopontocerebellar atrophy
- prion-related diseases
- vitamin B12–associated neurologic diseases
- Wegener granulomatosis

Whipple disease

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Neurologic Features of Systemic Whipple Disease

Table 2. Neurologic Phenomenology in Patients with Primary Whipple Disease of the Brain

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

The following should be considered in the differential diagnosis of Whipple disease:

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Table 3. The Diagnosis of Whipple Disease of the Brain

Management

Table 4. Antibiotic Guidelines to Treat Whipple Disease of the Brain

Outcomes

Special considerations

Pregnancy

Anesthesia

References

Contributors

Author

Editor

Former Authors

ICD & OMIM codes

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