Additional file 1, Table S1.

Title: Summary of 20 patients with T. whipplei chronic encephalitis.

Description: The characteristics of our 5 patients with T. whipplei encephalitis and 15

patients from the literature are summarised in this Table.

1
Patients Sex/ Neurological signs Extraneurological Specific diagnosis Pretreatment examinations Treatment Follow-up
[Respective Age signs
references] (y)
CERTAIN DIAGNOSIS OF T. WHIPPLEI ENCEPHALITIS
Diagnosis based on T. whipplei PCR of CSF and/or brain biopsy
1
Patient 1 M/39 First symptoms: Dysarthria Previous: 3 years Brain biopsy: SGPT = 123 UI/L and SGOT = 51 UI/L. Doxycycline Quick
Symptoms: Dysarthria, cognitive before, unexplained Astrocytar gliosis and CSF: 4 g/l of protein, glucose level normal, no 200 mg improvement.
impairment (dementia), diarrhoea for 3 weeks, neoangiogenesis cells and Relapse one
choreiform movements, apathy, cytolytic hepatitis, PAS -, IHC -, regular Brain CT scan: Somewhat diminished density hydroxy- year after the
depression and intermittent weight gain PCR : -, repeat PCR + involving the right lenticuloinsular area and chloroquine end of the
diplopia Contemporary: First CSF: diminished density of the right frontal 200 mg 3 treatment.
Dysphagia, cytolytic Regular PCR: - convexity times/day, New treatment
hepatitis, weight gain Repeat PCR: + Brain MRI: Several high-signal lesions (T2) and for 52 months.
Second CSF: with a heterogenous contrast (T1) in the TMP-SMX Quick
Regular PCR: - cerebral trunk, the anterior hypothalamus, the 320-1,600 improvement.
Repeat PCR: + anterior limbs of the internal capsules and the mg/day 3 No sequelae.
Gastric and SB right centrum semi-ovale. times/day
biopsy: for
PAS -, IHC -, PCR - 18 months
Saliva: PCR -
Stools: PCR -
1
Patient 2 M/35 First symptoms: Dysuria and Previous: Asthenia First CSF: CSF: 2 g/l of protein, glucose level normal, 9 Doxycycline Quick
hypothalamic signs (impotence) Contemporary: Regular PCR: - white blood cells/mm3. 200 mg improvement.
Symptoms: Gait ataxia, Asthenia Repeat PCR: + Brain MRI: High-signal lesions (T2) in the and No sequelae.
vertiginous sensation and Second CSF: centrum ovale, particularly in the hydroxy- Four years of
pyramidal syndrome Regular PCR: - periventricular area on the left; one of the same chloroquine follow-up.
Repeat PCR: + type of lesion was observed in the left 200 mg 3
Gastric and SB cerebellar area. A lesion that increased after times/day,
biopsy: gadolinium injection was present in the left and
PAS -, IHC -, PCR - parieto-occipital area in the white matter. TMP-SMX
Saliva: 320-1,600
Regular PCR: - mg/day 3
Repeat PCR: + times/day
Stools: for
Regular PCR: - 18 months
Repeat PCR: +
1
Patient 3 M/52 First symptoms: Cerebellar form Previous: First CSF: SGPT = 107 UI/L and SGOT = 51 UI/L Doxycycline Quick
(dysarthria and gait ataxia), Unexplained acute Regular PCR: - CSF: 0.79 g/l of protein, glucose level normal, 200 mg improvement

2
 cognitive impairment (memory diarrhoea, abdominal Repeat PCR: + 9 white blood cells/mm3 (80% lymphocytes and and No sequelaes
impairment and disorientation), pain and fever one Second CSF: 20% mononuclear cells). hydroxy- Relapse one
and pyramidal syndrome month before Regular PCR: - Brain-CT scan: Normal chloroquine year after the
Contemporary: Repeat PCR: + Brain-MRI: Normal 200 mg 3 end of the
Dysphagia, abdominal Gastric and SB times/day, treatment, with
pain, fever biopsy: and a discrete
PAS -, IHC -, PCR - TMP-SMX cerebellar
Saliva: PCR - 320-1,600 syndrome and a
Stools: PCR - mg/day 3 weight gain of
times/day 12 kg.
for New treatment
18 months for 12 months.
Quick
improvement
two months
later, with the
loss of 7 kg.
No sequelae.
1
Patient 4 M/53 First symptoms: Gait ataxia, Previous: First CSF: CSF: 0.44 g/l of protein, glucose level normal, Ceftriaxone Slight
cognitive impairment (memory Unexplained acute Regular PCR: - 20 white blood cells/mm3 (mainly 2 g/day improvement.
impairment and confusion), diarrhoea three weeks Repeat PCR: + lymphocytes). and Few sequelae.
central nystagmus, and pyramidal before Second CSF: Brain-MRI: Normal TMP-STX We were not
syndrome Contemporary: Regular PCR: - 320-1,600 able to continue
None. Repeat- PCR: + mg/day contact with
Gastric and SB for 15 months this patient.
biopsy:
PAS -, IHC -, PCR –
Stools: PCR -
Blood: PCR -
1
Patient 5 F/33 First symptoms: Headache, None Brain biopsy: PAS -, CSF: 0.38 g/l of protein, glucose level normal, Ceftriaxone Slight
diplopia and seizure IHC -, PCR - 22 white blood cells/mm3 (mainly 2 g/day improvement.
Symptoms: Cerebellar form CSF: PCR + lymphocytes). and Few sequelae.
(dysarthria and gait ataxia), Blood: PCR – Brain MRI: Mass lesion on the head of left TMP-STX Relapse six
cognitive impairment (reasoning Gastric and SB caudate nuclei 320-1,600 months after
impairment), choreiform biopsy: PAS -, IHC -, mg/day the end of the
movements, oculomasticatory PCR – for 18 months; first treatment.
myorhythmia, right facial Saliva: PCR – Doxycycline Slight
paralysis, nystagmus, and muscle Stools: PCR - 200 mg improvement.
weakness and Few sequelae.

3
 hydroxy-
chloroquine
200 mg 3
times/day
and
sulfadiazine
1g/day 3
times/day
2
Patient 6 F/72 First symptoms: Previous: Weight loss Serum: PCR + CSF: 45 white blood cells/mm3, (mainly TMP-SMX Quick
[30] Personality changes (very Contemporary: CSF: PCR + lymphocytes) and elevated protein content improvement.
anxious), apathy, and cognitive Weight loss Duodenum and EEG: Slowing of the background activity and No sequelae.
impairment (memory impairment ileum biopsies: PAS - recurrent diffuse synchronous slow and sharp
and confusion) wave discharges.
Symptoms: Gait ataxia, cognitive Brain MRI: Mild cortical and subcortical
impairment (disorientation), atrophy, with diffusely distributed lacunary
extrapyramidal signs, and upper lesions that were hypointense on T1-weighted
motor neuron disorder and hyperintense on T2-weighted images. No
enhancement after gadolinium administration.
2
Patient 7 M/72 First symptoms: Dizziness Previous: Anorexia, CSF: PCR + Brain MRI: Significant T1, T2, and fluid- Ceftriaxone and No
[34,37] Symptoms: Cognitive fatigue Duodenal biopsy: attenuated inversion recovery signalled streptomycin, improvement.
impairment (memory impairment Contemporary: PAS - abnormalities in the cerebellar vermis, bilateral TMP-SMX Death.
and incoherent speech), ataxia, Anorexia, fatigue cerebellar peduncles, and superior and
supranuclear ophthalmoplegia, posterolateral medulla as well as bilateral foci
and hypersomnia enhancement in the cerebellar subcortical white
matter.
2
Patient 8 M/44 First symptoms: None CSF: PCR + from 3 CSF: Pleocytosis (10-36/mm3) and mildly TMP-SMX and Slow
[35] Focal jerks of the left hand and consecutive lumbar increased CSF protein (0.54-1 g/l). ceftriaxone. improvement.
the forearm punctures EEG: Intermittent bilateral frontotemporal Adjuvant
Symptoms: Cognitive Duodenal biopsy: theta activity and no epileptiform discharges. immunotherapy
impairment, supranuclear PAS - Brain MRI: Bilateral lesions around the with polyvalent
ophthalmoplegia and myoclonus parahippocampal gyri, the third ventricle and immunoglobulins
of the left arm and shoulder dorsal pons consistent with limbic encephalitis
extending to the upper brainstem.
2
Patient 9 M/46 First symptoms: None CSF: PCR+ CSF: 464 white blood cells/mm3 (90% Meropenem for 2 Slow
[36] Cognitive impairment (memory Duodenal biopsy: polymorphs, 10% lymphocytes) and decreased weeks, TMP- improvement.
impairment) PAS -, PCR - CSF protein (0.03 g/l) and glucose (1.6 SMX for 13 Sequelae.
Symptoms: mmol/l). months
Ataxia, cognitive impairment November 2003 Brain -MRI: Atrophy and
(confusion and memory gliosis of right hippocampal formation.

4
 impairment), supranuclear March 2004 Brain MRI:
ophthalmoplegia, seizures, Development of nodular enhancing lesions
SIADH, and insomnia (right temporal lobe, caudate nuclei, anterior
commissure, right globus pallidus, left insula
cortex, left hippocampal formation, lenticular
striate territory, mesencephalon and
perivascular spaces).
2
Patient 10 F/39 First symptoms: Speech Previous: Blood sample: PCR + Brain MRI: Bilateral hemispheric high signal TMP-SMX Slow
[43] disturbance and weakness Unexplained acute Brain biopsy: PAS +, on T2-weighted images. improvement.
Symptoms: diarrhoea 10 months EM + and PCR + Sequelae.
Cognitive impairment (memory before, associated with Digestive biopsy:
impairment), depression, a petechial rash PAS -
decreased level of Contemporary: Fever
conscientiousness, personality
change, seizures, supranuclear
ophthalmoplegia, left hemiplegia,
urinary incontinence, and
paresthesias
Diagnosis based on positive T. whipplei PCR on samples other than CSF and brain biopsy
2
Patient 11 M/65 First symptoms: Gait ataxia, None Blood sample: CSF: Normal. Penicillin and Quick
[28] supranuclear ophthalmoplegia, PCR + Brain MRI: Mild to moderate cortical atrophy streptomycin, Improvement.
hypothalamic signs (daytime Brain autopsy: without focal abnormalities. followed by Sudden death
somnolence and nocturnal PAS + TMP-SMX due to a
insomnia) Digestive biopsy: mesenteric
Symptoms: Decreasing level of PAS - thrombosis.
conscientiousness, hemiparesia,
myorhythmia, myoclonus, and
upper motor neuron disorder

5
2
Patient 12 F/47 First symptoms: Previous: Arthritis. CSF: PAS - CSF: Protein levels from 0.5 to 0.55 g/l, Ceftriaxone 2g/d Improvement
[27] Oculomasticatory myorhythmia Contemporary: Duodenal biopsy: normal glucose level, and 0 to 70 mononuclear for 6 months
and nystagmus Fever, submandubular PAS -, PCR + cells. TMP-SMX Recurrence
Symptoms: lymph node EEG: Mildly generalised slow background. with TMP-
Cognitive impairment (memory enlargement Brain-CT: Normal. SMX
impairment), cerebellar form Brain-MRI: Arnold-Chiari type 1 Sequelaes
(dysarthria and ataxia), malformation with no brainstem compression.
hypothalamic signs (insomnia
and intermittent
hypersomnolence), depression,
supranuclear gaze palsy, and
upper motor neuron disorder
2
Patient 13 F/54 First symptoms: Blurred vision None Jejunal biopsy: Brain-MRI: A venous angioma in the left TMP-SMX Slow
[31] Symptoms: PAS - and PCR + cerebellar hemisphere. followed by improvement
Gait ataxia, supranuclear ceftriaxone No sequelaes
ophthalmoplegia, myorhythmia,
extra-pyramidal signs and upper
motor neuron disorder
POSSIBLE DIAGNOSIS OF T. WHIPPLEI ENCEPHALITIS
Diagnosis based on positive PAS-staining and electron microscopy of brain biopsy
2
Patient 14 M/40 First symptoms: Headache and None Brain necropsy : CSF: Pleocytosis and occasional level of -* Death
[38] seizures PAS + and EM + protein.
Symptoms: Cerebellar form (gait Digestive biopsy:
ataxia and dysarthria), cognitive PAS -
impairment (dementia, memory
impairment, confusion), decrease
level of conscientiousness, urine
incontinence, and upper motor
neuron disorder
2
Patient 15 M/32 First symptoms: Headache None Brain biopsy: PAS + CSF: Normal excepted oligoclonal bands. Penicillin and Slow
[39] Symptoms: Decreasing level of and EM + Brain MRI: Large high-signal mass lesions streptomycin for improvement.
conscientiousness, cognitive Duodenal and with peripheral ring enhancement after 2 weeks, Sequelae.
impairment (dementia, jejunal biopsies: gadolinium injection. followed by
disorientation, memory PAS - TMP-SMX for
impairment), apathy, upper motor 11 months
neuron disorder, and seven nerve
palsy
2
Patient 16 M/58 Symptoms: Previous: Arthralgias CSF: PAS - CSF: 100 mg/dl of protein, 99 mg/dl of Chloramphenicol Death 6 months

6
[32] Cerebellar form (dysarthria and Contemporary: Low- Brain biopsy: PAS + glucose, 9,330 red blood cells and 4 TCN after diagnosis
gait ataxia), cognitive impairment grade fever and EM + lymphocytes.
(memory impairment), Jejunal biopsy: Brain CT scan: Round areas of low density
supranuclear ophthalmoplegia, PAS - without mass effect in the right medial
dizziness, personality change, temporal lobe and right pontine tegmentum.
nystagmus, upper motor neuron After the infusion of intravenous contrast
disorder, hypothalamic signs material, these lesions demonstrated increased
(impotence), and paresthesias intensity. There was slight central and cortical
atrophy.
2
Patient 17 F/63 First symptoms: Myorhythmia Previous: Arthralgia Jejunal biopsy: CSF: Normal. No antibiotic Death
[40] Symptoms: Cerebellar form for 10 years PAS -, PCR - EEG: Normal.
(ataxia and dysarthria), cognitive Contemporary: None Brain necropsy: Brain CT scan: Normal.
impairment (memory PAS+ and EM + Brain MRI: Normal.
impairment), decreased level of
consciousness, supranuclear
ophthalmoplegia, myoclonus,
hemiparesia, depression, extra-
pyramidal signs, and personality
changes
2
Patient 18 F/63 First symptoms: Cognitive None Brain autopsy: CSF: Normal. Penicillin, TMP- Death
[41] impairment (memory PAS + and EM + Brain MRI: Abnormal high signal intensity in SMX, rifampin,
impairment), somnolence and Digestive biopsy: the hypothalamus, uncus, and medial temporal chloramphenicol
ataxia PAS - lobes on T2-weighted images.
Symptoms: Cognitive
impairment (disorientation),
supranuclear ophthalmoplegia,
hypothalamic signs
(hyperphagia), and upper motor
neuron disorder
2
Patient 19 F/55 First symptoms: Somnolence, Previous: Arthralgia Brain autopsy: CSF: Normal. None Death
[42] cognitive impairment (confusion, Contemporary: PAS + and EM + EEG: Diffusely slow with frontal, intermittent,
and memory impairment) Arthralgia Duodenal biopsy: rhythmic delta waves.
Symptoms: Cognitive PAS - Brain RMI: Increased signal density around
impairment (disorientation), third ventricle.
decrease level of
conscientiousness,
oculomasticatory myorhythmia,
and supranuclear
ophthalmoplegia

7
Diagnosis based exclusively on oculomasticatory myorhythmia that is considered by some authors as pathognomonic of T. whipplei
2
Patient 20 M/54 First symptoms: None Oculomasticatory - TCN 1g/d. No benefit
[27] Cognitive impairment (dementia), myorhythmia Prior treatment
supranuclear ophthalmoplegia, Digestive biopsy: lost to follow-up.
extra pyramidal signs PAS -
Symptoms: Gait ataxia,
cognitive impairment (memory
impairment), depression, and
oculomasticatory myorhythmia

8
1
: Patients were seen and followed by one of the authors (DR) in consultation.
2
: Patients were from the literature review.

*: The diagnosis of T. whipplei infection was made after post-mortem examination.

SGPT : Serum glutamate pyruvate transaminases

SGOT : Serum glutamic oxaloacetic transaminases

PAS+: Light microscopy showing PAS-positive macrophages in infected tissues

EM+: Electron microscopy showing Whipple bacilli in infected tissues

PCR TW+: Polymerase chain reaction showing T. whipplei DNA

MRI: Magnetic resonance imaging

TMP-SMX: Trimethoprim-sulfamethoxazole

TCN: Tetracycline

FLAIR: Fluid attenuation inversion recovery

SIADH: Syndrome of inappropriate ADH secretion