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Diagnostic guidelines in central nervous system Whipple's disease.

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NEUROLOGICAL PROGRESS
Diamostic Guidelines in Central Nervous
System mpple’s Disease
U
E. D. Louis, MD, MS,*t T. Lynch, MRCPI,* P. Kaufmann, MD,* S. Fahn, MD,* and J. Odel, MD$
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Many cases of central nervous system (CNS) Whipple’s disease are not diagnosed until postmortem. Few reviews of
CNS Whipple’s disease have delineated the frequencies of abnormalities on neurological examination, cerebrospinal fluid
studies, neuroimaging, and intestinal biopsy studies. Guidelines for diagnosis and treatment have not been proposed. In
this review we present 3 new cases of CNS Whipple’s disease and summarize the literature to determine the frequencies
of neurological signs and abnormalities on diagnostic testing. We propose guidelines for diagnostic screening, selection
for biopsy, and treatment. Review of the 84 cases of CNS Whipple’s disease (81 in the literature, 3 new) revealed that
80% of the patients had systemic signs. Cognitive changes were frequent (71%), and 47% with cognitive changes also
had psychiatric signs. Oculomasticatory myorhythmia and oculo-facial-skeletal myorhythmia, pathognomic for CNS
Whipple’s disease, were present in 20% of patients, and were always accompanied by a supranuclear vertical gaze palsy.
Tissue biopsy was a sensitive technique; 89% of those who had biopsies had positive biopsy results. Diagnosis and
treatment of definite CNS Whipple’s disease should be based on the presence of pathognomic signs (oculomasticatory
myorhythmia or ocdo-facial-skeletal myorhythmia) or positive biopsy or polymerase chain reaction results. Possible
CNS Whipple’s disease should be diagnosed in the setting of unexplained systemic symptoms and neurological signs
(supranuclear vertical gaze palsy, rhythmic myoclonus, dementia with psychiatric symptoms, or hypothalamic manifestations). Those with possible CNS Whipple’s disease should undergo small-bowel biopsy.
Louis ED, Lynch T, Kaufmann P, Fahn S, Odel J. Diagnostic guidelines in central
nervous system Whipple’s disease. Ann Neurol 1996;40:561-568
Whipple’s disease (WD) is a relapsing systemic illness
characterized by migratory polyarthralgias, chronic diarrhea, and fever of unknown origin [l,21, The pathogen,
Tropheyma wbippelii, is a gram-positive bacillus [3].
Fewer than 800 cases have been reported [2].While 5%
of patients present with neurological manifestations [4],
symptomatic central nervous system (CNS) involvement
eventually occurs in 6 ro 43% [5-71.
Prompt diagnosis is imperative. If untreated, CNS
disease may have a fulminant course, progressing to
death in as little as 1 month [8-101. The literature on
CNS WD consists largely of single case reports or small
case series, totaling 81 cases [4,6-75]. With one exception [2],reviews have not delineated the frequencies
of neurological signs or the frequencies of abnormalities in cerebrospinal fluid (CSF), neuroimaging, or intestinal biopsy studies [5, 6, 14, 76-84]. Guidelines
for diagnosis and treatment have not been proposed,
and over one third of the reported cases of CNS WD
are not diagnosed until post mortem [13-15, 17, 18,
20, 25-27, 29, 36, 43, 50, 601. We present 3 new
cases of CNS WD; summarize the literature to determine the frequency of abnormalities on neurological
examination and diagnostic testing; and propose practi-
From the *Department of Neurology, the tGertrude H. Sergievsky
Center, and the $Department of Ophthalmology, Columbia University, College of Physicians and Surgeons, New York, NY.
Copyright
cal guidelines for diagnostic screening, selection for biopsy, and treatment.
Patient Histories
Patient 1
A 55-year-old man developed right facial twitching without
other neurological signs [ 8 5 ] . Hemifacial spasm was diagnosed. Carbamazepine (600 mg daily) and baclofen (60 mg
daily) had no benefit. Five months later, he complained of
somnolence, blurred vision, and poor balance. O n e month
later, the facial twitching spread to his neck and tongue,
persisting with sleep. H e developed dysarthria and complained of poor memory, change in personality, malaise, intermittent fevers, increased sweating, loss of erections, and
inability to ejaculate. Past history was relevant for 6 years of
migratory joint pains.
On our initial assessment, 1 year after the onset of facial
twitching, orientation, memory, and language were normal.
H e was intermittently inattentive and had marked dysarthria
due to rhythmic lingual retraction and masticatory myorhythmia coinciding with rhythmic contraction of the right
side of the face, neck, and chest and the right arm. The
contractions spread irregularly to the left side of the face and
chest and left arm and leg. Vertical gaze was limited, but
improved with the oculocephalic maneuver. Saccades were
slow in all directions. Pendular vergence oscillatioiis of the
Received Mar 13, 1996, and in revised form May 3. Accepted for
publication May 23, 1996.
Address correspondence to Dr Louis, Unit 198, Neurological Instirute, 710 West 168th Street, New York, NY 10032.
0 1996 by the American Neurological Association 561
right more than of left eye (frequency = 1 H7,) were synchronous with the masticatory and skeletal myorhythmia (ix.,
oculofacial-skeletal myorhythmia [OFSM]). Muscle tone,
strength, sensation, deep tendon reflexes, plantar responses,
and postural stability were normal. Gait was mildly ataxic.
Serum chemistries; complete blood count (CBC); serum
Venereal Disease Research Laboratory test (VDRL) result;
serum lyme titer; thyroid function test (TFT) results; antinuclear antibody (ANA) titer; human immunodeficiency virus
(HIV) test result; vitamin B,? (BI2);folate; CSF protein, and
glucose levels, cell count; and electroencephalogram (EEG)
were normal. Brain magnetic resonance imaging (MRI) with
gadolinium revealed a left frontal periventricular punctate
hyperintensity. Technetium 99m hexamethylpropyleneamine
oxime ( 99”’Tc= HMPAO) single-photon emission computed
tomography (SPECT) revealed decreased activity in the right
cerebellar hemisphere. Electromyographic analysis revealed
400-msec bursts of bilateral rhythmic activity. This activity
originated at the level of cranial nerve VII, and spread rostrally to involve the muscles of mastication, and caudally to
involve muscles of the neck, arms, and legs.
A duodenal biopsy specimen obtained 12 months after the
onset of facial twitching was initially normal (periodic acidSchiff [PAS] stain negative, electron microscopy [EM] not
performed). After 1 month, a repeat biopsy with Crosbie
capsule revealed foamy macrophages that stained positively
with PAS and silver stains, and negatively with acid-fast
stain. PAS and Grocott methenamine silver stains demonstrated intracytoplasmic granular rod-shaped structures consistent with Whipple’s bacillus. CNS WD was diagnosed.
Trimethoprim-sulfamethoxazole (TMP-SMX) (1 doublestrength [DS] tablet twice a day) resulted in improvement
in malaise and the ocular component of the myorhythmia.
When diarrhea developed, TMP-SMX was discontinued, and
intravenous ceftriaxone ( 2 gm daily) resulted in resolution
of the diarrhea and sweating, decrement in the myorhythmia,
and increase in alertness. After 1 month, he was switched to
receive doxycycline monohydrate (200 mg twice a day), with
worsening of hemifacial spasms, malaise, and lethargy over
the ensuing 9 months. Ceftriaxone (2 gm day) was resumed,
with improvement in hemifacial spasms, malaise, and lethargy over the ensuing 3 months, After 2 years of follow-up,
he was taking TMP-SMX (1 DS tablet twice a day). H e
still had right facial twitching, complaints of poor memory,
increased sweating, loss of erections, and inability to ejaculate. There was moderate improvement in limb myorhythmia, malaise, and vertical gaze palsy.
Patient 2
A 47-year-old woman developed severe progressive insomnia
unresponsive to medication, a 10-lb weight loss, double vision, fevers, and submandibular lymph node enlargement.
Past history was notable for arthritis. N o diarrhea, steatorrhea, abdominal distention, or other gastrointestinal symptoms were noted.
O n examination, vertical and horizontal saccades were
slow, with diminished abduction of the left eye. Downgaze
was full; upgaze was mildly limited. There were spontaneous
convergent nystagmoid movements in the right eye unaccompanied by miosis. These movements increased with
downward moving optokinetic stimuli.
Over the ensuing 8 months, a progressive ophthalmopar-
562 Annals of Neurology Vol 40 No 4 October 1996
esis resulted in complete loss of voluntary eye movements
except for adduction of the right eye. She developed shortterm memory loss, depressive symptoms, difficulty swallowing, blurred vision, intermittent hypersomnolence, and
increasing postural instability. O n reexamination, she was
intermittently unarousable, with hypomimia and severe dysarthria. Pendular vergence oscillations of both eyes that were
synchronous with the masticatory myorhythmia (oculomasticatory myorhythmia [OMM]) were present. There was mild
hypertonia, and normal strength and sensation. Deep tendon
reflexes were brisk. Gait was slow, with shuffling, difficulty
turning, and postural instability. Levodopa-carbidopa and
prednisone (20 mg daily) were without benefit.
Serum chemistries, CBC, serum lyme titers, coagulation
screen results, ANA titer, BIZ,and folate levels, T F T results,
serum protein electrophoresis, and VDRL and HIV test results were normal. EEG revealed a mildly generalized slow
background. CSF analyses revealed protein levels of 50 to
55 mg/dl with a normal glucose concentration, and 0 to 7 0
PAS-negative mononuclear cells. Brain computed tomography (CT) scans appeared normal and MRI revealed an Arnold-Chiari type I malformation with no brainstem compression. Specimens obtained at two duodenal biopsies indicated
mild chronic nonspecific duodenitis. N o PAS staining or
other changes consistent with WD were detected. EM was
not performed. Lymph node biopsy, which has a high diagnostic yield, was not performed. CNS WD was diagnosed
based on clinical findings (i.e., OMM). Intravenous ceftriaxone (2 gm daily) for 6 months resulted in complete resolution of OMM and improvement in the supranuclear gaze
palsy and malaise. After switching to TMP-SMX (1 DS tablet twice a day), the supranuclear gaze palsy, lethargy, and
malaise recurred. After 6 years of follow-up, she was restricted to a wheelchair and fed by gastrostomy.
Patient 3
A 54-year-old man presented with supranuclear gaze palsy,
parkinsonism, and progressive dementia. Three years prior,
he developed motor slowing with poor balance. Parkinson’s
disease was diagnosed. Bromocriptine (15 mg daily) was ineffective. H e stopped working at age 53 due to difficulty concentrating and poor memory. Fluoxetine (20 mg daily) was
started for depressive symptoms. Past medical history was
notable for right shoulder pain for 5 years. H e had no weight
loss, diarrhea, or other gastrointestinal symptoms.
O n examination, he recalled one of three objects at 5 minutes. There was hypomimia, marked axial and appendicular
bradykinesia, slow and incomplete saccades, markedly impaired voluntary vertical eye movements, full vertical gaze
with the oculocephalic reflex, and a broad-based ataxic gait
with a tendency to fall backward spontaneously. He was diagnosed as having progressive supranuclear palsy, although
CNS WD was suspected. Serum folate and vitamin B,,, E,
and A levels; serum VDRL test result; CBC; serum chemistries; CSF protein, glucose levels, and cell count; and a head
MRI were normal. HIV status was not determined. Duodenal biopsy revealed lymphocytes and plasma cells in the lamina propria, but no PAS staining or other changes consistent
with WD. EM was not performed.
Two years later, the patient began falling. Levodopa-carbidopa (1,125 mg daily) and tetracycline (1,000 mg daily) were
not beneficial. Reexamination revealed new loss of all volun-
ease,” “CNS,” “neurological,” “brain,” “cerebral,” “dementia,” “OMM,” “CSF,” and “psychiatric.” There were
numerous cases of CNS WD, despite the fact that the title
had not implied a neurological disorder [13, 14, 15, 25,
34, 42, 641. As our primary interest was the frequency of
neurological signs, cases with CNS pathology at postrnortcm
examination hut without accompanying neurological signs
were not included in this analysis. Additionally, those with
isolated posterior eye disease (posterior uveitis, retinitis, optic
neuritis) were excluded.
Table 1. Neurological Signs in 84 Patients with CNS
Wbipplei Disease
95%
Cognitive change
Supranuclear gaze palsy
Altered level of consciousness
Psychiatric signs
U M N signs
Hypothalamic manifestations
Cranial nerve abnormalities
Myoclonus
Seizures
Ataxia
OMM or OFSM
Sensory deficits
Frequency
(YO)
Confidence
Interval
71
51
50
44
37
31
25
25
23
20
20
12
61-81
40-62
39-61
33-55
27-47
21-41
16-34
16-34
14-32
11-29
11-29
5-19
DeJnitions
Neurological signs were defined as follows (Tables 1-3): “Altered level of consciousness” included somnolence, lethargy,
stupor, and coma. “Cognitive change” included abnormalities with orientation, memory, or reasoning. “Supranuclear
gaze palsy” was defined as a conjugate inability to move both
eyes in a vertical or horizontal direction in the absence of
peripheral causes. “Hypothalamic manifestations” included
polydipsia, hyperphagia, change in libido, amenorrhea,
changes in sleep-wake cycle, insomnia, but not isolated somnolence. “Sensory deficit” included both central and peripheral causes. Deficits within the trigeminal distribution were
categorized as cranial nerve abnormalities. “OMM” was defined as pendular vergence oscillations of the eyes that were
synchronous with masticatory myorhythmia. “OFSM,” similiar to OMM, also involved myorhythmia of nonfacial skeletal muscle. “Myoclonus,” which is nonrhythmic, was distinct
from OFSM and O M M . “Psychiatric signs” included depression, euphoria, anxiety, psychosis, or personality change.
OMM = oculomasticatory myorhythmia; OFSM = oculo-facialskeletal myorhythmia; UMN = upper motor neuron signs.
tary vertical eye movements, less than 10 degrees of horizontal eye movements bilaterally, and full range of vertical and
horizontal motion with oculocephalic maneuvers. There was
subtle rhythmic pendular horizontal convergence of the left
eye on primary gaze, which was synchronous with masticatory myorhythmia (OMM). A clinical diagnosis of WD was
made, although, on a repeat jejunal biopsy, there was no
PAS staining or other changes consistent with W D . EM was
not performed. The patient was lost to follow-up prior to
treatment.
Statistics
Ninety-five percent confidence intervals were calculated for
several proportions.
Methods
Literature Search
Results of Literature Review
A Medline search (1966- 1996) was conducted using the fol-
There were 84 patients with WD with neurological
signs, including our 3 [4, 6-75]. Eighty-two (98%) of
Patients
lowing terms alone and in combinations: “Whipple’s dis-
Table 2. Combinations of Neurological Signs in 84 Patients with CNS Whipple?Disease“
Cog
ALC
Gaze
Psych
UMN
HYPO
CN
Myocl
Seiz
Atax
OMM
Sens
Cog
ALC
Gaze
Psych
UMN
Hypo
CN
Myocl
Seiz
Atax
OMM
Sens
71
42
50
42
32
51
33
23
23
44
25
23
18
23
37
23
19
20
17
13
18
12
8
10
25
17
14
21
12
7
17
11
15
14
20
10
8
8
18
13
12
13
11
10
7
5
2
6
10
4
11
25
2
0
23
18
13
31
8
11
14
8
2
5
20
6
8
8
7
1
4
20
1
0
7
4
0
12
’The number in each cell represents the percentage of the total number of subjects (N = 84) with a specific combination of neurological
signs. For example, 42% of subjects had both cognitive changes and altered level of consciousness. A value in bold (on the diagonal axis)
represents the percentage of the total number of subjects with a particular neurological sign, and corresponds to the frequency for that
individual neurological sign as shown in Table 1. For example, 71Vo of subjects bad cognitive changes.
Cog = cognitive change; ALC = altered level of consciousness; Gaze = supranuclear gaze palsy; Psych = psychiatric signs; UMN = upper
motor neuron signs; Hypo = hypothalamic manifestations; CN = cranial nerve abnormalities; Myocl = myoclonus; Seiz = seizures; Atax
= ataxia; Sens = sensory deficit.
Neurological Progress: Louis et al: CNS Whipple’s Disease: Diagnosis
563
Table 3. Eye Findings in 40 Patients witb CNS Wbipplei
Disease
Eye Finding
Vertical supranuclear gaze
palsy
Horizontal supranuclear
gaze palsy
Both horizontal and vertical supranuclear gaze
Frequency
(YO)
95%
Confidence
Interval
37.5
22.5-52.5
0
0
50
35-65
10
1-19
2.5 (Isolated
cranial nerve
I11 palsy)
43
43
0-7.5
palsies
Supranuclear gaze palsy,
direction not specified
Cranial nerve palsy (111,
IV, or VI)
OMM or OFSM
OMM or OFSM with
vertical supranuclear
gaze palsy
Pupillary abnormality (an-
28-58
28-58
18
6-30
23
10-36
isocoria or nonreactive
pupil)
Ptosis
OMM = oculomasticatory myorhythmia; OFSM = oculo-facialskeletal myorhythmia.
84 diagnoses were based on histology (premortem or
postmortem) or polymerase chain reaction (PCR) analysis. Diagnoses were made during life in 51 (61%) of
the 84 patients (including biopsy in 47, PCR analysis
in 1 , and clinical signs in 3). Of the 3 diagnosed on
the basis of clinical signs, 2 were our patients ( 2 and 3),
and a third exhibited supranuclear vertical gaze palsy,
cognitive changes, and hypothalamic manifestations
[ S ] . The diagnosis was later confirmed at autopsy [ 8 ] .
Thirty-three (39%) of 84 patients were diagnosed postmortem. Twenty-five (76%) of 33 diagnosed postmortem had at least one systemic symptom or sign, and
27 (820/0) had neurological signs other than cognitive
changes or altered level of consciousness (including 15
with supranuclear gaze palsy).
Systemic Symptoms and Signs
Of the 84 patients, 67 (80%) had systemic symptoms
or signs: chronic migratory arthralgias or polyarthralgias, 40 (48%), unexplained weight loss, 39 (46%),
gastrointestinal complaints 38 ( [45%]; including
chronic diarrhea in 33 [39%], abdominal pain in 17
[20%],steatorrhea in 1 1 [130/0],and abdominal distention in 7 [SYo]),fever of unknown origin, 34 ( d o % ) ,
lymphadenopathy, 18 (21%), malaise, 24 (29%), night
sweats, 3 (4%), and uveitis, 2 (2%).
Neurological Signs
Frequencies of neurological signs are shown in Table
1 . Nine (1 1 %) of 84 patients had cognitive change or
564 Annals of Neurology Vol 40 No 4
October 1996
altered level of consciousness without other neurological signs. Sixty-eight (81%) of 84 had either cognitive
change or supranuclear gaze palsy; 35 (42%) of 84 had
both. Forty-seven percent of those with cognitive
change had psychiatric signs (depression, euphoria,
anxiety, psychosis, or personality change). Combinations of neurological signs are shown (in Table 2). For
40 patients, eye findings were described in detail (see
Table 3). None (0%) had isolated horizontal supranuclear gaze palsy. Twenty (50%) had both supranuclear
vertical and horizontal gaze palsy, 15 (37.5%) had supranuclear vertical gaze palsy, in 4 (10%) the direction
was not specified, and 1 (2.5%) had a cranial nerve
VI palsy (see Table 3). OMM or OFSM was always
accompanied by supranuclear vertical gaze palsy.
Neuroimaging
Forty-three patients had head CT or MRI scans: 18
(42%) had mild to moderate atrophy, 2 (5%) had obstructive hydrocephalus, and 23 (53%) had focal abnormalities. Focal abnormalities included focal lesions
without mass effect [4, 7 , 48, 54, 60, 67, 701 and large
numbers of enhancing lesions with mass effect [ 5 1 ,
691. Four had at least two normal-appearing MRI or
CT scans. Three with normal CT findings had a focal
abnormality on MRI; there were no instances of the
converse. An additional 9 had pneumoencephalography: 6 (67%) showed atrophy.
Cerebrospinal Fluid Studies
CSF protein was elevated in 27 (46%) of 59 patients
(range, 47-158; mean, 75; standard deviation [SD],
24 mg/dl.). There were 5 or more leukocytes per micro
liter in 28 (47%) of 59 (range, 5-900; mean, 91; SD,
172). CSF leukocyte differentials described in the literature divide leukocytes into two categories: polymorphonuclear leukocytes (PMLs) versus mononuclear
cells. The percentage of the total number of leukocytes
that are PMLs varied from 0 to 100% (0% [6, 32, 35,
36, 46, 54, 57, 751, 2% [62],13% [36, 661, 17% [48],
19% [36],20% [21],25% [35],39% [32],43% [32],
53% [36], 59% [ l o ] , 86% [36],90% [ 4 ] , 100% [8,
36, 37, 601). Thirty-five CSF samples in 24 patients
were analyzed with PAS staining; 10 (29%) were PAS
positive.
Biopsies
Fifty-three (63%) of 84 patients underwent tissue biopsy (of the small bowel, brain, lymph node, or vitreous fluid); 47 (89%) of the 53 had diagnostic biopsies
(either PAS positive or bacteria seen on EM).
Forty-seven had small-bowel biopsies; 33 (70%)
were diagnostic (including 4 for whom biopsy was initially nondiagnostic but diagnostic when repeated).
Twenty-nine (88%) of 33 with diagnostic small-bowel
biopsies had chronic diarrhea; 4 (12%) did not.
Twenty-nine (88%) of 33 with diagnostic small-bowel
biopsies had other gastrointestinal symptoms (steatorrhea, abdominal pain, or distention). Fourteen patients
(30%) had nondiagnostic small-bowel biopsies.
Several factors may have contributed to the 14 nondiagnostic small-bowel biopsies: Specimens were not
examined by EM in 14 (100%); there was an absence
of chronic diarrhea in 1 1 (79%); biopsy was not repeated in 10 (71%);and biopsies were not endoscopically guided in 8 (57%). Eight (57%) of the 14 with
nondiagnostic small-bowel biopsies later had diagnostic
biopsies of other tissues (6, brain; 1 , lymph node; and
1 , vitreous fluid); in I other, diagnosis was confirmed
by PCR analysis of CSF.
Of the 47 patients undergoing small-bowel biopsy,
4 had three or more nondiagnostic small-bowel biopsies. Of these 4 , 2 (50%) did not have chronic diarrhea; 1 (25%) did not have an endoscopically guided
biopsy, and none (0%) had EM. Three (75%) had
diagnostic biopsies of other tissues (1, brain; 1 , lymph
node; and 1 , vitreous fluid).
Lymph node biopsy samples were either PAS positive or displayed bacteria on EM, in 14 (93%) of 15
patients. The remaining sample was PAS negative and
not examined by EM.
Twelve patients had brain biopsies. Ten (83%) were
diagnostic; 2 were not. EM was not performed in either of the 2 who had nondiagnostic brain biopsies.
Ten (83%) of the 12 also had small-bowel biopsies (6
nondiagnostic, 4 diagnostic).
Acid-fast staining was performed for 7 of 53 patients
who underwent biopsy [4, 7 , 9, 54, 62, 691.
Polymerase Chain Reaction
PCR analysis of intestinal tissue [3, 861, peripheral
blood [87, 881, pleural fluid [88],cardiac tissue [89],
and lymph node tissue [3] was used to confirm the
diagnosis of WD in 10 patients without neurological
manifestations. PCR analysis of ocular and intestinal
tissue was used to confirm the diagnosis of WD in 1
patient with uveitis and mild neurological manifestations (difficulty concentrating and memory loss) [72],
and PCR analysis of CSF was diagnostic in another
patient with gaze palsy and cerebellar signs [75].However, results of several of these studies should be interpreted with caution due to methodological concerns,
including failure to fully characterize amplicons [75]
or provide methodology for sequence analysis [86].
Discussion
The neurological signs commonly reported in CNS
WD are dementia [2, 4, 6, 32, 48, 49, 60, 63, 7 0 , 76,
821, supranuclear gaze palsy [2, 4, 6 , 32, 48, 49, 60,
62, 63, 70, 76, 821, myoclonus [2, 4 , 6, 32, 48, 49,
63, 70, 76, 821, ataxia [32, 48, 491, hypothalamic dysfunction [4, 62, 701, and altered level of consciousness
[48, 60, 70, 821. Data on the precise frequencies of
these signs are limited. The most thorough review to
date, by Dobbins [2],analyzed 39 reports of WD with
either ophthalmological or neurological manifestations.
The most frequent signs were dementia (56%), ophthalmoplegia (33%), and myoclonus (28%).The triad
was noted in l o % , and two of three signs, in 41% [2].
Since Dobbin’s 1987 review [2],the literature on CNS
WD has more than doubled. We reviewed 81 cases of
CNS WD and add 3 more to the literature. We also
propose diagnostic guidelines for CNS WD, based on
the frequencies of neurological signs and abnormalities
on diagnostic testing.
Cognitive changes, supranuclear gaze palsy, and altered level of consciousness were the most frequent
neurological signs (see Table 1 ) . Forty-seven percent
with cognitive changes also had psychiatric signs. The
triad of dementia, supranuclear gaze palsy, and myoclonus was noted in only 13 patients (15%).The combination of cognitive changes and gaze palsy was noted
in 35 (42%) of 84 patients (see Table 2).
OMM and OFSM are conditions that have never
been documented as present in a disease other than
CNS WD. Hence, they are pathognomic for CNS WD
[6, 19, 22, 32, 41, 60-63, 65, 66, 681. Two of our
patients were clinically diagnosed as having CNS WD
on the basis of these signs. We also noted that OMM
or OFSM was always accompanied by a supranuclear
vertical gaze palsy. While very specific for CNS WD,
the sensitivity of OMM or OFSM was only 20%.
Almost all of those with eye findings had supranuclear gaze palsies; only 1 patient had a cranial nerve
VI palsy (see Table 3). Additionally, the supranuclear
gaze palsy was never an isolated horizontal supranuclear
gaze palsy; the gaze palsy had a vertical component
in all patients for whom information on direction was
available (see Table 3 ) .
While myoclonus and ataxia are reportedly common, each was present in only 20 to 25vo of patients.
Conversely, while seizures are reportedly rare [ 2 ] ,they
were present in almost one fourth of patients. Under
one half (46%) had a movement disorder (i.e., OMM,
OFSM, myoclonus, or ataxia).
Others [49, 791 suggested that constellations of signs
divide CNS WD into two distinct syndromes: ( 1 ) dementia, myoclonus, gaze palsy, and ataxia, versus (2)
hypothalamic manifestations. We found no evidence
for this (see Table 2). Of the 84 patients, none had
isolated hypothalamic manifestations.
Biopsy was a sensitive technique, and is a powerful
diagnostic tool once clinical suspicion has been established. The majority of both intestinal biopsies (70%)
and all biopsies (89%) were diagnostic. However, it is
difficult to comment precisely on the sensitivity of tissue biopsy. First, it is unlikely that putative CNS WD
would be reported in the absence of a positive biopsy
Neurological Progress: Louis et al: CNS Whipple’s Disease: Diagnosis 565
result. Hence, the sensitivity of biopsy may be lower
than 70%. Conversely, the sensitivity of intestinal biopsy could be higher than 70%, as many nondiagnostic
intestinal biopsies were (1) not endoscopically guided,
(2) performed on subjects without chronic diarrhea,
( 3 ) or not repeated. Additionally, tissue often was not
examined by EM.
PCR analysis of a variety of tissues had been used
to confirm the diagnosis of WD, including in 1 patient
with gaze palsy and cerebellar signs [ 3 , 7 5 , 86-89].
More importantly, this technique is emerging as a way
to establish a diagnosis of WD in the setting of nondiagnostic tissue biopsies [75].
Focal abnormalities on neuroimaging often result in
literature reports [48, 67, 691, and this aspect of the
diagnosis has not been emphasized [ 2 ] .Over one half
of patients had a focal abnormality on neuroimaging,
ranging from focal lesions without mass effect to large
numbers of enhancing lesions with mass effect. However, these abnormalities were not specific to WD.
Both elevated CSF protein and CSF leukocytosis
have been reported in WD [49, 761. In our series, 5
or more leukocytes per microliter was noted in nearly
one half; nearly one third of these also had PAS-positive material in the CSF.
This study had limitations. CNS WD is a rare disease that is often diagnosed postmortem, and our data
were derived from a retrospective literature review.
Hence, data were not always complete. Additionally,
there is an inherent bias. Patients who exhibit “traditional” clinical features are preferentially investigated
and reported, and nontraditional or variant presentations are often not investigated. Despite these limitations, we present the largest compilation of data describing the neurological manifestations of CNS WD.
Guidelines for diagnosis and treatment of CNS WD
have not been proposed. We propose guidelines for the
purposes of diagnostic screening, selection for biopsy,
and treatment (Appendix). Those with definite CNS
WD should undergo appropriate treatment with antibiotics. A large number of antibiotics have been used
with variable efficacy, most commonly, tetracycline [9,
28, 32, 36, 42-46, 48, 49, 51, 54, 60, 68, 691, penicillin [8, 10, 20, 28, 32, 34, 35, 44, 46, 49, 60, 62, 65,
66, 69, 721, TMP-SMX [6-8, 57, 60, 62, 65-70, 72,
741, and chloramphenicol [7, 8, 32, 44, 48, 49, 54,
64, 65, 68, 741. Others are demeclocycline [ 8 ] ,doxycycline [44, 661, oxytetracycline [32, 371, minocycline
[ 5 1 ] ,gentamicin [36],streptomycin [6, 20, 33, 35, 44,
46, 69, 721, amoxicillin [ l o , 491, ampicillin [36, 44,
641, pefloxacine [68],erythromycin [32, 66, 681, ciprofloxacin [ 6 ] , vancomycin [54], ceftriaxone [6, 7 ,
661, and cephalexin [36]. Antibiotic treatment in 88
patients with WD was reviewed by Keinath and colleagues [90].
Those with possible CNS WD should undergo
566 Annals of Neurology Vol 40
No 4
October 1996
small-bowel biopsy. In order to minimize false-negative
biopsy results, the biopsy should be an endoscopically
guided biopsy of multiple jejunal sites. As demonstration of PAS staining alone may be seen in other infectious processes (i.e., mycobacteria infection), EM
should be performed to identify the Whipple’s bacillus
and confirm the diagnosis. If two small-bowel biopsies
are not diagnostic, another tissue should be biopsied
(lymph node, brain lesion, or vitreous fluid, where appropriate).
Twenty percent of those with CNS WD had no
systemic symptoms or signs, and 11% had no neurological features other than cognitive changes or altered
level of consciousness; thus, even following our guidelines, some cases of CNS WD may not be diagnosed
premortem. Despite this, these guidelines provide a
reasonable template on which to base diagnostic
screening, selection for biopsy, and treatment of CNS
WD.
Appendix: Guidelines for Diagnostic Screening,
Biopsy, and Treatment of CNS Whipple’s
D’isease
Definite CNS WD
Must have any 1 of the following 3 criteria:
1 . OMM or OFSM
2. Positive tissue biopsy
3. Positive PCR analysis
If histological or PCR analysis was not performed on
CNS tissue, then the patient must also demonstrate
neurological signs. If histological or PCR analysis was
performed on CNS tissue, then the patient need not
demonstrate neurological signs (i.e., asymptomatic
CNS infection).
Possible CNS WD
Must have any 1 of 4 systemic symptoms, not due to
another known etiology:
1. Fever of unknown origin
2. Gastrointestinal symptoms (steatorrhea, chronic diarrhea, abdominal distention, or pain)
3. Chronic migratory arthralgias or polyarthralgias
4. Unexplained lymphadenopathy, night sweats, or
malaise
Also must have any 1 of 4 neurological signs, not due
to another known etiology:
1. Supranuclear vertical gaze palsy
2. Rhythmic myoclonus
3. Dementia with psychiatric symptoms
4. Hypothalamic manifestations
The work was supported by National Institutes of Health grant
NS010863, the Lowenstein Foundation, and the Parkinson’s Disease Foundation.
We would like to thank Dr Paul Greene and Dr Richelle Kirrane
for their thoughtful review of this paper.
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