Progressive Cerebral Disease in
Lymphomatoid Granulomatosis
Causes Anterograde Amnesia
and Neuropsychiatric Disorder

Dominic A. Carone, PhD
Ralph H. B. Benedict, PhD
Robert Zivadinov, MD
Baljinder Singh, MD
Julian L. Ambrus, MD

ABSTRACT
The authors report neuropsychological (NP) and serial quantitative
magnetic resonance imaging (MRI) findings of a 29-year-old woman
with lymphomatoid granulomatosis (LG). Disease course was characterized by acute psychosis, tremor, fever, seizures, and progressive
cognitive impairment. At the time of symptom onset, brain MRI revealed
mild lesion volume and normal parenchymal volume. This was followed
by dramatic progression of brain lesions and atrophy over 2 years, at
which point the patient expired. Atrophy was most prominent in the
mesial temporal lobes. NP testing revealed marked amnesia and mild
impairments in other cognitive domains. To our knowledge, this is the
first recorded case of LG in which bilateral temporal lobe atrophy is evident and accompanied by anterograde amnesia. We speculate that
temporal lobe atrophy was influenced by the established susceptibility
of this region in various neurological diseases.
Key words: Lymphomatoid granulomatosis, quantitative magnetic resonance imaging (MRI), temporal lobe atrophy, neuropsychological testing, anterograde amnesia.

Carone DA, Benedict RHB, Zivadinov R, Singh B, Ambrus JL.
Progressive cerebral disease in lymphomatoid granulomatosis
causes anterograde amnesia and neuropsychiatric disorder.
J Neuroimaging 2006;16:163-166.
DOI: 10.1111/j.1552-6569.2006.00019.x

Lymphomatoid granulomatosis (LG) is an uncommon disease
characterized by lymphoid infiltrates, angiitis, necrosis, and
pulmonary symptoms. Malignant proliferation of lymphocytes

Received July 5, 2005, and in revised form August 19, 2005.
Accepted for publication August 9, 2005.
From the Department of Neurology, State University of New
York (SUNY) at Buffalo School of Medicine, and the Jacobs
Neurological Institute (DAC, RHBB, RZ, BS, JLA); Buffalo
General Hospital (DAC, RHBB, RZ, BS, JLA); and Buffalo
Neuroimaging Analysis Center, Buffalo, New York (DAC,
RHBB, RZ, BS).
Address correspondence to Ralph Benedict, PhD, Buffalo General Hospital, Suite D-6, 100 High Street, Buffalo, NY 14203.
E-mail: benedict@buffalo.edu.

within blood vessels can cause blood vessel occlusions and angiocentric immunoproliferative brain lesions in the cerebral cortex and white matter.1,2 Neurological symptoms occur in 30%
of the cases3 and sometimes represent the only manifestation of
the disease.4 Several studies5-8 reported progressive lesion volume on MRI in LG but only a few reports9,10 described brain
atrophy. There are no reported cases of NP test performance in
patients with LG, save one report of borderline IQ.11 We report
the first case of detailed NP testing in LG and believe this to be
the only recorded case of progressive bilateral temporal lobe
atrophy associated with anterograde amnesia in this disease.

Case Presentation
In February 2002, our 29-year-old patient developed severe
headaches, left arm numbness, labile affect, and bizarre behaviors. Brain MRI showed three T2 lesions in the right
frontal periventricular white matter (PVWM). She was treated
with prochlorperazine but hospitalized 2 months later with
another psychiatric exacerbation. She had lower extremity hyperreflexia and elevated antinuclear antibody titer (1:160), suggesting upper motor neuron disease and autoimmune reaction, respectively. In May 2002, she was admitted with acute
psychosis, upper extremity tremor, and medication noncompliance. Haloperidol and lorazepam were administered, but
delusions, profuse crying, mutism, and catatonia followed. Temperature increased to 40.2◦ C. MRI showed T2 hyperintensities
in the cerebral white matter.
Although viral meningoencephalitis was suspected, serologic and cerebrospinal fluid (CSF) studies were negative and
a plethora of viral etiologies were ruled out. The workup
at the time included human immunodeficiency virus testing,
acid-fast bacillus smear testing, fungal cultures, polymerase
chain reaction testing for herpes simplex, herpes zoster, cytomegalovirus, rabies, Epstein–Barr virus, California serogroup
viruses, LaCrosse, and other arbovirus-induced diseases including St. Louis encephalitis, West Nile virus, and Eastern equine
encephalitis. All of these tests were negative, as was testing
for anticardiolipid antibodies. She was discharged in afebrile
condition.
In August 2002, she was admitted with disorientation, ataxia,
upper/lower extremity tremors, and motor paroxysms. Neurological exam was nonfocal. Brain MRI showed large confluent T2 lesions in bilateral frontal and left posterior parietooccipital PVWM. Cerebral angiogram and routine blood work

C 2006 by the American Society of Neuroimaging
Copyright ◦

163

was negative. CSF studies revealed lymphocytic pleocytosis and
increased protein (400 mg/dL).
Without a definitive diagnosis, she underwent right dura
mater and frontal cortex biopsy. The former was normal but the
latter showed vasocentric lymphoproliferation that infiltrated
and occluded the blood vessel walls. Rare B cells and histiocytes with granuloma formation were present. There were no
viral cytopathic inclusions. She was diagnosed with LG and
treated with dexamethasone. Mental status gradually improved
and she was discharged with prednisone and methotrexate.
In February 2003, she was admitted with complex partial seizures, fever of 39.2◦ C, and paranoid delusions. MRI
showed extensive confluent PVWM lesions on fluid attenuated
inversion recovery (FLAIR) and T2 sequences. Old petechial
hemorrhage was noted in the left PVWM. Brain biopsy was
reviewed again by a multidisciplinary team confirming diagnosis of LG. She was treated with dexamethasone, cyclophosphamide, phenytoin, oxcarbazepine, and antibiotics. In June
2003 she was admitted with psychotic symptoms and spastic
paraparesis. Cervical and thoracic MRI showed cord swelling.
CSF again showed elevated proteins and lymphocytes. Meningitis was considered but no viral or infectious etiology was discovered. She was treated with methylprednisone. Brain MRI
in February and August 2004 revealed extensive confluent
periventricular lesions and demyelination, prominent widening
of cerebral sulci, and enlarged lateral ventricles, consistent with
advanced cortical and central atrophy. She expired in September 2004 from pulmonary edema and acute respiratory distress.
From FLAIR images we obtained the following quantitative
measures from the five scan dates: FLAIR lesion volume (FLV),
third ventricular width (3VW), bicaudate ratio (BCR), lateral
ventricular volume (LVV), and lobar brain atrophy. FLV was
calculated using a highly reproducible semiautomatic thresholding technique for lesion segmentation.11 3VW and BCR
were measured using previously detailed methods.12 BCR (a
measure of subcortical atrophy) is the ratio of the intercaudate distance to the brain width along the same line. Lateral ventricles were outlined using a semiautomated contouring method. Ventricular volumes were automatically calculated
from outlined regions by multiplying total area outlined by
slice thickness. We calculated a measure of whole brain atrophy
(brain parenchymal fraction; BPF) for the final two scans using commercially available software and previously described
methods.16 The BPF is the total parenchymal volume by total intracranial volume. BPF calculations were precluded on
2002/2003 images due to motion artifact. In our normal sample
of 17 controls,13 we obtained the following mean values for the
quantified MRI measures: 3VW = 1.65 millimeters (SD = .33),
BCR = 0.08 (SD = .01), BPF = 0.90 (SD = .05). Lobar atrophy
(ie, frontal, temporal, and parietal-occipital) was measured with
a previously described qualitative method14,15 (ie, 0 = absent,
1 = mild, 2 = moderate, and 3 = severe).
Table 1 and Figure 1 show progressive FLV and brain atrophy over 2 years, particularly in the temporal lobes on the last
two scans. Severe progression of FLV occurred prior to severe
atrophy progression. For example, FLV increased 1453% from

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Journal of Neuroimaging Vol 16 No 2 April 2006

Table 1.

Quantified and Qualitative Neuroimaging Data from
April 2002 to August 2004

Date

April 2002
May 2002
August 2002
February 2003
February 2004
August 2004

FLV

1.58∗
3.11
48.17
54.28
69.88
107.57

3VW

BCR

LVV

1.80 .078
2.25
2.76∗ .098
2.49
3.37 .134∗
4.96
3.81 .134
8.62
7.54
.175 39.29
8.03 .248 48.82

FA TA POA

0
0
1
1
2
2

0
1
3
3
3
3

0
0
1
1
1
1

3VW = Third ventricular width, BCR = bicaudate ratio, FA = Frontal
atrophy rating, FLV= FLAIR Lesion volume, LVV = lateral ventricle
volume, POA = parieto-occipital atrophy rating, TA = temporal
atrophy rating. 3VW is expressed in millimeters. FLV and LVV results
are expressed in milliliters.
∗ Exceeds threshold of below the 1st percentile.

May to August 2002 whereas the greatest atrophy change in
that time period was for LVV (120%). From this point on, however, atrophy progression was quite dramatic, with an 884%
increase in LVV 1 month prior to death. For the last two scan
dates, BPF declined from 0.81 to 0.66, consistent with severe
and dramatically progressive whole brain atrophy (ie, 18% loss
in 6 months).
Outpatient NP evaluation (February 2004) was in a quiescent
phase of illness. She was alert, moved in a wheel chair, and had
quadriparesis. Speech was fluent, but circumstantial and tangential. Pseudobulbar affect was noted. Mood varied from depressed to euphoric. There were no delusions or hallucinations
but thought process was disorganized. Insight was poor. Estimated premorbid IQ was average based on word reading performance. Language (ie, generative verbal fluency) and visualspatial abilities (ie, judgment of line orientation and complex
figure drawing) were preserved. Verbal memory was severely
impaired with a flat learning curve. She recalled 0 of 12 words after a 20-minute delay. Delayed verbal recognition memory was
impaired. Severe visual learning (eg, negative learning curve)
and memory defects were also noted. Overall, both encoding
and retrieval of verbal and visual information were deficient.
Information processing speed and verbal abstraction were impaired. She performed in the normal range on a card sorting
test (ie, visual abstraction). On a depression inventory, she
reported irritability, reduced appetite, poor motivation, and
hypersomnia. On a neuropsychiatric inventory, her mother
reported severe caregiver distress and severe neuropsychiatric symptoms such as delusions, hallucinations, agitation/
aggression, depression, anxiety, apathy/indifference, disinhibition, and irritability.

Discussion
This case of LG was characterized by dementia, neuropsychiatric deterioration, rapidly progressing lesion volume, and
development of severe brain atrophy on serial brain MRI, particularly in the bilateral temporal lobes. Although typically associated with pulmonary involvement, this study emphasizes that

Fig 1.

Axial FLAIR images taken at the same slice level on several serial MRI scans obtained throughout the course of illness, from
symptomatic onset to 1 month prior to death. The images clearly document the progression of widespread lesion formation and bilateral
temporal lobe atrophy that is most prominent in the mesial region.

LG can present with dramatic central nervous system disease.
Although temporal lobe atrophy has been documented in some
cases of LG,16,17 severe and rapidly progressive atrophy of both
mesial temporal lobes has not. In a study where atrophy was
confined to the right temporal lobe,18 biopsy revealed hemorrhagic congestion due to venous infarction, the cause of which
was thought to be acute vasculitis, primarily in large cortical
veins. We do not know that the same neuropathological process
was present in our patient, since temporal lobe biopsy was not
obtained. We do know that a lymphoproliferative process infiltrated and occluded the vessel walls in the frontal lobe, and that
serial quantitative MRI documented markedly abnormal FLV
prior to severe brain atrophy (Table 1). The most significant
temporal lobe atrophy appears to have occurred at least a year
after the acute phase, following the dramatic increase in lesion
volume. We speculate that severe bilateral temporal lobe atrophy in this patient was caused by the documented progressive
infiltration of rare lymphocytes in blood vessels. Such infiltration can cause microvascular occlusions, multi-focal ischemic
events, followed by atrophy. The temporal lobes may be most
affected because of the known susceptibility of this area of the
brain to numerous neuropathological process.19,20-22
Mesial temporal lobe and limbic structures, such as the hippocampus, subiculum, entorhinal cortex, and parahippocampal
gyrus are crucial for memory formation and affective regulation,
which were the primary deficiencies on NP testing. This finding
corresponds to the patient’s severe bilateral temporal lobe atrophy. Another striking NP feature is the relative preservation of
higher executive functioning (eg, card sorting), an ability mediated by dorsolateral prefrontal cortex, which was relatively

spared in this case prior to NP testing. Moderate deficiencies in
attention and processing speed were most likely due to diffuse
cerebral pathology. This case adds yet another rare disease to
the differential diagnosis of dementia in young adults.
The authors acknowledge Ram Prakash and Jordan Lema for technical
assistance.

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