Review
Cerebrovasc Dis 2012;33:104–115
DOI: 10.1159/000332036

Received: August 16, 2011
Accepted: August 17, 2011
Published online: December 14, 2011

Diffusion-Weighted Imaging for the
Differential Diagnosis of Disorders
Affecting the Hippocampus
A. Förster M. Griebe A. Gass R. Kern M.G. Hennerici K. Szabo

Key Words
Hippocampus ⴢ Diffusion-weighted imaging ⴢ Stroke ⴢ
Transient global amnesia ⴢ Seizure ⴢ Encephalitis

Abstract
Background: The human hippocampus can be affected in a
large variety of very different neurological diseases, of which
acute ischemic stroke, transient global amnesia, epilepsy,
and limbic encephalitis are the most common. Less frequent
etiologies include various infections and encephalopathy of
different origins. Clinical presentation notably comprises
confusional state, altered vigilance, memory deficits of various extent and seizures. While in hypoxic or hypoglycemic
encephalopathy, clinical presentation and surrounding circumstances provide some clues to reach the correct diagnosis, in the above-listed more common disorders, signs and
symptoms might overlap, making the differential diagnosis
difficult. This review presents recent studies using the diffusion-weighted imaging (DWI) technique in diseases involving the hippocampus. Methods: References for the review
were identified through searches of PubMed from 1965 to
January 2011. Only papers published in English were reviewed. Full articles were obtained and references were
checked for additional material where appropriate. Results:
All pathologies affecting the hippocampus are associated

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with distinct lesion patterns on magnetic resonance imaging, and especially DWI has the ability to demonstrate even
minute and transient hippocampal lesions. In acute ischemic
stroke in the posterior cerebral artery territory, involvement
of the hippocampal formation occurs in four distinct patterns on DWI that can be easily differentiated and correspond to the known vascular anatomy of the hippocampus.
In the subacute phase after transient global amnesia (TGA),
dot-like hyperintense lesions are regularly found in the lateral aspect of the hippocampus on DWI. The DWI lesions described after prolonged seizures or status epilepticus include unilateral or bilateral hippocampal, thalamic, and cortical lesions of various extent, not restricted to vascular
territories. In limbic encephalitis, DWI lesions are only infrequently found and usually affect the hippocampus, uncus
and amygdala. Furthermore, in some rare cases DWI lesions
of different etiology may coexist. Conclusion: In patients
with diseases affecting the hippocampus, DWI appears to be
useful in differentiating between underlying pathologies
and may facilitate a definite diagnosis conducive to an optimal treatment. With a careful clinical examination, experience with the interpretation of DWI findings and knowledge
of associated phenomena, it is indeed possible to differentiate between ischemic, ictal, metabolic, and TGA-associated
findings.
Copyright © 2011 S. Karger AG, Basel

Alex Förster, MD
Department of Neurology, UniversitätsMedizin Mannheim, University of Heidelberg
Theodor-Kutzer-Ufer 1–3
DE–68167 Mannheim (Germany)
Tel. +49 621 383 2885, E-Mail a.foerster @ neuro.ma.uni-heidelberg.de

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Department of Neurology, UniversitätsMedizin Mannheim, University of Heidelberg, Mannheim, Germany

Fig. 1. Anatomy and arterial vasculariza-

tion of the human hippocampus. Drawing
of axial section of the left hippocampus (a,
b) and coronal section at mid body of the
left hippocampus (c, d). The arterial blood
vessels shown (b, d) are the PCA (1), the
middle hippocampal artery (2), and the
posterior hippocampal artery (3) as well as
their smaller branches (4). Normal axial
T2-weighted (e) and DWI (f) of the hippocampus in a 32-year-old man.

a

b

c

d

The hippocampus, as part of the limbic system, is a
unique and particularly interesting anatomical structure
not only because of its critical role in learning [1], memory and emotional behavior [2] but also because of its involvement in endocrinologic stress regulation [3] and its
ability for neurogenesis in human adults [4]. Furthermore, the hippocampus can be affected by acute and
chronic neurological disorders presenting with more or
less characteristic clinical syndromes. These characteristics make the hippocampus one of the most fascinating
regions of the human brain for neuroimaging studies.
The hippocampus is part of the limbic lobe, more precisely of the inner limbic gyrus on the medial surface of
the cerebral hemispheres, and can be subdivided into
three segments: the anterior head, the body and the posterior tail (fig. 1a). On anatomical coronal sections, the
hippocampus is usually shown at the mid body, where it
comprises two intertwining layers of gray matter: the cornu ammonis (Ammon’s horn) and the dentate gyrus. The
former consists of four zones of granular cells on microscopic slice preparations: CA1, CA2, CA3, and CA4
(fig. 1c). The hippocampus receives arterial blood mainly
from the posterior cerebral artery (PCA) that gives rise to
three major arteries or group of arteries: the anterior,
middle and posterior hippocampal arteries (fig. 1b, d).
The anterior hippocampal artery arises from the spinal
artery, a branch of the PCA, the middle and posterior
hippocampal arteries either directly from the PCA or
from its inferior temporal branches. The contribution of
branches of the anterior choroidal artery to the vascular
supply of the hippocampal head is highly variable and
may be prominent [5].
DWI for the Diagnosis of Disorders
Affecting the Hippocampus

f

Diffusion-weighted imaging (DWI) has been introduced and established as a routine imaging procedure in
acute ischemic stroke in the late 90s and since then a large
number of studies covering numerous different aspects
of ischemic stroke have been published. DWI is exquisitely sensitive to demonstrate even minute acute ischemic lesions [6]. Due to their lack of mobility, as a consequence of cytotoxic edema in ischemic tissue water proton light up strongly against the dark background of
healthy tissue on DWI, which provides a very high lesionto-background contrast, and is seen as hypointensity on
quantitative maps of the apparent diffusion coefficient
(ADC). However, this finding is not specific to brain tissue damage after acute ischemic stroke and, as a consequence, DWI studies have identified acute signal changes
in brain tissue in several other, quite different neurological disorders [7]. Interestingly, DWI abnormalities located in the hippocampus have recently been described in
several acute neurological disorders.
Knowledge of the characteristic features of these – in
many cases specific – hippocampal changes may give diagnostic clues and thus aid the clinician in differentiating
the underlying pathology. In this article, we aimed to review the medical literature concerning the use of DWI in
various neurological disorders affecting the hippocampus.

Search Strategy
References for the review were indentified through searches of
PubMed with the search terms ‘hippocamp*’ [title] AND (‘DWI*’
[title] OR ‘diffusion weighted’ [title]) from 1965 to January 2011.
Only papers published in English were reviewed. The abstracts of
retrieved citations were reviewed and prioritized by relevant con-

Cerebrovasc Dis 2012;33:104–115

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Introduction

e

tent. Only case reports with well-documented clinical summaries
and relevant information were included in the review. Studies and
review articles concerning MRI modalities other than DWI were
not included. Full articles were obtained and references were
checked for additional material where appropriate.

Acute Ischemic Stroke

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Cerebrovasc Dis 2012;33:104–115

Transient Global Amnesia

Transient global amnesia (TGA) is a neurological disorder characterized by a sudden onset of antero- and retrograde amnesia, and complete recovery from this cognitive disturbance within 24 h. Since the first description
in the 1950s [18, 19] neurologists were fascinated by the
unique clinical presentation of this relatively rare neurological disease (the incidence has been estimated at
5–10/100,000/year). The underlying etiology is unknown,
but cortical spreading depression, ischemic stroke and
venous congestion have been proposed as possible
pathomechanisms.
In the late 1990s, the first case reports on TGA patients with circumscribed regions of altered diffusion on
DWI appeared in the medical literature. Strupp et al.
[20] reported a case series of TGA patients with widespread unilateral or bilateral signal abnormalities in the
hippocampus on DWI. This finding was interpreted as
evidence for spreading depression. Other authors reported on TGA patients with multiple DWI lesions in
the PCA territory (hippocampus, thalamus, splenium,
occipital lobe) [21, 22] or only small hippocampal DWI
lesions [23], but the question whether these DWI lesions
were a typical finding in TGA was not satisfactorily answered, especially so as other authors failed to find similar results [24–26]. A large series of TGA patients systematically studied with serial MRI examinations was
not published until 2004 [27]. While no DWI or T2
changes were detected in the acute phase of the disease,
serial DWI showed very small, dot-like DWI lesions with
a diameter of approximately 1–2 mm in the lateral aspect
of the hippocampus that became visible after 48 h (see
Förster/Griebe/Gass/Kern/Hennerici/
Szabo

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Acute ischemic stroke causes disruption of the cerebral energy metabolism, leading to failure of the Na+/K+
adenosine triphosphatase pump, a loss of ionic gradients
and a net translocation of water from the extracellular to
the intracellular compartments. This is now the commonly accepted theory of reduced diffusion in acute
stroke that leads to a high signal on DWI and a reduction
of ADC. Although acute ischemic stroke is a very common disease, there are only a few case reports on PCA
territory infarction involving the hippocampus [8–10],
and the medical literature is even more scarce when it
comes to MRI investigation of hippocampal infarction
[11, 12] and its clinical presentation. This may at least
partly be explained by the lower rate of posterior circulation strokes, which is about 15% of all ischemic strokes
[13, 14]. In 2009, the first comprehensive study was published that focused solely on hippocampal infarction as
a subtype of PCA territory infarction and its clinical,
neuropsychological and MRI characteristics [15]. On
DWI, four typical patterns of hippocampal infarction
were recognized and distinguished: involvement of (1)
the complete, (2) the lateral, or (3) the dorsal hippocampus (fig. 2), and (4) circumscribed small lesions in the
lateral hippocampus. These infarction patterns correspond well with the vascular anatomy of the hippocampus. Most important, additional ischemic lesions in the
posterior circulation were found in all patients, suggesting that isolated hippocampal stroke is a rare finding.
Clinical signs caused by the lesions outside the hippocampus were the common leading clinical symptoms,
whereas evident memory deficits were observed in only
one sixth of the patients. However, thorough neuropsychological examination with a comprehensive neuropsychological assessment battery revealed deficits of verbal
episodic long-term memory in left and of nonverbal episodic long-term memory in right hippocampal infarction. Bilateral hippocampal infarction, which has been
shown to be associated with a pronounced amnesic syndrome [8], is far less frequent and may be considered as
an exception to these findings (fig. 3). In the presented
case series, only 3 (5%) patients had bilateral hippocam-

pal infarction; 2 of these had an obvious amnesic syndrome, while the 3rd was too severely affected to be examined.
A more recent article focused on patients with PCA
territory stroke treated with thrombolysis in an extended
time window guided by the DWI/perfusion weighted imaging (PWI) mismatch concept [16]. Interestingly, 3 of
these patients had initial ischemic involvement only in
the hippocampus – while on follow-up MRI, extrahippocampal structures were affected in all the cases. As these
patients were examined earlier than those in the first
study (maximum 6 h vs. maximum 72 h), this phenomenon might be explained by the vulnerability of the hippocampus to hypoxia known from experimental studies
[17].

Etiology

DWI high

ADC low

T2-weighted FLAIR high

Stroke

TGA

DWI high

ADC normal/increased

T2-weighted FLAIR high

LE

Fig. 2. Differential diagnosis for hippo-

campal lesions with a high diffusion signal. LE = Limbic encephalitis; TGA = transient global amnesia.

fig. 2 for an example). In most cases, the observed lesions
appeared as a small area with reduced signal on ADC
maps and a high signal on T2-weighted images. Time
between onset and MRI seems to be crucial for detecting
DWI lesions in TGA as about 70–80% of the patients

displayed punctate hippocampal DWI changes after 24–
48 h, but only about 6% of patients did so in the acute
phase. After reevaluation, the lesions were also visible on
the initial DW MRI in about one third of TGA patients.
This important finding may also explain the lack of

DWI for the Diagnosis of Disorders
Affecting the Hippocampus

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Seizure

b

a

b

c

d

c

d

Fig. 3. Case report 1: bilateral hippocampal stroke. Example of an

81-year-old man with acute gait disorder and sensorimotor hemiparesis as well as a prominent anterograde amnestic syndrome:
DWI (a, b) shows bilaterally located acute ischemic lesions in the
hippocampus. Delay of contrast agent arrival on the time-to-peak
map (white arrows) of the perfusion image (c) is explained by occlusion of both PCAs (black arrows) on MRA (d).

DWI lesions in previous studies that only focused upon
MRI in the acute phase. Other groups have confirmed
these findings since then [28]. Subsequent studies have
refined and endorsed our knowledge about the typical
DWI abnormalities in TGA, describing the selective affection of the CA1 sector of the hippocampus [29, 30],
association of lesion location and neuropsychological
deficits in the subacute phase [29], evolution of the hippocampal lesion over time [31], or the optimal diffusionweighted imaging protocol [32]. In light of this knowledge, the first case reports mentioned above [21, 22] may
be regarded as rather unusual examples. Although the
described typical clinical presentation leaves no doubt
about the clinical diagnosis, both cases might represent
the infrequent coincidence of acute ischemic stroke in
the PCA territory and TGA. For a similar example see
figure 4. Although the lesion pattern in TGA is arguably
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Cerebrovasc Dis 2012;33:104–115

Fig. 4. Case report 2: PCA stroke and TGA. Example of a 59-yearold teacher with an acute gait disorder, right homonymous hemianopia, and word-finding difficulties occurring at work: initial
DWI (a) and ADC (b) show an acute ischemic lesion in the right
PCA territory (arrowhead). MRA is unremarkable (c). In the clinical course, the patient – who was extremely embarrassed by
stroke onset – developed a typical TGA episode with antero- and
retrograde amnesia from which she recovered within 15 h. DWI
(d) showed a new small lesion in the lateral aspect of the right hippocampus (arrow) on follow-up.

comparable to hippocampal stroke pattern 4 as described above, it is still difficult to consider these lesions
as typical ischemic lesions, mostly as these stroke patients do not exhibit TGA-like features.
The underlying pathology of the DWI changes associated with TGA is still unclear. While delayed ischemic
or hypoxic mechanisms have been proposed, it remains
difficult to perceive these lesions as typical vascular
ischemic changes. In agreement with this position, Toledo et al. [33] did not find any perfusion abnormalities
on PWI in TGA patients during the acute or subacute
phase nor did they detect vascular pathologies on MR
angiography. Comparison of TGA patients and healthy
controls did not reveal any significant differences with
regard to vascular risk factors, concomitant chronic
white matter lesions, degree of atherosclerosis, or cardiac abnormalities, and the same held true for TGA paFörster/Griebe/Gass/Kern/Hennerici/
Szabo

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a

tients with and without typical hippocampal DWI lesions [34]. However, as these DWI abnormalities may be
regarded as pathognomonic of TGA, it may be reasonable to include them as an alternative criterion in addition to Hodges and Warlow’s [35] criteria for definite
TGA. Especially in cases with uncertain onset or less
characteristic presentation, this might be useful to support the diagnosis.

Seizures and Status Epilepticus

DWI for the Diagnosis of Disorders
Affecting the Hippocampus

Fig. 5. Pathophysiological consequences in local (ischemic stroke,

seizures) and global (hypoxia, hypoglycemia, methanol and carbon monoxide poisoning) conditions impairing neuronal energy
metabolism affecting diffusion. CBF = Cerebral blood flow; O2 =
oxygen; CMR = cerebral metabolic rate; HbCO = carbon monoxide hemoglobin; ATP = adenosine triphosphate; NAA = N-acetylaspartate.

normalized on follow-up MRI performed after 2 weeks
or later [40]. In contrast to these findings, Bonaventura
et al. [41] detected hippocampal diffusion changes in
only 2 out of 10 patients with complex partial status epilepticus, although DWI revealed signal alterations in all
patients. Similarly, these signal changes had resolved
completely on follow-up MRI. Another case series of patients with symptomatic seizures or status epilepticus
showed hippocampal diffusion abnormalities in all 12
patients and bilateral lesions in 5 of these. In most patients, the whole hippocampus was affected; only in a
subset of patients was altered diffusion limited to the
head and body or body and tail. Cortical involvement
was found in about half of the patients, all of whom suffered from encephalitis or systemic lupus erythematosus
[42]. Not surprisingly, the hippocampal diffusion signal
changes after seizures or status epilepticus have been
demonstrated to be closely related to ipsilateral EEG abnormalities [40–44] or to the side of clinical seizure onset [44].
The pathogenesis of these DWI abnormalities in seizures and status epilepticus is believed to be due to compromised energy metabolism as prolonged ictal activity
is known to increase glucose utilization, the increase of
which is not adequately matched by the enhanced blood
flow. Consequently, this imbalance of supply and deCerebrovasc Dis 2012;33:104–115

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The first reports on hippocampal DWI changes in patients with seizures were published at the beginning of
this century. Kim et al. [36] presented a case series of patients with generalized tonic-clonic seizures or status epilepticus and demonstrated increased signal intensity on
DWI in the hippocampus in 3 patients and in the parahippocampal gyrus in 1 patient [36]. Similarly, increased
signal intensity in the parahippocampal gyrus was found
on DWI in 2 patients with intractable temporal lobe epilepsy and single short seizures or status epilepticus [37].
Another case report described an increased DWI signal
in the hippocampus, temporoparietal cortex and cerebellum, and hyperperfusion in the ipsilateral hemisphere in
a patient with focal convulsive status epilepticus [38]. In
children with new-onset psychomotor seizures, diffusion
abnormalities were found in the whole hippocampus. Interestingly, all patients developed hippocampal atrophy
as detected on follow-up MRI and continued to have occasional seizures or even developed intractable complex
partial epilepsy [39].
In 2005, a case series of patients with symptomatic
complex partial status epilepticus and diffusion abnormalities was published that showed hippocampal hyperintensity in 8 out of 10 patients. Interestingly, the most
frequent location of these findings was the hippocampal
formation together with the pulvinar region of the thalamus, whereas isolated involvement of the hippocampal
formation or of cortical regions occurred less often.
Matching areas of decreased ADC signal were found in
all cases as well as slight focal swelling accompanied by
hyperintensity on T2-weighted images. For examples of
postictal DWI changes in the hippocampus, see figure
2. Furthermore, a closely matching area of hyperperfusion was found in all patients most likely representing a
compensatory mechanism in response to ictal overactivation. On follow-up MRI, slight DWI hyperintensity
was still noted in 4 patients, whereas in the remaining
patients, DWI abnormalities resolved gradually and had

of DWI lesions caused by ischemic stroke and seizures is
a challenging constellation of findings, but with a careful
clinical examination and experience with ictal phenomena on MRI, it is indeed possible to differentiate between
ischemic and ictal or metabolic lesions.

Infections and Inflammatory Diseases

b

c

d

Fig. 6. Case report 3: postictal DWI findings. Example of a
76-year-old woman who was admitted to the Stroke Unit due to
acute onset of sensory aphasia from which she recovered within 1
day. On day 3, she developed sudden confusion with disorientation, stereotypical repetitive actions and amnesia. On DWI, an
acute ischemic lesion in the left middle cerebral artery (MCA) territory (a) and a vascular pathology in the left MCA on MRA (c)
were seen (black arrows). Additionally, a hyperintense signal
change on DWI (b) was noted in the left hippocampus associated
with signs of hyperperfusion in the PCA territory on MRA (c) and
on time-to-peak maps on PWI (d, white arrows). The left PCA
territory showed focal hyperperfusion, indicating that not ischemia but ictal activity, that was confirmed subsequently by a pathological EEG, was responsible for the morphological changes in
the hippocampus.

mand may lead to cytotoxic cell swelling and vasogenic
edema resulting in restricted diffusion detected on DWI
and ADC (fig. 5). In contrast to acute ischemia, where
DWI reveals diffusion abnormalities within 30 min and
before any T2 signal changes appear, in ongoing status
epilepticus, DWI and T2 signal changes may occur simultaneously. This finding probably indicates a different
pathophysiology, with cytotoxic edema induced by the
ictal activity preceding a manifest energy deficiency. In
turn, this might explain the frequently observed reversibility of DWI changes in patients with seizures or status
epilepticus [40, 42]. As shown in figure 6, the coincidence
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a

The most common inflammatory disease affecting
the hippocampus is limbic encephalitis that occurs in
three major forms: (1) a paraneoplastic subtype which is
related to onconeural antibodies in patients with malignant tumors, (2) a nonparaneoplastic subtype that is
mainly caused by voltage-gated potassium channel antibodies and (3) an infectious subtype caused by herpesvirus. The clinical presentation is characterized by subacute onset of seizures, memory deficits, confusional
state, altered vigilance and psychiatric symptoms.
In paraneoplastic and nonparaneoplastic limbic encephalitis, only a few case reports [45, 46] and a single
case series [47] detected hippocampal DWI abnormalities, and it remained unclear whether these represented
cytotoxic changes in water distribution or mainly a T2
shine-through effect. Figure 2 shows typical MRI findings in a patient with nonparaneoplastic limbic encephalitis. Limbic encephalitis has also been increasingly recognized as a typical finding in immunocompromised patients, in particular after allogeneic hematopoietic stem
cell transplantation in hematologic malignancies. The
clinical presentation is not different to that observed in
paraneoplastic or nonparaneoplastic limbic encephalitis.
It is caused by human herpes virus-6, an ubiquitous neurotropic DNA virus known to cause exanthema subitum
and sometimes febrile seizures in childhood and to persist lifelong in about 90% of adults. The first case reports
on hippocampal DWI hyperintensities in human herpes
virus-6 encephalitis were published in 2006 [48, 49].
While in the first report the ADC was reduced in only 1
patient and was considered by the authors to be a consequence of recent seizures, the authors of the second study
ascribed a substantial part of the acute pathology of human herpes virus-6 encephalitis to cytotoxic edema. In a
more comprehensive case series, Seeley et al. [50] described the clinical and MRI findings in 8 patients with
human herpes virus-6 encephalitis. All patients demonstrated hyperintensities within the uncus, amygdala, and
the hippocampus, extending to the entorhinal cortex and
subiculum on DWI. However, ADC maps (available in 4
patients) suggested impaired diffusion in only 1 patient

Anoxic Encephalopathy and Encephalopathies of
Other Etiology

Diffusion abnormalities in different brain regions may
also be present in patients with anoxic encephalopathy;
they can be subdivided into hypoxic-ischemic encephalopathy (e.g. caused by cardiac arrest), hypoxic hypoxia
(e.g. caused by suicide by hanging), histotoxic hypoxia
(e.g. caused by carbon monoxide poisoning) and anemic
hypoxia according to its pathophysiology.
In hypoxic-ischemic encephalopathy, DWI demonstrates widespread signal abnormalities in the basal ganglia, caudate nucleus, striate nucleus and thalamus, followed by the cortex and subcortical white matter, cerebellum and hippocampus. Wijdicks et al. [54] followed
patients who remained comatose after cardiopulmonary
resuscitation for a period of 12 months. While all patients who underwent MRI except 1 showed hippocampal signal abnormalities on fluid-attenuated inversion
recovery (FLAIR) images, only 1 patient had increased
DWI for the Diagnosis of Disorders
Affecting the Hippocampus

signal intensity in the hippocampus on DWI. Only those
patients without or minimal signal changes on MRI
awakened later. In a case report of a 66-year-old man
who was resuscitated after cardiorespiratory arrest, the
authors found a delayed manifestation of DWI abnormalities in the hippocampus, corpus callosum and deep
white matter, whereas other brain structures, such as the
cerebellum, cerebral cortex, caudate nucleus and putamen, were affected earlier [55]. In a more differentiated
approach, Mlynash et al. [56] qualitatively and quantitatively assessed predefined brain regions in comatose
survivors of cardiac arrest and compared the results to
normal controls. Moderate to severe DWI signal changes in the hippocampal formation were significantly
more often observed in patients with a poor outcome.
Interestingly, while patients with poor outcome exhibited a nonsignificant decrease in ADC values compared
to patients with a good outcome; the latter showed increased ADC values in the hippocampus compared to
healthy control subjects and this finding was interpreted
as mild vasogenic edema caused by transient increased
blood-brain barrier permeability. With regard to hippocampal abnormalities on DWI in patients with hypoxic
hypoxia or histotoxic hypoxia, only a few case reports
have been published until today. In patients with carbon
monoxide poisoning, DWI abnormalities in the hippocampus may be the only finding or may occur in combination with DWI signal changes in other brain regions, such as the globus pallidus, occipital and temporal lobes and cerebellum [57]. After attempted suicidal
hanging, hippocampal DWI lesions can be observed in
addition to widespread lesions in the striate nucleus,
thalamus, and occipital and parietal cortices [57]. A differentiation of pathophysiology in anoxic encephalopathy based on DWI findings is not supported by the literature.
Hypoglycemic coma can be associated with extensive
DWI hyperintensities notably involving the cerebral
cortex, the hippocampus and the basal ganglia. The first
case report of DWI findings in a patient with hypoglycemic coma was published in 2001 and demonstrated
symmetrical lesions in the hippocampus, caudate nucleus, putamen and temporal cortex [58]. In another case
report from 2006, hippocampal lesions were relatively
small, and the authors concluded that the hippocampus
might be more resistant to prolonged hypoglycemia
than to global hypoxia [59]. In contrast to this finding,
Lim et al. [60] found hippocampal signal abnormalities
on DWI in all patients with severe hypoglycemia who
had consumed an illegal sexual enhancement product
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and a T2 shine-through effect in the remaining cases. In
comparison to the widespread DWI abnormalities in herpes simplex virus encephalitis including the hippocampal formation and amygdala but also other brain regions,
such as the insular, frontal, temporal or parietooccipital
cortices, increased DWI signal intensity is limited to the
hippocampus and amygdala in patients with human herpes virus-6 encephalitis. With regard to the lesion characteristics during the clinical course with an increased
DWI signal and reduced ADC values in the early and
middle phase (0–30 days after onset) and disappearance
of these changes in the late phase (more than 30 days after
onset), there were no significant differences between the
two conditions [51].
Other infections associated with changes in hippocampal DWI signals are very rare. Poon et al. [52] reported on a patient with a cerebellar variant of CreutzfeldtJakob disease, who had increased DWI signal in both hippocampi in addition to extensive signal changes in the
basal ganglia, thalamus and cerebellum. Although the
hippocampal formation is frequently affected histopathologically in patients with Creutzfeldt-Jakob disease, this
is a rather unusual finding. Another form of infectious
encephalitis that occasionally may be the cause of hippocampal DWI abnormalities is Japanese encephalitis.
Again, hippocampal DWI changes were accompanied by
increased DWI signal in other brain regions (both thalami) in the reported case [53].

Table 1. Common clinical constellations and DWI findings in different neurological disorders affecting the hippocampus

Clinical presentation

DWI findings

Stroke

Sudden onset of homonymous quadrantanopia or hemianopia,
hemivisual neglect, verbal dyslexia
Obvious memory deficits (if left or both hippocampi involved)
Sensory loss, dysesthesias, hemiparesis, choreoathetosis, spasms
of hand

Patterns according to vascular pathology:
(1) complete, (2) dorsal, (3) lateral, (4) small
circumscribed lesion
Additional lesions in the PCA territory

TGA

Sudden onset of anterograde amnesia
Complete resolution within 24 h
No disturbance of consciousness
No other neurological deficit or features of ictal activity

Small circumscribed lesions of 1–2 mm in
diameter
Lateral part of the hippocampus, CA-1 region
Delayed occurrence

Seizure

Nonspecific symptoms (altered vigilance, confusion,
alterations in mental status, aphasia, hemiparesis)
Single seizure (febrile, psychomotor, generalized tonic-clonic)
Repetitive seizures and status epileticus (nonconvulsive, focal
convulsive, complex partial, generalized tonic-clonic)

Involvement of the lateral hippocampus
Additional hyperintensities in the pulvinar or
cortex

Limbic
encephalitis

Subacute onset of altered vigilance, confusion
Memory deficits and psychiatric symptoms
Seizures

Uncus, amygdale, hippocampus
Extending to the entorhinal cortex and
subiculum

TGA = Transient global amnesia; DWI = diffusion-weighted imaging.

adulterated with glibenclamide, an oral antidiabetic
drug. Further lesions were detected in the parietal, temporal, occipital and frontal cortices, and, in many cases,
the splenium of the corpus callosum whereas lesions of
the internal capsule and basal ganglia were observed in
only 1 patient. About one third of patients in a larger series of patients with hypoglycemic coma exhibited hippocampal DWI hyperintensities, and in a subset of patients, these signal changes had completely disappeared
on follow-up MRI [61]. While some authors reported
hippocampal involvement to be a negative predictor of
clinical outcome, this was not the case in the series described by Kang et al. [61]. Several pathomechanisms
have been suggested for diffusion abnormalities in hypoglycemic encephalopathy: (1) breakdown of energy
metabolism, (2) excitotoxic edema caused by an increased extracellular glutamate concentration, and (3)
unequal cerebral blood flow impairment by focal loss of
autoregulation.
Other encephalopathies, such as hyperammonemic
encephalopathy [62] and intoxications with glufosinate, a
herbicide [63], or methanol [64], are rarely accompanied
by changes in DWI signal in the hippocampus.

112

Cerebrovasc Dis 2012;33:104–115

Conclusions

The hippocampus can be affected in different neurological diseases, such as global or focal hypoxia, TGA,
epilepsy, infections and autoimmune conditions, and this
may result in hyperintense DWI signal. Although all of
these pathologies are associated with a more or less characteristic clinical presentation, signs and symptoms may
overlap (table 1) and differential diagnosis based on clinical presentation alone may be challenging. However, on
the basis of distinct lesion patterns (fig. 3), DWI can provide additional diagnostic information that may facilitate
and support the final diagnosis, especially if clinical
symptoms are inconclusive.
In acute ischemic stroke in the PCA territory, involvement of the hippocampal formation as a result of cytotoxic edema occurs in four distinct patterns that can be
easily differentiated and correspond to the known vascular anatomy of the hippocampus. Furthermore, additional lesions involving other cerebral structures supplied by the PCA, such as the thalamus, the splenium, or
the occipital lobe, can almost always be found in completed hippocampal stroke. Ischemic lesions of the hippocampus may be accompanied by a persistent abnormality of the PCA and corresponding hypoperfusion.
While unilateral hippocampal involvement in stroke
Förster/Griebe/Gass/Kern/Hennerici/
Szabo

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Etiology

DWI lesions are infrequently found in limbic encephalitis, and usually they affect the hippocampus, uncus
and amygdala. Whether these represent a characteristic
finding in a specific stage of the pathophysiology or rather a T2 shine-through effect remains unclear. Furthermore, as seizures are a typical symptom, postictal and
inflammatory DWI changes may indistinguishably overlap.
In contrast to the above-described etiologies, extensive DWI abnormalities in both hemispheres and independent of vascular territories may be detected in global
hypoxia. In other encephalopathies induced by agents
that compromise the neuronal energy metabolism via the
respiratory chain by very different mechanisms, such as
hypoglycemia, carbon monoxide poisoning, or methanol
intoxication (fig. 5), lesion patterns may be similar to
those observed in global hypoxia.
In diseases affecting the hippocampus, besides the
clinical presentation, other investigations including
EEG, Doppler/duplex ultrasound, laboratory tests, and
MRI, in particular DWI, appear to be useful to differentiate between underlying pathologies and may facilitate
a definite diagnosis conducive to an optimal treatment.
In some – admittedly rare – cases, DWI lesions of different etiology may coexist. With a careful clinical examination and experience with DWI hyperintense phenomena on MRI, it is indeed possible to differentiate
between ischemic, ictal, metabolic, and TGA-associated
findings.

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