PART 7 Cavernomas
409 Natural History of Cavernous Malformations
Joseph M. Zabramski and M. Yashar S. Kalani
Before the availability of modern imaging technology, cavernous
malformations were considered rare lesions. In 1976, Voigt and
Ya argil described their clinical experience with one patient and
thoroughly reviewed the world literature, but found only 126
reported cases.1 Soon after the publication of their article, com-
puted tomography (CT) became widely available, but CT lacked
both sensitivity and specificity for identifying cavernous malfor-
mations. Only partially calcified or recently hemorrhagic lesions
could be readily visualized, and diagnosis still required pathologic
confirmation. The lack of a reliable diagnostic test resulted in
significant confusion in the early literature on this topic, with
many publications referring to these lesions as angiographically
occult, thrombosed, or cryptic vascular malformations.
The introduction of magnetic resonance imaging (MRI) in the
mid-1980s revolutionized our understanding of cavernous mal-
formations. The MRI characteristics of these lesions are suffi-
ciently unique to allow a diagnosis of cavernous malformation to
be made in the majority of cases on the basis of MRI findings
alone (Fig. 409-1).2-6 The widespread availability of MRI has
increased the recognition of cavernous malformations in both
symptomatic and asymptomatic patients and thus the number of
requests for neurosurgical consultations. Appropriate manage-
ment of these patients requires a thorough understanding of the
epidemiology and natural history of these lesions. The goals of
this chapter are to provide the reader with an in-depth review of
the available literature on this topic and to examine the implica-
tions related to the treatment of these patients.
EPIDEMIOLOGY
Cavernous malformations are more common than generally sus-
pected. Postmortem studies from the 1980s demonstrated that
cavernous malformations affect 0.37% to 0.5% of the popula-
tion.7,8 Remarkably similar results were reported by three groups
reviewing more than 24,000 MRI examinations, for which inci-
dence rates of 0.4% to 0.5% were calculated.9,10 Based on these
studies, it is estimated that 1 in every 200 to 250 people, or
approximately 34 million individuals worldwide, are affected by
cavernous malformations (Table 409-1).
Cavernous malformations occur in two forms: spontaneous
and familial. The spontaneous form occurs as an isolated event,
with patients most commonly having a single lesion, whereas the
familial form is characterized by multiple lesions (Fig. 409-2) and
an autosomal dominant mode of inheritance.11-14 Three distinct
gene foci on chromosomes 7q, 7p, and 3q have each been linked
to familial cavernous malformations.15-17 The proteins encoded
by these genes appear to interact with the endothelial cytoskel-
eton during angiogenesis in the central nervous system and
may explain the development of these lesions. A more detailed
review of the genetics of familial cavernous malformations is
beyond the scope of this chapter; interested readers are referred
to Chapter 410.
The presence of three or more lesions and a family history of
seizures are essentially pathognomonic for the familial form of
this disease. Seizures are the most common presentation in
patients with the familial form of this disease, and a careful family
history regarding seizures is key to the diagnosis in patients with
409
multiple lesions. It is equally important, when evaluating patients
for possible familial cavernous malformations, to include gradient-
echo MRI sequences. In a series of 132 patients with familial
cavernous malformations, Denier and coworkers reported that
80% had multiple lesions detected on T2-weighted magnetic
resonance images and 90% had multiple lesions on gradient-echo
images, with an average of five lesions per patient on T2-weighted
images and 20 per patient on gradient-echo sequences.18
Cavernous malformations occur throughout the central
nervous system in rough proportion to the volume of the various
compartments; 80% supratentorial, 15% brainstem and basal
ganglia, and 5% spinal cord. They have been well described in
infants and children but are seldom symptomatic until the second
and third decades of life. Large population studies have demon-
strated that cavernous malformations occur with equal frequency
in both sexes.9,10 Some data suggest that women may more com-
monly have symptomatic hemorrhage on presentation, but the
evidence is far from conclusive. The issues of gender and preg-
nancy are covered later in this chapter.
Not all patients with cavernous malformations are clinically
symptomatic, and 20% to 30% of sporadic lesions are incidental
findings discovered during evaluations for headache or other
unrelated symptoms.9,10,19 Approximately 40% of patients with
the familial form of the disease remain asymptomatic despite the
presence of multiple lesions.14,20
CLINICAL PRESENTATION
MRI evidence of hemorrhage is a constant feature of cavernous
malformations regardless of whether the lesions are symptomatic
or not. Hemorrhages of various ages, combined with the deposi-
tion of hemosiderin in cerebral tissue surrounding the cavernous
malformation, produce the unique MRI characteristics of these
lesions (see Figs. 409-1 and 409-2). Increases in size may result
from repeated small hemorrhages within the lesion and from
spontaneous thrombosis of the blood-filled caverns. Organiza-
tion and endothelialization within these hemorrhagic or throm-
botic cavities create the potential for further growth. More rarely,
these lesions will rupture outside their capsule and produce
“overt” hemorrhage into the surrounding brain tissue (Figs. 409-
3 and 409-4). Because cavernous malformations are low-flow,
low-pressure lesions, hemorrhage (even “overt” hemorrhage
outside the lesion) typically displaces and compresses adjacent
neural tissue rather than destroying it. The clinical presentation
caused by the hemorrhage is related to location of the cavernous
malformation, as well as the volume and type of hemorrhage
(intralesional or extralesional). When deficits develop, they are
often transient, resolving over days to weeks as the blood is
absorbed.
Hemispheric Lesions
Seizures are the most common clinical manifestation associated
with cavernous malformations involving the cerebral hemi-
spheres, accounting for 40% to 80% of the initial symp-
toms.9,10,13,14,21-24 Despite the prevalence of seizures associated
with hemispheric lesions, remarkably few data are available
3537
3538 SECTION 12 Vascular

regarding the annual risk for the onset of seizures. Only five
studies have directly addressed this issue, reporting rates for the
new onset of seizures of 0.9% to 2.4% per person-year.9,20,25-27
The onset or exacerbation of seizure activity in these patients is
often associated with MRI evidence of acute and/or subacute
hemorrhage (Fig. 409-5). The exact mechanism that leads to the
seizure activity in these lesions is unknown. Cavernous malforma-
tions do not typically contain neuronal tissue and are therefore
not intrinsically epileptogenic. The lesions likely induce seizures
through their effects on surrounding brain tissue. Such effects
may include focal gliosis, hemosiderin deposition, and cellular
and humoral inflammatory responses. Pathologically, cavernous
malformations are surrounded by a yellow-brown–stained border
that is heavily infiltrated with hemosiderin-laden macrophages
and iron (Fig. 409-6). Iron is a well-known epileptogenic material
used to induce seizures in laboratory models of epilepsy.28,29 Focal
neurological deficits secondary to mass effect are rarely associated
with supratentorial lesions unless the lesion is located in the basal
ganglia or thalamus.

Brainstem Lesions
The sudden onset of focal neurological deficits is the most
frequent presentation reported in patients with cavernous

TABLE 409-1 Incidence of Cavernous Malformations

No. of Lesions/
Figure 409-1. Axial T2-weighted magnetic resonance image Incidence Rate
No. of Patients of Cavernous
demonstrates the classic appearance of a cavernous
Study Studied Malformations
malformation. The core of the lesion has a reticulated “salt-and-
pepper” pattern and is surrounded by a halo of low signal intensity. McCormick, 19847 5,734 19/0.33%
Histologically, these lesions are composed of loculated areas of Otten et al., 19898 24,535 131/0.53%
hemorrhage and thrombosis of various age surrounded by gliotic, Del Curling et al., 19919 8,131 32/0.39%
Robinson et al., 199110 14,035 66/0.47%
hemosiderin-stained brain tissue. Note the absence of mass effect
Vernooij et al., 200719 2,000 8/0.40%
and edema. This pattern is pathognomonic for a cavernous TOTAL 54,435 256/0.47%
malformation.

A B
Figure 409-2. Two axial T2-weighted magnetic resonance images in a patient with a new onset of
seizures and familial cavernous malformations. Four distinct lesions are seen at these two levels, including
three type II lesions (A and B, straight arrows) and one type III lesion (A, curved arrow). A fifth lesion was
identified in the cerebellum (not shown). Multiple lesions and a family history of seizures are characteristic of
the familial form of this disease. See Table 409-2 for the classification of lesion types.
 CHAPTER 409 Natural History of Cavernous Malformations 3539

409

A B
Figure 409-3. Two coronal T1-weighted magnetic resonance images from the same scan in a 10-year-
old boy with a cavernous malformation (curved arrows). His history was remarkable for an episode of
seizure activity at 4 years of age and a negative computed tomographic study. The patient had a sudden onset
of mild weakness and decreased sensation in his left upper extremity. Magnetic resonance imaging shows a
cavernous malformation (A and B, curved arrows). Note the focal area of subacute blood (B, straight arrow)
extending outside the capsule of the lesion and producing “overt” extralesional (type IA) hemorrhage. See Table
409-2 for the classification of lesion types. (From Zabramski JM. Cavernous malformations. In: Aminoff M, Daroff
RB, eds. Encyclopedia of the Neurological Sciences. Boston: Academic Press; 2003. Used with permission.)

malformations involving the brainstem and basal ganglia.30-33
Abla and coauthors reported their experience with the surgical
treatment of a total of 300 patients with brainstem cavernous
malformations. In their series, 97% of patients had a history of
acute symptomatic hemorrhage.34,35 The development of symp-
toms in patients with hemorrhage from brainstem cavernous
malformations is characteristically acute and maximal at onset
(see Fig. 409-4A-D). However, the neurological deficits from the
first episode of clinically symptomatic hemorrhage typically tend
to resolve as the hemorrhage is organized and absorbed. In con-
trast, recurrent episodes of hemorrhage are apt to be associated
with progressively more severe deficits and an increased risk for
permanent neurological impairment (see Fig. 409-4E-F). This
stuttering clinical course with improvement of symptoms between
episodes may lead to a misdiagnosis of multiple sclerosis if the
evaluation of the patient does not include MRI. Occasionally,
large brainstem lesions develop that are associated with only
minimal deficits; particularly in the pons, the mass can gradually
displace the densely packed ascending and descending fiber tracts
(Fig. 409-7). Death is rare without multiple episodes of symp-
tomatic hemorrhage.
Spinal Cord Lesions
Intramedullary spinal cord cavernous malformations have a vari-
able clinical presentation that can be readily confused with demy-
elinating disease, intramedullary spinal neoplasms, and spinal
arteriovenous malformations. In general, most authors divide
patients into three subgroups based on the type of clinical pre-
sentation: (1) acute onset of major neurological deficits, (2) repet-
itive stepwise deterioration, and (3) slow progressive deterioration.
Various combinations of these presentations occur frequently.
Presentation in the first two groups is related to episodes of acute
hemorrhage with sudden onset of symptoms, whereas the severity
of neurological deficits is related to the exact location of the
lesion (level and position within the cord) as well as the volume
and type of hemorrhage (intralesional, extralesional, or both).
Presentation in the third group is probably related to minor
bleeding episodes (microhemorrhages), focal thrombosis, and
gliosis, resulting in the gradual growth of the lesion. Painful
dysesthesias are a typical feature in this last group and may be
related to the neurotoxic effects of hemosiderin.
Both radicular and myelopathic symptoms are common at
initial evaluation. Pain is a significant component in 40% to
64% of patients with intramedullary spinal cord cavernous
malformations.36-43 In a series of 53 patients with intramedullary
lesions, Kim and colleagues reported that 23 patients (43%) had
pain as the major complaint—12 with central pain, 7 with radicu-
lopathy, and 4 with both. In 7 patients the pain was severe and
debilitating, and in 6 patients it was the only symptom on
presentation.40
It is important to note that patients with spinal cord cavernous
malformations appear to be at significantly increased risk of har-
boring intracranial lesions. Vishteh and colleagues reported that
47% of patients with symptomatic spinal cord lesions who under-
went MRI of the complete neuraxis were found to have intracra-
nial lesions.44 Cohen-Gadol and coworkers confirmed this finding
and reported a 40% incidence of intracranial lesions in a series
of 33 patients with spinal cord cavernous malformations who
underwent both cranial and spinal imaging studies.45 These
reports suggest that it may be prudent to perform MRI of the
brain in this population.
NATURAL HISTORY
Numerous studies have been published on the natural history
of cavernous malformations.a Hemorrhage rates vary widely
from series to series, depending on the authors’ definition of
a
References 9, 10, 14, 20, 26, 27, 30, 31, 36, 37, 39, 41, 42, 45-63.
3540 SECTION 12 Vascular
A B
C D
E F
hemorrhage and the population being studied. Not surprisingly,
hemorrhage rates tend to be higher in surgical series because
patients with symptomatic lesions are more likely to be referred
for neurosurgical intervention. In addition, there are essentially
four different methods of calculating hemorrhage rates, including
retrospective and prospective methods, either of which can be
reported as risk for hemorrhage per patient or per lesion. The
Figure 409-4. This 38-year-old woman was seen
at an outside emergency room with complaints
of severe headache and nausea. A basic head
computed tomographic scan revealed a subtle area
of increased density in the right pons. T1-weighted
(A and B) and T2-weighted (C and D) magnetic
resonance (MR) images revealed a 1.6-cm area of
subacute blood consistent with recent “overt”
extralesional (type IA) hemorrhage from a small
cavernous malformation (arrow), which is best seen
on the T2-weighted image (D). The patient was
seen in neurosurgical consultation approximately 1
month after this episode when all symptoms had
resolved. She initially declined surgical intervention.
Two months later, she had an acute onset of
left-sided weakness and hemisensory deficits.
Repeated T1-weighted MR images (E and F)
revealed a dramatic increase in the size of the
lesion, which was composed almost entirely of
acute and subacute blood. Surgical pathologic
evaluation confirmed the diagnosis of cavernous
malformation. After resection of this lesion, she
made a complete recovery. See Table 409-2 for
the classification of lesion types. (C and D, From
Zabramski JM, Spetzler RF. Management of
brainstem cavernous malformations. In: Batjer HH,
Loftus CM, eds. Textbook of Neurological Surgery.
Philadelphia: Lippincott Williams & Wilkins; 2003.
Used with permission. E and F, From Robinson JR,
Zabramski JM. Cavernous malformations of the
cervicomedullary junction. In: Dickman CA,
Spetzler RF, Sonntag VKH, eds. Surgery of the
Craniovertebral Junction. New York: Thieme; 1998.
Used with permission.)
retrospective method assumes that all lesions have been present
since birth. Using this assumption, Del Curling and collaborators
calculated an annual hemorrhage rate of 0.25% per patient.9
Kondziolka and coauthors reported a rate of 1.3% per patient
per year,26 and Kim and associates calculated a rate of 2.3% per
patient per year.54 This method of calculation, which depends on
the patient’s recall to define episodes of hemorrhage and assumes
 CHAPTER 409 Natural History of Cavernous Malformations 3541

that all lesions are present from birth, is likely to underestimate

Figure 409-5. Intermediate-weighted, axial, spin-echo magnetic
resonance image of a 23-year-old man with acute exacerbation
of temporal lobe seizure activity. Note the focal area of high-signal
intensity (arrow) compatible with subacute hemorrhage in the region of
the left hippocampus. A ring of low signal intensity surrounds the
entire lesion, consistent with a focal, intralesional hemorrhage. Surgical
pathologic evaluation confirmed the diagnosis of cavernous
malformation.
the actual risk of significant bleeding. Once considered congeni- 409
tal in origin, increasing evidence suggests that new lesions may
appear de novo in both the sporadic and familial forms of the
disease.12,14,64-74
Another confounding factor is the varying nature of these
lesions. Zabramski and colleagues classified cavernous malforma-
tions into four subtypes based on MRI characteristics (Table
409-2).14 The risk for hemorrhage appears to be greatest with
type I and type II lesions, which are more likely to be symptom-
atic.10,20,46,48,56,75 Most clinical and surgical series are heavily biased
toward these two subtypes of lesions, which are readily identified
on MRI studies because they do not require gradient-echo
sequences. These uncertainties emphasize the need to rely on
prospective natural history data in this population.
Robinson and coworkers prospectively monitored 57 patients
with serial clinical and MRI studies for an average of 26 months
and found a risk for symptomatic hemorrhage of 0.7% per lesion
per year.10 Kondziolka and coauthors reported a slightly higher
hemorrhage rate of 2.6% per year but noted that the risk for
hemorrhage was strongly related to the patient’s signs and symp-
toms.26 They prospectively monitored 122 patients with cavern-
ous malformations (mean, 34 months) and found that the
hemorrhage rate was significantly lower in patients with inciden-
tal lesions, 0.6% per year (n = 61), than in those with a history
of previous symptomatic hemorrhage, 4.5% per year (n = 61).
Aiba and associates observed 110 patients with cavernous malfor-
mations for a mean of 4.5 years and reported a 0% hemorrhage
rate in patients with incidental lesions versus 0.4% per year in
those with seizures.46
Porter and coauthors reported a somewhat higher annual
event rate of 4.2%.59 This group defined an event as any neuro-
logical worsening of symptoms with or without radiologically
proven hemorrhage. The authors observed 110 patients with
cavernous malformations for an average of 46 months, represent-
ing 427 patient-years of observation. In this study, location was
the most important factor for predicting future events, with a
significantly higher rate for deeply located lesions (i.e., brainstem

A B C
Figure 409-6. Whole-brain sections from a 26-year-old man who died of septic complications. A, An
unstained formalin-fixed section reveals a type II cavernous malformation (black arrow) in the right posterior
frontal lobe and a small type III cavernous malformation (red arrow) adjacent to the right occipital horn.
B, Close-up view of the same lesions. C, The same section stained with Prussian blue for iron emphasizes
the extent of hemosiderin and iron deposition. The hemosiderin and iron surrounding these lesions are
responsible for the areas of low signal intensity (known as blooming artifact) seen on T2-weighted and
gradient-echo magnetic resonance images. See Table 409-2 for the classification of lesion types. (A and
B, From Zabramski JM. Cavernous malformations. In: Aminoff M, Daroff RB, eds. Encyclopedia of the
Neurological Sciences. Boston: Academic Press; 2003. Used with permission. C, Used with permission from
Barrow Neurological Institute.)
3542 SECTION 12 Vascular

A B
Figure 409-7. Two T1-weighted magnetic resonance images in a 39-year-old woman with a history of
an acute onset of mild right-sided weakness that had completely resolved over a period of 3 to 4
weeks. The hyperintense regions represent areas of subacute hemorrhage within the more chronic matrix of
this pontine cavernous malformation (A and B). This lesion reached considerable size with only minimal
deficits by gradually displacing the dense fiber tracts within the pons. Compare this pattern with the “overt”
pontine hemorrhage sustained by the patient shown in Figure 409-4.

TABLE 409-2 Magnetic Resonance (MR) Imaging Classification for Cavernous Malformation
Lesion Type MR Signal Characteristic Pathologic Characteristics Natural History: Risk of Hemorrhage
Type IA T1: hyperintense focus of hemorrhage “Overt” extralesional focus of Almost all lesions are symptomatic.
T2: hyperintense or hypointense focus of hemorrhage extending outside the High risk of recurrent symptomatic
hemorrhage extending through at least one lesion capsule. hemorrhage of up to 60%/yr for
wall of the hypointense rim that surrounds the brainstem lesions (mean, 25%-30%/yr).
lesion (see Figs. 409-3 and 409-4); focal
edema* may be present (see Fig. 409-8)
Type IB T1: hyperintense focus of hemorrhage Subacute focus of intralesional Risk of symptomatic hemorrhage related
T2: hyperintense or hypointense focus of hemorrhage. to presentation and location. Higher for
hemorrhage surrounded by a hypointense rim symptomatic lesions in the brainstem
(see Fig. 409-5) and basal ganglia (5%-10%/yr). Lower
in asymptomatic lesions (0.5%-1%/yr).
Type II T1: reticulated mixed signal core Loculated areas of hemorrhage and Risk of symptomatic hemorrhage related
T2: reticulated mixed signal core thrombosis of varying age to presentation. In symptomatic
surrounded by a hypointense rim surrounded by gliotic, hemosiderin- patients risk of recurrent hemorrhage
(see Figs. 409-1 and 409-2, straight arrows) stained brain; in large lesions, areas 4%-5%/yr. Low risk for asymptomatic
of calcification may be seen. lesions (0.5%-1%/yr).
Type III T1: isointense or hypointense Chronic resolved hemorrhage with Rarely symptomatic. Lesions have a low
T2: hypointense with hypointense rim that hemosiderin staining within and risk of hemorrhage (<0.5%/yr).
magnifies the size of lesion around the lesion.
GE: hypointense with greater magnification than
T2 (see Fig. 409-9)
Type IV T1: poorly seen or not visualized at all Two lesions in the category have been Never symptomatic. Very low risk of
T2: poorly seen or not visualized at all pathologically documented to be hemorrhage.
GE: punctate hypointense lesions (see Fig. 409-9) telangiectasias.
Modified from Zabramski JM, Wascher T M, Spetzler RF, et al. The natural history of familiar cavernous malformations: results of an ongoing study.
J Neurosurg. 1994;80:422-432. Used with permission.
GE, gradient-echo sequences; T1 and T2 denote T1- and T2-weighted MR images, respectively.
*Focal edema may surround the extralesional portion of hemorrhage in Type IA lesions; however, if more extensive, it should raise concerns regarding
the diagnosis.

and basal ganglia) of 10.6% per patient-year, versus 0% per
patient-year for superficially located lesions.
Hemorrhage rates appear to be particularly high in patients
initially seen after bleeding episodes that violate the lesion capsule
and produce an extralesional, or so-called “overt,” hemorrhage
into the surrounding brain parenchyma, which is often associated
with edema (type IA lesion; see Figs. 409-3 and 409-4). Aiba
and colleagues monitored a group of 62 patients with “overt”
hemorrhages for a mean of 3.12 years and noted a risk for recur-
rent symptomatic hemorrhage of 22.3% per lesion-year.46 Barker
 CHAPTER 409 Natural History of Cavernous Malformations 3543

and colleagues reported a similar experience in 141 patients
selected for intervention who had “overt” hemorrhages.48 In
this series, 63 patients experienced a second hemorrhage before
treatment. Hemorrhages clustered around the initial event, with
a repeat hemorrhage rate of 25.2% per year for the first 28
months. Comparable rates of rebleeding have been reported after
incomplete resection of cavernous malformations, presumably
because of interruption of the lesion capsule, thus stressing
the importance of complete resection during the initial surgical
procedure.30,57,76,77
Brainstem Cavernous Malformations
In general, the natural history of brainstem cavernous malforma-
tions parallels that of lesions elsewhere in the central nervous
system. However, because of the eloquence of surrounding struc-
tures, episodes of hemorrhage are much more likely to be symp-
tomatic, and clinically apparent. A conservative estimate, based
on the assumption that lesions are present from birth to the
first symptom, places the risk for first symptomatic hemorrhage
in the range of 2.5% to 6.8% per year (mean, 4.5% per
lesion-year).30,31,35,50,55,61,63,78
For patients with a history of previous symptomatic hemor-
rhage, the risk of rebleeding ranged from 5.1% to 60% (mean,
29.8% per lesion-year),30,31,35,50,57,78 with higher rates reported in
those with recent hemorrhage48,63 or evidence of extralesional
hemorrhage, mass effect, and associated edema (type 1A lesion;
Fig. 409-8).46,55,78 High rates of recurrent symptomatic hemor-
rhage have also been reported after incomplete surgical removal.
In a recent review of 68 surgical series from the literature, Gross
and colleagues identified 105 cases of partially resected cavernous
malformations and reported that 62% had rebleeding, and that
mortality caused by rebleeding of residual cavernous malforma-
tions was 6%.79
Although surgery has the potential to eliminate the risk of
recurrent hemorrhage from brainstem cavernous malformations,
it is important to recognize that resection of these lesions is
associated with a high risk of complications. Early postoperative
deficits are reported in 40% to 50% of patients, with roughly half
of these deficits being permanent.79 In view of such risks, surgery
is typically reserved for patients with one or more of the follow- 409
ing indications: (1) a history of multiple hemorrhages, (2) severe
or progressive symptoms, and (3) acute or subacute hemorrhage
and significant mass effect.
Considering that a history of multiple symptomatic hemor-
rhages is one of the major indications for surgical intervention in
patients with brainstem cavernous malformations, it should not
come as a surprise to the reader that rebleeding rates of 30% or
more are common in surgical series. Rebleeding rates are signifi-
cantly lower when conservative management is recommended by
the surgical team.55,80 Li and colleagues prospectively followed a
group of 331 patients managed nonoperatively for a mean of 6.5
years and reported an overall hemorrhage rate of 13.6% per year;
the risk of hemorrhage was higher in patients with a history of
previous symptomatic hemorrhage and persistent deficits (15.9%
per patient-year) compared with those with hemorrhage and no
residual deficits (12.4% per patient-year) and patients with inci-
dental lesions (8.7% per patient-year).80
Spinal Cord Cavernous Malformations
Cavernous malformations of the spinal cord are rarely diagnosed
before the onset of symptoms. Data on the natural history of
these lesions are primarily derived from surgical series. The risk
for symptomatic hemorrhage based on the age at symptom onset
and the assumption that lesions are present from birth ranges
from 1.4% to 4.5% per patient-year.36,42,60,81 In a review of 27
studies published in 2010, the mean hemorrhage rate in 352
patients was 2.5% per patient-year.82
Early reports suggested that once lesions become symptom-
atic, patients tend to experience progressive neurological deterio-
ration, with prospective rehemorrhage rates as high as 66% per
patient-year.60,81 More recently, however, multiple groups have
published the results of conservative management of spinal cord
lesions, and prospective symptomatic hemorrhage rates were
determined to be 0% to 1.7% per patient-year.39,45,83,84
The marked variation in recurrent hemorrhage rates reported
by these different groups emphasizes the influence that selection

A B C
Figure 409-8. A 34-year-old woman was transferred from an outside facility 3 weeks after the sudden
onset of right-sided weakness, hemisensory deficits, and blurred vision. Preoperative magnetic
resonance imaging demonstrates a type 1A lesion with subacute hemorrhage extending outside the capsule
(arrows) on the T1-weighted (A and B) and T2-weighted (C) images. Note the presence of edema
(arrowheads) and mass effect on the forth ventricle on the T2-weighted image (C). (See Table 409-2 for the
classification of lesion types.) Surgical pathology confirmed the diagnosis of cavernous malformation. (Used
with permission from Barrow Neurological Institute.)
3544 SECTION 12 Vascular
bias can play, particularly in retrospective studies. Patients with
rapidly progressive deficits and recurrent hemorrhages typically
undergo surgical resection, leaving a separate cohort of less
severely affected, or asymptomatic, patients to be managed
conservatively.
The importance that clinical presentation has on the risk
of hemorrhage was recently emphasized in a publication by
Kim and colleagues.83 In a group of 24 patients followed conser-
vatively for a mean of 5 years, the authors reported the risk of
hemorrhage was 1.7% per patient-year; however, no hemor-
rhages occurred in the 10 patients who had only pain (n = 5) or
were asymptomatic (n = 5) at the time of presentation. These
studies demonstrate that nonoperative treatment is an acceptable
option in select patients with intramedullary spinal cord cavern-
ous malformations.
Familial Cavernous Malformations
The natural history of the familial form of cavernous malforma-
tions is analogous to that of its spontaneous counterpart. Clinical
penetrance is highly variable, with 40% to 60% of patients
reporting being free of symptoms.14,20,56 The most common mani-
festations are seizures and headaches with supratentorial lesions,
and focal neurological deficits with those lesions involving the
brainstem, basal ganglia, and spinal cord. Several prospective
studies have examined the natural history of this population.
Zabramski and colleagues identified 59 members of 6 families
with the familial form of cavernous malformations.14 From this
cohort, 21 patients harboring a total of 128 lesions (mean, 6.5
lesions per patient) were prospectively monitored for a mean of
2.2 years by clinical examinations and serial MRI studies at 6- to
12-month intervals. Clinically silent hemorrhages were common.
MRI evidence of hemorrhage (defined as signal changes consis-
tent with acute or subacute hemorrhage) occurred in 28% of
patients, but only half of these episodes were associated with
symptoms. The overall hemorrhage rate was 11.8% per person-
year with a rate of symptomatic hemorrhage of 6.5% per lesion-
year. This report also documented the ongoing development of
new lesions. During the follow-up period, new lesions developed
in 29% of the patients. Altogether, 17 de novo lesions were iden-
tified, for a rate of 0.4 new lesions per patient-year.
Labauge and coworkers identified 264 patients in 51 families
with familial cavernous malformations.56 Forty of these patients,
who had a total of 232 lesions (mean, 5.9 lesions per patient),
underwent at least two clinical and MRI studies. The mean
follow-up was 3.2 years. New lesions were noted in 27% of
patients, for a rate of 0.2 new lesions per patient per year. The
authors observed 21 acute hemorrhages in 14 patients, for an
overall hemorrhage rate of 2.5% per lesion-year. The rate was
higher for infratentorial lesions (5% per lesion-year) than for
those in the supratentorial compartment (1.9% per lesion-year).
A third of the hemorrhages were symptomatic. Hemorrhage was
most common with type I and type II lesions (see Table 409-2);
32% of type I and 14% of type II lesions demonstrated evidence
of hemorrhage on follow-up MRI. In contrast, only 2.8% of type
III lesions (Fig. 409-9) and 0% of type IV lesions showed evi-
dence of hemorrhage. In a subsequent study by Labauge and
colleagues, serial clinical and MRI examinations were used to
prospectively monitor 33 asymptomatic patients with familial
cavernous malformations for a mean of 2.1 years.20 On initial
evaluation, 234 lesions were identified for a mean of 7.1 lesions
per patient. New lesions occurred in 30% of the patients during
follow-up, for an average rate of 0.4 new lesions per patient-year.
MRI evidence of hemorrhage was noted in three patients (9%),
but hemorrhages were symptomatic in only two patients (6%),
for a symptomatic hemorrhage rate of 0.4% per lesion-year and
2.8% per patient-year. Hemorrhage was detected only in patients
with type II lesions.
Pregnancy and Gender
Although it is widely believed that pregnancy and the puerperium
are associated with an increased risk for hemorrhage and aggres-
sive behavior of cavernous malformations, quantitative data sup-
porting this assumption are scarce. Cavernous malformations
have been reported to increase in size during pregnancy,85,86 and
exacerbation of other symptoms related to acute hemorrhage has
been documented.10,31,36,70,85,87,88 Overall, however, the number of
reports in the literature documenting such events is small, par-
ticularly considering that, based on available census data, there
are more than 150 million births per year worldwide, and that on
average we can expect that at least 600,000 of those pregnancies
(0.4%) involve women who harbor a cavernous malformation.
Importantly, there have been no reports documenting an increased
risk for symptomatic hemorrhage associated with pregnancy in
women with the familial form of this disease, in which the average
patient harbors five to seven lesions.
Two recent publications have looked carefully at this issue and
found no evidence of increased risk of hemorrhage associated
with pregnancy or delivery. Witiw and colleagues reviewed the
University of Toronto Vascular Malformation Study Group data
on women with cerebral cavernous malformations.89 They identi-
fied 186 patients (349 pregnancies and 283 live births) who expe-
rienced 49 hemorrhages during childbearing years, only 3 of
which were during pregnancy and none during delivery or within
6 weeks postpartum. They calculated a hemorrhage rate of 1.15%
per person-year for pregnant women and 1.01% per person-year
for nonpregnant women. Kalani and Zabramski reviewed the
prospective data on female patients enrolled as a part of the
Barrow Neurological Institute cerebral cavernous malformation
natural history study.90 They identified 64 women (28 sporadic
and 36 familial patients) with 168 pregnancies. They identified 5
cases of symptomatic hemorrhage (defined as new-onset or exac-
erbation of seizure activity or any neurological change). None of
the hemorrhages occurred during delivery or the puerperium.
The most common symptom in this group was seizure (identified
in 4 cases). The overall risk of symptomatic hemorrhage for
pregnant women in the sporadic group was 2% per person-year
and 4% per person-year in the familial group, which is well
within the range noted in the aforementioned natural history
studies.
Management of symptomatic hemorrhage from cavernous
malformations during pregnancy should be based on the severity
of the episode and the imaging characteristics of the lesion. If
symptoms are severe and endanger maternal and fetal life, surgi-
cal resection should proceed. The medical welfare of the mother
should never be jeopardized by withholding essential evaluation
or treatment because of fear of detrimental effects on the fetus.
Fortunately, the need for emergency neurosurgical treatment
during pregnancy has been rare.91,92
In addition to pregnancy, some authors have suggested that
female gender may be associated with an increased risk for hem-
orrhage. Several groups have reported a marked female prepon-
derance in patients with symptomatic hemorrhage, particularly
in those with brainstem and spinal cord lesions, with female-to-
male ratios as high as 1.6 : 1 and 2.3 : 1, respectively.31,60 In other
reports, however, the ratios are reversed and males predominate
by similar ratios.52,63 Such disparity suggests that referral bias may
be playing a significant, although unappreciated role.
To examine this question further, we reviewed the MedLine
and PubMed data bases for all available English-language surgical
reports on cavernous malformations published from 1988 to
2014. Any series containing at least five cases was included. Mul-
tiple reports from the same institution were screened, and in cases
where updates included previously published patients, only the
most recent study was included. Only those series in which gender
data were available were analyzed. Limiting the review to surgical
 CHAPTER 409 Natural History of Cavernous Malformations 3545

409

A B C

D E F
Figure 409-9. Magnetic resonance images from an asymptomatic 32-year-old woman with a known
history of familial cavernous malformations. T1-weighted (A and B), T2-weighted (C and D), and gradient-
echo (E and F) images demonstrate three distinct cavernous malformations, including a classic-appearing
small type II lesion in the left anterior frontal lobe, a tiny type III lesion in the left posterior frontal lobe, and a
punctate type IV lesion in the right posterior frontal lobe (visible only on the gradient-echo images). See Table
409-2 for the classification of lesion types. (Used with permission from Barrow Neurological Institute.)

series ensured that nearly all patients were symptomatic from
hemorrhage. Restricting the analysis to patients with brainstem
cavernous malformations, we identified 1797 cases—907 females
and 890 males, for a female-male ratio of approximately 1 : 1.
Likewise, restricting the analysis to the reports of intramedullary
spinal cord cavernous malformations yielded 491 cases, including
235 females and 256 males, for a 1 : 1.1 female-male ratio. These
results support the hypothesis that hemorrhage rates are equal in
both sexes and argue against a significant hormonal effect.
CONCLUSION
Cavernous malformations are relatively common lesions that
affect 0.4% to 0.5% of the population. They occur in two forms:
a sporadic form characterized by isolated lesions and a familial
form characterized by multiple lesions and an autosomal domi-
nant mode of inheritance. Cavernous malformations are found
throughout the central nervous system in rough proportion to
tissue volume: 80% supratentorially, 15% in the posterior fossa,
and 5% in the spinal cord. The lesions are composed of dilated
capillary vessels with no intervening brain tissue. They have a
propensity for focal hemorrhage and hemosiderin deposition,
which are hallmarks for their diagnosis by MRI. Symptoms result
when recurrent episodes of hemorrhage or thrombosis lead to
seizure activity for supratentorial lesions or to focal neurological
deficits for lesions located in the brainstem, basal ganglia, and
spinal cord.
The natural history of cavernous malformations is related to
their presentation (symptomatic or asymptomatic), imaging char-
acteristics, and location of the lesions. Incidental lesions and
those diagnosed during evaluation for nonspecific symptoms,
such as headache, have a low risk of symptomatic hemorrhage, in
the range is 0.5% to 1% per year for superficial lesions, 2% per
year in the spinal cord, and 5% per year for those located in the
brainstem.
The risk for recurrent symptomatic hemorrhage is higher in
patients with symptomatic lesions and varies with the type of
hemorrhage and the interval from the bleeding episode. The
recurrent hemorrhage rate approaches 30% per year in patients
with acute episodes of “overt,” extralesional hemorrhage that
disrupts the lesion capsule (type IA). Patients with acute intra-
lesional hemorrhage (type IB) or with symptomatic type II lesions
have an intermediate risk of rebleeding (range, 5%-10% per
patient-year).
Reasonable evidence suggests that the risk of rebleeding after
an episode of “overt,” extralesional hemorrhage is increased for
3546 SECTION 12 Vascular
2 to 3 years and then gradually declines. Patients with symptom-
atic, “overt” extralesional hemorrhage from cavernous malforma-
tions in the brainstem, basal ganglia, and spinal cord are
at greatest risk for permanent disability and death from
rebleeding.
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