Neuroimmunology in Clinical Practice - part 8 ppt

188 BERNADETTE KALMAN
imaging study. J Neurol Neurosurg Psychiatry, 68,
170–7.
Sarwar, H., McGrath, H. Jr. and Espinoza, L.R.
2005. Successful treatment of long-standing neuro-
Behçet’s disease with infliximab. J Rheumatol, 32,
181–3.
Wadia, N. and Williams, E. 1957. Behçet’s syndrome
with neurological complications. Brain, 80, 59–
71.
Wechsler, B., Huong, L.T., de Gennes, L.C., et al. 1989.
Arterial involvement in Behçet’s disease. Rev Med
Interne, 10, 303–11.
Wolf, S.M., Schotland, D.L. and Phillips, L.L., 1965.
Involvement of nervous system in Behçet’s syn-
drome. Arch Neurol, 12, 315–25.
Yurdakul, S., Gunaydin, I., Tuzun, Y. et al. 1988. The
prevalence of Behçet’s syndrome in a rural area in
northern Turkey. J Rheumatol, 15, 820–2.
NICP_C12 03/05/2007 10:39 AM Page 188
Hashimoto’s thyroiditis is caused by a chronic lym-
phocytic inflammation in 3–4% of the population.
It typically occurs in middle-aged women. Affected
individuals may be hypo-, hyper- or euthyroid.
Multiple antithyroid antibodies, most commonly
including those to thyroid peroxidase and thyroglo-
bulin, are present. Ultrasonogram shows hypoechoic
thyroid tissue, and fine-needle biopsy reveals infiltra-
tion by T lymphocytes, plasma cells, and colloid
accumulation and cell detritus in the thyroid gland
(Seipelt et al., 2005).

The first patient with Hashimoto’s thyroiditis
and altered consciousness, myoclonus, and stroke-
like episodes was reported by Brain et al. (1966).
“Hashimoto’s encephalopathy” was soon coined
for the central nervous system (CNS) disorder asso-
ciated with autoimmune thyroiditis and varying
thyroid function. The existence of Hashimoto’s
encephalopathy as an entity, however, has been
debated because of the lack of evidence indicative
of a causative relationship between thyroid auto-
immunity and encephalitis (Sunil and Mariash, 2001).
Mahmud et al. (2003) recently proposed using the
term “Steroid responsive encephalopathy associated
with Hashimoto’s thyroiditis” (SREHT), which is
being adopted here.
SREHT is a rare, potentially life-threatening but
treatable condition characterized by intermittent con-
fusions, impaired consciousness, psychosis, hallu-
cinations, seizures, stroke-like episodes, myoclonus,
and tremor (Shaw et al., 1991). The seizures may be
myoclonic, tonic-clonic generalized, or nonconvul-
sive status epilepticus that is difficult to control. Less
common presentations of SREHT include isolated
global amnesia or amnesia with other features of
encephalopathy ( Jacobs et al., 2006). The clinical
presentation has been attributed to an underlying
vasculitic process. The pathogenic significance of
antithyroid antibodies remains uncertain. These
antibodies are detected in 3–4% of the general
population, and their presence may only indicate a

predisposition to developing multiple autoantibodies
(McKnight et al., 2005). The electroencephalogram
(EEG) typically shows slowing and elevated proteins
may be present in the cerebrospinal fluid (CSF).
Magnetic resonance imaging (MRI) may show
multifocal abnormalities in the cerebral white matter
or brain atrophy, but imaging is unrevealing in
about half of the patients. Autopsy reports usually
reveal perivenular and arteriolar infiltration by pre-
dominantly T lymphocytes throughout the brain
including the hemispheral gray and white matter,
basal ganglia, brainstem, and the leptomeninges.
Diffuse gliosis is present in the cortical and deep gray
matter, hippocampi, and the parenchymal white
matter (Duffey et al., 2003; Nolte et al., 2000;
Shibata et al., 1992). The extent of inflammatory
changes in postmortem studies is often influenced by
the preceding high-dose corticosteroid therapy. The
recent observation that euthyroid patients with auto-
immune thyroiditis have impaired brain perfusion
on single photon emission computed tomography
further supports the relationship between a cerebral
involvement and Hashimoto’s thyroiditis (Zettinig
et al., 2003).
The short list of differential diagnosis for SREHT
includes Creutzfeld–Jakob disease, Sjögren’s syn-
drome, CNS complications of other connective tissue
disorders and vasculitides, which usually can be
sorted out based on EEG, serological and CSF studies,
and thyroid work up. A nonvasculitic autoimmune

inflammatory meningoencephalitis has also been
described in patients with Hashimoto’s thyroiditis,
Sjögren’s syndrome, and systemic lupus erythemato-
sus ( Joseph et al., 2004).
Despite the obscure etiology, SREHT is a treatable
condition. Thyroid replacement therapy alone may
improve some aspects of the cognitive abnormalities,
while the neurological condition best responds to
corticosteroids or plasma exchange.
13
Steroid-responsive encephalopathy associated with
Hashimoto’s thyroiditis
Bernadette Kalman
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190 BERNADETTE KALMAN
Summary
Hashimoto’s thyroiditis may be associated with
a life-threatening but treatable encephalopathy
characterized by altered consciousness, memory
disturbances, seizures, myoclonus, psychosis, and
stroke-like episodes. The causative relationship
between thyroid autoimmunity and encephalitis
remains uncertain, but the CNS pathology displays
signs of a T-cell mediated vasculitic process affecting
both the gray and white matter. A thorough diag-
nostic work up is necessary to distinguish SREHT
from other encephalopathies of immune and non-
immune etiology, and to implement effective treat-
ments as early as possible.
References

Brain, L., Jellinek, E.H. and Ball, K. 1966. Hashimoto’s
disease and encephalopathy. Lancet, 2, 512–14.
Duffey, P., Yee, S., Reid, I.N. and Bridges, L.R.
2003. Hashimoto’s encephalopathy: Postmortem
findings after fatal status epilepticus. Neurology, 61,
1124–6.
Jacobs, A., Root, J. and van Gorp, W. 2006, Isolated
global amnesia associated with autoimmune thy-
roiditis. Neurology, 66, 605.
Josephs, K.A., Rubino, F.A. and Dickson, D.W. 2004.
Nonvasculitic autoimmune inflammatory meningo-
encephalitis. Neuropathology, 24, 149–52.
Mahmud, F.H., Lteif, A.N., Renaud, D.L., Reed, A.M.
and Brands, C.K. 2003. Steroid-responsive encephalo-
pathy associated with Hashimoto’s thyroiditis in
an adolescent with chronic hallucinations and
depression: Case report and review. Pediatrics, 112,
686–90.
McKnight, K., Jiang, Y., Hart, Y. et al. 2005. Serum
antibodies in epilepsy and seizure-associated dis-
orders. Neurology, 65, 1730–6.
Nolte, K.W., Unbehaun, A., Sieker, H., Kloss, T.M.
and Paulus, W. 2000. Hashimoto encephalopathy:
A brainstem vasculitis? Neurology, 54, 769–70.
Seipelt, M., Zerr, I., Nau, R. et al. 1999. Hashimoto’s
encephalitis as a differential diagnosis of Creutzfeldt-
Jakob disease. J Neurol Neurosurg Psychiatry, 66,
172–6.
Sunil, G.S. and Mariash, C.N. 2001. Hashimoto’s
encephalitis. J Clin Endocrinol Metab, 86, 947.

Shaw, P.J., Walls, T.J., Newman, P.K., Cleland, P.G. and
Cartlidge, N.E. 1991. Hashimoto’s encephalopathy:
A steroid-responsive disorder associated with high
anti-thyroid antibody titers – Report of 5 cases.
Neurology, 41, 228–33.
Shibata, N., Yamamoto, Y., Sunami, N., Suga, M.
and Yamashita, Y. 1992. Isolated angiitis of the
CNS associated with Hashimoto’s disease. Rinsho
Shinkeigaku, 32, 191–8.
Zettinig, G., Asenbaum, S., Fueger, B.J. et al. 2003.
Increased prevalence of subclinical brain perfusion
abnormalitis in patients with autoimmune thyroi-
ditis: Evidence of Hashimoto’s encephalitis? Clin
Endocrinol, 59, 637–43.
NICP_C13 03/05/2007 10:40 AM Page 190
Rasmussen et al. (1958) reported three patients
with focal seizures associated with chronic encepha-
litis. Subsequently, the occurrence of chronic focal
encephalitis with seizures was named Rasmussen’s
encephalitis (RE) or Rasmussen’s syndrome (Piatt
et al., 1988). A European consensus statement recently
summarized the accumulated knowledge concern-
ing the pathogenesis, diagnosis, and treatment of RE
(Bien et al., 2005).
RE is a sporadic disorder with unknown etiology.
Because of the lymphocytic infiltration and microglial
activation in the brain lesions, a viral cause was
proposed (Rasmussen et al., 1958). However, sub-
sequent studies failed to unequivocally support a viral
etiology. The cause of immune activation remains

to be determined.
Clinical characteristics
RE usually presents in childhood with six years
the average age of onset, but approximately 10%
of patients have adult onset (Oguni et al., 1991).
Typically, partial motor seizures arise to affect vari-
ous parts in the same side of the body and gradually
expand over time. A focal motor deficit follows the
onset of seizures and gradually progresses to hemi-
paresis. The electroencephalogram (EEG) correlate
of these abnormalities is a unilateral deterioration of
the background activity with focal repetitive rhythmic
discharges migrating from one area of the cortex to
another one, but only in the same side. The question
has been raised if the seizures directly contribute
to neuronal loss and dysfunction or indirectly con-
tribute to further pathological damage and neuro-
logical deterioration by opening the blood–brain
barrier to immune mediators (Bien et al., 2005).
The time course and natural history of RE greatly
vary among patients. In the initial “prodromal
stage,” patients typically have low seizure frequency
and occasionally mild hemiparesis with a median
duration of 7.1 months (0 month to 8.1 years). In the
“acute stage,” the seizures usually present as simple
partial motor seizures or epilepsia partialis continua
(EPC) with rising frequency, and a progressive neuro-
logical deterioration develops with severe hemi-
paresis, hemianopia, cognitive decline, and aphasia,
if the dominant hemisphere is involved. In one-third

of patients, this is the initial presentation of RE.
The median duration of this stage is 8 months (4–
8 months). In the third or “residual stage,” patients
still have frequent seizures but also suffer from per-
manent neurological deficits (Bien et al., 2005).
The seizures in RE are characterized by polymor-
phism, frequent occurrence of EPC, and resistance to
therapy. In the series of Oguni et al. (1991), simple
partial motor seizures with unilateral motor deficits
was the most common presentation noted in 77% of
cases. Secondary generalized tonic-clonic seizures were
detected in 42%, complex partial seizures with auto-
matisms in 19%, and with subsequent unilateral motor
spread in 31% of patients, while postural seizures were
noted in 24% and somatosensory seizures in 21% of
their 48 patients. EPC was observed in 56–92% of
patients (Granata et al., 2003; Oguni et al., 1991).
RE is very rarely associated with bilateral cerebral
involvement with secondary spread of focal seizures
or interictal activity and atrophy in the contralateral
hemisphere (Hart and Andermann, 2000).
Immune abnormalities
The original observation implicating antibodies to
the subunit 3 of the ionotropic glutamate receptor
(GluR3) in RE was made in rabbits, which developed
RE-like pathology and seizures after immunization
with a GluR3 fusion protein for raising antibodies.
Rogers et al. (1994) detected anti-GluR3 antibodies
in the sera of three out of four patients with RE, one of
whom responded to plasma exchange. Plasmapheresis

or selective IgG immunoabsorption then became
the standard treatment, but with varying success
(Andrews et al., 1996; Antozzi et al., 1998). While
14
Rasmussen’s encephalitis
Bernadette Kalman
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192 BERNADETTE KALMAN
evidence suggests that anti-GluR3 antibodies mediate
cytotoxic activation of the glutamate receptor in vitro
and in vivo (Levite and Hermelin, 1999; Twyman
et al., 1995) with or without complement activation
in neurons and glial cells (He et al., 1998; Whitney
and McNamara, 2000), recent studies argue against
the specificity of GluR3 antibodies in RE. GluR3 anti-
bodies are not present in the sera and cerebrospinal
fluid (CSF) of all patients with RE, while they are
detected in the sera and CSF of patients with other
types of epilepsy syndromes in a proportion similar
to that found in RE (Mantegazza et al., 2002; Wiendl
et al., 2001). Therefore, the pathogenic significance
and diagnostic relevance of anti-GluR3 antibodies in
RE have been rejected. However, observations sup-
port an immunoglobulin and complement-mediated
pathogenesis, and ongoing research is investigating
the role of antibodies other than anti-GluR3 in RE
(Lang et al., 2004; Yang et al., 2002). Most recently,
antibodies to human α7 nicotinic acetylcholine
receptors (α7nAChR) were detected in two patients
with acute phase disease out of nine patients with

RE (Watson et al., 2005). These antibodies blocked
acetylcholine-induced increase in intracellular free
calcium and inhibited
125
I-α-bungarotoxin bind-
ing in cells expressing α7nAChR. The authors
postulate that these antibodies may act by blocking
the α7nAChR that influence the release of a variety
of excitatory neurotransmitters in the brain. In
addition, these antibodies themselves may mediate
immune attacks on neurons.
A study of inflammatory infiltrates in brains of
RE patients revealed T cells with restricted T-cell
receptor (TCR) Vβ utilization and CDR3 (complement-
arity determining region 3) conservation, suggest-
ing the expansion of a few T-cell clones in RE lesions
(Li et al., 1997). It was also proposed that cytotoxic T
lymphocytes with granzyme B granules may attack
neurons expressing major histocompatibility com-
plex (MHC) class I antigens and induce neuronal
apoptosis (Bien et al., 2002). Cleavage of the GluR3
molecule by granzyme B may generate immuno-
genic epitopes for further cellular and humoral
activation (Gahring et al., 2001). However, in the
light of conflicting observations concerning the role
of GluR3-specific antibodies in the pathogenesis of
RE, this latter observation needs to be interpreted
with caution, and the antigen specificity of cytotoxic
T cells remains to be determined (Bien et al., 2005).
Nevertheless, these studies suggest that RE is a prim-

arily T-cell driven and immunoglobulin-mediated
autoimmune condition.
Pathology
Robitaille (1991) classified the cortical pathology of
RE into four stages that were recently adapted and
further refined by Pardo et al. (2004) based on a
comprehensive work up of 45 patients who under-
went hemispherectomy for the treatment of RE.
The four stages are characterized by the following
changes:
1 Early stage: Focal inflammation, focal microglial
and astroglial reaction, minimal or no neuronal
injury, and perivascular or perineural T lympho-
cytes in the superficial and deep neuronal layers
of the cerebral cortex.
2 Intermediate stage: Increase in the magnitude
of lymphocytic infiltration as well as in the
microglial and astroglial reactions from focal
to panlaminar distribution. Neuronal injury is
evidenced by the presence of cytoplasmic and
nuclear changes and by the increased amounts of
perineuronal satellitosis. Neuronal degeneration,
patchy neuronal dropout, and cytoarchitectural
changes are also present. The lymphocytes are
predominantly CD3+ T cells with predominantly
CD8, but also CD4 expression. The presence of
B cells and plasma cells is not characteristic.
3 Late stage: Significant decrease in the neuronal
population in large focal or panlaminar distribu-
tion along with gemistocytic astroglial reaction

and microglial activation. Cortical atrophy and
focal spongiosis are present.
4 End stage: Extensive destruction of the cerebral
cortex with signs of cortical vacuolation or com-
plete panlaminar neuronal dropout. Residual
astrogliosis with minimal or no inflammatory
changes are characteristic.
These histological observations are consistent with
a progressive immune-mediated process of neuronal
damage associated with T lymphocytic and neuro-
glial responses similar to that noted in other auto-
immune central nervous system (CNS) diseases.
This study also emphasizes the multifocal distribu-
tion of pathology and the intraindividual hetero-
geneity of stages in cortical lesions. The patchy
nature of pathology implies that the site of biopsy,
if needed, has to be carefully determined in early
suspected RE, and that partial cortical resection
cannot be therapeutic. The earlier the onset and the
longer the duration of RE the heavier is the dis-
ease burden, which underscores the importance
NICP_C14 04/05/2007 12:25PM Page 192
Rasmussen’s encephalitis 193
of aggressive and early therapeutic interventions
(Pardo et al., 2004).
Electroencephalogram, EEG
Polymorphic delta waves mixed with epileptiform
activity can be detected early during the course over
the affected hemisphere in most patients. In later
stages, the background activity further deteriorates,

and epileptiform discharges may occur not only over
the ipsilateral but also over the contralateral hemi-
sphere. Multifocal ictal discharges are usually seen
only in the affected side. Subclinical ictal activity
may also occur.
Imaging
Despite the inflammatory nature of pathology,
gadolinium enhancement on T1-weighted MRI is
very rare in RE (Bien et al., 2002; Granata et al., 2003).
A progressive tissue loss is the predominant feature
noted in longitudinal MRI monitoring (Fig. 14.1)
(Bien et al., 2002, 2005; Chiapparini et al., 2003).
Initially, a unilateral enlargement of CSF compart-
ments, particularly in the peri-insular/peri-Sylvian
region, with T2-weighted and FLAIR hyperintensity
and occasional swelling in the cortical/subcortical
regions may be noted. In addition to the hemispheral
atrophy, the head of the caudate nucleus may also
be diminished. The atrophic changes gradually pro-
gress across the hemisphere. No calcification develops
in the chronic atrophied lesions. In correlation with
these images, Bien et al. (2002) also noted higher
numbers of T lymphocytes and activated glial cells in
the earlier as compared to later surgical specimens
in 10 patients who were serially scanned and under-
went surgical procedures. In another serial MRI
study of seven children with pathology-proven RE
between 12 months before and nine months after
the onset of EPC, Kim et al. (2002) identified three
patterns:

1 Normal initial MRI followed by hyperintensity
and cortical atrophy over time.
2 Initial focal hyperintensity followed by decrease
in extent and degree of signal intensity.
3 Sustained hyperintensity on all follow-up scans.
Positron emission tomography (PET) and single
photon emission computer tomography (SPECT)
typically show decreased metabolism in the inter-
ictal, and hypermetabolism in the ictal scans. These
(a) (b)
Fig. 14.1 Axial FLAIR images of a patient with RE. The onset of RE started with EPC initially affecting the right side of the face at
age 7.5 years in this patient. MRI image (a) at age 8.5 years shows slight atrophy with hyperintense signal in the left hemisphere.
The second image (b) four years later reveals marked left hemiatrophy. A few months later, the patient underwent hemispheral
deafferentation. Histology showed typical features of RE. Since surgery, the patient has been free of seizures. The MRI studies
were performed by Horst Urbach, M.D., Department of Radiology/Neuroradiology, University of Bonn, Germany, and generously
provided by Christian G. Bien, M.D., Department of Epileptology, University of Bonn, Germany.
NICP_C14 04/05/2007 12:25PM Page 193
194 BERNADETTE KALMAN
images may guide brain biopsy, if needed, for sup-
porting the diagnosis.
Cerebrospinal fluid, CSF
CSF studies are primarily needed to exclude the
possibility of encephalitis of infectious etiology. Half
of the patients with RE have normal CSF, while the
remaining patients have mild lymphocytic pleocy-
tosis, mildly elevated protein, and occasionally
oligoclonal bands.
Diagnostic criteria for RE
Clinical, EEG, and MRI characteristics usually make
the diagnosis of RE straightforward (Box 14.1) and

leave only a short list of differential diagnoses. The
alternative diagnoses may include viral, paraneo-
plastic, or other autoimmune forms of encephalitides
(e.g. anti-voltage-gated potassium channel (VGKC)
antibody-mediated limbic encephalitis, Hashimoto
encephalitis, vasculitides), unihemispheric epileptic
syndromes (cortical dysplasia, tuberous sclerosis,
stroke, Sturge–Weber syndrome), inherited metabolic
disorders (mitochondrial encephalopathies, Alpers
syndrome, Kufs disease), and acquired metabolic
disorders associated with EPC (ketotic or nonketotic
hyperglycaemia, type I diabetes and anti-GAD65
antibodies, renal and hepatic encephalopathies)
(Bien et al., 2005).
Treatment
To prevent the progressive tissue loss and clinical
deterioration, an early diagnosis with immune mod-
ulatory (corticosteroids, plasma exchange, immuno-
suppression) intervention or epilepsy surgery is
necessary as soon as possible. Symptomatic treat-
ments with antiepileptic drugs alone have consist-
ently failed to control seizures in RE. Corticosteroids,
plasmapheresis, IVIg, IgG immunoabsorption tech-
niques, immunosuppression with tacrolimus, and
the combination of these methods have resulted in
variable outcomes, but only delayed the inevitable
hemispherectomy (Bien et al., 2005). The effective-
ness of immune ablative therapies is currently being
investigated.
Epilepsy surgery is eventually needed in all cases.

Focal cortical resections are ineffective. Hemi-
spherectomy or modern disconnective techniques are
the only treatments that efficiently control seizures
in RE. The latter techniques are superior because of
the low procedure-related morbidity and no mortal-
ity. The timing of surgery has to be individually evalu-
ated taking into account potential consequences
of surgery (hemiparesis, hemianopia, and language
dysfunction in the case of the dominant hemisphere)
and the damage caused by the ongoing pathology
and seizure activity. Earlier surgery is advocated
when the pathology is in the left hemisphere and
the child approaches the teenage years (Freeman,
A
1 Clinical: Focal seizures with or without
EPC and unilateral cortical deficits
2 EEG: Unilateral slowing with or without
epileptiform discharges and unilateral
seizure onset
3 MRI: Unilateral focal cortical atrophy
and at least one of the following:
– Hyperintense T2/FLAIR signal in
gray and white matter
– Hyperintense T2/FLAIR signal or
atrophy in the ipsilateral caudate head
B
1 Clinical: EPC or progressive unilateral
cortical deficits
2 MRI: Progressive unilateral focal cortical
atrophy

3 MRI: Histopathology: T-cell dominated
encephalitis, activated microglial cells
and reactive astrogliosis; no significant
presence of parenchymal macrophages,
B cells or plasma cells and absence of
viral inclusion bodies
RE can be diagnosed if all three criteria
of part A or two of three criteria in part B
are present. Consideration of Part B is
recommended only if the criteria in part A
are not fulfilled. MRI needs to be performed
with gadolinium to exclude enhancement,
and a CT scan is necessary to exclude
calcification. Gadolinium enhancement
and calcification are features noted in
unihemispheric vasculitis but not in RE.
Box 14.1 Diagnostic criteria for RE (after Bien et al., 2005).
NICP_C14 04/05/2007 12:25PM Page 194
Rasmussen’s encephalitis 195
2005). Complications of surgery potentially include
intraoperative bleeding, hydrocephalus usually fol-
lowing surgery by a few days to weeks, and super-
ficial cortical hemosiderosis with hydrocephalus
10–20 years after the surgery. With the advent of
computer tomography (CT) and MRI, early recog-
nition and surgical treatment (shunting) of these
complications became possible (Freeman 2005).
Summary
RE is considered to be a T-cell driven and
immunoglobulin-mediated disorder of the brain

with progressive unihemispheral tissue loss, accumu-
lation of contralateral motor deficits, and seizures.
The seizures are characterized by polymorphisms,
EPC, and resistance to therapy. The multifocal
distribution of pathology and the various stages of
cortical lesions suggest that the site of biopsy, if
needed, has to be carefully chosen in an early
disease and that a partial resection cannot be thera-
peutic. Immune modulatory treatments may delay
but do not circumvent the ultimately always
necessary hemispherectomy or disconnective sur-
gical interventions.
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1994. Autoantibodies to glutamate receptor GluR3
in Rasmussen’s encephalitis. Science, 265, 648–51.
Twyman, R.E., Gahring, L.C., Spiess, J. and Rogers, S.W.
1995. Glutamate receptor antibodies activate a
subset of receptors and reveal an agonist binding
site. Neuron, 14, 755–62.
NICP_C14 04/05/2007 12:25PM Page 195
196 BERNADETTE KALMAN
Watson, R., Jepson, J.E.S., Bermudez, I., et al. 2005. α7-
Acetylcholine receptor antibodies in two patients with
Rasmussen encephalitis. Neurology, 65, 1802–4.
Whitney, K.D. and McNamara, J.O. 2000. GluR3
autoantibodies destroy neural cells in a complement-
dependent manner modulated by complement regu-
latory proteins. J Neurosci, 20, 7307–16.
Wiendl, H., Bien, C.G., Bernasconi, P. et al. 2001.
GluR3 antibodies: Prevalence in focal epilepsy but no
specificity for Rasmussen’s encephalitis. Neurology,
57, 1511–14.
Yang, R., Puranam, R.S., Butler, L.S. et al. 2000.
Autoimmunity to munc-18 in Rasmussen’s encepha-
litis. Neuron, 28, 375–83.
NICP_C14 04/05/2007 12:25PM Page 196
Susac et al. (1979) described the triad of encephalo-
pathy, branch retinal artery occlusion, and deafness

as a microangiopathy syndrome of the brain, retina,
and cochlea; and Hoyt coined the term “Susac’s
syndrome” (Neuroophthalmological Symposium,
San Francisco, 1986). The prevalence of Susac’s
syndrome is unknown, but numerous cases, pre-
dominantly women aged 16–58, have been reported.
The female to male ratio is 3:1. The disorder is often
misdiagnosed as multiple sclerosis (MS) or acute dis-
seminated encephalomyelitis (ADEM) (Susac, 1994;
Susac et al., 2003).
Clinical characteristics
The course is usually relapsing-remitting or less
frequently progressive, and becomes self-limited
after 2–4 years with usually mild residual visual,
hearing, or cognitive symptoms. A proportion of
patients develop the sequelae of severe deafness and
moderate dementia. Patients may not be aware of
their hearing loss or visual impairment, particularly
when the first symptom is encephalopathy. Some
affected individuals present with incomplete triad
(Susac, 1994).
Encephalopathy
Headaches frequently precede by a month or several
months or coincide with the onset of a subacute
encephalopathy. Migraine headaches are most fre-
quently seen in those patients who present with
branch retinal artery occlusion or hearing loss. The
subacute encephalopathy usually presents with con-
fusion, memory disturbances, bizarre or paranoid
behavioral changes, and other psychiatric features.

The encephalopathy occasionally progresses to stupor.
The most characteristic neurological abnormalities
include bilateral extensor plantar responses and
pseudobulbar speech. Myoclonus and seizures also
may develop. Some patients have focal neurological
signs reflecting brainstem or cerebellar lesions, or
transient paresthesias and hemiparesis not to be
confused with transient ischemic attacks.
Branch retinal artery occlusion
The sequence of index events varies. The branch
retinal artery occlusion may be a presenting symp-
tom or follow the onset of the encephalopathy.
The arterial occlusions are usually bilateral, and the
infarcts involve varying segments of the retina with
striking or unnoticed subjective visual impairment,
depending on the central or peripheral location of
infarcts (Fig. 15.1). Fluorescein angiography is a
helpful tool for the diagnosis of branch retinal artery
occlusions. In chronic stages, silver streaks replace
the appearance of occluded arterioles in the fundus.
Retinal artery wall (Gass) plaques may preferentially
occur in the mid-segments of retinal arterioles.
Hearing loss
Bilateral hearing loss, tinnitus, vertigo, and nystagmus
may also be the presentation of Susac’s syndrome.
The underlying pathology includes microinfarcts in
the apical part of the cochlea and in the semicircular
canals resulting in hearing loss predominantly for
the low to moderate frequency tones and prominent
jerk nystagmus, respectively (Susac, 1994).

Paraclinical studies
Electroencephalogram (EEG) may reveal diffuse
slowing during an acute episode of encephalopathy.
T2-weighted and FLAIR (fluid-attenuated inversion
recovery) MRI (magnetic resonance imaging) images
demonstrate microinfarcts in the periventricular
white matter, centrum semiovale, corpus callosum, as
well as in the deep and cortical gray matter, cerebel-
lum, and brainstem (Fig. 15.2). In acute and subacute
phases, the lesions may enhance on T1-weighted
15
Susac’s syndrome
Bernadette Kalman
NICP_C15 03/05/2007 10:41 AM Page 197
198 BERNADETTE KALMAN
postgadolinium images. Leptomeningeal enhance-
ment may also be seen. The typically 3–7 mm in
size, or occasionally larger, snowball-type of central
callosal lesions are distinct from the undersurface
plaques of MS and ADEM, and follow the distribu-
tion of the microvasculature with infarcts and holes
in the central fibers. The inclusion of thin, sagittal
T1 and T2/FLAIR-weighted images may facilitate
the detection of lesions. Nevertheless, small cortical
lesions noted in biopsied specimens are usually missed
by current imaging techniques. Infarcted regions
undergo atrophy in chronic stages. Increased pro-
tein levels in the range of 100 mg to 3 g and mild
pleocytosis have been noted in the cerebrospinal
fluid (CSF). The pathology of microangiopathy is

usually undetectable by conventional angiography.
Laboratory tests for connective tissue disorders,
coagulapathy, or infectious diseases are unrevealing.
The sedimentation rate is elevated in some cases.
Pathological evaluations of biopsied brain tissues
revealed chronic stages of angiitis with thickening
and sclerosis in the media and adventitia of precapil-
lary arterioles, multiple infarcts, gliosis, and neuronal
loss (Bogousslavsky et al., 1989; Monteiro et al., 1985;
Susac et al., 1979). Necrosis is not present in the vessel
walls, therefore, the use of term “vasculopathy” is
(a) (b)
(a) (b)
Fig. 15.2 Brain MRI in Susac’s syndrome. Coronal (a) and sagittal (b) FLAIR images of the brain show multiple hyperintense
lesions in the periventricular and subcortical white matter, centrum semiovale, and the deep nuclei and cortical gray matter.
Note the snowball-like lesions on both the coronal and sagittal MRI. The images are from a 24-year-old male patient who
developed encephalopathy and headaches, followed by hearing loss and branch retinal artery occlusion. He was treated with
steroids and IVIg, and went back to work a year after the onset of symptoms. Courtesy of Dr. John O. Susac, Winterhaven, FL.
Fig. 15.1 Branch retinal
artery occlusion. (a) Right
fundus with branch retinal
artery occlusion. The picture
shows multiple retinal
infarcts including the
macular region (partial
cherry-red spot). (b) Left
fundus with asymptomatic
branch retinal artery
occlusion. The patient was
left with 20/30 and dense

nasal field defect in the right
eye, but 20/20 and full field in
the left. Courtesy of Dr. John
O. Susac, Winterhaven, FL.
NICP_C15 03/05/2007 10:41 AM Page 198
Susac’s syndrome 199
more correct than “vasculitis” in this condition. The
hypothesis of an immune-mediated etiology recently
gained support by the identification of antiendo-
thelial cell antibodies in these patients (Susac et al.,
2005).
Therapy
The course of Susac’s syndrome is usually self-
limited and patients have been empirically treated.
Nevertheless, there is now sufficient experience to treat
the disease with immunosuppression. Steroids are the
mainstay in conjunction with intravenous immuno-
globulins and cyclophosphamide (Rennebohm and
Susac, 2005; Susac, 1994, 2004). Patients with severe
hearing loss may benefit from cochlear implants.
Summary
Susac’s syndrome is a recently described triad of
encephalopathy, branch retinal artery occlusion,
and deafness associated with an immune-mediated
microangiopathy of the brain, retina, and cochlea.
While its distinct imaging characteristics have been
well described, its immune pathogenesis is the subject
of active ongoing research. Recommended empirical
treatment modalities include corticosteroids, intra-
venous immunoglobulins, and cyclophosphamide.

References
Bogousslavsky, J., Gaio, J.M., Caplan, L.R. et al.
1989. Encephalopathy, deafness and blindness
in young women: A distinct retinocochleocerebral
arteriolopathy? J Neurol Neurosurg Psychiatry, 52,
43–6.
Monteiro, M.L., Swanson, R.A., Coppeto, J.R., Cuneo,
R.A., DeArmond, S.J. and Prusiner, S.B. 1985.
A microangiopathic syndrome of encephalopathy,
hearing loss, and retinal arteriolar occlusions. Neuro-
logy, 35, 1113–21.
Rennebohm, R.M. and Susac, J.O. 2005. Treatment of
Susac’s syndrome. Presented at the Fourth Inter-
national Congress on Vascular Dementia. Porto,
Portugal, October 21.
Susac, J.O. 1994. Susac’s syndrome: The triad of
microangiopathy of the brain and retina with hear-
ing loss in young women. Neurology, 44, 591–3.
Susac, J.O. 2004. Susac’s syndrome. Am J Neuroradiol,
25, 351–2.
Susac, J.O., Egan, R.A. and Rennebohm, R.M. Susac’s
syndrome: 1975–2005. 2005. Microangiopathy/
Autoimmune endotheliopathy. Presented at the
Fourth International Congress on Vascular Dementia.
Porto, Portugal, October 21.
Susac, J.O., Hardman, J.M. and Selhorst, J.B. 1979.
Microangiopathy of the brain and retina. Neurology,
29, 313–16.
Susac, J.O., Murtagh, F.R., Egan, R.A. et al., 2003.
MRI findings in Susac’s syndrome. Neurology, 61,

1783–7.
NICP_C15 03/05/2007 10:41 AM Page 199
David Cogan (1945) reported four patients with
nonsyphilitic interstitial keratitis (IK) and Ménière’s-
like syndrome including vertigo, ataxia, tinnitus,
nausea, vomiting, and hearing loss; and recognized
the constellation of these abnormalities as an entity.
Haynes et al. (1980) and Vollertsen et al. (1986)
reviewed their own case series of 13 and 18 patients
with Cogan’s syndrome (CS) along with those in
the literature. St. Clair et al. (1999) reviewed epi-
demiological, clinical, and basic science data of the
disorder. Grasland et al. (2004) reported 32 patients
with typical and atypical CS from a multicenter series
along with reviewing the literature. Haynes et al.
(1980) and Grasland et al. (2004) proposed that
the definition of CS should be extended to include
patients not only with IK and audiovestibular symp-
toms, but also with additional ocular and systemic
manifestations. Up to date, fewer than 250 cases with
CS have been reported, but the figure continues to
grow (Cundiff et al., 2006; Grasland et al., 2004).
Clinical characteristics
CS predominantly affects young adults without
gender predominance. Occasionally, children and
elderly people may also be affected. IK is associated
with pain, photophobia, blurred vision, and redness
of the eye. Slit-lamp examination is necessary to reveal
the granular corneal infiltrates. In early stages, the
corneal finding may resemble viral keratitis. In most

cases, IK is bilateral. In atypical cases, conjunctivitis,
episcleritis, scleritis, uveitis, retinal vasculitis and
hemorrhage, optic neuritis, glaucoma, central retinal
artery trombosis, xerophthalmia, ptosis, or papilla
edema may develop with or without IK (Haynes et al.,
1980; Grasland et al., 2004; St. Clair et al., 1999;
Vollertsen et al., 1986).
The vestibulocochlear dysfunction presents with
acute Ménière’s-like symptoms including vertigo,
nausea, vomiting, tinnitus, and hearing loss. Oscill-
opsia occurs secondary to the vestibular dysfunction.
The vestibular abnormalities may be assessed by
caloric, electronystagmographic, and rotational tests.
Audiometry usually shows sensorineural hearing
loss and poor speech discrimination (St. Clair et al.,
1999). The hearing loss is often bilateral. The symp-
toms may fluctuate, but eventually permanent hear-
ing loss develops in a great proportion of patients.
While the involvement of eyes and ears is typically
isolated, a subgroup of patients develops signs of
systemic vasculitis resembling Takayasu’s arteritis
and polyartheritis nodosa. Systemic manifestations
have been reported in up to 78% of patients with
CS (Grasland et al., 2004). Active vasculitis may be
associated with constitutional features such as fever
and weight loss. Secondary occlusions of the coron-
ary arteries, aortic aneurism and stenosis, or aortic
valve regurgitation may develop. Veins can also be
affected by inflammatory changes. Systemic necrot-
izing vasculitis can cause a severe multiorgan dis-

order with gastric ulcers, claudication in the limbs,
mesenteric insufficiency, stenosis, and spontaneous
ruptures of major vessels. CS may occur in associ-
ation with Crohn’s disease and ulcerative colitis.
Central and peripheral nervous system involvement
such as cerebellar or meningeal syndromes and
peripheral neuropathy is detected in up to 50% of
patients (Albayram et al., 2001).
Diagnostic criteria
The current diagnostic criteria for typical CS in-
clude: (i) ocular symptoms of nonsyphilitic IK that
may be associated with conjunctivitis, conjuctival or
subconjuctival bleeding, or iritis; (ii) audiovestibular
symptoms similar to those of Ménière’s syndrome
usually progressing to deafness in 1–3 months; and
(iii) a less than two-year interval between the index
events. Diagnostic criteria for atypical CS include:
(i) additional inflammatory ocular symptoms –
as detailed above; (ii) typical ocular manifestation
associated in two years with an audiovestibular
16
Cogan’s syndrome
Bernadette Kalman
NICP_C16 03/05/2007 10:42 AM Page 200
Cogan’s syndrome 201
symptom different from Ménière’s-like episodes;
and (iii) an episode longer than two years between
the typical index events (Grasland et al., 2004;
Haynes et al., 1980).
Paraclinical findings

Cranial MRI and CT typically show normal brain
structures, but reveal abnormal soft tissues and
calcification in the vestibular system and cochlear
labyrinth. Gadolinium enhancement may be seen
in these structures in acute stages.
The pathology of CS shows chronic inflammation
with lymphocytic infiltration in early stages, and
neovascularization and scarring in late stages in
the corneal tissue. Histologic exams of the temporal
bones reveal lymphocytic infiltrates in the spiral
ligament, endolymphatic hydrops, and degenerative
changes of the sensory receptors and supporting
structures in the cochlea and the vestibular appar-
atus. The inflammatory process in the extracellular
matrix of the inner ear leads to endolymphatic
hydrops. The degree of matrix accumulation cor-
relates with the severity of hearing loss in animal
studies. Ossification of the cochlea is a late and
severe complication that develops if the inflam-
matory process is not treated early and aggressively
(St. Clair et al., 1999). Demyelination and degenera-
tion may be seen in the vestibular and cochlear
branches of the VIIIth nerve.
Although the onset of CS is often preceded by upper
respiratory tract infections, the etiology remains
unknown. Because of the similarities between syphilis
and CS, investigators implicated spirochetes such
as Borrelia burgdorferi in the pathogenesis, but no
direct proof was found. Similarly, the involvements
of Chlamydia trachomatis, pneumoniae and psittaci

remain uncertain. Based on histologic changes in
the affected tissues, an underlying immune mechan-
ism has been postulated. The detection of humoral
and cellular immune response to inner ear and corneal
or retinal antigens supported the autoimmune hypo-
thesis of CS (St. Clair et al., 1999), which was fur-
ther strengthened by the presence of rheumatoid
factor and antineutrophil antibodies in some patients
(Hughes et al., 1983; Ikeda et al., 2002). Using pooled
immunoglobulins of eight patients with CS for the
screening of a random peptide library, Lunardi et al.
(2002) identified an immunodominant peptide similar
to autoantigens such as SSA/Ro and reovirus III
major core protein lambda I. The peptide sequence
shared similarities with the cell-density enhanced
protein tyrosine phosphatase-1 (DEP-1/CD148),
which is expressed by the sensory epithelia in the
inner ear and by endothelial cells. IgG purified from
patients’ sera recognized the DEP-1/CS148 protein,
bound to connexin 26 and human cochlea, and
exerted antiproliferative effects on cells expressing
DEP-1/CD148. These antibodies also had the capa-
city to induce a disease resembling CS in mice.
By computer-assisted search, Benvenga et al. (2003)
further explored the concept of molecular mimicry
and identified additional potential antigenic deter-
minants mostly including adhesion molecules
expressed in the inner ear.
Therapy
Systemic corticosteroids for the vestibulocochlear

and topical corticosteroids for the ocular inflamma-
tion remain the mainstay of treatment. Occasion-
ally, azathioprine or cyclophosphamide is necessary
in steroid-resistant cases. For patients with perman-
ent hearing loss, cochlear implants may offer some
benefit.
Summary
CS is a rare disorder characterized by nonsyphilitic
IK and Ménière’s-like syndrome. Additional ocular
and systemic manifestations of the disease were also
recognized leading to a wider definition of CS. The
pathology of affected organs includes lymphocytic
infiltrates in early and degenerative changes in late
stages of the disease. While the etiology remains
unknown, recent studies implicate molecular mimicry
in the pathogenesis, and identify adhesion molecules
expressed in the inner ear as potential antigenic
determinants of autoreactive immunoglobulins.
References
Albayram, M.S., Wityk, R., Yousem, D.M. and
Zinreich, S.J. 2001. The cerebral angiographic
findings in Cogan syndrome. AJNR Am J Neuroradiol,
22, 751–4.
Benvenga, S. and Trimarch, F. 2003. Cogan’s syndrome
as an autoimmune disease. Lancet, 361, 530–1.
Cogan, D.S. 1945. Syndrome of nonsyphilitic inter-
stitial keratitis and vestibuloauditory symptoms. Arch
Ophthalmol, 33, 144–9.
Cundiff, J., Kansal, S., Kumar, A., Goldstein, D.A. and
Tessler, H.H. 2006. Cogan’s syndrome: A cause of

progressive hearing deafness. Am J Otolaryngol, 27,
68–70.
NICP_C16 03/05/2007 10:42 AM Page 201
202 BERNADETTE KALMAN
Grasland, A., Pouchot, J., Hachulla, E., Bletry, O., Papo, T.
and Vinceneux, P.; Study Group for Cogan’s Syn-
drome. 2004. Typical and atypical Cogan’s syndrome:
32 cases and review of the literature. Rheumatology
(Oxford), 43, 1007–15.
Haynes, B.F., Kaiser-Kupfer, M.I., Mason, P. and
Fauci, A.S. 1980. Cogan syndrome: Studies in
thirteen patients, long-term follow-up, and a review
of the literature. Medicine, 59, 426–41.
Hughes, G.B., Kinney, S.E., Barna, B.P., Tomsak, R.L.
and Calabrese, L.H. 1983. Autoimmune reactivity in
Cogan’s syndrome: a preliminary report. Otolaryngol
Head Neck Surg, 91, 24–32.
Ikeda, M., Okazaki, H. and Minota, S. 2002. Cogan’s
syndrome with antineutrophil cytoplasmic autoanti-
body. Ann Rheum Dis, 61, 761–2.
Lunardi, C., Bason, C., Leandri, M. et al. 2002. Auto-
antibodies to inner ear and endothelial antigens in
Cogan’s syndrome. Lancet, 360, 915–21.
St. Clair, E.W. and McCallum, R.M. 1999. Cogan’s syn-
drome (Vasculitis syndromes). Curr Opin Rheumatol,
11, 47–52.
Vollertsen, R.S., McDonald, T.J., Younge, B.R., Banks,
P.M., Stanson, A.W. and Ilstrup, D.M. 1986. Cogan’s
syndrome: 18 cases and a review of the literature.
Mayo Clin Proc, 61, 344–61.

NICP_C16 03/05/2007 10:42 AM Page 202
The recognition of sarcoidosis started with the
description of a skin lesion (Hutchinson, 1869). Boeck
(1899) reported the histological characteristics of
lesions in a patient with skin involvement and
lymphadenopathy. Subsequently, Heerford (1909)
discussed three patients with iridocyclitis and paro-
titis, plus optic neuritis in one case; facial paresis
and dysphagia in another one; and facial paresis and
sensory symptoms in the third case, giving rise to the
eponym of Heerford’s syndrome for the set of uveitis,
parotitis, fever, and facial palsy. Schumann (1916)
emphasized the multiorgan nature of pathology and
established sarcoidosis as an entity. Colover (1948)
presented in detail the most common neurological
manifestations of the disease, and Delaney (1977)
identified 244 patients with neurosarcoidosis among
5092 patients with sarcoidosis in the literature (5%).
The etiology of sarcoidosis is unknown. The peak
age of onset is between 20 and 40 years with a slight
female predominance. The lifetime risk for sarcoidosis
is 0.85% for whites and 2.4% for blacks in the US.
Scandinavian whites, however, have a risk for sarc-
oidosis similar to that of US blacks. While the disease
is generally considered sporadic, a genetic suscept-
ibility to certain environmental factors is possible.
Several viruses and bacteria have been implicated
in lesion development, but the findings remain to be
replicated. Even though the pathology of sarcoidosis
shows great similarities to those of granulomatous

infections, particularly tuberculosis, the presence of
microbes could not be demonstrated. Associations
of human leukocyte antigen (HLA) and protein trans-
porter gene alleles with sarcoidosis have been extens-
ively investigated (Burns, 2003; Zajicek, 2000). By
fine mapping of the HLA region identified as a sus-
ceptibility locus in a full-genome scan (Schurmann
et al., 2001), recently a variant of the butyrophilin-
like 2 (BTNL2) gene was found to be associated
with the disease in German, North-American white,
and African American cohorts (Rybicki et al., 2005;
Valentonyte et al., 2005). This association appeared
to be independent of the DRB1 gene locus. A BTNL2
single nucleotide polymorphism (G->A) leads to the
introduction of a cryptic splice site and results in a
premature stop in the spliced mRNA. The protein
product is lacking its transmembrane part and has
disturbed membrane localization, thereby preventing
the costimulatory function of the molecule. Although
further studies are needed to better understand the
role of the BTNL2 molecule in the development of
sarcoidosis, the above finding appears to be another
break through in the elucidation of how a genetic
variant can contribute to a disease phenotype.
Clinical characteristics
Sarcoidosis is a multiorgan granulomatous disorder
with a predominant involvement of the lung and
lymphoid system. Uveitis, iridocyclitis, parotitis, and
polyarthritis are also relatively common, but any
organ may be affected. The most frequently affected

parts of the nervous system include the anterior optic
pathway (retina, optic nerves, chiasm, and tracts) and
cranial nerves VII, IX, and X. However, pathological
changes may develop in any other cranial nerves.
In the fundus, optic disc pallor, edema or granuloma,
periphlebitis or vascular sheathing may be seen.
Less frequent ophthalmoscopic findings include disc
hemorrhage, optic disc telangectasia, macular exud-
ates, optic disc shunt vessels, and vitreous “snowballs”
(Frohman et al., 2003). The granulomatous infiltrate
can also invade the pars intermedia of the pituitary
gland and pituitary stalk, and cause meningoencep-
halitis and meningomyelitis or tumor-like growth in
various axial or extra-axial central nervous system
(CNS) structures. Consequently, patients present with
diabetes insipidus, abulia, visual field defects, seizures,
cognitive decline, dementia, focal neurological symp-
toms, myelopathy, or cauda equine syndrome.
Pachymeningitis or tumor-like lesions can lead to
the development of communicating and noncommun-
icating (obstructive) hydrocephalus. Polyradiculitis,
17
Neurosarcoidosis
Bernadette Kalman
NICP_C17 04/05/2007 02:43PM Page 203
204 BERNADETTE KALMAN
plexopathies, polyneuritis, mononeuritis, and mono-
neuritis multiplex result from granulomas localized
in the perineurium and the epineurium with local
effects of demyelination and axonal damage. How-

ever, granulomas in the muscle, vasa nervorum, or
the arterioles to the muscle may also cause nerve
damage. The muscle pathology is often asymptomatic
and overlooked, but muscle biopsy may reveal pos-
itive findings in a great proportion of cases. Fatigue
is a frequent nonlocalizing complaint of patients
with neurosarcoidosis (Burns, 2003; Kellinghaus,
2004).
Paraclinical findings
The lesions are composed of noncaseating epithelioid
cell granulomas surrounded by lymphocytes. An
extensive general work up is necessary to define the
distribution of pathology. Biopsy of systemic or cent-
ral and peripheral nervous system (CNS and PNS)
lesions is usually needed to establish the diagnosis
and to exclude the possibility of other granulomatous
disorders. X-ray of the chest is frequently false
negative (Kellinghaus et al., 2004). Chest computer-
ized tomography (CT) and fiberoptic bronchoscopy
with bronchoalveolar lavage usually better support
the diagnosis. A positive mediastinal or total-body
gallium scan can be particularly helpful, but it should
be performed before corticosteroid treatment. The
Kweim test (a skin reaction elicited by intradermal
inoculation of sarcoid lymph node tissue) is not in
use anymore (Kweim, 1941).
Hypercalcemia and elevation of the angiotensin-
convertase enzyme (ACE) in the serum can support
(a) (b)
(c) (d)

Fig. 17.1 Brain MRI of a patient with sarcoidosis. Parenchymal infiltration and pachymeningitis in neurosarcoidosis. The axial
FLAIR image (a) shows an extensive lesion in the medulla that enhances on the postgadolinium T1-weighted sagittal scan (c) and
extends into the upper cervical cord. Similar to the sagittal image (c), the axial (b) and coronal (d) postgadolinium T1-weighted
scans also show extensive dural/meningeal enhancement. Enhancement of the fifth nerve (arrow) can be seen on the axial image
(b). The sagittal scan (c) suggests the involvement of the anterior optic pathways.
NICP_C17 04/05/2007 02:43PM Page 204
Neurosarcoidosis 205
the diagnosis. The cerebrospinal fluid (CSF) proteins
may be moderately elevated while glucose is normal
or slightly decreased in neurosarcoidosis. The spinal
and adhesive arachnoiditis variants may be asso-
ciated with a significant elevation of CSF proteins.
A moderate, predominantly lymphocytic pleocytosis
is present in about 80% of patients. Intrathecal IgG
synthesis and oligoclonal bands are less frequent.
Recent data suggest that an elevated CSF ACE can
support the diagnosis of neurosarcoidosis with high
specificity (94–95%) but the test has low sensitivity
(24–55%) (Dale and O’Brian, 1999; Tahmoush et al.,
2002). Therefore, the CSF ACE result should be inter-
preted with caution and in the context of clinical
findings (Kellinghaus et al., 2004; Zajicek, 2000).
T2-weighted and FLAIR magnetic resonance
images (MRI) of the brain and spinal cord can
reveal the anatomical distribution of granulomatous
lesions, while postgadolinium T1-weighted images
may indicate meningeal, parenchymal, or radicular
enhancement (Fig. 17.1). MRI with gadolinium pro-
vides a sensitivity rate of 80–90%, but with a low
specificity (Zajicek, 2000). Multiple white-matter

lesions caused by neurosarcoidosis in the CNS are
sometimes misclassified as MS.
Diagnostic criteria
Zajicek et al. (1999) proposed a diagnostic classi-
fication for neurosarcoidosis based on a retrospect-
ive analysis of 68 patients. Diagnosis of definite
neurosarcoidosis requires: (i) clinical symptoms
suggesting neurosarcoidosis; (ii) exclusion of other
diseases; (iii) histology of granuloma in the nervous
system in the absence of mycobacterium or other
causes of granuloma; (iv) the histology should
indicate noncaseating granuloma with epithelioid
cells and macrophages, without central necrosis,
surrounded by lymphocytes, plasma cells and mast
cells, and variable connective tissue reaction. Prob-
able cases of neurosarcoidosis have (i) and (ii) from
above, and (iii) laboratory results suggesting inflam-
mation in the CNS (increased protein, oligoclonal
bands in the CSF, and MRI suggesting inflammatory
lesions) and (iv) tissue evidence of systemic sarcoido-
sis or at least two of the following indicators: positive
gallium scintigraphy, elevated ACE in the serum,
and positive chest imaging. Patients with symptoms
of neurosarcoidosis who do not qualify for the defin-
ite or probable diagnostic criteria may be classified
as possible neurosarcoidosis, if other disorders were
excluded.
Treatment
Corticosteroids usually effectively control the disease
activity in most tissues including lung, skin, liver,

lymph nodes, lachrymal and parotid glands, eye,
and the CNS or PNS. While acute lesions generally
respond well to corticosteroids, it remains uncertain
whether or not this regimen changes the natural his-
tory of the disease. In chronic and steroid-resistant
cases, azathioprine, cyclophosphamide, methotrexate,
cyclosporine, and chloroquine have been tried. Low-
dose methotrexate may be effective in panuveitis,
and can be used in combination with steroids and
hydroxychloroquine (Zajicek, 2000). Recent data
suggest that refractory neurosarcoidosis may also
be successfully treated with agents possessing anti-
tumor necrosis factor α (TNF-α) activity such as
thalidomide, pentoxyfilline and infliximab. Infliximab
is a chimeric human-murine antibody directed against
TNF-α, which holds great promises in the treatment
of sarcoidosis (Pettersen et al., 2002).
Summary
Sarcoidosis is a granulomatous multiorgan disorder
that also affects the nervous system in a small pro-
portion of patients. While the disease is typically
sporadic, evidence supports the existence of genetic
susceptibility factors. In neurosarcoidosis, any part
of the neuroaxis may be affected with most frequent
involvement of the anterior optic pathways, cranial
nerves, and the pituitary gland. Other presentations
include meningoencephalitis and meningomyelitis
or granulomatous changes in the peripheral nerv-
ous system. Sarcoidosis in the muscle appears to be
underestimated. The diagnostic evaluation of neuro-

sarcoidosis is well assisted by recently established
diagnostic criteria. Most patients respond to corticos-
teroids, but more aggressive and newer therapeutic
modalities are also available.
References
Boeck, C. 1899. Multiple benign sarkoid of the skin.
J Cutan Genitourin Dis, 17, 545–50.
Burns, T.M. 2003. Neurosarcoidosis. Arch Neurol, 60,
1166–8.
Colover, J. 1948. Sarcoidosis with involvement of the
nervous system. Brain, 71, 451–75.
Dale, J.C. and O’Brian, J.F. 1999. Determination
of angiotensin-converting enzyme levels in cere-
brospinal fluid is not a useful test for the diagnosis of
neurosarcoidosis. Mayo Clin Proc, 74, 535.
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Delaney, P. 1977. Neurologic manifestations in
sarcoidosis: review of the literature, with a report
of 23 cases. Ann Intern Med, 87, 336–45.
Frohman, L.P., Guirgis, M., Turbin, R.E. and Bielory, L.
2003. Sarcoidosis of the anterior visual pathway:
24 new cases. J Neuro-ophthalmol, 23, 190–7.
Heerfordt, C.F. 1909. Uber eine “Febris uveo-parotidea
subchronica,” an der Glandula parotis und der
Uvea des Auges lokalisiert und haufig mit Paresen
cerebrospinaler Nerven kompliziert. Graefes Arch
Ophthalmol, 70, 254–73.
Hutchinson, J.A. 1877. Illustrations of Clinical Surgery,
J&A Churchill, London, pp. 42–3.

Kellinghaus, C., Schilling, M. and Ludemann, P. 2004.
Neurosarcoidosis: Clinical experience and diagnostic
pitfalls. Eur Neurol, 51, 84–8.
Kweim, A. 1941. En ny og spesifikk kutan-reaksjon ved
Boescks sarcoid. Nord Med, 9, 169–72.
Pettersen, J.A., Zochodne, D.W., Bell, R.B., Martin, L.
and Hill, M.D. 2002. Refractory neurosarcoidosis
responding to infliximab. Neurology, 59, 1660–1.
Rybicki, B.A., Walewski, J.L., Maliarik, M.J., Kian, H.
and Iannuzzi, M.C.; ACCESS Research Group. 2005.
The BTNL2 gene and sarcoidosis susceptibility in
African Americans and Whites. Am J Hum Genet, 77,
491–9.
Schumann, J. 1916. Etude sur le lupus pernio et ses
rapports avec les sarcoides et la tuberculose. Ann
Dermatol Syphilol, 6, 357–73.
Schurmann, M., Reichel, P., Muller-Myhsok, B.,
Schlaak, M., Muller-Quernheim, J. and Schwinger, E.
2001. Results from a genome-wide search for pre-
disposing genes in sarcoidosis. Am J Respir Crit Care
Med, 164, 840–6.
Tahmoush, A.J., Amir, M.S., Connor, W.W. et al. 2002.
CSF-ACE activity in probable CNS neurosarcoidosis.
Sarcoidosis Vasculitis and Diffuse Lung Disease, 19,
191–7.
Valentonyte, R., Hampe, J., Huse, K. et al. 2005.
Sarcoidosis is associated with a truncating splice
site mutation in BTNL2. Nat Genet, 37, 357–64.
Zajicek, J.P. 2000. Neurosarcoidosis. Curr Op Neurol,
13, 323–5.

Zajicek, J.P., Scolding, N.J., Foster, O. et al. 1999.
Central nervous system sarcoidosis – diagnosis and
management. QJM, 92, 103–17.
NICP_C17 04/05/2007 02:43PM Page 206
Morvan’s syndrome, Isaacs’ syndrome, and limbic
encephalitis are immune-mediated disorders of
either paraneoplastic or autoimmune etiology. The
paraneoplastic variants are discussed in detail in
Chapter 19.
Isaacs’ and Morvan’s syndromes
Morvan (1890) described a patient with myokymia,
pain, excessive sweating and sleep disorder, a condi-
tion named after him Morvan’s fibrillary chorea. A
similar disorder with widespread myokymia, muscle
cramping and delayed muscle relaxation but with-
out central nervous system (CNS) involvement was
later reported as neuromyotonia or Isaacs’ syndrome
(Isaacs, 1961). While motor nerve hyperexcitability
(muscle stiffness, cramps, fasciculations, myokymia,
and neuromyotonia) dominates, sensory symptoms
may also be present in one-third of patients with
these acquired peripheral nerve hyperexcitability
syndromes. The sensory symptoms are described
as numbness, tingling or paroxysmal electric sensa-
tions in generalized or focal distribution in the
extremities, trunk or neck in usually brief episodic
presentations lasting for weeks to years (Herskovitz
et al., 2005). Multiple Tinel’s signs may be elicited.
The electrophysiological correlate of motor hyper-
excitability is a spontaneous firing of single motor

units as doublet, triplet, or multiple discharges with
high intraburst frequency. Nerve conduction studies
may show compound muscle action potential repetit-
ive afterdischarges usually without polyneuropathy.
The hyperexcitability in Isaacs’ and Morvan’s
syndromes is related to the presence of antibodies
to the α-dendrotoxin-sensitive peripheral voltage-
gated potassium channels (VGKCs) in about 40% of
patients. The VGKCs are formed of heterooligomers
of various subunits in the CNS and peripheral nervous
system (PNS). The cross-linking of VGKCs by anti-
bodies results in decreased K
+
currents which inhibit
repolarization and lead to hyperexcitability in the
preterminal motor and sensory axons (Herskovitz
et al., 2005; Tomimitsu et al., 2004). Patients with
Morvan’s syndrome carry antibodies targeting both
PNS- and CNS-specific subtypes of the VGKCs (Hart
et al., 2002; Vernino and Lennon, 2002). These
patients not only have peripheral (neuromyotonia)
but also CNS symptoms (personality changes, halluci-
nations, sleep disturbances, spatial and temporal dis-
orientation, memory problems and confusion), signs
of dysautonomia (cardiac arrhythmias, excessive
sweating, severe constipation, urinary incontinence,
bronchial secretion, lacrymation and salivation), and
weight loss (Liguori et al., 2001).
Patients with peripheral nerve hyperexcitability
syndromes often have additional antibodies including

those to the neuronal acetylcholine receptor. Para-
neoplastic forms of neuromyotonia may be associ-
ated with thymoma and co-occur with myasthenia
gravis, but lung or other cancers may also be
involved (Liguori et al., 2001). The anti-VGKC anti-
bodies in the idiopathic forms are believed to be
related to an autoimmune pathogenesis.
Patients with Isaacs’ and Morvan’s syndromes
usually respond well to plasma exchange and other
immune modulatory therapies, particularly when
the immunopathogenesis is idiopathic. Gabapentin
and phenytoin have been successfully used to con-
trol the hyperexcitability symptoms.
Idiopathic limbic encephalitis
Limbic encephalitis (LE) is most commonly recog-
nized as a paraneoplastic disorder, but it seems to
be related to an idiopathic or autoimmune etiology
in a subgroup of patients. The paraneoplastic form
has a poor prognosis. It is most commonly associated
with small-cell lung cancer or less commonly with
breast, testicular cancer, thymoma, and other tumors.
The list of pathognostic paraneoplastic antibodies
includes anti-Hu (in half of the patients with LE),
anti-Ma2, and anti-CRMP5 (CV2). In anti-Hu negative
18
Anti-VGKC syndromes: Isaacs’ syndrome, Morvan’s
syndrome, and autoimmune limbic encephalitis
Bernadette Kalman
NICP_C18 03/05/2007 10:47 AM Page 207
208 BERNADETTE KALMAN

patients with LE and cancer, the pathology is usually
limited to the limbic system, and improves more
often after the removal of the primary cancer than in
anti-Hu positive patients, but even in the anti-Hu
negative cases the overall prognosis is poor. The pre-
sentation of autoimmune form is both clinically
and radiologically indistinguishable from the para-
neoplastic variant, and usually is associated with the
presence of anti-VGKC antibodies.
The clinical symptoms of LE include subacute
development of short-term memory loss, complex
partial, generalized tonic-clonic or other seizure
types, behavioral abnormalities and confusion. T2-
weighted and FLAIR MRI images usually demon-
strate hyperintense lesions in the mesial temporal
lobe involving the hippocampus and amygdale
(Fig. 18.1). Postgadolinium enhancement may be
seen on T1-weighted imaging. The histopathology
includes perivascular inflammatory infiltrates, neuro-
nal loss and gliosis in the mesio-temporal regions.
An electroencephalogram (EEG) may demonstrate
bitemporal spikes and slowing or generalized slow-
ing. The cerebrospinal fluid (CSF) can be normal, but
the protein level may be elevated and oligoclonal
bands occur occasionally. A thorough work up and
long-term monitoring cannot detect primary tumors
in patients with idiopathic LE.
Antibodies to the VGKCs were first identified in
two anti-Hu negative patients who presented with
cognitive and behavioral changes, excessive saliva-

tion, sweating and bronchial secretion but without
signs of neuromyotonia (Buckley et al., 2001). One
of these patients had thymoma and myasthenia
gravis, while the other patient was tumor free during
a two-year follow up. Anti-VGKC antibodies in the
serum of patients with LE bind to α-dendrotoxin-
sensitive potassium channels including the Kv1.1,
1.2, and 1.6 subtypes that are expressed throughout
the brain and PNS. It is not completely understood
why the clinical phenotype includes limbic and auto-
nomous symptoms without PNS hyperexcitability
(neuromyotonia) in these patients. In immunohis-
tochemical studies, the anti-VGKC antibodies from
the serum of LE patients bind to the middle one-
third of the molecular layer of the dentate gyrus in
the hippocampus, a pattern similar to that observed
with the commercial anti-Kv1.2 antibody. While the
detection of these antibodies in patients with LE
supports the diagnosis, evidence for a direct patho-
genic significance of these antibodies remains to be
presented.
Screening 15 patients with LE, Pozo-Rosich et al.
(2003) found four patients with anti-VGKC. Two
patients had idiopathic LE with high levels of the
antibody that correlated with a clinical response to
immunotherapy. Two additional patients with lower
levels of the anti-VGKC antibodies had lung cancer,
and one of them improved on immunotherapy. The
remaining 11 patients with LE and without anti-
VGKC had either anti-Hu or anti-Ma2.

Thieben et al. (2004) identified seven patients
with LE and anti-VGKC antibodies. The clinical and
imaging characteristics of LE were similar in these
patients with and without tumors, allowing no dis-
tinction between paraneoplastic and idiopathic forms.
Four patients had additional antibodies to the muscle
acetylcholine receptor, striational, P/Q type of cal-
cium channel or GAD65, and two patients had anti-
thyroperoxidase antibodies. Cancer was detected in
two patients. There was one spontaneous improve-
ment. Three patients of the six treated with IV
methylprednisolone improved significantly.
Vincent et al. (2004) reviewed clinical, immuno-
logical, and neuropsychological features of 10 patients
with history of memory loss, confusion and seizures,
low plasma sodium concentrations initially resistant
to correction, and MRI suggestive of LE. All these
patients tested negative for paraneoplastic anti-
bodies, but had increased anti-VGKC serum levels.
Fig. 18.1 Axial FLAIR MRI image of the brain of a patient
with idiopathic LE and anti-VGKC antibody. The bilateral
hyperintense signals in the hippocampal regions indicate
the distribution of pathology in such a patient. Courtesy
of Dr. Mark Keegan, Department of Neurology, Mayo
Clinic, Rochester, MN.
NICP_C18 03/05/2007 10:47 AM Page 208
Anti-VGKC syndromes 209
One of these patients had neuromyotonia, while
the others had no electrophysiological signs of peri-
pheral involvement. Neuropsychological work up

revealed severe and global memory impairment
with relatively preserved general intellect in most
patients. The clinical improvement was paralleled
by the fall of anti-VGKC drop following various
combinations of steroids, plasma exchange or IVIg
in seven patients. However, cerebral atrophy and
some residual cognitive impairment were commonly
noted in late stages of the disease.
Altogether, these studies demonstrate that anti-
VGKC antibodies are a valuable marker of a potenti-
ally reversible autoimmune LE, but may also be
detected in the paraneoplastic variant. The temporal
correlation between the serum antibody levels and
the neurological symptoms suggests the involvement
of anti-VGKCs in the pathogenesis of LE. Patients
with idiopathic LE and anti-VGKC antibodies gener-
ally respond well to high-dose corticosteroid therapy
or plasma exchange, particularly if administered
early after the onset of clinical symptoms.
Summary
Patients with Isaacs’ syndrome, Morvan’s syndrome,
or LE may carry anti-VGKC antibodies of para-
neoplastic or autoimmune etiology. The two forms
cannot be distinguished on clinical, radiological, and
immunological basis. Therefore, a thorough work
up is necessary for the exclusion of cancer, and
even tumor-negative patients need periodic tumor
screening. VGKCs represent a heterogeneous group
of molecules with numerous tissue-specific subtypes
which may explain the various anti-VGKC antibody-

mediated PNS and CNS disease phenotypes. The pre-
sence of autonomous symptoms in patients with LE
may suggest the presence of anti-VGKC antibodies
particularly in anti-HU negative patients. The anti-
VGKC antibodies are frequently associated with other
autoantibodies. While their functional importance
is supported by in vitro patch clamp studies, their
pathogenic significance remains to be further inves-
tigated (Tomimitsu et al., 2004). Early high-dose
corticosteroid treatment, plasma exchange and IVIg
can significantly improve the clinical, radiological,
and electrophysiological features of these disorders
in correlation with the reduction of the anti-VGKC
antibody serum levels.
References
Buckley, C., Oger, J., Clover, L. et al. 2001. Potassium
channel antibodies in two patients with reversible
limbic encephalitis. Ann Neurol, 50, 73–8.
Herskovitz, S., Song, H., Cozien, D. and Scelsa, S.N.
2005. Sensory symptoms in acquired neuromyoto-
nia. Neurology, 65, 1330–1.
Isaacs, H. 1961. A syndrome of continuous muscle-
fiber activity. J Neurol Neurosurg Psychiatry, 24,
319–25.
Liguori, R., Vincent, A., Clover, L. et al. 2001. Morvan’s
syndrome: Peripheral and central nervous system
and cardiac involvement with antibodies to voltage-
gated potassium channels. Brain, 124, 2417–26.
Morvan, A. 1890. de la choree fibrillaire. Gaz Hebd Med
Chir, 27, 173–200.

Pozo-Rosich, P., Clover, L., Saiz, A., Vincent, A. and
Graus, F. 2003. Voltage-gated potassium channel
antibodies in limbic encephalitis. Ann Neurol, 54,
530–3.
Thieben, M.J., Lennon, V.A., Boeve, B.F., Aksamit, A.J.,
Keegan, M. and Vernino, S. 2004. Potentially
reversible autoimmune limbic encephalitis with
neuronal potassium channel antibody. Neurology,
62, 1177–82.
Tomimitsu, H., Arimura, K., Nagado, T. et al. 2004.
Mechanism of action of voltage-gated K
+
channel
antibodies in acquired neuromyotonia. Ann Neurol,
56, 440–4.
Vernino, S. and Lennon, V.A. 2002. Ion channel and
striational antibodies define a continuum of autoim-
mune neuromuscular hyperexcitability. Muscle
Nerve, 26, 702–7.
Vincent, A., Buckley, C., Schott, J.M. et al. 2004.
Potassium channel antibody-associated encephalo-
pathy: A potentially immunotherapy-responsive
form of limbic encephalitis. Brain, 127, 701–12.
NICP_C18 03/05/2007 10:47 AM Page 209
Definition
Paraneoplastic disorders are cancer-associated
conditions that cannot be explained by a tumor’s
direct invasion of tissue, or by its treatment or conse-
quences. Skin, bone marrow, endocrine, and nervous
systems are most often affected. Some paraneoplastic

disorders reflect ectopic secretion of hormones by the
tumor, but most paraneoplastic neurological dis-
orders reflect a nervous system-specific autoimmune
attack initiated by onconeural antigens released to
peripheral lymphoid tissues from an unsuspected
primary or recurrent neoplasm (Darnell, 1996).
Presentation
In most cases, autoimmune neurological disorders
that are recognized today as paraneoplastic complic-
ate relatively few types of cancer. The neurological
illness typically precedes discovery of the tumor or its
recurrence and is subacute in onset. It often progresses
rapidly to affect more than one level of the nervous
system. Historically, several well-characterized neuro-
logical syndromes were described in association
with certain cancers, and in the early years of para-
neoplastic autoantibody discovery, one or more
serological markers were defined in the context of
discrete neurological syndromes. However, experi-
ence in the past two decades has revealed that the
patient’s symptoms, in most cases, do not fulfill
classic syndromic criteria. Multiple levels of the
nervous system are usually affected and multiple
autoantibody markers are detectable in the patient’s
serum (Table 19.1). It is now recognized that pre-
sentation as a classical neurological syndrome asso-
ciated with a single autoantibody marker in a patient
with cancer is the exception rather than the rule.
A patient’s past medical history or family history
of any form of autoimmunity is a valuable clue to

the diagnosis of paraneoplastic autoimmunity. The
diagnosis of cancer (usually malignant) sometimes
requires an exhaustive search, and continued
surveillance over an extended period. If the cancer
found is of a type other than that predicted by
the patient’s autoantibody profile (Table 19.2), the
search for the predicted cancer should not be aban-
doned. In 15% of patients, a coexisting neoplasm will
be found that is more obvious but unrelated to the
predicted cancer (Lucchinetti et al., 1998; Yu et al.,
2000). The failure to find a neoplasm, even at
autopsy, occurs in less than 15% of patients with an
autoantibody profile that strongly predicts cancer.
Those cases likely represent patients in whom the
immune response has successfully eradicated the
cancer. Seronegativity for all currently recognized
autoantibody markers of neurological autoimmunity
does not exclude the diagnosis of cancer in a patient
with a subacute neurological presentation, with or
without known risk factors for cancer or recogniz-
able stigmata of autoimmunity (e.g., Graves ophthal-
mopathy, hypothyroidism, or vitiligo). Although the
number of autoantibodies recognized as markers
of paraneoplastic (and idiopathic) neurological
autoimmunity has greatly increased in the past two
decades, many more clearly remain to be described.
Recent reports affirm this concept (Ances et al.,
2005; Bataller and Dalmau, 2004; Lachance et al.,
2006; Vitaliani et al., 2005). The factors determin-
ing the occurrence of autoimmunity in the context

of cancer are complex and only partly understood
(Darnell et al., 2003). These include genes influencing
the patient’s immune responsiveness, a multitude
of potential onconeural antigens and endogenous
“adjuvant” molecules in individual neoplasms, as
well as environmental and therapeutic modulating
factors.
It is not the intent of this chapter to describe
the syndromic neurological disorders traditionally
recognized with paraneoplastic autoimmunity (listed
in Table 19.1). Such descriptions are readily accessed
in recent reviews (Bataller and Dalmau, 2004;
Shams’ili and Sillevis Smitt, 2005). The subacute
19
Paraneoplastic neurological autoimmunity
Daniel H. Lachance and Vanda A. Lennon
NICP_C19 04/05/2007 12:25PM Page 210
Paraneoplastic neurological autoimmunity 211
presentation of most patients with paraneoplastic
autoimmunity initially mimics common disorders
such as stroke, a peripheral neuropathy, or multiple
sclerosis. Others present with a bizarre constellation
of symptoms and signs that is mistaken for hysteria.
The correct diagnosis therefore requires a high index
of suspicion. The clinician is best advised to analyze a
patient’s illness by the localization of neurological
signs and symptoms, to inquire routinely about per-
sonal and family history of autoimmunity and cancer,
and to utilize appropriate laboratory and radiolog-
ical tests. If the central nervous system is involved,

these tests should include cerebrospinal fluid (CSF)
analysis for inflammatory cells, protein, evidence of
intrathecal IgG synthesis and autoantibody profile.
Table 19.1 organizes neurological and serological
associations as one would approach the anatomic
localization of the patient’s deficits.
Serological markers of paraneoplastic
autoimmunity and nomenclature
Table 19.2 lists the currently recognized antibody
markers of paraneoplastic autoimmunity, their asso-
ciated tumors, and the frequency of coexisting
autoantibodies. These autoantibodies are classified
by their reactivity with predominantly nuclear, cyto-
plasmic, or plasma-membrane components of cells
Table 19.1 Neurological manifestations of paraneoplastic autoimmunity by level of neuraxis.
Level
Cerebral cortex
Diencephalon
Basal ganglia
Cerebellum
Brainstem
Cranial nerves
Spinal cord
Peripheral somatic
nerves and ganglia
Autonomic and
enteric nervous
system
Neuromuscular
junction

Muscle
“Syndromic” disorder
Limbic encephalitis
Encephalopathy
Hypothalamic dysfunction
Chorea
Hemi-ballismus
Parkinsonism
Myoclonus
Cerebellar ataxia
Brainstem encephalitis
Opsoclonus/Myoclonus
Stiff-person phenomena
Bulbar motor neuropathies
Optic neuropathy
Hearing loss
Retinopathy
Myelopathy
Transverse myelitis
Myoclonus
Sensory neuronopathy
Sensorimotor neuropathies
Motor neuropathy
Brachial plexopathy
Hyperexcitability syndromes
Dysautonomias
Gastrointestinal dysmotilities
Lambert–Eaton syndrome
Myasthenia gravis
Polymyositis/Dermatomyositis

Serological associations (see Table 19.2)
CRMP-5; AGNA-1; ANNA-1,3; VGKC; PCA-2; Ma2;
neuropil
AGNA-1; ANNA-1,2,3; PCA-2; amphiphysin; CRMP-5;
ganglionic AChR; VGCC (P/Q or N); striational; GAD65;
EFA6A
Ma2; ANNA-1
CRMP-5
VGKC
PCA-1,2,Tr; CRMP-5; AGNA-1; ANNA-1,2,3; VGCC
(P/Q>N-type); GAD65; Zic4; GluR1
AGNA-1; ANNA-1,2,3; PCA-2; Ma2; CRMP-5; VGCC
(P/Q>N-type)
Amphiphysin
CRMP-5; ANNA-1; 2, PCA-2
CRMP-5; recoverin
CRMP-5; VGCC; amphiphysin; ganglionic AChR; VGKC;
ANNA-1,2
ANNA-1; CRMP-5; ganglionic AChR; muscle AChR;
amphiphysin; VGKC; paraproteins
Ganglionic AChR; VGKC; CRMP-5; muscle AChR
Ganglionic AChR; VGCC (N>P/Q-type); CRMP-5;
ANNA-1; striational; VGKC; muscle AChR; GAD65
VGCC (P/Q>N-type); muscle AChR; striational;
ganglionic AChR; AGNA-1/ANNA-4
Muscle AChR; striational; ganglionic AChR; VGKC;
GAD65
Anti-Jo
NICP_C19 04/05/2007 12:25PM Page 211
212 DANIEL H. LACHANCE AND VANDA A. LENNON

Table 19.2 Oncological associations of paraneoplastic autoantibodies.
Antibody
Neuronal and glial nuclear antibodies
ANNA-1
(Lucchinetti et al., 1998)
ANNA-2
(Pittock et al., 2003)
ANNA-3
(Chan et al., 2001)
AGNA-1/ANNA-4
(Lachance et al., 2006;
Graus et al., 2005)
Zic 4
(Bataller et al., 2004)
Neuronal, glial and muscle cytoplasmic antibodies
PCA-1
(Peterson et al., 1992)
PCA-2
(Vernino and Lennon, 2000)
PCA-Tr
(Bernal et al., 2003)
Amphiphysin
(Pittock et al., 2005)
CRMP-5-IgG
(Yu et al., 200; Cross et al., 2003)
Striational (sarcomeric proteins)
Neuronal and muscle plasma membrane antibodies
VGCC, N
(Lennon et al., 1995)
VGCC, P/Q

(Lennon et al., 1995)
AChR, muscle
(Vernino and Lennon, 2004)
AChR, ganglionic
(Vernino et al., 1998)
(Pittock et al., 2004)
VGKC
(Thieben et al., 2004)
(Vincent et al., 2004)
GluR1
(Sillevis-Smitt et al., 2000)
“Neuropil”
(Ances et al., 2005)
EFA 6A
(Vitaliani et al., 2005)
*Commonly accompanies other paraneoplastic autoantibodies, but not found in the context of thymoma. N-type VGCC Ab
alone raises suspicion for carcinoma (usually lung or breast). Cancer-predictive value of P/Q-type VGCC alone is less certain.
Neoplasm predicted by
autoantibody
Small-cell lung cancer (SCLC),
neuroblastoma, thymoma
Lung or breast carcinoma
Lung or upper airway carcinoma
SCLC
SCLC
Ovarian, fallopian, endometrial,
breast carcinoma
SCLC
Hodgkin’s lymphoma
Breast or lung carcinoma

SCLC, thymoma, thyroid, or renal
carcinoma
SCLC, thymoma, breast carcinoma
Lung, breast or ovarian carcinoma
SCLC
Thymoma, SCLC
Thymoma, SCLC, others
Thymoma, SCLC
Hodgkin’s lymphoma
Thymoma, teratoma, thymic,
thyroid carcinoma
Ovarian teratoma
Neoplasm
found (%)
81
86
90
90
92
90
80
90
80
80
Unknown
Unknown*
Unknown*
Unknown
Unknown
Unknown

Unknown
Unknown
Unknown
Frequency
of coexisting
antibodies (%)
43
73
30
50
27
9
63
Unknown
38
57
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
Unknown
NICP_C19 04/05/2007 12:25PM Page 212