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Paraneoplastic neurological

and muscular syndromes


Short compendium
Version 4.0, September 2014

By
Finn E. Somnier, M.D., D.Sc. (Med.), copyright
Department of Clinical Biochemistry, Immunology & Genetics
Statens Serum Institut, Copenhagen, Denmark

15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Table of contents
PARANEOPLASTIC NEUROLOGICAL SYNDROMES .................................................... 4
DEFINITION, SPECIAL FEATURES, IMMUNE MECHANISMS ................................................................ 4
SHORT INTRODUCTION TO THE IMMUNE SYSTEM .................................................. 7
DIAGNOSTIC STRATEGY ..................................................................................................... 12
THERAPEUTIC CONSIDERATIONS .................................................................................. 18
SYNDROMES OF THE CENTRAL NERVOUS SYSTEM ................................................ 22
MORVANS FIBRILLARY CHOREA ................................................................................................ 22
PARANEOPLASTIC CEREBELLAR DEGENERATION (PCD) ...................................................... 24
Anti-Hu syndrome .................................................................................................................. 25
Anti-Yo syndrome ................................................................................................................... 26
Anti-CV2 / CRMP5 syndrome ............................................................................................. 26
Anti-Ma1 syndrome ............................................................................................................... 27
Anti-PCA2 syndrome ............................................................................................................. 28
Anti-Tr (PCA-Tr) syndrome ................................................................................................. 28
Anti-mGluR1 syndrome ........................................................................................................ 29
Anti-CARP8 syndrome .......................................................................................................... 29
Anti-GAD syndrome ............................................................................................................... 29
Anti-ZIC4-syndrome ............................................................................................................. 30
LEMS-associated ..................................................................................................................... 30
Anti-ARHGAP26 (GRAF) ....................................................................................................... 30
Anti-PKC gamma .................................................................................................................... 30
PARANEOPLASTIC CHOREO-ATHETOSIS ................................................................................... 31
PARANEOPLASTIC MORE CLASSICAL CNS DISORDERS ......................................................... 32
Paraneoplastic encephalomyelitis (PEM) ....................................................................... 33
Paraneoplastic limbic encephalitis (PLE),may include other structures ............ 34
A variety of associated autoatibodies ...................................................................................................... 35

Paraneoplastic brainstem encephalitis ........................................................................... 36


Anti-Ta (Ma2) syndrome .......................................................................................................................... 37

Paraneoplastic myelitis / myelopathy ............................................................................. 37


PARANEOPLASTIC MOTOR NEURON DISEASE? ........................................................................ 39
PARANEOPLASTIC OPSOCLONUS / MYOCLONUS (POM) ..................................................... 41
POM in children ....................................................................................................................... 41
POM in adults ........................................................................................................................... 42
Anti-Hu, Yo, Ta (Ma2) syndromes ............................................................................................................ 42
Anti-Ri syndrome...................................................................................................................................... 42

PARANEOPLASTIC OPTIC NEURITIS ........................................................................................... 44


PARANEOPLASTIC RETINOPATHY (CAR, MAR) .................................................................... 46
STIFF-PERSON SPECTRUM OF SYMPTOMS (SPS AND PERM) ............................................ 50
SPS variants ............................................................................................................................. 52
SYNDROMES OF THE PERIPHERAL NERVOUS SYSTEM ........................................ 55
PARANEOPLASTIC AUTONOMIC NEUROPATHY ......................................................................... 55
CHRONIC GASTROINTESTINAL PSEUDOOBSTRUCTION .......................................................... 56
PARANEOPLASTIC MOTOR NEUROPATHY .................................................................................. 57
PARANEOPLASTIC SENSORY-MOTOR NEUROPATHY ............................................................... 57
PARANEOPLASTIC SENSORY NEURONOPATHY (SSN, PSN) ............................................... 59
SYNDROMES OF THE NEUROMUSCULAR JUNCTION .............................................. 62
LAMBERT-EATON MYASTHENIC SYNDROME ............................................................................. 63
ACQUIRED NEUROMYOTONIA, ISAACS SYNDROME ............................................................... 65
MORVANS FIBRILLARY CHOREA ................................................................................................ 65

15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

PARANEOPLASTIC SEROPOSITIVE MYASTHENIA GRAVIS WITH THYMOMA ....................... 69


PARANEOPLASTIC MYOPATHIES .................................................................................... 74
POLYMYOSITIS, DERMATOMYOSITIS......................................................................................... 74
ACUTE NECROTIZING MYOPATHY ............................................................................................... 76
SPORADIC INCLUSION BODY MOSITIS ...................................................................................... 76
MYASTHENIA GRAVIS-ASSOCIATED MYOPATHY ..................................................................... 78
SPORADIC RIPLING MUSCLE SYNDROME .................................................................................. 83
SYMPTOMATIC OVERVIEW ................................................................................................ 85
PARANEOPLASTIC ATAXIA ........................................................................................................... 85
PARANEOPLASTIC EPILEPSY........................................................................................................ 85
PARANEOPLASTIC EXTRAPYRAMIDAL DISORDERS ................................................................. 87
PARANEOPLASTIC PAIN............................................................................................................... 87
MATERNAL AUTOANTIBODIES AND PASSIVE TRANSFER IN HUMANS ........ 88
AUTOANTIBODIES ASSOCIATED WITH PNS ............................................................. 93
PARANEOPLASTIC ANTIBODIES TARGETING THE NERVOUS SYSTEM OR
STRIATED MUSCLES VERSUS NEOPLASMS ................................................................ 96
DIAGNOSTIC CRITERIA - OVERVIEW ......................................................................... 105
OVERVIEW OF MANAGEMENT ........................................................................................ 106
LISTING OF SOME BOOKS AND REVIEWS ................................................................ 107
SUBJECT INDEX ..................................................................................................................... 108
AUTOIMMUNE ENCEPHALITIS, PLEASE SEE SEPARATE COMPENDIUM .... 111
CHANNELOPATHIES, RECEPTOR AND SOLUTE CARRIERS DISORDERS IN
NEUROLOGY, PLEASE SEE SEPARATE COMPENDIUM ......................................... 112

Throughout this book, text is colour coded as follows:


Clinical features
Treatment

printed in blue
printed in green

Underlined text is hyperlinked


If you want to purchase an electronic version, please contact
the author

15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Figure 1:

Immunoreactivity of some of the most common oncological anti-neuronal


antibodies

Top left: Anti-Hu staining of neuronal nuclei (cerebellar granule & Purkinje cells)
Top right: Anti-Yo staining of Purkinje cell cytoplasm; the red nuclei in the

granular layer stained by ethidium bromide


Second level left & right: Anti-Ri immunoreactivity is identical to that of anti-Hu
on neurons of the central nervous system. Unlike anti-Hu however, anti-Ri
antibodies do not immunoreact with neurons of the peripheral nervous system.
Third level left: Immunoreactivity of anti-amphiphysin (protein of nerve
terminals) detected by immunofluorescence on cerebellum. Notice that the
cytoplasm of Purkinje cells is negative.
Third level right: The immunoreactivity of anti-CV2 antibodies on cerebellum is
mainly restricted to a subpopulation of oligodendrocytes.
Bottom left: A. Anti-Ta (Ma2) immunoreactivity with subnuclear brain structures
and in a dot-like pattern
Bottom right: B. Anti-Ta (Ma2) immunoreactivity with large nuclei and cytoplasm
of the brainstem & deep cerebellar neurons

15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Paraneoplastic neurological syndromes


Definition, special features, immune mechanisms
Paraneoplastic neurological syndromes (PNSs) are accumulations of clinically
recognizable and connected symptoms thought to arise as remote effects of
cancer on the nervous system. These syndromes are significantly more frequently occurring in patients with cancer than in those without. Still, the precise
initial mechanisms leading to the syndromes are essentially unknown, even
though various immunopathological features have been clarified.
The criterion remote effects
of cancer signifies that PNSs per
definition cannot be attributable to:
Mechanical, inflammatory or
neoplastic effects in continuity
with neoplasms, including metastasis and meningeal carcinomatosis
Cancer-related cachexia and
anorexia
Neurotoxicity from chemotherapy
Adverse effects of radiation
therapy
Vascular or metabolic disorders
Infections
All other not cancer-related
causes
Adhering to this definition, mild or
subclinical muscular weakness or peripheral neuropathies are features in
up to 20% of patients with cancer.
However, a clinically significant PNS
occurs in less than 1% of such patients.
PNSs are heralding neoplasms
As a rule, such syndromes are early
symptoms (or set of symptoms) that
might indicate the start of a neoplastic disease before specific symptoms occur (prodromes). The symptoms and signs may even precede
the diagnosis of a neoplasm by several months and sometimes years.
This may also be true even after an
intensive search for a tumour. In
such a case, consider one or more

follow-up examinations at appropriate intervals.


Often quite disabling neurologic
features
Another characteristic is that the
neurologic features in themselves
may be much more disabling that the
other effects of the cancer. Although
relatively uncommon, the PNSs
therefore are important causes of severe and permanent neurologic disability. Early diagnosis of the neurologic disorder and prompt initiation of
tumour treatment probably increase
the likelihood of neurologic improvement.
Occurrence of onconeural antibodies
Several autoantibodies have a syndromic association, although none of
them appears to predict a specific
neurological syndrome. Conversely, a
positive autoantibody profile has
80% to 90% predictive value for a
specific cancer. It is not uncommon
for more than 1 paraneoplastic autoantibody to be detected, each predictive of the same cancer.
The great majority (>90%) of patients with PNSs have circulating onconeural antibodies which can be
useful in identifying the neurologic
disorder as paraneoplastic and in
finding the associated neoplasm.
However, such autoantibodies can
also be a feature of some patients
with cancer and without neurological
symptoms. The strongest association
between neoplasia and neurological
disorders is that between small-cell

15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

lung cancer (SCLC) and anti-Hu


(Hull) antibodies. The seropositive
incidence is about 17% in SCLC patients. Accordingly, these autoantibodies are important markers of PNS
and neoplasms.
As a rule: the classical onconeural
antibodies (anti-Hu, Yo, Ma2, CV2
(CRMP-5), amphiphysin and Ri) are
directed against intracellular antigens
and are strongly associated with underlying malignancy. By contrast,
onconeural
antibodies
directed
against cell surface antigens (e.g.,
anti-NMDAR, VGKC, AChR) have a
weaker tumour association.
Discussion
It is tempting to speculate that PNSs
may be attributable to immune responses against tumours that express neural antigens. The majority
of the onconeural antibodies are specific for intracellular antigens, and
only a minor fraction of them is
exposed to extracellular structures,
such as receptors and channels (Table 9).
The central and peripheral nervous
systems are usually considered immune privileged sites, so the paraneoplastic immune response must be
capable of breaching the blood-brain
or the blood-nerve barrier in order to
cause neurological pathology. The
neuromuscular junction (NMJ) is an
exception, since no barrier is protecting this location. It is quite uncertain
to which extent intrathecal synthesis
of onconeural antibodies may account for pathology. The intracellular
localization of many paraneoplastic
antigens adds further to the difficulty
in understanding the putative pathological role of onconeural antibodies.
Accordingly, these antibodies may be
important diagnostic tools but are
not necessarily causing the manifestations of PNS, at least not alone.
The value of antibodies is to protect
against foreign agents. They should
gain access wherever required, included in the cerebrospinal fluid
(CSF) and inside cells. Onconeural

antibodies are indeed a feature of


both the NMJ and CSF in PNS. As one
may expect, there is strong evidence
to suggest that active mechanisms
are facilitating the passage of antibodies across membranes. The internalization of proteins located in
membranes is normally a process of
endocytosis as part of a recycling
process. Presumably, internalizing
antibodies enter cells by the same
mode, although various other similar
mechanisms may be operational as
well.
Onconeural antibodies are organ
specific. For example, anti-Hu and
anti-Ri (Richards) antibodies are both
immunoreactive with nuclear structures of the central nervous system,
but in contrast to anti-Hu, anti-Ri antibodies do not bind to nuclei of neurons in the peripheral nervous system. Therefore, anti-Hu and anti-Ri
are also known as anti-neuronuclear
antibodies type one & two (ANNA1,
ANNA2), respectively. Likewise, the
occurrence of anti-Ri is not associated with any peripheral PNS, while an
anti-Hu finding is associated with
PNS of both locations. It is also
noteworthy that more than nine onconeural antibodies recognize intracellular structures of the Purkinje
cells, which are some of the largest
neurons in the brain. However, passive or more direct transfer models
with purified IgG from such patients
have failed to produce any PNS in
animals, apart from anti-mGluR1. On
the other hand, reports have shown
that transfer of specific T-cells provokes neurological disorders in animal models. Therefore, it appears
that intracellular antigen related
PNSs also involve an autoimmune Tcell component. Accordingly, it is
possible that merely, neuronal autoantibodies are markers of a destructive process, or else may signify direct toxicity of the activated immune
system.
Associated both with and without
neoplasms, it is now possible to
diagnose
autoimmune
synaptic
encephalitis. The targets may be cell

15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

membrane proteins (receptors and


channels), a protein within a synapse
(e.g. LGI1) or structures that are
expressed presynaptically (e.g. an
enzyme necessary for the synthesis
of a neurotransmitter). Currently
known such autoantibodies are
directed
to
NMDAR,
AMPAR,
GABABR1, GlyR alpha1, AQP4, LGI1,
CASPR2, and GAD. It appears that
intrathecal synthesis of specific
autoantibodies and CNS infiltration of
plasma cells are features of some of
these disorders.
As related to autoantibodies to exposed extracellular structures, it is a
different story. There is clear evidence to show that such associated
antibodies play a direct role in autoimmune disorders of the NMJ and
other synapses. Using purified IgG
(or monoclonal antibodies) directed
to exposed epitopes, passive transfer
models have been quite successful in
producing direct pathology. There
are three major mechanisms. Modulating antibodies appear to signal
that a structure is already outdated,
i.e. it is time to replace it. This may
be a factor causing endocytosis
ahead of time. Alternatively, the autoantibodies may provoke complement-mediated destruction. The result is a scarcity of antigenic targets.
The antibodies may also act as competitive inhibitors of such receptors
or channels. Altogether, this autoimmune pathology is quite detrimental to the transmission.

Hypothesis
A dynamic hypothesis may therefore
be that PNSs either develop dependent on the synthesis and local influx
of autoantibodies or as T-cell mediated autoimmunity, and in many
cases maybe combined.
Knowledge is lacking about a variety
of co-factors. Genetics may also play
a major role. Further studies of PNSs
may provide clues to a better understanding of tumour immunology and
of how the nervous system becomes
involved.
Various other aspects
Since we know the location and function of many of the involved structures of the nervous system, a finding of specific autoantibodies provides an important clue to directly
linking such a feature to one or more
specific locations of the nervous system. Conversely, the clinical findings
may suggest one or more specific
autoantibodies to look for. In short,
knowledgeable and skilful neurologists are able to recognize the clinical
manifestations of neurologic paraneoplastic disorders, and to distinguish
them from other causes of neurologic
dysfunction in cancer patients. Early
diagnosis of a PNS maximizes the
likelihood of a favourable outcome of
both the oncologic and the neurologic
disease.

15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Short introduction to the immune system


The innate immune system
This is what we are born with
and it is non-specific
All antigens are attacked pretty much equally
It is genetically based and we
pass it on to our offspring
The adaptive or acquired immune system
Cell-mediated immunity
Humoral-mediated immunity

Overall classification
The innate immune system provides
essential protection already from
birth. The adaptive immune system
is there to provide additional protection against various hazards that
may happen later in life.
The immune system within a PNS
context
The current concept is that the expression of neuronal proteins by the
cancer triggers an immune response
against the tumour and that is misdirected against the nervous system,
resulting in the paraneoplastic disorder. This immune response is characterized by high titer of serum antibodies (often accompanied by cytotoxic T-cell responses) that specifically react with proteins exclusively
expressed by neurons and the cancer
cells (onconeuronal antigens). Detection of these serum antibodies allows
for a major step as a part of the diagnosis of these neurologic disorders
as paraneoplastic.
Such autoimmunity often involves
pathological mechanisms of the innate immune system and in particular toll-like receptors. Conceivably,
however, PNSs may arise either as
inadequate innate immunity, as inappropriate adaptive or acquired
immunity, or as combined and even
more complex autoimmunity. Metaphorically, the occurrence of PNSs
may be looked upon as an own

goal. It is of course quite favourable


that the immune system is there to
protect against neoplasms, but it is
unfortunate when this also implies
the nervous system to become malfunctioned. Clearly, the immune system is not perfect.
Model disease
The immunopathogenesis of PNSs is
very complex. In order to discover
various mechanisms therefore, the
study of experimental disorders are
important.
If a structure is not protected by any
barriers (BBB = the blood brain barrier; BNB = blood nerve barrier) and
the antigen is an exposed extracellular molecule, then it is technically
more simple to create models. Conversely, there are also sequestered
structures in existence, i.e. they are
invisible to the immune system due
to a BBB or BNB or an intracellular
location. In such latter cases, special
measures are necessary in order to
circumvent these hindrances. A first
step may be transfer of encephalitisinducing T-cells to make the barrier
leaky. This may also happen by an
immunization using Freunds adjuvant. Having solved these obstacles,
the final steps consist in either immunization with a purified antigen or
transfer of disease-provoking agents
such as specific T-cells or antibodies
(for example purified immunoglobulin
or specific monoclonals).
Unprotected locations are at the
NMJs. In the peripheral nervous system, there are also less protected
areas as follows: distal nerve terminals, nodes of Ranvier, areas close to
the cell body, and ganglia. In such
cases with more or less easy accessibility, a transfer by various direct
routes may be possible: intravenous,
intraperitoneal, intrathecal, or by local injection.

15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

In analogy with other autoimmune


disorders, a useful categorization of
the PNSs is:
1. Antibody (humoral)-mediated

2. T-cell-mediated
Most of them are T-cell-mediated.

Criteria to be satisfied to accept a disorder as autoantibody mediated


1. Key starting point: relevant antibodies are present in patients with the
disease, although not necessarily circulating
2. Smoking gun: antibody reactivity results in the clinical phenotype, and
loss of structures expressing the antigen
3. Passive transfer of IgG from affected patient (or better matching monoclonal antibody) to experimental animal reproduces the phenotype
4. A model disease: immunization of experimental animal with purified antigen leads to development of the relevant antibody and subsequently the
same phenotype
5. Amelioration of disease: reduction in titres of the antibody (e.g., therapy) leads to clinical improvement or stabilization

Table 1a: The following disorders appear


to a lesser extent
Disorder
Seropositive myasthenia gravis
(SPMG)
Paraneoplastic SPMG (thymoma)
Early-onset SPMG
Late-onset SPMG
Neonatal SPMG
Acquired arthrogryposis multiplex in SPMG
Autoimmune autonomic neuropathy
(AAN)
Lambert-Eaton myasthenic syndrome (LEMS)
Morvans fibrillary chorea
Paraneoplastic limbic encephalitis
Acquired neuromyotonia (Isaacs
syndrome)
Paraneoplastic ataxia
Stiff-person syndrome?
Paraneoplastic opsoclonus,
myoclonus?

to satisfy these criteria, either totally or


Autoantibodies

Anti-AChR to the nicotinic receptor of


adult- and embryonic type

Anti-AChR to the nicotinic receptor of


alpha3-type
Anti-vg-Ca-channel of P/Q- and Ntype, anti-AChR to the muscarinic receptor of M1-type
Anti-Accessory proteins at vg-Kchannels
Anti-Acessory proteins at vg-Kchannels, anti-NMDAR, anti-mGluR1,
anti-mGluR5, anti-Amphiphysin?
Anti-Accessory proteins at vg-Kchannels
Anti-mGluR1
Anti-Amphiphysin
Anti-Amphiphysin

15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Table 1b: Experimental autoimmune encephalitis

o 2003: passive transfer of mGluR1 antibodies [Ann Neurol 2003; 53 (3): 325-36.]
o 2004: transfer of T-cells specific for the onconeural antigen Ma1 [Brain 2004; 127:
18221830]

o 2005: passive transfer of anti-Amphiphysin [Lancet. 2005; 365 (9468): 1406-11]


o 2009: passive transfer of anti-AQP4 [Ann Neurol 2009; 66 (5): 617-29; Ann Neurol 2009; 66 (5):
630-43; Brain 2010; 133 (2): 349-61]
o

2010: passive transfer of anti-Amphiphysin [Brain (2010) 133 (11): 3166-3180]

2010: passive transfer of anti-NMDAR [J Neurosci. 2010 April 28; 30(17): 58665875 ]
2012: Lewis rat animal model of Sydenham chorea and related neuropsychiatric
disorders [http://www.nature.com/npp/journal/v37/n9/abs/npp201256a.html]

Milestones in experimental
disease, including PNSs
A. Without a barrier of protection

Myasthenia gravis
Immunization with purified
ACHR (rabbit model 1975)
Transfer of purified IgG
(1975)
Transfer of monoclonals
(1981)
Immunization with peptide
sequences of ACHR (1994)
LEMS
Transfer of purified IgG
(1983)
Immunization with cholinergic
synaptosomes (1990)
Neuromyotonia
Transfer of purified IgG
(2003)
Autoimmune autonomic neuropathy
Transfer of purified IgG
(2004)

B. With barriers of protection

Presumed humoral mediated


Pioneer CNS model 2003:
passive transfer of mGluR1
antibodies
Presumed T-cell mediated
Pioneer CNS model 2004:
transfer of T-cells specific for
the onconeural antigen Ma1
Passive transfer in rats by
means of IgG to amphiphysin
(2005, 2010)

The role of onconeural autoantibodies


Such autoantibodies are a feature of
the serum in more than 90% of patients with PNSs. The finding in itself
is strong evidence of a coexisting neoplasm, which currently may even
escape detection by other means due
to a too small size or a location,
which is unfavourable to diagnostics.
The breakdown of tolerance appears
to be quite selective, since there is
an almost exclusive finding of highly
organ-specific onconeural antibodies
in PNSs.
An illustrative example:
Polymyositis is associated with coexisting cancer. Due to binding of all
the myositis specific and overlap antibodies, there are lesions and repair
mechanisms, including local infiltrations with lymphocytes. Accordingly,
the immune system is exposed to
titin, the largest molecule in the body.
Anyhow, anti-Titin antibodies are
never a feature of this disorder. On
the other hand, anti-Titin antibodies
are indeed markers of postsynaptic
NMJ disorders associated with myopathy, for example in paraneoplastic
myasthenia gravis (thymoma).
A lesson learned is that an already
tolerated structure that becomes exposed does not provoke autoimmunity in itself. To doing so, it may have
to be located within a danger zone
(Matzingers hypothesis), which in a
PNS context would mean a neoplasm.

15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Although still controversial and also


in contrast to classical immunology,
this theory deals with an extra step costimulation on peripheral sites saying that the cells of the body
must signal distress (danger) prior
to awakening the immune system,
and that the mere presence of a foreign antigen is not enough for any
action to be taken. In short, the danger metaphor involves the use of the
innate immune system to break peripheral tolerance possibly leading to
activation of the adaptive immune
system.
Bypass of T cell tolerance: some
initial steps into autoimmunity
Foreign epitopes do provoke useful
immune defences. They may come
into the body from the environment
or arise as neo-antigens. Modification
of an already tolerated structure may
be an adverse effect of drugs or other environmental agents. The T-cells
are on the alert and ready to recognise them upon proper presentation,
and a counterattack may set in.
Cross-reacting epitopes on the other
hand, are targets shared by neoplasms or invading microorganisms
and existent structures of the body
(molecular mimicry). Mimicry between epitopes of the body and an
invader or neoplasm can be classified
as similar or dissimilar dependant
on the extent of identity from a biochemical point of view. Accordingly,
cross-reactive antibodies, which recognize dissimilar epitopes - comparing that of the provoking invader to
the targeted one of the body, may be
a case of a structural 3-D configuration in itself being sufficient for binding.
If targets are located intracellularly
or protected by barriers, such as the
blood-brain/nerve barrier, then supposedly they are invisible (sequestered) to the immune system. In
such a situation, no autoimmunity
but only useful immunoprotection
sets in. Unfortunately, if the immune
system eventually gains access to
such epitopes, then autoimmunity is

at play. The triggering event could be


a danger zone somewhere in the
body and even remote from the location of the auto-attack.
Another mechanism in autoimmunity
may be epitope spreading (ES), associating such pathology with chronic
virus infections or neoplasia. The
term ES means the development of
immune responses to epitopes distinct from and non-cross-reactive
with the dominant primary epitope.
In autoimmunity, the process of ES
may begin with molecular mimicry
which then spread to different
epitopes (secondary epitopes) on one
protein (intramolecular ES), or to
epitopes on other proteins (intermolecular ES). Accordingly, the secondary epitopes, which are often cryptic
epitopes on the same molecule or
dominant epitopes on neighbouring
molecules, are those to which responses arise later. Theoretically, individuals harbouring mutated gene
products are more likely to be exposed to cross-reacting autoantibodies due to molecular mimicry or to ES
than controls without.
The theories about autoimmunity also comprise bystander activation,
and superantigens that activate polyclonal groups of T-cells. In particular,
activation of cytotoxic T-cells may be
an important mechanism. There are
two major groups of autoimmune
disorders: T-cell- and humoralmediated ones.
Summary
In short, it appears that in-host tolerated targets are in jeopardy, if
special conditions present similar
epitopes to the immune system.
Such an exposure could be in conjunction with neoplasia or certain infections, thereby giving rise to a
danger zone. Immunization with a
purified substance in Freunds adjuvant also creates such an area.
It is far beyond the scope of this text
to go into all the details. The precise
mechanisms are complex and quite
often largely unknown.

10

15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Short summary of the complexity


The synthesis of autoantibodies is linked with genetics
Complex interaction: T-cells, B-cells, cytokines, chemokines, etc.
A tumour is heterogeneous, i.e. only a part of a neoplasm or its metastases
may express neural antigens; and in another case, not at all
In a specific patient, the target may have to be upregulated prior to becoming antigenic
The extent of protection against provoked complement attack may vary
considerably on various surfaces

11

15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Diagnostic strategy
A PNS diagnosis requires
combined clinical and serological
findings
In relation to PNSs, four situations
may exist; please see the following
paragraphs A to D below. In all these
instances, there is strong evidence in
favour of the existence of a cancer
under development.
A. No onconeural antibodies are
found in the serum, even though
a PNS is likely
The sensitivity of the autoantibody assay is too low
The autoantibody may only be
found in the cerebrospinal fluid
It is a case of not circulating but
sequestered autoantibody, i.e. it
is only present in situ at the various lesions
A relevant autoantibody has not
yet been discovered
It is a case of a T-cell-mediated
disorder with no particular role of
any circulating autoantibodies
Clearly, the fulfilment of other diagnostic criteria is desirable.
B. Onconeural antibodies are
found in the serum, although
there are no symptoms or signs
consistent with a PNS
This is a common situation. Anti-Hu
antibodies are a finding in more than
15% of patients with SCLC, but only
about 1% does exhibit a significant
PNS. A diagnosis always requires
clinical manifestations, and serological findings in themselves are not diagnostic of any PNS.
C. Onconeural antibodies are
found in the serum, and a humoral-mediated PNS is likely
Assuming that the antibody is an associated one rather than irrelevant,
such autoantibodies are directly
pathogenic to exposed neurological
structures. Therefore, unmistakeably
and distinct serological support of the
diagnosis is available. The nonfinding of autoantibody does not exclude the diagnosis; see alternative A.

Furthermore, in such a case, the clinical severity of the PNS is likely to be


proportional to the titre of the autoantibody, enabling a performance of
longitudinal monitoring of the disorder also by means of serum samples.
D. Onconeural antibodies are
found in the serum, and a T-cellmediated PNS is likely
A relevant seropositive finding is
available, but a broader spectrum of
the immune defence must be in operation to cause any neurological
disorder such as T-cells, cytokines &
chemokines, and other co-factors.
Accordingly,
serological
evidence
supports the diagnosis, but the fulfilment of additional criteria is desirable. Once again, failure to detect
an autoantibody does not exclude
the diagnosis; see alternative A.
The starting point
The typical PNS-diagnostic procedure
begins by a patient seeking medical
assistance for symptoms evolving at
a chronology consistent with such a
disorder.
With only few exceptions, the clinical
findings should be explicable in terms
of a bilateral and symmetrical neurological disorder. This follows by several features. The remote effects are
due to malfunction of antigenic structures wherever they are located in
the nervous system, and thus characterized by being bilateral and
symmetric. The onconeural antibodies and the pathological T-cells are
organ-specific. The bloodstream is a
common pass-way at some step. The
breaches of barriers are supposedly
symmetric and located at the most
vulnerable sites.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Step one
A focused clinical neurological
examination
Perform a thorough neurological
scrutiny and go as far as possible to
document that the findings are bilateral, symmetric and most likely also
located to one or more foci as outlined above. Furthermore, take care
not to mistake any single element of
the findings for another.

Cognition, personality changes,


other mental symptoms: mimicking a psychiatric disorder or more
likely of a neurologic nature?
Mapping ataxia, coordination of
movements
Striated muscles: central or peripheral pattern of paresis; muscle tonus; atrophy; myokymia;
neuromyotonia; chorea; athetosis; opsoclonus; myoclonus. Does
rest or exercise influence muscular symptoms? What may provoke
or
relieve
involuntary
movements? Consider observations during sleep, etc.
Polyneuropathy
is the most
common paraneoplastic neurological disorder, so a very detailed
examination is called for
Examination of reflexes
Look for signs of autonomic neuropathy
Video recordings of neurological
signs may also be useful and in
particular when viewed by a
knowledgeable neurologist

Step two
The finding of onconeural
antibodies in serum or CSF
Several autoantibodies have a syndromic association, but no autoantibody predicts a specific neurological
syndrome. Conversely, a positive autoantibody profile has 80% to 90%
predictive value for a specific cancer.
It is not uncommon for more than 1
paraneoplastic autoantibody to be
detected, each predictive of the same
cancer.
By the end of this textbook, please
find a categorized table showing PNS

versus onconeural antibodies, which


may be useful in choosing an adequate serological screening. The specific findings of this step may point
directly to one or only a few significant first-line tests (cf. also the
chapter Onconeural antibody targets
.. for additional clues), or alternatively, choose a package covering
more than 60% of the spectrum
(Table 9). Multifocal clinical findings
are quite likely associated with antiHu antibodies.
It is also worth bearing in mind a
possible co-existence of more than
one of these autoantibodies, so consider an inclusion of all relevant ones.
A typical example is anti-Hu together
with any of the following: anti-CV2,
anti-Amphiphysin, anti-Ri, anti-vgCa-channel and anti-Zic4. In such
cases, SCLC is the expected underlying finding. Optionally, consider
postponement of supplemental tests
to a second-line procedure. However,
if you are planning a treatment with
high-dose IgG, then the infusion of
such antibodies may seriously hamper the interpretation of subsequent
antibody analyses for a long period.
Circumvention of this situation is
possible by storage of a sufficient
number of serum samples on beforehand.
In diagnosing a humoral-mediated
PNS, the finding of a relevant onconeural autoantibody is providing
quite strong evidence in favour of the
supposed disorder. This is in contrast
to T-cell-mediated ones, in which an
onconeural marker is only providing
indirect evidence of the diagnosis.
Moreover, it is not rare to encounter
a seropositive patient without any
features of a PNS, which is explicable
in terms of the immune system trying to combat a neoplasm somewhere in the body, although without
causing any harm to the nervous
system. With few exceptions therefore, the onconeural antibodies are
valuable markers of neoplasm, which
may even escape other means of detection at an unfavourable point in
time.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Step three
Diagnostics by imagery
CT provides rapid, non-invasive imaging of the CNS.
MRI offers better resolution of neural
structures than that of CT. Currently,
MRI is the preferred first-line choice
for detection of autoimmune inflammatory areas, demyelinising plaques,
neoplasms, metastases, early infarction, subclinical brain oedema, and
much more. For example, visualization of inflammatory, demyelinising,
or neoplastic lesions may require enhancement with intravenous paramagnetic contrast agents, such as
gadolinium. The use of diffusionweighted MRI allows rapid and early
detection of the various disorders.
As related to MRI, the expected finding in PNSs of the CNS is a bilateral,
symmetric and somewhat diffuse pathology. It may be bi-focal such as in
a pure syndrome of limbic encephalitis, cerebellar degeneration,
chorea or athetosis (basal ganglia).
Alternatively, it could also be multifocal although still symmetrical. This
is the expected finding in two situations: the existence of multiple sites
of a targeted specific epitope; in cases with more than one onconeural
antibody, there is a situation of different targeted epitopes.
Be aware that in paraneoplastic cerebellar degeneration, MRI typically
does not reveal any pathology at the
onset or even long time during the
course, although it may eventually
show atrophy.
In short: in a context of PNSs, MRI
often serves to exclude that there
are unilateral findings such as signs
of brain tumour, metastasis, stroke,
vasculitis, etc. Asymmetrical bilateral
findings would point towards glioblastoma, metastases, inflammatory
demyelinising disorder, vascular disease etc., rendering a paraneoplastic
diagnosis more unlikely.

High definition magnetic resonance imaging (HD MRI) captures


images at a much higher resolution
than ever seen before. With this new
technique, radiologists can shorten
scan times and see highly detailed
pictures. Although the true value of
this new technology of imaging still is
unknown, it may turn out to be significant also in the diagnostics of
PNSs.
Positron emission tomography
(PET)
PET neuroimaging is based on an assumption that areas of high radioactivity are associated with brain activity. The technology is using radioisotopes with a very short half-life, so a
cyclotron must be available not too
far away in delivery-time to the PET
scanner. PET uses isotopes incorporated into compounds normally used
by the organ under examination, for
example glucose. Such labelled compounds are known as radiotracers. In
neurology, fluorodeoxyglucose (FDG)
is a common tracer, and the abbreviation for this imaging is FDG-PET.
Single photon emission computed
tomography (SPECT)
This imaging technique is using
gamma rays, and it is providing true
3D information. Brain SPECT is using
technetium-99m.
In relation to paraneoplastic CNS
disorders, PET or SPECT may be useful, when classic MRI fails to reveal
any findings, although they are supposedly there.
Some paraneoplastic CNS disorders
are truly multifocal or showing clinical continuity with a pattern that
may vary among patients. In such
instances PET, SPECT or MRI combined may result in a much more
precise mapping of the pathology.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Step four
Find intrathecal evidence in favour of on-going immunological
processes and exclude meningeal
carcinomatosis
Lumbar puncture can be a helpful
tool, since CSF inflammation is a
common feature of PNS patients. The
likelihood of pathological findings is
gradually decreasing by time after
onset of neurological symptoms.
Presence of a mass that could precipitate transtentorial or cerebellar herniation constitutes a risk. As a rule
therefore, consider CT or MRI prior to
any examination of the cerebrospinal
fluid (CSF).
Table 2 provides a summarization of
the findings
Increased total protein (hyperproteinorachia) is a sensitive but nonspecific measure of disease.
Elevated immunoglobulin and oligoclonal banding are also frequent findings, although unspecific and a feature in a variety of
other disorders, such as demyelinising ones and various infections of the CNS.
Pleiocytosis - with not too many
lymphocytes (usually < 25) - is
an expected early finding in about
50%. However, depending on the
specific nature of the disorder,
pleocytosis may be present for
longer periods. A cell count above
for example > 100 should alert
you to look for other diseases.
Per definition, a finding of malignant
cells in the CSF excludes the possibility of a PNS. Sometimes the search
for malignant cells may involve consecutive lumbar punctures over time,
since the initial ones could be falsely
negative.
CSF findings are a reflection of ongoing immune processes in the CNS.
They fade away along with the eradication of antigenic structures. If immunosuppressive treatment is under
consideration, then current CSF pathology is an argument in favour of
such a treatment. Please also see the
arguments for early treatment in the

next chapter. Key word may be a


medical urgency.

Step five (neurophysiology)


EEG, evoked potentials, EMG,
nerve conduction velocity studies,
repetitive nerve stimulation, single-fibre EMG
EEG is a method to detect electrical
pathology associated with seizure
disorders, sleep disorders, and metabolic or structural encephalopathies.
Abnormal wave patterns may be
non-specific (for example paraneoplastic epilepsy with epileptiform
sharp waves) or diagnostic (e.g. in
Creutzfeldt-Jakob disease as a differential diagnosis to paraneoplastic
chorea).
Measurement of evoked potentials is a method using visual, auditory, or tactile stimuli to activate corresponding areas of the cerebral cortex, resulting in measurable and distinct focal cortical electrical activity.
Computer processing cancels out
noise to allow detection of abnormal
waveforms. Evoked responses are
particularly useful for detecting clinically unapparent deficits, which may
also be of interest in the diagnosis of
PNSs. For example, consider such an
examination in an anti-Hu or antiCV2 (CRMP5) seropositive patient.
Such cases are likely to have a multifocal disorder including areas, which
may escape detection by other examinations.
Electromyography
and
nerve
conduction velocity studies are
both of great value to identify affected nerves and muscles. It may be
clinically difficult to make out whether a muscular weakness is due to
nerve, muscle, or neuromuscular
junctional disorder. Neurophysiology
also enables a more precise location
of sensory dysfunctions. In addition,
neuropathies can be classified into
demyelinising and axonal ones,
which has important implications to
both a proper diagnosis and adequate treatment.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

In addition, more precise detection


and correct identification of myokymia, neuromyotonia and myoclonus are tasks for a neurophysiologist.
Repetitive nerve stimulation is a
good method to diagnose myasthenia
gravis (paraneoplastic, thymoma)
and the Lambert-Eaton myasthenic
syndrome (LEMS). Single-fibre EMG
may also be of value.

Step six

Search for a neoplasm


By the end of this textbook,
please find a categorized table
showing Neoplasms versus onconeural antibodies, which may
be useful in searching for the
most common cancers associated
with any particular autoantibody.

The chapter Onconeural antibody


targets in the nervous system
and neoplasms may provide other clues.

Moreover, all neoplasms associated with any particular syn-

drome are listed in the various


chapters of this textbook dealing
with any specific disorder.

If an onconeural antibody is unmistakably present and currently,


a neoplasm cannot be found,
then
consider
supplementary
search procedures at suitable intervals. A non-finding of cancer
does not rule out a PNS diagnosis,
since an autopsy may reveal a
relevant neoplasm for the first
time.

Step seven
Systematically, exclude all relevant differential diagnoses
An important criterion of a PNS is the
exclusion of all known other disorders with similar symptoms. The
finding of onconeural antibodies may
be a pretext to somewhat restricting
the search for other diagnoses, and
this argument may be either supported or weakened by the outcome
of steps 3-6.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Table 2:
Cerebrospinal fluid findings in patients with paraneoplastic neurologic
syndromes: study of n = 295 such patient
Anti-Hu
58%

Anti-Yo
20%

Anti-CV2
8%
Within a
few
months

Relative to time of onset of


neurological symptoms
Hyperproteinorachia (protein
level)
Presence of oligoclonal bands
Pleiocytosis
Pleiocytosis without
hyperptroteinorachia

Anti-Ma/Ta
6%

Anti-Ri
5%

An exclusive
feature

Later

Anti-Tr
3%

Irrespectively of time
67%
63%

47%

28%

10%

More frequent early in evolution than later-on

One or more of these features

Median 94% [70-100]

Oligoclonal bands were not found in anti-Tr syndrome (0 out of 3)


Cell count usually < 25
The data above are for from:
Psimaras D, Carpentier AF, Rossi C. CSF study in paraneoplastic syndromes. J Neurol Neurosurg
Psychiatry, [Epub ahead of print] April 2009; doi:10.1136/jnnp.2008.159483

Arbitrary increasing scale

Cerebrospinal fluid findings in


paraneoplastic cerebellar degeneration
6
5
4
3
2
1
0
0

10 11 12

Months after onset

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Therapeutic considerations
An ascertainment of a PNS diagnosis is often heralding the coexistence of a neoplasm by several months before a patient otherwise becomes aware of it. Therefore, actions taken rapidly upon such a classification may significantly improve
the chances of a more beneficial outcome of oncologic modalities of treatment
than compared with a later perspective. Sometimes the prognosis of a neoplastic
disorder may even be more favourable in cases with a co-existent PNS than in
those without. A possible explanation may be that the immune system attempts
to combat the neoplasm much harder by a broader panel of autoantibodies. This
latter aspect however, may not be of much value or comfort to a particular patient, since - in themselves - PNSs often are much more disabling than other effects of a tumour. Removal of the neoplasm or at least a reduction of its impact
may result in less severe PNS, although once started, such provoked autoimmunity frequently appears to continue in spite of a successful oncologic treatment. If a
PNS satisfy the criteria for a humoral-mediated disorder, it follows that the clinical
course is proportional to the titres of autoantibodies. Therefore, a beneficial outcome of therapy is more likely, in view of the fact that it is often possible to diminish the synthesis of harmful autoantibodies, or to neutralize / remove them
(Table 2, 4 - 6). On the other hand, in cases of T-cell-mediated PNSs, adequate
treatment may not be available or only limited benefit achievable, please see under immunosuppression below.
Table 2: Classical modalities of therapy
Enumeration Modality
Oncologic treatment (beyond the scope of this text)
1
Improvement of transmission over synapses by various drugs
2
Anti-epileptics, extrapyramidal remedy, etc.
3
Other symptomatic drugs
4
Intravenous administration of high-dose IgG
5
Extracorporeal removal of autoantibodies (plasma exchange)
Immunosuppression (typically steroids, azathioprine, often com6
bined; various other agents

General therapeutic considerations


Myasthenia gravis is the prototype of
antibody-mediated autoimmunity in
neurology. The experience related to
the remedy of this disorder has been
developed over decades and should
at least be applicable to the PNSs
listed in Table 1.
Longitudinal monitoring of a disorder by antibody measurements
It is possible to monitor the severity
of the disorders of Table 1 both efficiently and conveniently by means of
consecutive measurements of the
relevant titres of serum autoantibodies at suitable intervals. This allows

for timely adjustments of the treatment.


Unfortunately, T-cell-mediated autoimmunity is not proportionate to serum titres of antibodies.
Choice of therapy
Table 2 proposes some principles of
a rational and efficient treatment of
PNSs. Oncologic therapy serves a
double purpose. Evidently, a treatable cancer should undergo an expertchoice of treatment with documented
effect. In addition, any removal / reduction of neoplastic tissue may help
to stop or at least diminish the impact of such provoked autoimmunity.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Antibody removal
In T-cell mediated disorders, treatment option 5 (Table 2) is not really
having
any
spectacular
effect,
whereas it may be quite efficient in
the autoantibody-mediated ones.
Therefore, this may be a proper
choice in cases of rapidly increasing
severity or crises in such PNSs (Table 1).
Since steroids and for example azathioprine may take many weeks and
sometimes months to reach their
maximum capacity of benefit, sessions of plasma exchanges may also
be an important remedy during the
waiting time for an accomplishment
of such an effect. Likewise, if sufficient control is unlikely to occur following treatment option 6 (Table 2),
then maintenance removals at suitable intervals are to be considered.
Unfortunately, this may also be the
proper (only?) choice in cases with
bad tolerance to immunosuppressants.
A treatment of one plasma volume
during each session often results in
an about 75% removal of the circulating pool of autoantibodies. Subsequently of course, antibodies from
the
extravascular
compartments
gradually filter back into the bloodstream. A series of removals with
one or a few days in between each
session is therefore often the method
of choice. There appears to be a remarkable tolerance to the original
plasma exchange procedure with replacement of only albumin and water
as well as to the newer immunosorption techniques.
Usually, repair of the affected structures sets in right after the start of
such treatment, and benefit is often
observable within days or weeks. The
so-called Lazarus effect, i.e. a severely paralyzed patient is able to
walk immediately after the first
plasma exchange, is attributable to
the immediate removal of blocking
antibodies. Unfortunately, the synthesis of autoantibodies continues in
spite treatment option 5. As a rule of

thumb therefore, one may expect 48 weeks of lasting effect, where after
it tapers off.

High-dose IgG
The prevailing theory about the effect of high-dose IgG (IVIG) is that
an infusion of anti-idiotypic antibodies results in a neutralization of autoantibodies.
Since only a minor fraction of the
substances is thought to have any
effect, and the remaining compounds
to be either superfluous or to cause
adverse effects, technical improvements of this method are warranted.
This may happen by purification,
safely and adequately eliminating
unwanted parts. On the other hand,
the benefit of high-dose IgG may also be attributable to a somewhat
broader spectrum of substances.
Currently therefore, one is left with a
treatment using the whole mixture of
IgG. In the treatment of PNSs, this
theoretical aspect of a broader mode
of action may be of a particular significance. Unfortunately, high-dose
IgG treatment is quite expensive.
If IVIG proves to be of benefit, the
duration of the effect will probably
only last weeks or a few months,
where after a relapse is expected to
occur. This may call for a repeated
intravenous high-dose IgG session
and probably on a full scale, rather
than a booster like in the GuillainBarr syndrome, the rationale being
an on-going cancer and not a past
infection.

Immunosuppression
The experience from long-term
treatment of myasthenics makes it
clear that every effort must be made
not to lose immunosuppressant control by an administration of a too low
dose, since once lost it may be quite
difficult to achieve stable remission
again. Unfortunately, all of the currently available immunosuppressive
drugs are symptomatic, so such

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

therapy must be kept at an efficient


level and as long as needed. The
principle or difficulty is to find an
optimal balance between the required
minimal dose and the risk of serious
adverse effects. Furthermore, this
must be worked out in a long-term
perspective.
The experience with steroids and Azathioprine is long. Methotrexate, Cyclosporine and Cyclophosphamide
are other drugs with documented
benefit, although also with a substantially higher risk of adverse effects. Tacrolimus is a newer and
maybe promising drug, although the
experience with this substance is
somewhat more limited in neurology.

Another concern in relation


to PNS

Other modalities of therapy


Also in relation to PNSs, such symptomatic treatment (Table 2, 1 - 3)
follows the usual procedures.

Newer
ment

Early destruction of the microenvironment around neurons or


neuronal death

Do not hesitate too long before


offering such therapy

A patient may sooner or later be


left with no therapeutic remedy

options

for

treat-

A chimeric monoclonal IgG1kappa antibody, Rituximab, that


binds specifically to the CD20 antigen and mediates B cell lysis,
may be beneficial to temporarily
decrease synthesis of harmful autoantibodies

Protection against harmful effects


of the membrane attack complexes (MAC) may be a promising
new remedy. Humanized monoclonal antibodies are appearing
on the scene. Eculizumab is a
new such drug, which is directed
to the complement protein C5,
and thereby inhibiting terminal
complement activation

Treatment targeting cytokines or


chemokines alternatively using
antisense suppression of various
enzymes may be other options.

Immunosuppression is the primary


treatment of choice in T-cellmediated disorders.
Therapeutic keywords in T-cell
mediated autoimmunity:
Often a medical emergency

The legitimacy of immunosuppression in a patient with cancer

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Algorithmic approach to diagnosis and treatment of encephalitis with antibodies to intracellular and cell surface neuronal
antigens

From: Lancaster E et al. Neurology 2011; 77: 179-189

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Syndromes of the central nervous system


Morvans fibrillary chorea
Morvans fibrillary chorea is a rare autoimmune synaptic
encephalopathy characterized by chorea and sometimes combined with limbic features, myotonia, neuropathy, and perspiration. The true targets of the associated autoantibodies are leucine rich glioma inactivated 1 protein (LGI1) or contactinassociated protein-2 (CASPR2), accessory proteins and integrated in vg-KC complexes. This disorder appears to fulfil the
criteria of an antibody-mediated autoimmunity.
Anti-CASPR2 disorders:
Acquired neuromyotonia
Peripheral nerve hyperexcitability

Morvans syndrome

Neuromyotonia with autonomic and


CNS involvement

Limbic encephalitis

CNS manifestations without peripheral involvement

Clinical features

Attacks of involuntary fibrillary


contraction (chorea) in muscles at rest
o Involving the muscles of the
calves, the posterior parts of
the thighs, and rarely the
trunk
Other CNS dysfunction
o Limbic encephalitis with loss
of memory
o Insomnia (agrypnia)
o Hallucinations
o Disorientation
o Seizures
Neuromyotonia
Hyperhidrosis
Polyneuropathy

Course

Associated disorders

Anti-AChR antibody seropositive


myasthenia gravis (SPMG)
LEMS

Autoantibodies
Anti-LGI1 (leucine-rich, glioma
inactivated 1 protein)

Anti-CASPR2 (contactin-associated

(Anti-voltage-gated K-channels)

protein-2)

The targets are located at the dentate gyrus of


hippocampus and at the neuromuscular junction. In RIAs, using 2 % digitonin extract of
radio-labelled dendrotoxin, antibodies to
Shaker types Kv1.1, 1.2, 1.6 are detectable,
although not differentiated. Moreover, such
VGKC extract are complexed with two other
channel-complex proteins, leucine-rich, glioma
inactivated 1 protein and contactin-associated
protein-2 in limbic encephalitis. Therefore, this
assay is not specific to anti-VGPC.

Anti-DPPX (DPP5)

MG, LEMS laboratory:


Anti-AChR (adult-type, foetaltype)
Anti-Titin
Anti-voltage-gated-Ca-channel
(P/Q-, N-type)

Some differential diagnoses

May improve spontaneously or with


immunosuppression

See examples under paraneoplastic


choreo-athetosis.

Associated neoplasm

Treatment

Thymoma

High-dose IgG or plasma exchange


Immunosuppression

Selected references
1.
2.

Morvan AM. De la chore fibrillaire. Gazette hebdomadaire de mdecine et de chirurgie, Paris,


1890; 27: 173-176, 186-189, 200-202.
Roger H, Alliez J, Roger J. [Morvan's fibrillary chorea; 70 observations with 30 personal cases.]
Rev Neurol (Paris) 1953; 88 (3):164-73.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

3.

Madrid A, Gil-Peralta A, Gil-Neciga E, Gonzalez JR, Jarrin S. Morvan's fibrillary chorea: remission
after plasmapheresis. J Neurol 1996; 243 (4): 350-3.
4. Maselli RA, Agius M, Lee EK, Bakshi N, Mandler RN, Ellis W. Morvan's fibrillary chorea.
Electrodiagnostic and in vitro microelectrode findings. Ann N Y Acad Sci 1998; 841: 497-500.
5. Agius MA, Zhu S, Lee EK, Aarli JA, Kirvan C, Fairclough RH, Maselli R. Antibodies to AChR,
synapse-organizing proteins, titin, and other muscle proteins in Morvan's fibrillary chorea. Ann N
Y Acad Sci 1998; 841: 522-4.
6. Lee EK, Maselli RA, Ellis WG, Agius MA. Morvan's fibrillary chorea: a paraneoplastic manifestation
of thymoma. J Neurol Neurosurg Psychiatry 1998; 65 (6): 857-62.
7. Liguori R, Vincent A, Clover L, Avoni P, Plazzi G, Cortelli P, Baruzzi A, Carey T, Gambetti P,
Lugaresi E, Montagna P. Morvan's syndrome: peripheral and central nervous system and cardiac
involvement with antibodies to voltage-gated potassium channels. Brain 2001; 124 (Pt 12): 241726.
8. Montagna P, Lugaresi E. Agrypnia Excitata: a generalized overactivity syndrome and a useful
concept in the neurophysiopathology of sleep [Review]. Clin Neurophysiol; 113 (4): 552-60.
9. Lscher WN, Wanschitz J, Reiners K, Quasthoff S. Morvan's syndrome: clinical, laboratory, and in
vitro electrophysiological studies. Muscle Nerve 2004; 30 (2): 157-63.
10. Kleopa KA, Elman LB, Lang B, Vincent A, Scherer SS. Neuromyotonia and limbic encephalitis sera
target mature Shaker-type K+ channels: subunit specificity correlates with clinical manifestations.
Brain 2006; 129: 15701584.
11. Irani SR, Sian Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, Peles E, Buckley C, Lang
B, Vincent A. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma
inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvans syndrome
and acquired neuromyotonia. Brain 2010; 133 (9): 2734-2748.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Paraneoplastic cerebellar degeneration (PCD)


Paraneoplastic cerebellar degeneration is a
classical PNS with a rapidly progressive gait disorder, which
eventually stabilizes. It is associated with a great variety of
neoplasms and onconeural autoantibodies. Early treatment
is of outmost importance, since Purkinje cells may be lost
quite soon.

Antibodies predominantly
associated with PCD

Predominant syndrome

Associated cancer

Anti-Yo (PCA-1) antibodies

PCD

Breast , small-cell lung (SCLC), ovarian, prostatic

Anti-Tr antibodies

PCD (+occasionally: limbic encephalitis,


optic neuritis)

Hodgkin's lymphoma

Anti-mGluR1 antibodies

PCD

Hodgkin's lymphoma, ovarian

Anti-ZIC4 antibodies

PCD

SCLC , lung adenocarcinoma

Anti- ARHGAP26 (GRAF)

PCD

Ovarian

Anti-HOMER3

PCD with ataxia, headache, nausea,


confusion

None

Sometimes Associated With


PCD

Ataxia and other findings

Anti-Hu (ANNA-1) antibodies

Encephalomyelitis, PCD, sensory neuronopathy

SCLC, lung adenocarcinoma, other


cancers

Anti-Ri (ANNA-2) antibodies

PCD, brain-stem encephalitis, paraneoplastic opsoclonus-myoclonus

Breast, SCLC, gynaecologic

Anti-CV2/CRMP5 antibodies

Encephalomyelitis, PCD, chorea, peripheral neuropathy, uveitis

SCLC, thymoma, other cancers

Anti-PCA2

Encephalomyelitis, PCD

SCLC

Anti-Ta (Ma2), Ma1 protein


antibodies

Limbic, hypothalamic, brain-stem encephalitis, infrequently PCD

Breast, lung adenocarcinoma, testis, ovarian, other cancers

Anti-Amphiphysin antibodies

Stiff-person syndrome, encephalomyelitis, PCD

Breast, SCLC

Anti-VGCC antibodies

Eaton-Lambert syndrome, PCD

SCLC, lymphoma

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Overview of paraneoplastic
ataxia
Onset
Although varying, PCD often sets in
before the diagnosis of a neoplasm.

Evolution
Usually, this disorder rapidly progresses over weeks to months, then
stabilization.

Associated neoplasms and onconeural antibodies


(Only the most common)
SCLC: anti-Hu, anti-CV2, anti-Cachannel (P/Q-, N-type), anti-ZIC4
Ovary (epithelial): anti-Yo
Breast: anti-Yo, anti-Ri
Hodgkins disease: anti-Hu, anti-Tr

Other investigations

MRI may be unrevealing at onset


and even long time thereafter.
Eventually and late in the course,
atrophy may be revealed, so alternatively consider PET, SPECT
or high-resolution MRI
CSF
o Protein, cells, and IgG moderately high
o Oligoclonal bands
o A feature only during the first
month after onset, and fading
away along with the disappearance of Purkinje cells

Differential diagnoses
Sequential MRI of slowly progressive cerebellar atrophy

General clinical features


Symmetric pancerebellar syndrome
with vertigo

Pathology
Loss of Purkinje cells

A
B
C
D
E
F
G
H
I
J
K
L

Table3:
Listing

PCD-associated autoantibody
Anti-Hu
Anti-Yo
Anti-CV2 / CRMP5
Anti-Ma1
Anti-PCA2
Anti-Tr (PCA-Tr)
Anti-mGluR1
Anti-CARP8
Anti-GAD
Anti-ZIC4
LEMS-associated, anti-vgCa-channel
Other autoantibodies

Alcohol related ataxia


Gluten associated ataxia (antiTG6)
Autosomal dominant cerebellar
ataxias (ADCA)
Familial or sporadic ataxia
Idiopathic late-onset cerebellar
atrophy (ILOCA)
Multiple system atrophy (MSA),
cerebellar subtype
Epstein-Barr virus associated cerebellar encephalitis
Primary autoimmune cerebellar
ataxia (PACA)

A. Anti-Hu syndrome
Clinical features

Ataxia
Associated with a variety of other
PNS in the central and peripheral
nerve system
Please see elsewhere and in particular
paraneoplastic
encephalomyelitis (PEM) and
sensory neuronopathy (SSN).

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Neoplasm: small-cell lung.

Causes of death
Progression of neoplasm in 55%
Neurologic in 35%

Onset: before detection of cancer


Treatment
Oncologic
Significant tumour reduction may
stabilize the neurological features
Immunotherapy
Is rarely effective

Associated neoplasms

Breast
Ovary: epithelial
Male patients: gastric, parotid,
oesophageal adenocarcinoma
Metastases: invasion of regional
lymph nodes common (85%)
No neoplasm found in 10%

Investigations

B. Anti-Yo syndrome
Gender

Females in most of the cases


Males, only three patients are reported, two with gynaecomastia

Onset
Mean 60 years of age
Related to cancer
Before cancer: 60%
After start of tumour treatment: 25%
May begin with tumour relapse: 15%

Clinical features
Ataxia
Severe, pancerebellar
Located to trunk and limbs
Dysarthria, oculomotor
Nystagmus, including down beating
Oscillopsia and diplopia
Usually, other CNS & PNS systems are not involved.

Progression
The symptoms aggravate over weeks
to months, mean two to three
months. Eventually, the outcome is
non-ambulatory in 95%.
Survival
Mean two to six years
Dependent on tumour type
Breast: 100 months
Gynaecological: 22 months

Mammography
Pelvic examination and imaging
Serum
o Anti-Yo antibody
o Carcinoembryonic
antigen
(CEA) and cancer antigen
(CA) 125
o Titre may decrease after tumour resection
CSF
o Protein: mildly elevated
o Cells: mild mononuclear pleocytosis
o Anti-Yo antibody present

Treatment
Oncologic
Such therapy does only rarely result
in improvement of the ataxia
Immunotherapy
Cyclophosphamide may possibly be
of some benefit

C. Anti-CV2 / CRMP5
syndrome
Ataxia with antibodies to collapsin response-mediator protein 5

Clinical features
The symptoms are quite varied
Cerebellar (50%)
Ataxia
Nystagmus
Dysarthria
Limbic encephalopathy (30%)
Dementia
Mental status and mood changes
Seizures

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Opsoclonus/myoclonus (5%)
Movement disorders (15%)
Basal ganglia: chorea
Cranial nerve disorders (15%)
Optic neuropathy
Abnormal olfaction or taste
Myelopathy (16%)
Peripheral nervous system
Sensory or sensory-motor disorders (45%)
Autonomic dysfunction (30%),
especially
isolated
gastrointestinal; also multiple systems
Polyradiculopathy (5%)
o Sensory-motor
o Legs > arms
o Symmetric
o Onset: subacute
o Pathology: axonal loss; inflammation (50%)
Neuromuscular junction (10%)
LEMS
Other associated syndromes
Optic neuritis
Uveitis
Intestinal pseudo-obstruction

Anti-CV2 / CRMP5 antibody


Antigen
A 66 kDa neural specific protein with
homology to UNC-33 and ULIP
Cellular distribution
Synapse-rich regions of brain and
gut
Small DRG neurons
Small-cell neoplasms
Oligodendrocytes: cytoplasm
Cerebellum, brainstem, spinal
cord and optic chiasm
Please note that in some patients,
anti-Hu, or anti-amphiphysin, anti-RI,
and anti-ZIC4 are features as well.

Investigations

CSF
o Pleocytosis (lymphocytes)
o High protein
Anti-CV2 / CRMP5 antibodies
(IgG)
Present in both serum and CSF

Thymoma (5%)
Other: uterine sarcoma

Treatment
Tumour removal may result in some
improvement

D. Anti-Ma1 syndrome
Typically, in this syndrome there
is a combination of cerebellar and
brainstem disorders.

Age at onset
55-65 years
Either up to one year before de-

tection of the neoplasms or concurrent with the cancer diagnosis

Clinical features: not uniform

Cerebellar: trunk and extremities


Brainstem: EOM limitation, dysphagia
Other: sensory loss, myokymia

Prognosis: death in about 50%


Antigen

Ma1 protein
o 37 and 40 kDa proteins located to neuronal & testicular
germ cell
o Homology to Ma2 (Ta) and
Ma3

Tumours: not uniform

Testis
Breast
Lung (large-cell)
Colon

Pathology
Gliosis of brainstem and cerebellar
nuclei; inflammation

Associated neoplasms (especially in the chest)


Small-cell lung (80%)

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

E. Syndrome with anti-PCA2 antibodies

Course: subacute

Gender
Females in 70%

Onset

40-85 years of age

Clinical features
Quite varied syndromes
Limbic encephalitis: 50%
Cerebellar ataxia: 30%
Lambert-Eaton myasthenic syndrome: 20%
Autonomic neuropathy: 10%
Motor syndrome: 10%
Stiff-person syndrome
No neurologic syndrome: 10%

Associations

Smokers
Lung cancer (small-cell)

Antigen

Protein: 280 kDa


Location: neuron-specific.
Purkinje cell cytoplasm in soma
and dendrites

Associated antibodies

Anti-PCA2 (IgG): serum + low


titres in CSF
Anti-vg-Ca-Channel (P/Q- & Ntype)
Anti-AChR (nicotinic adult- and
foetal-types)
Anti-AChR (nicotinic alpha3-type,
autonomic)

Usually irreversible
Spontaneous disappearance may
occur in cases with no tumour
Remissions (15%): more common in younger than after 40
years of age
Survival
o Mean > 9 years
o Longer than in anti-Hu or anti-Yo syndromes

Clinical features

Ataxia, moderate to severe


Variant syndromes
o Limbic encephalitis (7%): reversible
o Optic neuritis

Associated neoplasm

Hodgkins lymphoma (90%), especially nodular sclerosis


No neoplasm (10%)

Anti-PCA-Tr antibody
Antigen
Delta/Notch-like Epidermal Growth
Factor-Related Receptor (DNER)
Tissue staining
Cerebellum
o Purkinje cell cytoplasm and
dendrites
o Dotted pattern in molecular
cerebellar molecular layer
Neoplasm: only rarely stained
Tr cell localization
o Cytosol and outer surface of
endoplasmic reticulum
Location
o Usually present in serum and
CSF, maybe only in CSF

Cerebellar pathology

F. Anti-Tr (PCA-Tr)
syndrome

Loss of Purkinje cells


No inflammation

Gender
Males > females (3:1)

Onset

Age: median 61 years; range 15


to 75 years
Before (70%) or after cancer; also during remission

G. Ataxia with antimGluR1 antibodies


Ataxia associated with antibodies
to metabotropic glutamate receptor
R1. This disorder appears to fulfil the

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

criteria of an antibody-mediated autoimmunity.

Epidemiology: only one patient

Onset

Onset: 3 years after neoplasm

Months
(80%)

to

years

after

neoplasm

Course
Persistent or monophasic

Clinical features

Ataxia: truncal and gait


Intention tremor
Mental status: normal

Investigations
Antibodies
Anti-mGluR1
o Tissue staining
Cerebellum: Purkinje cell
bodies (punctuate) and
spines
Glomeruli
of
olfactory
bulb: neurons and neurophils
Cerebral cortex: superficial layer
Other: hippocampus (CA3),
thalamus, superior colliculus, spinal trigeminal nucleus
o Location: serum and CSF
Other laboratory
CSF: high total IgG and IgG index
MRI: normal

reported a 77-year-old female

Course: progressive ataxia


Clinical features: Pure cerebellar
syndrome
Ataxia: limb, truncal, gait, dysarthria
Ocular: horizontal nystagmus
Mental status: normal

Investigations
Antibodies
Anti-CARP8
o Tissue staining
Cerebellum: Purkinje cell
cytoplasm and dendrites
Weaker staining
Lateral nuclei of thalamus
Bronchial epithelial cells
Melanomas: one of seven
tested
Location: serum and CSF
Other laboratory
CSF
Lymphocytosis
Oligoclonal bands

Neoplasm: melanoma
Treatment: none

Neoplasm

I. Syndrome with anti-GAD antibodies

Hodgkin's lymphoma, during remission

Treatment
Immunosuppression may be of value.

Please see
drome: variants

H. Ataxia with antiCARP8 antibodies


Ataxia associated with antibodies to carbonic anhydrase-related
protein 8.

stiff-person

syn-

J. Syndrome with anti-ZIC4 antibodies


Clinical features

Ataxia, moderate to severe


Slurred speech
Vertigo

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Neoplasm: small-cell lung (SCLC)


Antibodies
Anti-ZIC4

Bearing in mind that SCLC is the associated neoplasm, consider looking


for other onconeuronal antibodies as
well. PEM rather than PCD is the
most likely diagnosis, should such
antibodies also be a feature.
In short, detection of Zic4 antibodies
often associates with
Anti-Hu or CV2 (CRMP5) antibodies

Antibodies
Anti-vg-Ca channels (P/Q- & N

type)
Increased incidence in
syndromes

anti-Hu

Neoplasm: small-cell lung


Treatment
See the Lambert-Eaton myasthenic
syndrome.

L. Ataxia with other


autoantibodies

On the other hand, patients with isolated Zic4 antibodies are more likely
to develop isolated cerebellar dysfunction than those with concurrent
immunities.

Antibodies

K. LEMS-associated

Neoplasm

Anti-ARHGAP26 (GRAF), antiProtein kinase C gamma (PKC gamma))

ovarian (anti-GRAF)
non-SCLC (anti-PCK gamma)

Ataxia associated with Lambert-Eaton myasthenic syndrome.

Selected references
1.

Peterson K, Rosenblum MK, Posner JB. Paraneoplastic cerebellar degeneration: a clinical analysis
of 55 anti-Yo antibody-positive patients. Neurology 1992; 42: 1931-37.
2. Mason WP, Graus F, Lang B, et al. Small-cell lung cancer, paraneoplastic cerebellar degeneration
and the Lambert-Eaton myasthenic syndrome. Brain 1997; 120: 1279-300.
3. Graus F, Lang B, Pozo-Rosich P, et al. P/Q type calcium-channel antibodies in paraneoplastic
cerebellar degeneration with lung cancer. Neurology 2002; 59: 764-6.
4. Shamsili S, Grefkens J, de Leeuw B, et al. Paraneoplastic cerebellar degeneration associated with
antineuronal antibodies: analysis of 50 patients. Brain 2003; 126: 1409-18.
5. Bataller L, Wade DF, Graus F, Stacey HD, Rosenfeld MR, Dalmau J. Antibodies to Zic4 in
paraneoplastic neurologic disorders and small-cell lung cancer. Neurology 2004; 62: 768-782.
6. Sabater L, Bataller L, Carpentier AF, AguirreCruz ML, Saiz A, Benyahia B, Dalmau J, Graus F .
Protein kinase C autoimmunity in paraneoplastic cerebellar degeneration and nonsmallcell lung
cancer. J Neurol Neurosurg Psychiatry 2006; 77 (12): 13591362.
7. Titulaer MJ, Klooster R, Potman M, Sabater L, Graus F, Hegeman IM, Thijssen PE, Wirtz PW,
Twijnstra A, Smitt PA, van der Maarel SM, Verschuuren JJ. SOX antibodies in small-cell lung
cancer and Lambert-Eaton myasthenic syndrome: frequency and relation with survival. J Clin
Oncol 2009; 27 (26): 4260-4267.
8. Jarius S, Martnez-Garca, P, Hernandez AL, et al. Two new cases of anti-Ca (antiARHGAP26/GRAF) autoantibody-associated cerebellar ataxia. Journal of Neuroinflammation 2013,
10:7
9. Eichler TW, Totland C, Haugen M, Qvale TH, Mazengia K, Storstein A, Haukanes BJ, Vedeler CA.
CDRL2Antibodies: A New Player in Paraneoplastic Cerebellar Degeneration. PLOS ONE 2013; 8
(6): 1-8
10. Hadjivassiliou M, Aeschlimann P, Sanders DS, et al. Transglutaminase 6 antibodies in the
diagnosis of gluten ataxia. Neurology 2013; 80 (19): 1740-5.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Paraneoplastic choreo-athetosis
Paraneoplastic choreo-athetosis is a rare encephalopathy characterized by extrapyramidal features such as chorea &
athetosis. Most frequently, this disorder is associated with antiCV2 (CRMP5) antibodies, rarely with anti-Hu. The diagnosis is only justified, if chorea is the single or predominant sign in association with these onconeural antibodies. The more common situation is a much wider spectrum of neurological findings in patients
with anti-CV2 or anti-Hu antibodies - see details elsewhere in this
book.
neoplastic CNS disorder, for example with ataxia, limbic encephalitis, myoclonus and more, then
a diagnosis of paraneoplastic choreo-athetosis is rendered unjustifiable,
see
PCD,
anti-CV2
(CRMP5) syndrome.

Associated neoplasm
Small-cell lung cancer (SCLC)
MRI through the basal ganglia
(A), reduced intensity is evident in the T1
weighted image of the bilateral caudate
head. (B), markedly increased intensity
is evident in the T2 weighted image

Clinical features

Chorea, i.e. involuntary brief, irregular, unpredictable, purposeless movements that flow from
one body part to another without
a rhythmic pattern and involving
movements over joints
Athetosis, i.e. involuntary writhing movements particularly of the
arms and hands

Associated antibodies

Anti-CV2 (CRMP5) is the finding


in most cases. Sometimes, antiHu, anti-Amphiphysin, anti-Ri,
and anti-Zic4 are features as well.
However, if the clinical appearance is that of a multifocal para-

Some differential diagnoses

Hereditary disorders with chorea,


such as Huntingtons disease,
neuroacanthocytosis. Metabolic
disorders such as Wilson disease
and others
Immunologic disorders, for example SLE
Paraneoplastic: Morvans fibrillary
chorea
Post-infectious: chorea (subsequent to group-A streptococci)
Infectious: Creutzfeldt-Jacob disease
Stroke
Senile chorea

Treatment
High-dose IgG
Immunosuppression
Oncologic
Possibly, Carboplatin-etoposid cycles
or similar drugs to treat the SCLC

Selected references
1.
2.

Tani T, Piao Y-S, Mori S, Ishihara N, Tanaka K, Wakabayashi K, Takahashi H. Chorea resulting
from paraneoplastic striatal encephalitis. J Neurol Neurosurg Psychiatry 2000; 69: 512-515.
Dorban S, Gille M, Kessler R, Pieret F, Declersq I, Sindic CJ. [Chorea-athetosis in the anti-Hu
syndrome]. [Article in French]. Rev Neurol (Paris) 2004; 160 (1): 126-129.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Paraneoplastic encephalitides
Paraneoplastic CNS disorders:
Whereas a majority of encephalitides are viral in nature, autoimmune encephalitis is increasingly being diagnosed and with a
variety of aetiologies - paraneoplastic, post-infectious, idiopathic.
Table 4:

Category of disorders
A
Paraneoplastic
B
Paraneoplastic
C
Paraneoplastic
D
Paraneoplastic
Additional

encephalomyelitis (PEM)
limbic encephalitis (PLE)
brainstem encephalitis
myelitis

Often PEM co-exists as part of a broader anti-Hu syndrome

Subacute sensory neuronopathy (SSN, PSN)

Moreover, PEM may comprise

Autonomic dysfunction including chronic intestinal pseudo-obstruction

Table 5:
Overview of paraneoplastic encephalitides: autoantibodies vs. neoplasms
Short name

Alias: anti-

(alphabetical order)

Anti-AGNA
Anti-AMPAR
Anti-Amphiphysin
Anti-BRSK2
Anti-CASPR2
Anti-CV2
Anti-EFA6A
Anti-GAD

SOX1
GluR1/2

Anti-GabaBR1
Anti-Hu
*Anti-K-channel
Anti-LGI1

GABBR1
ANNA-1
VGKC, VGPC

Anti-mGluR1
Anti-mGluR5
Anti-NMDAR
Anti-PCA-2
Anti-Ri
Anti-Ta
Anti-Tr
Anti-Yo

Primary
analysis

Associated neoplasms
SCLC
SCLC, non-SCLC, thymoma, breast

Yes

Breast, SCLC
SCLC
Thymoma

CRMP5,POP66

Yes

SCLC, thymoma
Ovarian

Yes

SCLC, thymoma, breast, renal,


Hodgkin
SCLC

Yes
Yes

SCLC, non-SCLC,
SCLC, thymoma
Thyroidea, kidney, thymus, ovarian
teratoma lung
Ovarian, morbus Hodgkin
Morbus Hodgkin

NR1 / NR2

Yes

Teratoma
SCLC

ANNA-2, Nova-1
Ma2, PNMA2
Purkinje cell (Tr)
APCA-1, CDR-62

SCLC, non-SCLC, breast, ovarian

Yes
Yes
Yes

Testicular, ovarian
Morbus Hodgkin
Breast, ovarian, SCLC

* LGI1 and CASPR2 are accessory proteins at VGKCs, and are the true targets

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A. Paraneoplastic
encephalomyelitis
(PEM)
The term paraneoplastic encephalomyelitis (PEM) comprises several
syndromes characterized by neuronal
loss, microglial proliferation, inflammatory infiltrates in the CNS and the
co-existence mainly of anti-Hu antibodies. Although some patients may
have clinical involvement of only one
location throughout the complete
clinical course, 75% of them present
with a multifocal disorder.

Overview of the general


clinical features
The symptoms and signs reflect the
variable anatomic involvement and
include
Encephalopathy (limbic en-

cephalitis)

This is the second most common


clinical syndrome, and it may remain isolated throughout the clinical evolution.

Brainstem
syndromes
(bulbar encephalitis)
These features reflect a predominant involvement of the floor of
the fourth ventricle and the inferior olives, resulting in vertigo,
nystagmus, oscillopsia, ataxia,
diplopia, dysarthria, and dysphagia.

Myelitis

Autonomic dysfunction

to damage of the neurons of the


myenteric plexus.

Subacute
sensory
neuronopathy (SSN, PSN)
This is the most common clinical
syndrome. In about 20% of the
patients, SSN is the only clinical
evidence of paraneoplastic disease.

Associated neoplasms
Small-cell lung cancer (SCLC) in
about 75%

Associated antibodies
Anti-Hu (most frequent)
Particularly in cases presenting with
isolated limbic encephalitis throughout the complete clinical course:
Anti-CV2 (CRMP5)
Anti-Amphiphysin
Anti-Ri
Anti-PCA2
Anti-Yo
Anti-ZIC4, less frequent
other antibodies, see Table 5
and below

Treatment
Oncologic
Significant tumour reduction may
stabilize the neurological features.
Immunotherapy
Rarely effective
Anyhow, intravenous high-dose IgG,
steroids or plasmapheresis may be
worth trying, since a few patients do
improve.

The dorsal root ganglia are affected. This is a feature of about


30% of these patients. The most
common symptoms are
o orthostatic hypotension
o urinary retention
o pupillary abnormalities,
o impotence
o dry mouth
Occasionally, there is also chronic
intestinal pseudo-obstruction due

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B. Paraneoplastic limbic encephalitis (PLE)


may include nonlimbic structures

b. MRI demonstrating temporal lobe abnormalities


c. EEG showing epileptic activity in the temporal lobes
Brain MRI showing bilateral
limbic pathology

Paraneoplastic limbic encephalitis


is a classical PNS with acute or subacute encephalopathy characterized
by involvement of the limbic system
and a variety of onconeural antibodies.
Limbic system

PLE is a rare disorder characterized


by personality changes (autoimmune
psychosis), irritability, depression,
seizures, memory loss and sometimes dementia. The diagnosis is difficult because clinical markers are often lacking, and symptoms usually
precede the diagnosis of cancer or
mimic other complications.
The diagnosis of PLE required neuropathological examination or the
presence of the four following criteria
1. A compatible clinical picture
2. An interval of <4 years between
the development of neurological
symptoms and tumour diagnosis
Do also consider autoimmune
synaptic encephalitis with no underlying neoplasm
3. Exclusion
of
other
neurooncological complications
4. At least one of the following
a. CSF with inflammatory
changes but no evidence
of infection

Onset
Most frequently (85%), there is a
subacute onset of confusion and
marked reduction of short-term
memory. Seizures are frequent, and
they may antedate by months the
onset of the cognitive deficits.
Other patients (15%) have a more
insidious onset with depression or
hallucinations, which can confuse the
diagnosis with that of a psychiatric
illness.

Clinical features
This disorder presents with a diversity of symptoms including:
Accordingly and in many cases, the
symptoms are not restricted to limbic
structures. Short-term memory loss
or amnesia, disorientation, confusion,
depression, agitation, anxiety are
typical features.
Typical findings
Loss of short-term
(85%)

memory

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Cognitive disturbance (15%)


Epileptic seizures (50%)
Acute
confusional
syndrome
(45%)
Additional psychiatric symptoms
(40%)
Personality change, hallucinations,
depression
Brainstem symptoms (25%)
Signs of hypothalamic involvement (20%)
Involvement of other neurological
structures (about 40%)
See also cerebellar syndromes
with anti-GAD & anti-PCA2
antibodies and Morvans fibrillary chorea.

Diagnostic criteria

Typical clinical symptoms


Less than four years to tumour
diagnosis
Brain MRI, SPECT or PET showing
the typical involvement of hippocampus
Exclusion of other diagnoses
o In particular, the more common non-paraneoplastic autoimmune limbic encephalitis
associated with autoantibodies to vg-K-channels and
which disorder, apart from the
neoplasm is clinically indistinguishable from PLE with a
thymoma.
o Also
exclusion
of
nonparaneoplastic
anti-NMDAR
encephalitis (idiotypic or SLE
with CNS involvement)

Other investigations
EEG
Cerebrospinal fluid
Pleocytosis and oligoclonal bands (in
about 60%)

Associated neoplasms

Small-cell lung cancer (50%)


Testicular tumour (20%)
Ovarian
Breast cancer (8%)
Thymoma
Hodgkins disease
Prostate
Teratoma

Thyroid
Renal cancer (anti-GAD)

Associated antibodies
Lung cancer
Anti-Hu
Anti-CV2 (CRMP5)
Anti-Amphiphysin
Anti-GAD
AGNA (anti-SOX1)
Anti-PCA2
Anti-AMPAR (GluR1/R2))
Anti-BRSK2
Anti-GabaBR1
Breast
Anti-AMPAR (GluR1/R2)
Thymoma
Anti-LGI1
Anti-CASPR2
Anti-AMPAR (GluR1/R2)
Testis cancer
Anti-Ta (Ma2) antibodies are a
feature in the great majority of
patients. Usually, these cases also present with diencephalic and
upper brainstem symptoms that
identify a characteristic syndrome. This antibody may also
be a finding in patients with other neoplasms, such as prostate,
ovarian teratoma, breast, and
pulmonary adenocarcinoma
Ovarian cancer
Anti-mGluR1
Anti-LGI1
Prostate or breast cancer
Anti-Yo
Hodgkins lymphoma
Anti-Tr
Anti.mGkuR1
Anti-mGluR5 (Ophelia syndrome)
Anti-GAD
Teratoma
Acute psychiatric symptoms, prolonged disturbance of consciousness, seizures (refractory status
epilepticus), autonomic instability,
central hypoventilation and various involuntary movements, dyskinesias, dystonia

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Anti-NMDAR (NR1)
Types of autoimmune antiNMDAR encephalitis
o Of unknown cause (postinfectious?)
o Paraneoplastic
Epidemiology of anti-NMDAR
seropositives
Recent research suggests that
non-paraneoplastic encephalitis may be the most frequent
Anti-NMDAR encephalitis is increasingly recognized in children, comprising 40% of all
cases with encephalitis of
previous unknown origin

In male patients, it appears


that teratomas are not a feature. This is consistent with
the rare incidence in the testes of pure benign teratomas,
accounting for only 3-5% of
germ cell tumours. Accordingly and anyhow, they should
be searched for
Female patients: decreasing
frequency of teratomas by
age

Table 6
Female patients
Age group,
Frequency of
years
teratomas
Older than 18
55%
14.1 18
30%
Up to 14
10%

Particular additional clinical


feature
Maybe also excessive daytime
sleepiness
In such cases, decreased / absent
hypocretin-1 may be a feature of
the CSF
Various
Anti-EFA6A (a guanine nucleotide
exchange factor)
Anti-nCMAg
(novel
cellmembrane antigens) which is
highly expressed in hippocampus
and cerebellum)
Anti-Adenylate kinase 5)
Anti-UBE2E1
About 40% are seronegative, and
the absence of onconeural anti-

bodies does not rule out the diagnosis

Treatment
In general (anti-Hu), this disorder
rarely improves with treatment.
Oncologic
Removal of the tumour may result in
a certain degree of reversal.
Symptomatic
Consider drug therapy of epilepsy
and psychiatric symptoms.
Immunotherapy
In particular, patients with antiTa (Ma2) antibodies or those
without detectable onconeural
antibodies may benefit

Probably, a finding of anti-vg-Kchannels or anti-NMDAR also


suggests a good response to immunotherapy
Vice versa, the presence of antiHu antibodies appears to predict
a poor response to such treatment
Options
o Intravenous high-dose IgG
o Plasmapheresis, which is an obvious choice, if anti-vg-K-channel
or anti-NMDAR antibodies are detected
o Steroids or other immunosuppressants

C. Paraneoplastic
brainstem encephalitis
Paraneoplastic brainstem encephalitis
Most frequently, this disorder is a
part of multifocal pathology:
Please look elsewhere for the
specific features of the various
syndromes
Paraneoplastic opsoclonus /
myoclonus (POM)
Paraneoplastic sensory neuropathy (SSN, PSN)
Stiff-person syndrome: variants, PERM

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Schematic representation

Short summary
1. Association with small-cell
lung cancer (SCLC)
The brainstem encephalitis usually also involves other locations of the
nervous system (encephalomyelitis).
2. Association with breast or gynaecological cancer
In about 75%, there is also opsoclonus.
If not so, then:
Oculomotor abnormalities, including gaze paresis, nystagmus, abnormal visual tracking, blepharospasm, and abnormal vestibuloocular reflexes
Truncal ataxia may predominate
and cause severe gait difficulty
and frequent falls
Limb ataxia is usually mild and
most patients retain the ability to
write and to feed themselves
Nausea, dizziness, dysarthria,
dysphagia, diplopia, rigidity, parkinsonism

MRI brain scans are usually


normal.

3. Association with testis cancer


and other neoplasms (anti-Ta
(Ma2) syndrome)
Usually combined with limbic encephalitis or diencephalic symptoms
Vertical gaze paresis or paralysis
Mild to moderate dysarthria,
dysphagia, facial weakness
Atypical parkinsonism with severe akinesia, facial masking,
rigidity, and tremor
Maybe,
excessive
daytime
sleepiness
In such cases, decreased / absent hypocretin-1 may be a
feature of the CSF

MRI may reveal hyperintense


T2-weighted images in the upper brainstem, hypothalamus,
thalamus, hippocampus, which
are rarely enhanced by contrast

Associated antibodies and


cancer

Anti-Hu: SCLC
Anti-CV2 (CRMP5): SCLC, thymoma
Anti-Amphiphysin: breast
Anti-Ri: breast
Anti-Ta (Ma2): testis, breast,
colon, lung adenocarcinoma
Anti-GAD: SCLC, breast, thymoma, Hodgkin and nonHodgkin lymphoma, renal cell
carcinoma

Treatment
The syndrome may stabilize or improve subsequent to a successful oncological treatment (e.g. anti-Ta
(Ma2)).
Immunotherapy
Although a few patients may benefit,
such therapy rarely is effective. In
particular however, patients with a
finding of anti-Ta antibodies and no
findings of other paraneoplastic autoantibodies are the most likely to
improve.
o Steroids or other immunosuppressants
o Intravenous high-dose IgG
o Plasmapheresis

D. Paraneoplastic
myelitis/myelopathy
Paraneoplastic myelitis / myelopathy, which may also be a part of
more multifocal pathology (PEM)

Anti-Hu-associated
Clinical features
Motor
Patchy weakness: arms > legs
May progress to neck
Fasciculations

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Eventually, respiratory failure

Sensory
Associated ganglionopathy

Associated neoplasm

Lung (small-cell)

Other options

Anti-CV2 (CRMP5) syndrome,


see
Paraneoplastic
cerebellar
syndrome (PCD)
Anti-Ri (ANNA2) syndrome,
see Opsoclonus / myoclonus

Selected references
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.

Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu-associated paraneoplastic


encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine 1992; 71: 5972.
Ball JA, Warner T, Reid P, et al. Central alveolar hypoventilation associated with paraneoplastic
brain-stem encephalitis and anti-Hu antibodies. J Neurol 1994; 241: 561-6.
Alamowitch S, Graus F, Uchuya M, Re R, Bescansa E, Delattre JY. Limbic encephalitis and small
cell lung cancer. Clinical and immunological features. Brain 1997; 120: 923-8.
Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients
seropositive for type 1 antineuronal nuclear antibodies. Neurology 1998; 50: 652-72.
Voltz R, Gultekin SH, Rosenfeld MR et al. A serologic marker of paraneoplastic limbic and brainstem encephalitis in patients with testicular cancer. N Engl J Med 1999; 340: 1788-95.
Gultekin SH, Rosenfeld MR, Voltz R, et al. Paraneoplastic limbic encephalitis: neurological
symptoms, immunological findings and tumour association in 50 patients. Brain 2000; 123: 148194.
Graus F, Keime-Guibert F, Re R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis:
analysis of 200 patients. Brain 2001; 124: 1138-48.
Yu Z, Kryzer TJ, Griesmann GE, et al. CRMP-5 neuronal autoantibody: Marker of lung cancer and
thymoma-related autoimmunity. Ann Neurol 2001; 49: 146-54.
Graus F, Keime-Guibert F, Re R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis:
analysis of 200 patients. Brain 2001; 124: 1138-48.
Rosenfeld MR, Eichen JG, Wade DF, et al. Molecular and clinical diversity in paraneoplastic
immunity to Ma proteins. Ann Neurol 2001; 50: 339-48.
Sutton IJ, Barnett MH, Watson JDG, et al. Paraneoplastic brainstem encephalitis and anti-Ri
antibodies. J Neurol 2002; 249: 1597-8.
Sillevis Smitt P, Grefkens J, de Leeuw B, et al. Survival and outcome in 73 anti-Hu positive
patients with paraneoplastic encephalomyelitis/sensory neuronopathy. J Neurol 2002; 249:745-53.
Pozo-Rosich P, Clover L, Saiz A, et al. Voltage-gated potassium channel antibodies in limbic
encephalitis. Ann Neurol 2003; 54: 530-3.
Thieben MJ, Lennon VA, Boeve BF, A. J. Aksamit, MD, Keegan M, Vernino S. Potentially reversible
autoimmune limbic encephalitis with neuronal potassium channel antibody. Neurology 2004; 62:
1177-1182.
Dalmau J, Graus F, Villarejo A, Posner JB, Blumenthal D, Thiessen B, Saiz A, Meneses P,
Rosenfeld MR. Clinical analysis of anti-Ma2-associated encephalitis. Brain 2004; 127 (8): 18311844.
Sabater L, Gmez-Choco M, Saiz A, Graus F. BR serine/threonine kinase 2: A new autoantigen in
paraneoplastic limbic encephalitis. J Neuroimmunol 2005; 170 (1): 186-190.
Graus F, Vincent A, Pozo-Rosich P, Sabater L, Saiz A, Lang B, Dalmau J. Anti-glial nuclear
antibody: Marker of lung cancer-related paraneoplastic neurological syndromes. J Neuroimmunol
2005; 165 (1): 166-171.
Vitaliani R, Mason W, Ances B, Zwerdling T, Jiang Z, Dalmau J. Paraneoplastic encephalitis,
psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol 2005; 58: 594-604.
Dalmau J, Bataller L. Clinical and Immunological Diversity of Limbic Encephalitis: A Model for
Paraneoplastic Neurologic Disorders. Hematol Oncol Clin North Am 2006; 20(6): 13191335.
Kleopa KA, Elman LB, Lang B, Vincent A, Scherer SS. Neuromyotonia and limbic encephalitis sera
target mature Shaker-type K+ channels: subunit specificity correlates with clinical manifestations.
Brain 2006; 129: 15701584.
Kowal C, DeGiorgio LA, Lee JY, Edgar MA, Huerta PT, Volpe BT, Diamond B. Human lupus
autoantibodies against NMDA receptors mediate cognitive impairment. PNAS 2006; 103 (52):
19854-19858.
Bataller L, Kleopa KA, Wu GF, Rossi JE, Rosenfeld MR, Dalmau J. Autoimmune Limbic Encephalitis
in 39 Patients: Immunophenotypes and Outcomes. J Neurol Neurosurg Psychiatry 2007; 78 (4):
651-5;
Emer BJ et al. Damage to the amygdala might cause neuropsychiatric symptoms in patients with
SLE. Nature Clinical Practice Rheumatology 2007; 3, 197 doi:10.1038.

38

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24. Tzn E, Jeffrey E. Rossi JE, Karner SF, Centurion AF, Dalmau J. Adenylate Kinase 5
Autoimmunity in Treatment Refractory Limbic Encephalitis. J Neuroimmunol 2007; 186 (1-2):
177180.
25. Sansing LH, Tzn E, Ko MW, Baccon J, Lynch DR, Dalmau J. A patient with encephalitis
associated with NMDA receptor antibodies. Nature Clinical Practice Neurology 2007; 3, 291-296.
26. Seki M, Suzuki S, Lizuka T, Shimizu T, Nihei Y, Suzuki N, Dalmau J . Neurological response to
early removal of ovarian teratoma in anti-NMDAR encephalitis. J Neurol Neurosurg Psychiat 2008;
79: 324-326.
27. Iizuka T, Sakai F, Ide T, Monzen T, Yoshii S, Iigaya M, Suzuki K, Lynch DR, Suzuki N, Hata T,
Dalmau J. Anti-NMDA receptor encephalitis in Japan. Neurology 2008; 70: 504-511.
28. Florance NR, Davis RL, Lam C, Szperka C, Zhou L, Ahmad S, Campen CJ, Moss H, Peter N,
Gleichman AJ, Glaser CA, Lynch DR, Rosenfeld MR, Dalmau J. Anti-N-methyl-D-aspartate receptor
(NMDAR) encephalitis in children and adolescents. Ann Neurol. 2009; 66 (1):11-18.
29. Lai M, Hughes EG, Peng X et al. AMPA receptor antibodies in limbic encephalitis alter synaptic
receptor location. Ann Neurol 2009; 65(4): 424434.
30. Irani SR, Sian Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, Peles E, Buckley C, Lang
B, Vincent A. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma
inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvans syndrome
and acquired neuromyotonia. Brain 2010; 133 (9): 2734-2748.
31. Lancaster E, Martinez-Hernandez E, Dalmau J. Encephalitis and antibodies to synaptic and
neuronal cell surface proteins. Neurology 2011; 77 (2): 179-89.
32. Lancaster E, Martinez-Hernandez E, Titulaer MJ, Boulos M, Weaver S, Antoine JC, Liebers E,
Kornblum C, Bien CG, Honnorat J, Wong S, Xu J, Contractor A, Balice-Gordon R, Dalmau J.
Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome. Neurology 2011; 77
(18): 1698-701.

Paraneoplastic motor neuron disease?


Paraneoplastic motor neuron disease (MND):
Several reports indicate that amyotrophic lateral sclerosis (ALS),
primary lateral sclerosis (PLS), and progressive muscular atrophy
(PMA) may develop coincidentally with a cancer. Although still
controversial in existence, some cases of motor neuron disease
(MND) may therefore be attributable to a paraneoplastic origin.

Clinical features
Motor
neuron
involvement
and anti-Hu syndrome
In up to 20% of paraneoplastic
encephalomyelitis (PEM), MND is
also a feature. This MND involves
both upper and lower motor neuron, and such neurology may
even be an early manifestation.
Otherwise, these patients do not
differ to any other aspect of PEM
without MND.
Amyotrophic lateral sclerosis
(ALS)
ALS may be a feature of oncologic patients, although this is a rare
event.

To date, the World Neurological Association does not recognize the existence of paraneoplastic ALS (EL Escorial Criteria for ALS, 1998).

Oncological patients with ALS do


not differ from individuals with
sporadic ALS.
No other anti-neuronal antibodies apart from anti-Hu
Cause of death: motor neuron
defiance
Comparable survival
Cancer
treatment
usually
does not improve neurological
status.
On the contrary, though, tumour progression might be
slower in patients with concomitant ALS.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

o
Primary lateral sclerosis (PLS)
Pure involvement of the upper
motor neurons
Rare disease observed in
women with a breast cancer
Also associated with adenocarcinoma in gall bladder and
duodenum (anti-Hu positive)
Accordingly, PLS is the most likely candidate in MND, which is attributable to a paraneoplastic
origin.
Course
o Chronic and progressive
o May eventually turn into a
fully expressed ALS
o The
coexistent
cancer
does not modify PLS progression.
Investigations
o Consider mammography
in a female patient with
PLS
o Possibly also anti-Hu in
MND
Progressive muscular atrophy
(PMA)
Also called: Subacute motor
neuronopathy
Clinical features
o Painless lower motor neuron

o
o

Weakness,
occasionally
accompanied by minor
sensory symptoms
Subacute often asymmetrical
Progressive

Associated neoplasms
o Hodgkins disease
o Non-Hodgkins lymphoma
Course
Independent from the cancer
Note that the World Association of
Neurology does not recognize the existence of a paraneoplastic PMA.

Motor neuron diseases and


lymphoproliferative disorders
(LPD)
MND (ALS, PLS and PMA) has
been observed in relation to
Waldestroms
macroglobulinaemia
Multiple myeloma
Chronic lymphocytic leukaemia
Follicular cell lymphoma
Hodgkins disease
Summary
It is unclear, if the association
is coincidental or of significance in LPD
MND in LPD patients implies a
poor prognosis due to MND
progression
Unfortunately, the treatment
of the LPD is unlikely to affect
the coexisting MND.

Selected references
1.
2.
3.
4.
5.

Gordon PH, Rowland LP, Younger DS; Sherman WH; Hays AP; Louis ED, Trojaborg, W, Lovelace
RE; Murphy PL; Latov N: Lymphoproliferative disorders and motor neuron disease: An update.
Neurology 1997; 48:1671-1675.
Forsyth PS, Dalmau J, Graus F, Cwik V, Rosemblum MK, Posner JB: Motor neuron syndromes in
cancer patients. Ann Neurol 1997; 41: 722-730.
Rowland LP: Paraneoplastic Primary Lateral Sclerosis and Amyotrophic Lateral Sclerosis. Ann
Neurol 1997; 41: 703-705.
Ogawa M, Nishie M, Kurahashi K, Kaimori M, Wakabayashi K. Anti-Hu associated paraneoplastic
sensory neuronopathy with upper motor neurone involvement. J Neurol Neurosurg Psychiat 2004;
75:1051-1053.
Criteria for the diagnosis of ALS.

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Paraneoplastic opsoclonus / myoclonus (POM)


Paraneoplastic opsoclonus / myoclonus:
This disorder is within the group of classical PNS. Involuntary
movements of the eyes and other striated muscles in any direction
characterize it. POM is associated with a variety of neoplasms and
onconeural antibodies.
Table 7:
The following paraneoplastic clonus
disorders are known
Category

Neurologic clinical features


Opsoclonus: conjugate saccades.

POM in children

POM in adults

Paraneoplastic opso-,
myoclonus (POM)

Anti-Hu, anti-Yo, antiTa (Ma2) syndromes

POM in adults
Anti-Ri syndrome

A. Opsoclonus / myoclonus in children

Involuntary
Multidirectional
Arrhythmic
Nearly continuous
High amplitude
Persist when the eyes are closed
and during sleep
Associated with blinking, myoclonus
Increases with visual pursuit and
voluntary refixation

Myoclonus (brief involuntary twitching of a muscle or of a group of muscles)


Cerebellar ataxia
Dysphagia and more
Note however, that neurologic features are present in only about two
percent of these patients with a neuroblastoma

Antibodies

Anti-neurofilaments
At other CNS antigens, for example anti-Hu, anti-ZIC4

Differential diagnosis in children with clonus

Neuroblastoma
Clinical Syndrome
Age at onset: mean about 18
months. Most before the age of five,
and rare in children older than 10
years
Gender: males slightly more often
than females
Onset: before or after cancer

Encephalitis: post-viral syndrome,


post-infectious autoimmunity e.g.
after group-A streptococci
Toxic: thallium, lithium, amitriptyline
Diabetic hyperosmolar coma
Intracranial lesions: other tumours, hydrocephalus, thalamic
haemorrhage

Differential diagnoses in children with neuroblastic tumours

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Neuroblastoma, ganglioneuroblastoma, ganglioneuroma


Rapid-onset obesity with hypothalamic dysfunction, hypoventilation,
and autonomic dysregulation
(ROHHAD syndrome)

Treatment
Corticosteroids
Residua: CNS signs are frequent

B. Opsoclonus /
myoclonus in adults:
anti-Hu, Yo, Ta (Ma2)
syndromes
Clinical features
Opsoclonus and myoclonus
Associated features
Encephalopathy
Seizures
Syndrome of SIADH (inappropriate antidiuretic hormone secretion)

Associated antibodies and neoplasms

Anti-Hu, anti-amphiphysin: smallcell lung


Anti-Yo: breast, ovarian
Anti-Ta (Ma2): testis
See also anti-Ri syndrome below

Other associations
Post-viral syndrome

Epidemiology
Onset age: 35 to 85 years
Male/female rate 1:2

Clinical features
Movement disorder
Opsoclonus (30%), triggered by
visual fixation
Myoclonus
Laryngospasm; dystonia (jaw
opening or neck)
Cerebellar: ataxia
The most common feature of an
anti-Ri-syndrome (50%)
Truncal ataxia and gait disorder
Nystagmus: 35%
Dysarthria: rare
Other associated disorders in
some patients
Peripheral neuropathy (25%),
sensory-motor with subacute onset
Myelopathy (20%)
Encephalopathy with confusion
and seizures
Cranial neuropathy: VI; VIII
(deafness or tinnitus)
Visual blurring
Polyradiculopathy
LEMS
Incontinence

Course

Treatment
Symptomatic
Thiamine
Clonazepam
Immunosuppression
High-dose IgG, prednisone

Remissions: May occur spontaneously

C. Opsoclonus / myoclonus in adults: antiRi syndrome

Quite variable
About 30% become wheelchairbound one month after the onset
Less long-term disability than
compared with the anti-Yo and
anti-Hu syndromes
Longer survival than in the antiYo and anti-Hu syndromes

Associated neoplasms (85%)

Breast
Lung (SCLC & non-SCLC)
Neoplasm discovered before neurological disorder: 15%
Distant metastases: 10%

Anti-Ri (ANNA2, NOVA1) antibodies


CNS antigens: 55 kDa (NOVA; RNA
binding) and 80 kDa proteins
Immunohistochemistry: antibodies bind to CNS, but not to peripheral
neurons

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Other associated antibodies


(75%):
Anti-Hu
Anti-Ta (Ma2)
Anti-Tr
ANNA3
Anti-CV2 (CRMP5)
Anti-AChR
Anti-vg-Ca channel (P/Q- & Ntype)

Investigations
CSF
High protein (35%)

Pleocytosis (40%)

CNS imaging
Normal in 65%, else there may be
findings in cortex, brainstem or cauda equina.

Treatment
Most patients experience neurological
improvement after tumour-directed
or immunomodulatory therapy.
Immunosuppression
Corticosteroids
Intravenous high-dose IgG

Selected references
1.
2.
3.
4.
5.

Anderson NE, Budde-Steffen C, Rosenblum MK, et al. Opsoclonus, myoclonus, ataxia and
encephalopathy in adults with cancer: A distinct paraneoplastic syndrome. Medicine 1988; 67:
100-9.
Luque FA, Furneaux HM, Ferziger R, et al. Anti-Ri: an antibody associated with paraneoplastic
opsoclonus and breast cancer. Ann Neurol 1991; 29: 241-51.
Pranzatelli MR. The neurobiology of the opsoclonus-myoclonus syndrome. Clin Neuropharmacol
1992; 15: 186-228.
Bataller, L.; Graus, F.; Saiz, F. et al. Clinical outcome in adult onset idiopathic or paraneoplastic
opsoclonus- myoclonus. Brain 2001; 124: 437- 43.
Sutton IJ, Barnett MH, Watson JDG, et al. Paraneoplastic brainstem encephalitis and anti-Ri
antibodies. J Neurol 2002; 249:1597-8.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Paraneoplastic optic neuritis


Paraneoplastic optic neuritis:
The characteristic features of this disorder are subacute optic
neuritis and retinitis, associated with anti-CV2 (CRMP5).
Most frequently, smokers with small-cell lung cancer are at
risk. Positive serology obviates the need for vitreous biopsy
and expedites the search for cancer.

MRI from an optic neuritis case.


T1-weighted and fat-suppressed spin
echo coronal through the orbits.
Arrows:
Enlargement
and
contrast
enhancement of the left optic nerve in
the retrobulbar portion

Onset
Subacute in patients aged 50-75
years and typically in smokers

Clinical features

Vision loss
Co-existing retinitis with vitreous inflammatory cells in about
30%
Multifocal
neurological
accompaniments with superficially
resemblance to Devic's disease at
presentation (myelopathy)

Investigations

Serum: anti-CV2 (SCLC); antiTr (Hodgkins disease)


Swollen optic discs and field defects
Vascular leakage, evident at and
remote from the disc
Abnormal electro-retinograms

Striking vitreous cells with reactive lymphocytosis, predominantly CD4+


Cerebrospinal fluid
o Lymphocytes (<35)
o Elevated protein
o Multiple oligoclonal immunoglobulin bands
o Anti-CV2 (CRMP5), IgG

Rule
out:
neuromyelitis optica
(NMO) (Devics disease) / optic
spinal multiple sclerosis (OSMS), for
example
by
testing
for
antiAquaporin4
(AQP4)
antibodies.
Consider testing for anti-MOG to
diagnose anti-AQP4 seronegative
recurrent opticus neuritis.

Associated neoplasms

Small-cell lung cancer


Lung adenocarcinoma
Renal or thyroid carcinoma
Hodgkins disease

Autopsy / biopsy
Full-length CRMP5 protein is identifiable in normal retina and optic
nerve by Western blot analyses.
Photoreceptor cells, retinal ganglion cells, and nerve fibres exhibit immunoreactivity specific to
CRMP5.

See also: Paraneoplastic cerebellar


degeneration with anti-CV2 (CRMP5)
syndrome.

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Selected references
1.
2.
3.
4.
5.
6.
7.
8.
9.

Pillay N, Gilbert JJ, Ebers GC, Brown JD. Internuclear ophthalmoplegia and "optic neuritis":
paraneoplastic effects of bronchial carcinoma. Neurology 1984; 34 (6):788-91.
Waterston JA, Gilligan BS. Paraneoplastic optic neuritis and external ophthalmoplegia. Aust N Z J
Med 1986; 16 (5):703-4.
de la Sayette V, Bertran F, Honnorat J, Schaeffer S, Iglesias S, Defer G. Paraneoplastic cerebellar
syndrome and optic neuritis with anti-CV2 antibodies: clinical response to excision of the primary
tumor. Arch Neurol 1998; 55 (3): 405-8.
Thambisetty MR, Scherzer CR, Yu Z, Lennon VA, Newman NJ. Paraneoplastic Optic Neuropathy
and Cerebellar Ataxia With Small Cell Carcinoma of the Lung. J Neuro Ophthal 2001; 21 (3): 164167.
Cross SA, Salomao DR, Parisi JE, Kryzer TJ, Bradley EA, Mines JA, Lam BL, Lennon VA.
Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG. [Review]. Ann
Neurol 2003; 54 (1):38-50.
Bataller L, Dalmau J. Neuro-ophthalmology and paraneoplastic syndromes. [Review]. Curr Opin
Neurol 2004; 17 (1):3-8.
Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, Nakashima I,
Weinshenker BG. A serum autoantibody marker of neuromyelitis optica: distinction from multiple
sclerosis. Lancet 2004; 364 (9451): 2106-12.
Thirkill CE. Cancer-induced, immune-mediated ocular degenerations. [Review]. Ocul Immunol
Inflamm 2005; 13 (2-3): 119-31.
Ducray F, Roos-Weil R, Garcia PY, Slesari J, Heinzlef O, Chatelain D, Toussaint P, Roullet E,
Honnorat J. Devics syndrome-like phenotype associated with thymoma and anti-CV2/CRMP5
antibodies. J Neurol Neurosurg Psychiatry 2007; 78: 325-327

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Paraneoplastic retinopathy (CAR, MAR)


Paraneoplastic retinopathy:
The clinical appearance is that of acute retinopathy with vision
loss, photosensitivity, night blindness and most frequently, a
finding
of
anti-Recoverin
antibodies.
Cancer-associated
retinopathy (CAR) is the common name for this disorder.
Melanoma-associated retinopathy (MAR) is another denomination.

Clinical features

Visual loss with unilateral onset,


often before detection of the
tumour
Scotomas, initially, peripheral
and ring, later-on central

Course
Fluctuating and rapidly progressive

Investigations
CSF: normal
Electrophysiology: ERG abnormal,
VER normal
Antibodies
Anti-Recoverin (23 kDa, calciumbinding protein)
Anti-Heat Shock Cognate Protein
HSC 70
Anti-CV2 (CRMP5)
Anti-Alpha-Enolase (ENO1)
Anti-Arrestin
Anti-TULIP-1
Anti-Photoreceptor cell-specific
nuclear receptor
Anti-Rod bipolar cell
Anti-Carbonic anhydrase
Anti-Trasducin B

Additional info
The sensitivity of these antibodytests is as follows: 60% of
patients
with
autoimmune
retinopathy (AR); in 40% of CAR
cases
The anti-Photoreceptor is directed
to nuclear steroid receptors in the
outer layer of retina and other
protein bands
The anti-Rod is a particular
feature of (MAR) as well as of
colon
cancer-associated
retinopathy
The alpha-Enolase target is at the
N-terminal
region
(amino
terminal),
located
in
retinal
ganglion cells and inner nuclear
layer cells
Anti-ENO1 is also a feature of
Hashimoto's encephalopathy and
some gastrointestinal disorders

Associated neoplasms

Small-cell lung cancer


Melanoma
Gynaecologic
Colon, lymphoma

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Proposed diagnostic criteria for paraneoplastic (autoimmune) retinopathy


Strong evidence
Supportive evidence
Helpful evidence

Diffuse retinal atrophy

Abnormal ERG findings

Negative waveform ERG


in conjunction with
findings
typical symptoms and

Anti-Arrestin antibody

Anti-Recoverin antibody
no pigment deposits

Anti-alpha-Enolase

Response to trial of

Sudden onset with


antibody
methylprednisolone (subphotopsias; vision

Negative family
tenons)
normal prior to onset
history of RP

CME in panretinal

Rapid progression by
degeneration
history or visual fields

History of cancer (CAR)

Family history of

History of autoimmune
autoimmune disease
disease in 50 % of
immediate family
Abbreviations: CAR, cancer-associated retinopathy; CME, cystoid macular oedema; ERG,
electroretinogram; RP, retinitis pigmentosa

Please also see: EyeWiki - Cancer associated retinopathy

Selected references
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.

Pillay N, Gilbert JJ, Ebers GC, Brown JD. Internuclear ophthalmoplegia and "optic neuritis":
paraneoplastic effects of bronchial carcinoma. Neurology 1984; 34:788.
Berson EL, Lessell S. Paraneoplastic night blindness with malignant melanoma. Am J Ophthalmol
1988; 106: 307.
Thirkill CE, FitzGerald P, Sergott RC, et al. Cancer-associated retinopathy (CAR syndrome) with
antibodies reacting with retinal, optic-nerve, and cancer cells. N Engl J Med 1989; 321: 1589-94..
Jacobson DM, Thirkill CE, Tipping SJ. A clinical triad to diagnose paraneoplastic retinopathy. Ann
Neurol 1990; 28:162-7.
Keltner JL, Thirkill CE, Tyler NK, Roth AM. Management and monitoring of cancer-associated
retinopathy. Arch Ophthalmol 1992; 110: 48.
Malik S, Furlan AJ, Sweeney PJ, et al. Optic neuropathy: a rare paraneoplastic syndrome. J Clin
Neuroophthalmol 1992; 12:137.
Polans AS, Burton MD, Haley TL, et al. Recoverin, but not visinin, is an autoantigen in the human
retina identified with a cancer-associated retinopathy. Invest Ophthalmol Vis Sci 1993; 34: 81-90.
Millan AH, Saari JC, Jacobson SG, et al. Autoantibodies against retinal bipolar cells in cutaneous
melanoma-associated retinopathy. Invest Opthalmol Vis Sci 1993; 34: 91-100
Weinstein JM, Kelman SE, Bresnick GH, et al. Paraneoplastic retinopathy associated with
antiretinal bipolar cell antibodies in cutaneous malignant melanoma. Ophthalmology 1994;
101:1236-43
Polans AS, Witkowska D, Haley TL, et al. Recoverin, a photoreceptor-specific calcium-binding
protein, is expressed by the tumor of a patient with cancer-associated retinopathy. Proc Natl Acad
Sci U S A 1995; 92:9176.
Adamus G, Aptsiauri N, Guy J, et al. The occurrence of serum autoantibodies against enolase in
cancer-associated retinopathy. Clin Immunol Immunopathol 1996; 78: 120-29
Murphy MA, Thirkill CE, Hart WM Jr. Paraneoplastic retinopathy: a novel autoantibody reaction
associated with small-cell lung carcinoma. J Neuroophthalmol 1997; 17: 77-83.
de la Sayette V, Bertran F, Honnorat J, et al. Paraneoplastic cerebellar syndrome and optic
neuritis with anti-CV2 antibodies: clinical response to excision of the primary tumor. Arch Neurol
1998; 55: 405-8
Luiz JE, Lee AG, Keltner JL, et al. Paraneoplastic optic neuropathy and autoantibody production in
small-cell carcinoma of the lung. J Neuroophthalmol 1998; 18: 178-81.
Boeck K, Hofmann S, Klopfer M, et al. Melanoma-associated paraneoplastic retinopathy: case
report and review of the literature. Br J Dermatol 1997; 137: 457-60.
Guy J, Aptsiauri N. Treatment of paraneoplastic visual loss with intravenous immunoglobulin:
report of 3 cases. Arch Ophthalmol 1999; 117: 471-7.
Heckenlively JR, Fawzi AA, Oversier J, et al. Autoimmune retinopathy: patients with antirecoverin
immunoreactivity and panretinal degeneration. Arch Ophthalmol 2000; 118: 1525-33.
Ritland JS, Eide N, Tausj J. Bilateral diffuse uveal melanocytic proliferation and uterine cancer. A
case report. Acta Ophthalmol Scand 2000; 78: 366-8.
Bazhin AV, Shifrina ON, Savchenko MS, et al. Low titre autoantibodies against recoverin in sera of
patients with small cell lung cancer but without a loss of vision. Lung Cancer 2001; 34: 99-105.
Keltner JL, Thirkill CE, Yip PT. Clinical and immunologic characteristics of melanoma-associated
retinopathy syndrome: eleven new cases and a review of 51 previously published cases. J
Neuroophthalmol 2001; 21: 173-87.
Eichen JG, Dalmau J, Demopoulos A, et al. The photoreceptor cell-specific nuclear receptor is an
autoantigen of paraneoplastic retinopathy. J Neuroophthalmol 2001; 21: 168-72.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

22. Thambisetty MR, Scherzer CR, Yu Z, et al. Paraneoplastic optic neuropathy and cerebellar ataxia
with small cell carcinoma of the lung. J Neuroophthlmol 2001; 21: 164-7.
23. Yu Z, Kryzer TJ, Griesmann GE, et al. CRMP-5 neuronal autoantibody: marker of lung cancer and
thymoma-related autoimmunity. Ann Neurol 2001; 49: 146-54.
24. Jacobson DM, Adamus G. Retinal anti-bipolar cell antibodies in a patient with paraneoplastic
retinopathy and colon carcinoma. Am J Ophthalmol 2001; 131: 806-8.
25. Chan C, O'Day J. Melanoma-associated retinopathy: does autoimmunity prolong survival? Clin
Experiment Ophthalmol 2001; 29: 235-8
26. Ohguro H, Nakazawa M. Pathological roles of recoverin in cancer-associated retinopathy. Adv Exp
Med Biol 2002; 514: 109-24.
27. Shiraga S, Adamus G. Mechanism of CAR syndrome: anti-recoverin antibodies are the inducers of
retinal cell apoptotic death via the caspase 9- and caspase 3-dependent pathway. J
Neuroimmunol 2002; 132: 72-82.
28. Potter MJ, Adamus G, Szabo SM, et al. Autoantibodies to transducin in a patient with melanomaassociated retinopathy. Am J Ophthalmol 2002; 134: 128-30.
29. Katsuta H, Okada M, Nakauchi T, et al. Cancer-associated retinopathy associated with invasive
thymoma. Am J Ophthalmol 2002; 134: 383.
30. O'Neal KD, Butnor KJ, Perkinson KR, Proia AD. Bilateral diffuse uveal melanocytic proliferation
associated with pancreatic carcinoma: a case report and literature review of this paraneoplastic
syndrome. Surv Ophthalmol 2003; 48: 613-25.
31. Chan JW. Paraneoplastic retinopathies and optic neuropathies. Surv Ophthalmol 2003; 48: 12-38.
32. Cross SA, Salomao DR, Parisi JE, et al. Paraneoplastic autoimmune optic neuritis with retinitis
defined by CRMP-5-IgG. Ann Neurol 2003; 54: 38-50.
33. Yamada G, Ohguro H, Aketa K, et al. Invasive thymoma with paraneoplastic retinopathy. Hum
Pathol 2003; 34: 717-19.
34. Adamus G, Ren G, Weleber RG. Autoantibodies against retinal proteins in paraneoplastic and
autoimmune retinopathy BMC Ophthalmol 2004; 4: 5.
35. Ren G, Adamus G. Cellular targets of anti-a-enolase autoantibodies of patients with autoimmune
retinopathy J Autoimmun 2004; 23: 161-167.
36. Jacobzone C, Cochard-Marianowski C, Kupfer I, et al. Corticosteroid treatment for melanomaassociated retinopathy: effect on visual acuity and electrophysiologic findings. Arch Dermatol
2004; 140: 1258-61.
37. Ohguro H, Yokoi Y, Ohguro I, et al. Clinical and immunologic aspects of cancer-associated
retinopathy. Am J Ophthalmol 2004; 137: 1117-19.
38. Chang PY, Yang CH, Yang CM. Cancer-associated retinopathy in a patient with hepatocellular
carcinoma: case report and literature review. Retina 2005; 25:1093.
39. Damek DM. Paraneoplastic Retinopathy/Optic Neuropathy. Curr Treat Options Neurol 2005; 7:
57-67.
40. Weleber RG, Watzke RC, Shults WT, Trzupek KM, Egan RA, Heckenlively J, Adamus G. Clinical
and electrophysiologic characterization of paraneoplastic and autoimmune retinopathies
associated with anti-enolase antibodies. Am J Ophthal 2005; 139: 780-794.
41. Dot C, Guigay J, Adamus G. Anti-alpha-enolase Antibodies in Cancer-associated Retinopathy with
Small Cell Carcinoma of the Lung Am J Ophthal 2005; 139: 746-747.
42. Sharan S, Thirkill CE, Grigg JR. Autoimmune retinopathy associated with intravesical BCG
therapy. Br J Ophthalmol. 2005 ; 89(7): 927928.
43. Hartmann TB, Bazhin AV, Schadendorf D, Eichmller SB. SEREX identification of new tumor
antigens linked to melanoma-associated retinopathy. Int J Cancer 2005; 114: 88-93.
44. Ladewig G, Reinhold U, Thirkill CE, et al. Incidence of antiretinal antibodies in melanoma:
screening of 77 serum samples from 51 patients with American Joint Committee on Cancer stage
I-IV. Br J Dermatol 2005; 152: 931-38.
45. Asproudis IC, Nikas AN, Psilas KG. Paraneoplastic optic neuropathy in a patient with a non-small
cell lung carcinoma: a case report. Eur J Ophthalmol 2005; 15: 420-23.
46. Saito W, Kase S, Yoshida K, et al. Bilateral diffuse uveal melanocytic proliferation in a patient with
cancer-associated retinopathy. Am J Ophthalmol 2005; 140: 942-45.
47. Wu S, Slakter JS, Shields JA, Spaide RF. Cancer-associated nummular loss of the pigment
epithelium. Am J Ophthalmol 2005; 139: 933-5.
48. Adamus G, Webb S, Shiraga S, Duvoisin RM. Anti-recoverin antibodies induce an increase in
intracellular calcium, leading to apoptosis in retinal cells J Autoimmun 2006; 26: 146-53.
49. Sen J, Clewes AR, Quah SA, et al. Presymptomatic diagnosis of bronchogenic carcinoma
associated with bilateral diffuse uveal melanocytic proliferation. Clin Experiment Ophthalmol
2006; 34: 156-8.
50. Sheorajpanday R, Slabbynck H, Van De Sompel W, et al. Small cell lung carcinoma presenting as
collapsin response-mediating protein (CRMP) -5 paraneoplastic optic neuropathy. J
Neuroophthalmol 2006; 26: 168-72.
51. Duong HV, McLean IW, Beahm DE. Bilateral diffuse melanocytic proliferation associated with
ovarian carcinoma and metastatic malignant amelanotic melanoma. Am J Ophthalmol 2006; 142:
693-5.
52. Espandar L, O'Brien S, Thirkill C, et al. Successful treatment of cancer-associated retinopathy with
alemtuzumab. J Neurooncol 2007; 83: 295-302.
53. Magrys A, Anekonda T, Ren G, Adamus G. The role of anti-alpha-enolase autoantibodies in
pathogenicity of autoimmune-mediated retinopathy. J Clin Immunol 2007; 27: 181-92.

48

15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

54. Pfhler C, Preuss KD, Tilgen W, et al. Mitofilin and titin as target antigens in melanoma-associated
retinopathy. Int J Cancer 2007; 120: 788-95.
55. Murakami Y, Yoshida S, Yoshikawa H, et al. CRMP-5-IgG in patient with paraneoplastic optic
neuritis with lung adenocarcinoma. Eye (Lond) 2007; 21: 860-2.
56. Ars-Luque A, Garca-Tun LA, Saiz A, et al. Isolated paraneoplastic optic neuropathy associated
with small-cell lung cancer and anti-CV2 antibodies. J Neurol 2007; 254: 1131-2.
57. Ducray F, Roos-Weil R, Garcia PY, et al. Devic's syndrome-like phenotype associated with
thymoma and anti-CV2/CRMP5 antibodies. J Neurol Neurosurg Psychiatry 2007; 78: 325-7.
58. Boghen D, Sebag M, Michaud J. Paraneoplastic optic neuritis and encephalomyelitis. Report of a
case. Arch Neurol 1988; 45: 353-6.
59. Pulido J, Cross SA, Lennon VA, et al. Bilateral autoimmune optic neuritis and vitreitis related to
CRMP-5-IgG: intravitreal triamcinolone acetonide therapy of four eyes. Eye (Lond) 2008;
22:1191-3
60. Ko MW, Dalmau J, Galetta SL. Neuro-ophthalmologic manifestations of paraneoplastic syndromes.
J Neuroophthalmol 2008; 28: 58-68.
61. Subhadra C, Dudek AZ, Rath PP, Lee MS. Improvement in visual fields in a patient with
melanoma-associated retinopathy treated with intravenous immunoglobulin. J Neuroophthalmol
2008; 28: 23-6.
62. Adamus G. Autoantibody targets and their cancer relationship in the pathogenicity of
paraneoplastic retinopathy. Autoimmun Rev 2009; 8: 410-4.
63. Bazhin AV, Dalke C, Willner N, et al. Cancer-retina antigens as potential paraneoplastic antigens
in melanoma-associated retinopathy. Int J Cancer 2009; 124:140-9.
64. Lu Y, Jia L, He S, et al. Melanoma-associated retinopathy: a paraneoplastic autoimmune
complication. Arch Ophthalmol 2009; 127: 1572-80.
65. Moss HE, Liu GT, Dalmau J. Glazed (vision) and confused. Surv Ophthalmol 2010; 55: 169-73.
66. Kiratli H, Erkan K. Loss of Retinal Pigment Epithelium Associated with Bilateral Diffuse Uveal
Melanocytic Proliferation. Ophthalmic Surg Lasers Imaging 2010; 5: 1-4
67. Besirli CG, Comer GM. High-resolution OCT imaging of RPE degeneration in bilateral diffuse uveal
melanocytic proliferation. Ophthalmic Surg Lasers Imaging 2010; 41 Suppl:S96-S100.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Stiff-person spectrum of symptoms


(SPS - also PERM)
Stiff-person syndrome:
The main features of this disorder are slowly progressive stiffness
with muscle spasms. Frequently, SPS is associated with anti-GAD
antibodies and in such cases likely to being T-cell-mediated. Other
SPS cases are associated with anti-Glycine alpha1 receptor (with or
without anti-GAD) and may turn out to fulfil the criteria of antibodymediated autoimmunity. Anti-Amphiphysin, anti-Gephyrin and / or
anti-CV2 may be additional findings.

Epidemiology

Females (70%)

Age at onset

Childhood or adult
Anti-GAD antibody positive:
o Most common 3rd to 5th decades, mean 40 years

Course

Usually, SPS is slowly progressive


(insidious) or static over years
Occasionally, the onset is rapid
Focal syndromes may progress to
more generalized involvement
In occasional patients, sudden
death may occur due to
o Cardiac arrhythmias
o Restrictive respiratory arrest
o Rapid tapering of intrathecal
baclofen

Prodromes
Episodic stiffness or falling, pains and
tightness in axial muscles

Clinical features
Stiffness
Especially, the distribution is in axial
and proximal limb muscles. Frequently, it is also asymmetric or
prominent in one leg. The involvement of limbs impairs walking. There
may be lumbar hyperlordosis, limiting truncal flexion.
These features are reduced in sleep,
and do usually fluctuate over time as
well.

Muscle spasms
May occur spontaneously or are triggered by
Stretching
Emotion
Sensory stimulation
Fear of open spaces
Typical cause
o Sudden myoclonic jerks that
may produce falling
o This is followed by tonic activity that subsides over seconds
Location of spasms
Arms: extension and pronation
Trunk: extension
Legs: extension and mild abduction; foot inversion
Co-contraction of agonist and antagonists
Abdominal and thoracic paraspinous muscles
Spasms
may
produce
little
movement due to co-contraction
around joints
Consequences and disability
May be associated with severe
pain
May also be severe enough to
cause fractures
Due to frequent falls, a cane or
walker is commonly needed
Relaxation of spasms
Sleep & benzodiazepines
Reflexes
Tendon reflexes: normal or increased
Abdominal cutaneous: may be
lost
Startle responses: increased
Gait: "Tin soldier"

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Autonomic dysfunction

Extraocular
movements:
(only
some patients)
Gaze-holding nystagmus
limited abduction
Vertical and horizontal ocular
misalignment
Deficient smooth pursuit
Impaired saccade initiation

Otherwise,
normal
neurologic
examination in most SPS patients

EMG
Continuous action potentials
Indistinguishable from voluntary
activity: normal motor units
Persist
during
attempts
at
relaxation
Most prominent in axial muscles
Rhythmic
and
synchronous
persistent 5 - 6 Hz bursts of 50 to
60 ms duration
Interruption of bursts by spasms
with
rapid
activity;
full
interference pattern; > 4 sec
Activity reduced by intravenous
diazepam.
No
fibrillations
or
grouped
rhythmic discharges
Poor relaxation after contraction

Associated neoplasms

Breast
Other: lung, thymoma, Hodgkin's
and non-Hodgkins lymphoma,
myeloma, renal cell carcinoma

Associated disorders
Epilepsy treated with anti-GABA
agents, suggests PERM variant.
Diabetes mellitus, type I (3060 %).
Immune disorders
Thyroiditis (15%)
Pernicious anaemia (10%)
Myasthenia gravis
Ovarian or adrenal failure, vitiligo
Similar immune disorders may
occur in family members
More common with anti-GAD antibodies
HLA: DR1 0301 (40-70 %)

CNS pathology
Perivascular inflammation
Spinal cord: neuronal loss
Lateral vestibular nucleus: loss of
neurons

Differential diagnosis
Hyperekplexia (Stiff-baby syndrome)
o Childhood onset: DYT1 gene
mutations
Rule out associated pernicious
anaemia

Investigations
Serum CK: transiently elevated
ANA (30%).
CSF
Oligoclonal bands (60%)
Protein high (20%)

Pleocytosis: 10% in SPS; 60% in


PERM variant
Normal: 40% in SPS; 10% in
PERM variant.
Anti-GAD antibodies, although
usually lower titre than in serum
Intrathecal anti-GAD synthesis
may occur

MRI of the CNS: non-diagnostic

Serum antibodies
Apart from the pancreas, GAD65 is
only expressed at GABA-ergic nerve
terminals, which co-localizes with
Amphiphysin and CV2 (CRMP5) while
GAD67 is spread evenly throughout
the cells. This difference is thought
to reflect a functional difference;
GAD67 synthesizes GABA for neuron
activity unrelated to neurotransmission, such as synaptogenesis and
protection from neural injury. This
function requires widespread, ubiquitous presence of GABA. GAD65,
however, synthesizes GABA for neurotransmission, and therefore is only
necessary at nerve terminals and
synapses.
Anti-GAD65 antibodies
Prevalence in SPS: 50-90 %.
Anti-GAD67 antibodies
The prevalence of anti-GAD67 is unknown, so currently, the significance
of anti-GAD65 versus anti-GAD67 is
relatively unexplored.

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Anti-GlyR alpha1 antibodies


About 10 % of patients with SPS
spectrum of symptoms (with or without associated GAD antibodies)
Anti-CV2 (CRMP5)
Anti-Amphiphysin
Anti-Gephyrin, rarely
Tissue staining pattern
GABA nerve terminals
Co-localizes with amphiphysin
and CRMP5
The levels of anti-GAD antibody titres
vary with clinical syndromes
High in Stiff-man syndrome
Usually much higher than in CSF
Specificity: more with higher antiGAD antibody titres
Anti-GAD antibodies may also be
a finding in other syndromes
1. Palatal myoclonus
2. Epilepsy (autoimmune
encephalitis)
Therapy-resistant,
localization-related
Frequency: 15%.
Anti-GAD antibody titres: high
or moderate
3. Cerebellar ataxia
4. Insulin-dependent diabetes
mellitus (IDDM)
Age spectrum: Childhood &
adolescence
Anti-GAD antibody titres: low
to moderate titre
5. In association with
Antibodies to tyrosine phosphatase IA-2
T-cell immunity
6. Autoimmune polyendocrine
syndrome II

Other antibodies associated


with SPS

Anti-Pancreatic
islet
cell
(60%)
Also found in type I diabetes, although with lower titre and a different staining pattern
Anti-PCA2

Therapy
Unfortunately, treatment is rarely
completely effective.
Symptomatic
Diazepam (very high doses; 20
mg to 300 mg/day)
Clonazepam
Baclofen
Oral: adjunct medication
Pump (intrathecal)
Indication: severe syndromes
Warning: acute withdrawal has
been fatal

Valproate
Tiagabine: 6 mg qd
Immunomodulatory therapies
Corticosteroids: high dose
solumedrol with tapering
Improvement over months
Intravenous high-dose IgG
Plasma exchange
Rituximab

Stiff-person
syndrome (SPS),
variants
The associated autoantibody is
Anti-GAD in all the variant syndromes
Table 8:
Enumeration
1
2
3
4
5

SSPS, variants
Focal SPS
Jerking SPS
PERM
In PCD, also with anti-GAD
Other SPS

1. Focal SPS
Most frequently, this is a stiff-leg
syndrome or alternatively, a stiff-arm
syndrome.

Onset 35 to 60 years
Clinical features
Stiffness
limbs

and

spasms

of lower

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Stimuli: especially voluntary movement; also reflex stimuli


Asymmetric
Posturing of feet
Trunk spared

Treatment (partial benefit)


Baclofen, Diazepam

2. Jerking SPS

Clinical features

Stiffness: axial and lower limb


Later features
Brainstem myoclonus
Upper motor neuron signs
PERM, see below

Progression over decade

3. Progressive encephalopathy with rigidity and reflex myoclonus (PERM)


Onset: subacute (weeks)
Clinical features
Stiffness
Distal > proximal at disease onset
Rigidity
Spasms: episodic
Muscle wasting & weakness
Autonomic
Hyperhidrosis associated with
spasms
Cranial nerves
EOM: nystagmus and ophthalmoplegia
Blindness
Deafness, dysarthria
Other CNS
Long tract
Vertigo
Preserved intellect

Progression

Over months and usually, death


within one to 39 months
Some cases remain mild

Investigations
Neurophysiology: similar to SPS
and brainstem myoclonus
Serum: anti-GAD, anti-Glycine receptor
CSF: inflammatory

Pathology

Perivascular inflammation
Gliosis in spinal cord, pons and
medulla
Neuronal loss: spinal gray

4. SPS in cerebellar
syndrome with anti-GAD
Epidemiology
Onset age: females 20 to 75 years

Clinical features
The onset is slowly progressive.
Ataxia: limb and trunk
Nystagmus
Dysarthria (50%)
Stiffness (15%)
No brainstem involvement

Associated disorders

Late-onset insulin-dependent
diabetes mellitus
Thyroiditis
Poly-endocrine syndrome

Additional antibodies

Anti-Parietal cell

MRI: non-diagnostic.

Treatment: not described

5. Other paraneoplastic
SPS
Suggestive features

SPS confined to upper limbs.

Rapid disease progression to


fixed joint deformities

Also associated

Sensory ganglionopathy

Neoplasms

Breast
Lung (small-cell)

Additional antibodies

Anti-Amphiphysin

Treatment: Not described

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Selected references
1.

De Camilli P, Thomas A, Cofiell R, et al. The synaptic vesicle-associated protein amphiphysin is


the 128-kD autoantigen of Stiff-Man Syndrome with breast cancer. J Exp Med 1993; 178: 22192223.
2. Solimena M, Folli F, Denis-Domini S, et al. Autoantibodies to glutamic acid decarboxylase in a
patient with Stiff-Man Syndrome, epilepsy, and type I diabetes mellitus. N Engl J Med 1988; 318:
1012-20.
3. Helfgott SM. Stiff-man syndrome. From the bedside to the bench. Arthritis & Rheumatism 1999;
42: 1312-20.
4. Brown P, Marsden CD. The stiff man syndrome and stiff man plus syndromes. J Neurol 1999;
246: 648-652.
5. Butler, MH, Hayashi A, Ohkoshi N, Villmann C, Becker CM, Feng G, De Camilli P, Solimena M.
Autoimmunity to Gephyrin in Stiff-Man syndrome. Neuron 2000; 26 (2): 307-312.
6. Dalakas MC, Li M, Fujii M, Jacobowitz D. Stiff person syndrome. Quantification, specificity and
intrathecal synthesis of GAD65 antibodies. Neurology 2001; 57: 780-784.
7. Dalakas MC, Fujii M, Li M, et al. High-dose intravenous immune globulin for stiff-person syndrome.
New Engl J Med 2001; 345: 1870-1876.
8. McHugh JC, Murray B, Renganathan R, Connolly S, Lynch T. GAD Antibody Positive Paraneoplastic
Stiff Person Syndrome in a Patient with Renal Cell Carcinoma. Movement Disorders 2007; 22 (9):
1343-1346.
9. Hutchinson M, Waters P, McHugh J, Gorman G, ORiordan S, Connolly S, Hager H, Yu C, Becker
CM, Vincent A. Progressive Encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor
antibody. Neurology 2008; 71: 1291-1292.
10. Burbelo PD, Sandra Groot S, Dalakas MC, Iadarola MJ. High Definition Profiling of Autoantibodies
to Glutamic Acid Decarboxylases GAD65/GAD67 in Stiff-Person Syndrome. Biochem Biophys Res
Commun 2008; 366 (1): 17.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Syndromes of the peripheral nervous system


The autonomic nervous system

Paraneoplastic autonomic neuropathy (AAN)


Paraneoplastic autonomic neuropathy:
Paraneoplastic autonomic dysfunction of the ganglions and parasympatic & sympatic nerves which is associated with a variety of
cancers and onconeural antibodies. This disorder is consistent
with an IgG-mediated rather than T cell-mediated pathogenesis.
[2]

1. Pandysautonomia
Autoimmune
autonomic
neuropathy
(AAN) appears to fulfil the criteria of an
antibody-mediated autoimmunity. This

disorder has also been nicknamed autonomic myasthenia gravis.

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Clinical features

Associated neoplasms

Orthostatic hypotension without


compensatory tachycardia
Gastrointestinal dysmotility
(80%)
Anhidrosis (60%)
Dry eyes and mouth
Pupillary response reduced (30%)
GU: urinary or erectile dysfunction (30%)
Sensory paraesthesia in extremities (25%)
Cough.

Investigations
CSF
Elevated protein in 60%
Typically, there are no cells
Antibody
Anti AChR (alpha3-type)
The nicotinic 3-AChR is located
at autonomic ganglions
This autoantibody may be a feature
of other disorders:
Isaacs syndrome (50%)
Lambert-Eaton myasthenic
syndrome (10%)
Myasthenia gravis (a few
patients)
See also autonomic features of the
anti-Hu and anti-CV2 (CRMP5) syndromes: subacute sensory neuronopathy (SSN), chronic gastrointestinal pseudo obstruction.

Thymoma
SCLC
Bladder
Rectum

Differential diagnosis

Multiple system atrophy (MSA)


with predominant autonomic failure (former term: Shy-Drager
syndrome)
Anti-Peripherin seropositive neuropathy with endocrinopathy

Treatment

Oncological therapy of associated neoplasm


Intravenous high-dose IgG,
early after onset or at progressing disability

2. The following syndromes


may also exhibit autonomic
dysfunction:

Paraneoplastic cerebellar syndromes: with anti-PCA2 antibodies; with CV2 (CRMP5) antibodies
Paraneoplastic sensory-motor
neuropathy with anti-CV2
(CRMP5) antibodies
Morvans fibrillary chorea
Opsoclonus / myoclonus
Stiff-person syndrome (SPS)
SPS variants: other paraneoplastic SPS

Selected references
1.

Chamberlain JL, Pittock SJ, Oprescu AM, Dege C, Apiwattanakul M, Kryzer TJ, Lennon VA.
Peripherin-IgG association with neurologic and endocrine autoimmunity. J Autoimmun 2010;
343(4):3469-77.

2.

J W Meeusen; K E Haselkorn; J P Fryer; T J Kryzer; S J Gibbons; Y Xiao; V A Lennon.


Gastrointestinal hypomotility with loss of enteric nicotinic acetylcholine receptors: active
immunization model in mice. Neurogastroenterol. Motil. 25, (2013)

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Paraneoplastic motor neuropathy


Paraneoplastic motor neuropathy:
Specific features please see also:
Paraneoplastic motor neuron disease?
Paraneoplastic sensory-motor neuropathy with anti-Hu antibodies
Cerebellar syndromes with anti-PCA2 antibodies

Onset
After diagnosis of tumour

Course: progressive then stabilization or improvement

Epidemiology

Associated neoplasms

Majority male & > 50 years

Clinical features
Weakness
Asymmetric; arms > legs
Mild and sometimes only lower
motor neuron
Normal bulbar
Cramps: painful
Painless in some patients

Non-Hodgkin Lymphoma
Also other lymphomas & myeloproliferative disorders
Ductal adenocarcinoma of breast

Investigations
CSF: No cells; mildly increased
protein
MRI: Spinal cord normal
? Neuronopathy

Paraneoplastic sensory-motor neuropathy


Paraneoplastic sensory-motor neuropathy:
Using the currently available assays, onconeural antibodies are detectable in about 30% of patients with solid cancer and sensorymotor neuropathies. Mixed-type neuropathy is also an observation
in malignant monoclonal gammopathies, associated with plasma cell
malignancies (i.e. myeloma), B-cell leukaemias, and lymphomas.

Sensory-motor neuropathy

Associated with anti-Hu or antiCV2 antibodies and in some patients both autoantibodies
Possibly, anti-Pyridoxal phosphatase
Paraproteinaemic disorders

Clinical features
Electrophysiology
Showing axonal and or demyelinising processes
Antibodies
Anti-Hu seropositive patients
Sensory or motor neuropathy in

about 15%-30% of these patients


Subacute sensory neuronopathy
(SSN)
Motor symptoms usually resulting
from motor neurone degeneration
In about 30%, there is an equal
proportion of sensory and motor
involvement
Frequently, the distribution is
asymmetrical or multifocal
Note: Both mononeuritis multiplex
and polyradiculopathy may resemble this disorder. Moreover, an
acute severe evolution in the four
limbs may mimic the Guillain-Barr
syndrome.

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Anti-CV2 seropositive patients


Polyneuropathy in about 60%
Most frequently, this is a sensory-motor neuropathy preferentially affecting the lower
limbs
Pain is less frequent than with
a finding of anti-Hu antibodies
Other features (in about 65%)
Central nervous system disorder
Autonomic neuropathy
Eye involvement

Paraproteinaemias (monoclonal
gammopathies)

M-components (IgA, IgG, IgM)

Anti-Pyridoxal
phosphatase
may also be a finding
This autoantibody is a finding in sera of
patients with lung cancer and welldifferentiated thyroid cancer. They may
also be a feature of an autoimmune thyroid disorder. Pyridoxal phosphatase is a
co-enzyme of vitamin B6 (pyridoxine).
Theoretically therefore, such antibodies
may cause seizures and in particular a
sensory-motor neuropathy with burning
paraesthesias and eventually motor deficits. However, there are no reports about
PNS related to anti-Pyridoxal, so such a
disorder awaits discovery.

Please, also see

Paraneoplastic cerebellar syndromes: CV2 (CRMP5) syndrome


Opsoclonus / myoclonus: anti-Ri
syndrome (due to other antibodies than anti-Ri)

Selected references
1.
2.
3.
4.
5.
6.
7.
8.

Vincent D, Dubas F, Haw JJ, et al. Nerve and muscle microvasculitis. J Neurol Neurosurg
Psychiatry 1986; 49:1007-10.
Younger DS, Dalmau J, Inghirami G, ET AL. Anti-Hu-associated peripheral nerve and muscle
microvasculitis. Neurology 1994; 44: 181-3.
Oh SJ. Paraneoplastic vasculitis of the peripheral nervous system. Vasculitis and the nervous
system. Neurologic Clinics 1997; 15 (4): 849-63.
Smitt PS, Posner JB. Paraneoplastic peripheral neuropathy. In Latov N, Wokke JH, Kelly JJ, eds.
Immunological and infectious diseases of the peripheral nerves. Cambridge: Cambridge University
Press, 1998:208-24.
Antoine JC, Mosnier JF, Absi L, et al. Carcinoma associated paraneoplastic peripheral neuropathies
in patients with and without anti-onconeural antibodies. J Neurol Neurosurg Psychiatry 1999;
67:7-14.
Rudnicki SA, Dalmau J. Paraneoplastic syndromes of the spinal cord, nerve, and muscle. Muscle
Nerve 2000; 23:1800-18.
Antoine JC, Honnorat J, Camdessanche JP, et al. Paraneoplastic anti-CV2 antibodies react with
peripheral nerve and are associated with a mixed axonal and demyelinating peripheral
neuropathy. Ann Neurol 2001; 49: 214-21.
Kloos L, Sillevis Smitt P, Ang C W, et al. Paraneoplastic ophthalmoplegia and subacute
motoraxonal neuropathy associated with anti-GQ1b antibodies in a patient with malignant
melanoma. J Neurol Neurosurg Psychiatry 2003; 74:5079.

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Paraneoplastic sensory neuronopathy (PSN, SSN)


Paraneoplastic sensory neuronopathy: This disorder is
a classical PNS characterized by subacute and rapidly progressive neuropathy with pain, paraesthesia, and sensory loss. Most
frequently, it is associated with SCLC and anti-Hu antibodies.
The disorder is also called: subacute sensory neuronopathy
(SSN), since the lesions are primarily located to the nerve cell
body (anti-Hu is a neuronuclear antibody, ANNA1), justifying the term neuronopathy. This disorder is also known as Denny-Brown's syndrome. Cf. also
PEM and PCD for more details about the anti-Hu syndrome.

Epidemiology
Males in about 20-85% (US &
European study, respectively).
The difference may be attributable to varied smoking patterns.
Age of onset
o Mean 60's (range 35-85 years
of age)
Tobacco smoking: > 95 %

Clinical features
Painful
paraesthesias
and
dysaesthesias (80%)
Asymmetric, distal or proximal
Sensory loss (95%), all modalities
are involved
Proprioceptive loss: prominent
Ataxia: sensory
Pseudoathetosis
Distribution
Proximal and distal
Asymmetric (35%) or symmetric
Upper limb only (25%)
Lower limb only (45%)
Motor
Normal (75%)
Occasional
sensory-motor
involvement (25%), possibly subclinical
The weakness may be proximal
or distal
In rare cases (5%), amyotrophy
or fasciculations

Course

Initial localized pain or sensory


loss
Then progression over days to six
months
Subsequently, plateau with little
improvement

Occasional
improvement
with
treatment-induced remission of
the neoplasm

Favourable PNS prognosis is associated with


Variable survival data: similar to
or better than in anti-Huseronegative patients
Significant response, related to
oncologic treatment
Limited disease at time of diagnosis
Initial metastases tend to spare
nervous system
Less common outcomes
Mild course
Acute (< 24 hrs. in about 3%)
Chronic (> six months in about
15-40%)
Survival: mean 28
months to 8 years)

months

(6

Associated

syndromes (4070%)
Limbic encephalitis seizures
(10%)
Epilepsy partialis continua
Cerebellar: ataxia and nystagmus
Brainstem encephalitis
Vestibular disorders
Oculomotor paresis
Bulbar palsy
Hearing loss
Myelitis: patchy weakness with
arms > legs
LEMS
Autonomic (30%)
Blood pressure: labile, hypotension (20%)

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Oesophageal achalasia
Gastro-paresis
Pseudo-obstruction
Constipation (10%)
Intestinal obstruction (10%)
Urinary dysfunction (10%)
IADHS (inappropriate ADH syndrome)
Maybe primary lateral sclerosis
(PLS)

Patients may also have a multifocal


CNS disorder:
paraneoplastic encephalomyelitis
(PEM), please see specific chapter.
Associated neoplasms (in 88%,
and often small & slow growing)
Small-cell lung cancer: strongest neoplasm association
Frequency: 80% of Hu positive serums
Prevalence: 17% of SCLC.
Others (rare)
Breast, ovary, renal, testis,
prostate,
oesophagus,
melanoma, thymoma, Hodgkins disease
These neoplasms may coexist
with small-cell lung cancer

Investigations

Note. SCLC may escape the initial


detection and only be disclosed upon
follow-up testing (30%).
MRI, PET.
Surgical examinations
Bronchoscopy,
mediastinoscopy,
thoracotomy
Electrodiagnostic
Sensory nerve action potentials
Diffusely absent or reduced.

Pathology

Patchy dorsal root ganglion inflammation and neuronal loss


About 50% with inflammation
elsewhere in spinal cord or brain
Spinal cord with loss of axons in
posterior columns
Intra-lesional lymphocytes of
CD45RO-type (memory cells)

May be variable among nerves


Motor studies show variable involvement
Often normal
Occasionally, there is axonal loss,
which may occur without associated weakness.
CSF
Cells: in about 50%, the number
of mononuclear cells is elevated
(2 to 26/mm3).
Protein: high (20 to 190) in 70%
Oligoclonal bands

Autoantibodies
IgG versus Hu (ANNA1).
Cell targets: selective staining of
nuclei
Neurons
(PNS
&
CNS),
adenohypophysis, adrenal cortex,
retina
Clinical correlations
Low titres are associated with
neoplasm not provoking neurologic symptoms
High titres are associated with
neoplasm and SSN
Antibody location: serum and CSF
Antibody type
All subtypes of IgG, although
predominantly IgG1
Hu antigens
RNA binding proteins
Hu is a family of 35 to 40 kDa
neuronal nuclear proteins. The
proteins are HuD, HuC, Hel-N1,
Hel-N2, ple21
Other antibodies
Anti-CV2 (CRMP5) in about
15%
Serum M-protein: not reported

Differential diagnosis
Toxic: cis-platinum
Pyridoxine deficiency
Sjgren's syndrome

Treatment
Unfortunately, it is rare to observe
any effect on the neurologic syndromes
Oncologic
Usually, the anti-Hu titre is reduced after tumour treatment

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Physical therapy may be of value

in cases with sensory ataxia.

Selected references
1.
2.
3.
4.
5.
6.
7.
8.
9.

Chinn JS and Schuffler MD. Paraneoplastic visceral neuropathy as a cause of severe


gastrointestinal motor dysfunction. Gastroenterology 1988; 95: 1279-86.
Lennon VA, Sas DF, Busk MF, et al. Enteric neuronal antibodies in pseudoobstruction with smallcell lung carcinoma. Gastroenterology 1991; 100: 137-42.
Chalk CH, Windebank AJ, Kimmel DW, et al. The distinctive clinical features of paraneoplastic
sensory neuronopathy. Can J Neurol Sci 1992; 19:346-51.
Graus F, Bonaventura I, Uchuya M, et al. Indolent anti-Hu-associated paraneoplastic sensory
neuropathy. Neurology 1994; 44: 2258-61.
Keime-Guibert F, Graus F, Fleury A, et al. Treatment of paraneoplastic neurological syndromes
with antineuronal antibodies (anti-Hu, anti-Yo) with a combination of immunoglobulins,
cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry 2000; 68: 479-82.
Graus F, Keime-Guibert F, Ren R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis:
analysis of 200 patients. Brain 2001; 124:1138-48.
Lee HR, Lennon VA, Camilleri M, et al. Paraneoplastic gastrointestinal motor dysfunction: clinical
and laboratory characteristics. Am J Gastroenterol 2001; 96: 373-9.
Camdessanch JP, Antoine JC, Honnorat J, et al. Paraneoplastic peripheral neuropathy associated
with anti-Hu antibodies. A clinical and electrophysiological study of 20 patients. Brain 2002;
125:166-75.
J W Meeusen; K E Haselkorn; J P Fryer; T J Kryzer; S J Gibbons; Y Xiao; V A Lennon.
Gastrointestinal hypomotility with loss of enteric nicotinic acetylcholine receptors: active
immunization model in mice. Neurogastroenterol. Motil. 25, (2013)

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Syndromes of the neuromuscular junction


In contrast to the central and peripheral nervous system, the NMJ is not
protected by any barrier, leaving it relatively unhindered exposed to toxins,
chemical agents, and autoantibodies.
The neuromuscular transmission is
known in details (Figure 2), including
the composition and function of many
structures. Accordingly, much of the
pathogenesis of NMJ disorders has been
determined down to a molecular level.
This knowledge has become the basis
for a rational and quite often very successful therapy. Compared to the treatment of PNS at other locations, this is also
true for the remedy of these syndromes at the NMJ.
Figure 2:

Various structures and autoimmune disorders of the NMJ


Abbreviations: AChR: acetylcholine receptor (nicotinic or muscarinic); TRPC3: transient
receptor potential channel 3; MuSK: muscle specific tyrosine kinase receptor; RyR1:
ryanodine receptor 1

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Lambert-Eaton myasthenic syndrome (LEMS)


Lambert-Eaton myasthenic syndrome:
An autoimmune presynaptic disorder of the NMJ, characterized by muscle weakness, autonomic features, and antibodies
directed to the voltage-gated Ca-channel (VGCC) of P/Q-type
and/or to the muscarinic AChR of M1-type. This disorder appears to fulfil the criteria of an antibody-mediated autoimmunity.

Clinical features
Muscle weakness
Typically, the chronology of the distribution of the weakness is the reverse of that of myasthenia gravis.
In more than 90%, the weakness
starts proximally in the legs. The paresis can then spread to other striated muscles in a caudo-cranial order.
In some patients, this might lead to
a need for artificial respiration. Ptosis
and ophthalmoplegia can be present,
but tend to be milder than in autoimmune myasthenia gravis.
Autonomic dysfunction
Dry mouth, dryness of the eyes,
blurred vision, impotence, constipation, impaired sweating, or orthostatic hypotension. The autonomic dysfunction is mostly mild to moderate,
in contrast to the severe disabling
autonomic dysfunction in the anti-Hu
syndrome.
Cerebellar degeneration
In rare cases, patients with LEMS
and SCLC develop such features. In
some patients, cerebellar degeneration is present together with anti-vgCa channel antibodies, but without
clinical signs or symptoms of myasthenic muscle weakness.
Maybe it is related to anti-SOX1 (antiGlial nuclear antibodies, AGNA), the target being the Bergman glia in the
Purkinje cell layer.

See

also: Cerebellar syndromes


with anti-PCA2 antibodies.

Associated neoplasm
In more than 50 % LEMS cases
small-cell lung cancer (SCLC) is co-

existent, and most frequently found


within two years after the diagnosis
of LEMS.
Pro-GRP (gastrin-releasing peptide)
and SOX1 antibodies both appear to
be highly associated SCLC markers,
also without a co-existent paraneoplastic syndrome.
Anti-SOX seropositivity is a feature of
about 60% of SCLC cases with LEMS.
Table 9

LEMS associated neoplasms


(n = 141)

Pulmonary malignancies
(Small cell lung carcinoma)
Lymphoma
Leukaemia
Miscellaneous

79
67
5
4
11

Prostate carcinoma
Laryngeal carcinoma
Lymph metastasis, unknown primary
Breast carcinoma
Gall bladder carcinoma
Rectal adenocarcinoma
Carcinoma of maxillary glandule
Malignant thymoma
Ameloblastoma

2
2
3
1
0.7
0.7
0.7
0.7
0.7

Diagnostic criteria
A typical history and clinical findings
with in addition at least one of the
following:
1. Low compound muscle action potential after nerve stimulation
with decrement at low frequency
stimulation (3 Hz) of more than
10%, and increment after high
frequency stimulation (more than
20 Hz) or preferably maximal

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voluntary contraction) of more


than 100%.
2. Anti-vg-Ca
channel
(P/Qtype) antibodies
This is a finding in about 90% of
the patients with no cancer; the
frequency being 100% in SCLC
cases with LEMS
3. Anti-AChR (muscarinic M1type) antibodies in about 80 %
These are directed to the presynaptic muscarinic AChR, which is
associated with the TRPC3 channel (a transient receptor potential
cation channel of subfamily C,
member 3), and which is a Cainflux channel. It appears that
this autoantibody is a feature of
all anti-vg-Ca channel seronegative LEMS patients.

Voltage-gated-Ca++-channel

Small cell lung cancer

Anti-VGCC (N-type) antibodies


These autoantibodies are a feature of
LEMS sera in about 50% of the patients. Their role in the muscle
weakness or autonomic dysfunction
is unclear. They are not of significant
value for diagnostic purposes.
Anti-SOX1 (AGNA, anti-Glial nuclear antibodies)
Autoantibodies against cerebellar
Bergmann glia are a feature of LEMS
sera in about 65% of the patients
(sensitivity). Vice versa, SOX antibodies has a specificity of 95% to
discriminate between LEMS with
SCLC and non-tumour LEMS.

Additional autoantibodies
In cases with SCLC and symptoms
other than muscle weakness
Anti-Hu
Anti-PCA2
Anti-CV2
Anti-Amphiphysin
Anti-GAD
Anti-Ri
Anti-AChR (alpha3)
Please see the various syndromes
associated with these autoantibodies.

Treatment
Symptomatic
3, 4-diaminopyridine, possibly
combined with pyridostigmine
Immunotherapy
Steroids
Plasma exchange
High-dose intravenous IgG
Rituximab
Azathioprine
Cyclophosphamide
Specific tumour treatment
In SCLC local resection, radiotherapy,
or chemotherapy may result in a remarkable recovery of the LEMS.

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Selected references
1.
2.
3.
4.
5.
6.

7.
8.
9.

O'Neill JH, Murray NM, Newsom-Davis J. The Lambert-Eaton myasthenic syndrome. A review of
50 cases. Brain 1988; 111: 577-96.
Motomura M, Johnston I, Lang B, Vincent A, Newsom-Davis J. An improved diagnostic assay for
Lambert-Eaton myasthenic syndrome. J Neurol Neurosurg Psychiatry. 1995; 58: 85-7.
Mason WP, Graus F, Lang B, Honnorat J, Delattre JY, Valldeoriola F, Antoine JC, Rosenblum MK,
Rosenfeld MR, Newsom-Davis J, Posner JB, Dalmau J. Small-cell lung cancer, paraneoplastic
cerebellar degeneration and the Lambert-Eaton myasthenic syndrome. Brain 1997; 120:1279-300.
O'Suilleabhain P, Low PA, Lennon VA. Autonomic dysfunction in the Lambert-Eaton myasthenic
syndrome: serologic and clinical correlates. Neurology 1998; 50: 88-93.
Maddison P, Newsom-Davis J, Mills KR, Souhami RL. Favourable prognosis in Lambert-Eaton
myasthenic syndrome and small-cell lung carcinoma. Lancet 1999; 353: 117-8.
Wirtz PW, Sotodeh M, Nijnuis M, Van Doorn PA, Van Engelen BG, Hintzen, RQ, De Kort PL, Kuks
JB, Twijnstra A, De Visser M, Visser LH, Wokke JH, Wintzen AR, Verschuuren JJ. Difference in
distribution of muscle weakness between myasthenia gravis and the Lambert-Eaton myasthenic
syndrome. J Neurol Neurosurg Psychiatry 2002; 73: 766-8.
Graus F, Vincent A, Pozo-Rosich P, Sabater L, Saiz A, Lang B, Dalmau J. Anti-glial nuclear
antibody: Marker of lung cancer-related paraneoplastic neurological syndromes. J Neuroimmunol
2005; 165 (1): 166-171.
Takamori M, Motomura M, Fukodome T, Yoshikawa H. Autoantibodies against M1 muscarinic
receptor in myasthenia gravis. Eur J Neurol 2007; 14 (11): 1230-1235.
Titulaer MJ, Klooster R, Potman M, Sabater L, Graus F, Hegeman IM, Thijssen PE, Wirtz PW,
Twijnstra A, Smitt PA, van der Maarel SM, Verschuuren JJ. SOX antibodies in small-cell lung
cancer and Lambert-Eaton myasthenic syndrome: frequency and relation with survival. J Clin
Oncol 2009; 27 (26): 4260-4267.

Neuromyotonia, Isaacs' syndrome


Acquired neuromyotonia with peripheral
nerve hyper-excitability
An autoimmune synaptic neuropathy characterized by
intermittent or continuous widespread involuntary
muscle contractions and autoantibodies directed to
contactin-associated protein-2 (CASPR2) - the true
target and being an accessory protein and integrated at vg-KC complexes.
The typical feature of this syndrome is continuous and quite pronounced muscle
fibre activity, which is also present during sleep. The underlying mechanism is a
severe instability of the terminal arborisations of motor nerves attributable to impaired function of the delayed rectifier K+ channels that are ordinarily responsible
for neuronal repolarisation following action potential firing. This disorder appears
to fulfil the criteria of an antibody-mediated autoimmunity.
The milder cramp-fasciculation syndrome is neuromyotonia without fibrillations.
There is also an overlap to Morvans syndrome. Moreover, see sporadic rippling
muscle syndrome.

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Anti-CASPR2 disorders:
Acquired neuromyotonia
Peripheral nerve hyper-excitability

Morvans syndrome

Neuromyotonia with autonomic and


CNS involvement

Limbic encephalitis

CNS manifestations without peripheral involvement

Mental disturbances (25%)


Morvan's syndrome, limbic encephalitis with personality change, insomnia, irritability
Other features
Sensory symptoms (30%), paraesthesias and numbness, hyperhidrosis
(35% to 55%)
Tendon reflexes are often normal.

Onset

With an onset, usually in late


childhood or early adulthood, familial and acquired (primarily autoimmune) forms have been reported
Most frequently < 60 years
(mean 46 years)
All origins: nine to 80 years

Differential diagnosis

Paraneoplastic opsoclonus / myoclonus (POM)

Clinical features
The symptoms may fluctuate in severity over periods of months. Typically, exercise or muscle contractions
are factors of precipitation.
Muscle twitching
Visible myokymia or neuromyotonia
is symptomatic in 10 to 40%. The intermittent cramps and stiffness occur
at rest, and may be induced or exacerbated by exercise. The predominant distribution of these features is
distally in the arms and legs. Face,
tongue and pharyngeal muscles may
be involved. Moreover, an observation is delayed muscle relaxation and
no percussion-induced contraction.
The muscle activity continues during
sleep.
Fatigue, hypertrophy
If existing, the weakness is absent or
mild in about 30%, especially in
overactive muscles. Muscle hypertrophy may occur in 20%. These features do not predict co-existence of
MG or polyneuropathy.

Voltage-gated-K+-channel

Course
Fluctuations,
remissions

but

no

spontaneous

Neurophysiology
EMG
Spontaneous axonal action potentials
In general, there is peripheral nerve
hyperexcitability due to potentials
arising along the course of motor axons and increased excitability of the
nodal membrane. The potentials persist during general anaesthesia. NMJ
blockade eliminates the abnormal
muscle activity.
Distribution: limbs > trunk & face
Fasciculations may be the only sign
of disease and may occur without
myokymia. This may be clinically
confused in the early stages with
amyotrophic lateral sclerosis.
Myokymia
This feature is absent in some patients, and may develop on subsequent study, often as a mild continuous spontaneous activity.

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These are spontaneous bursts of motor unit potentials of a brief duration,


less than one second. They consist of
two to five potentials per burst, with
a frequency of 5-70 Hz. They recur
regularly or irregularly (0.1 to 3 per
second) and may persist after treatment
Neuromyotonia
More persistent activity and muscle
contraction. These are spontaneous
bursts of single motor unit potentials,
prolonged (several seconds) and of a
frequency of 40 - 300 Hz. The bursts
are very irregular and associated
with persistent muscle contraction.
Treatment may be able to reduce
them. Another observation is repetitive F-waves.

Penicillamine treatment
Morvan's fibrillary chorea
Polyneuropathy: sensory-motor
with M-protein
HIV infection
Other associated immune disorders
o Thyroid
o Diabetes

Investigations
Serum CK: Elevated in 50%

Autoantibodies

Anti-CASPR2
(contactinassociated protein-2) in more
than 50 %
(Anti-voltage-gated K-channels)

Neoplasms
Lung
Thymus
Hodgkin's disease
Isaacs syndrome often predates the
diagnosis of these neoplasms.

The targets are located at the dentate gyrus of


hippocampus, at neural juxtaparanodes, and at
the neuromuscular junction. In RIAs, using
2 % digitonin extract of radio-labelled
dendrotoxin, antibodies to Shaker types Kv1.1,
1.2, 1.6 are detectable, although not differentiated. Moreover, such VGKC extract are complexed with two other channel-complex
proteins, leucine-rich, glioma inactivated 1
protein and contactin-associated protein-2 in
limbic encephalitis. Therefore, this assay is not
specific to anti-VGPC.

Associated disorders

Associated neoplasms

Myasthenia gravis (seropositive,


anti-AChR antibodies)
The over activity begins with or
after MG. The frequency of
Isaacs syndrome in myasthenics
is estimated at about 10 to 20%
and observed with a thymoma in
patients > 40 years
CSF may occasionally show abnormality
Oligoclonal bands
Slightly increased protein
Muscle biopsy: fibre hypertrophy of
type-I predominance

Other disorders with K+channel antibodies:

Cramp-fasciculation syndrome
Limbic encephalitis
Morvan's fibrillary chorea
KCNA1 mutations in episodic
ataxia 1 (hereditary IsaacsMertens syndrome, myokymia 1)

Anti-AChR (autonomic alpha3type, 50%)


Anti-AChR (adult-type, foetaltype), in co-existing paraneoplastic MG

Nerve conduction studies are usually normal.

Treatment
Symptomatic
Carbamazepine (200 to 600
mg/day)
Phenytoin (200 to 400 mg/day)
Mexiletine
Immunosuppression
Plasma exchange (short-term
benefit).
Prednisone

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Selected references
1.
2.
3.
4.
5.
6.
7.
8.
9.

Newsom-Davis J, Mills KR. Immunological associations of acquired neuromyotonia (Isaacs'


Syndrome). Report of five cases and literature review. Brain 1993; 116: 453-469.
Hart IK, Waters C, Vincent A, et al. Autoantibodies detected to expressed potassium channels are
implicated in neuromyotonia. Ann Neurology 1997; 41: 238-246.
Toepfer M, Schroeder M, Unger JM et al. Neuromyotonia, myoclonus, sensory neuropathy and
cerebellar symptoms in a patient with antibodies to neuronal nucleoproteins (anti-Hu-antibodies).
Clin Neurol Neurosurg 1999; 101:207-209.
Liguori R, Vincent A, Clover L, et al. Morvans syndrome: peripheral and central nervous system
and cardiac involvement with antibodies to voltage-gated potassium channels. Brain 2001; 124:
2417-2426.
Buckley C, Oger J, Clover L, et al. Potassium channel antibodies in two patients with reversible
limbic encephalitis. Ann Neurol 2001 50: 74-79.
Hart IK, Maddison P, Newsom-Davis J, Vincent A, Mills KR. 2002. Phenotypic variants of
peripheral nerve hyperexcitability. Brain 2002, 125 (Pt 8), 1887-1895.
Vincent A, Buckley C, Schott JM et al. Potassium channel antibody-associated encephalopathy: a
potentially immunotherapy-responsive form of limbic encephalitis. Brain 2004; 127 (Pt 3): 701-12.
Kleopa KA, Elman LB, Lang B, Vincent A, Scherer SS. Neuromyotonia and limbic encephalitis sera
target mature Shaker-type K+ channels: subunit specificity correlates with clinical manifestations.
Brain 2006; 129: 15701584.
Irani SR, Sian Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, Peles E, Buckley C, Lang
B, Vincent A. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma
inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvans syndrome
and acquired neuromyotonia. Brain 2010; 133 (9): 2734-2748.

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Paraneoplastic seropositive myasthenia gravis


with thymoma
Paraneoplastic seropositive* myasthenia gravis (SPMG with a
thymoma):
An autoimmune postsynaptic disorder of the neuromuscular junction, characterized by the cooccurrence of a thymoma, myasthenic muscle weakness and autoantibodies directed to the acetylcholine
receptor (AChR) in 100%, and in about 75% also by
additional antibodies to other structures of the striated muscle cells (titin and the ryanodine 1 receptor).
In contrast to the co-existent myopathy, the myasthenic part of the disorder fulfils the criteria of an antibody-mediated autoimmunity. See also myastheniagravis-associated myopathy and sporadic rippling
muscle syndrome.

Mixed epithelial / lymphocyticcortical thymoma

(*Seropositive = anti-AChR antibodies seropositive)

Presumably, this neoplasm therefore


provokes a synthesis of such autoantibodies and maybe to other targets
as well under such conditions.

Chest x-ray: thymoma

Thymomas vs. autoimmunity


The normal job of the thymus is to
educate and export T-cells to the rest
of the body, in order to help B-cells
to make antibodies and stimulate
other cells to protect against infections and neoplasms.
Unfortunately, the emergence of a
thymoma often results in a vast excess of harmful T-cells, provoking
various autoimmune disorders. It
appears that a dangerous tumour
microenvironment is created with
both pre-activation and antibodies to
cytokines (IF-alpha, IL-12). Normally,
AChRs of embryonic (foetal)-type are
a feature of myoid cells of the thymus, very much in contrast to Titin
and RyR1 epitopes. Unfortunately,
these latter epitopes are characteristics of thymomas (cortical type?).

SPMG is co-existent in about 50% of


patients with a thymoma. Otherwise,
this neoplasm is associated with a
variety of other autoimmune disorders and corresponding autoantibodies.
Frequently, thymoma patients are
diagnosed with more than one such
disorder.
Unrelated to a thymoma, MG is in itself associated with other antibodies,
apart from maybe ANA
Anti-Lymphocyte (60%)
Anti-Nuclear (ANA, 30%)
Anti-Thyroid (microsomal & thyroglobulin), 30%
Rheumatoid factor (25%)
Anti-Platelet (25%)
Anti-Parietal cell (15%)
Anti-Smooth muscle (10%)
Coombs (10%)

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Epidemiology in MG

Nicotinic acetylcholine
receptors

Rate x 10-6

The frequency of this neoplasm is


about 10% of all myasthenics. The
peak age at onset of thymoma-SPMG
is in-between early- and late-onset
MG (dichotomy by 50 years of age). For
more details, see the adjacent figure.
18
16
14
12
10
8
6
4
2
0

1,4
Non-thymoma

1,2

Thymoma-MG

0,8
0,6
0,4
0,2
0

80-89

70-79

60-69

50-59

40-49

30-39

20-29

10-19

0-9

Trimodal occurrence
Mean annual incidence
myasthenia
gravis
in
Denmark 1970-99.

rates of
Eastern-

The rates are per million population and by


age group. Note the different scales of the
value axes, the right one is for paraneoplastic
SPMG, and that the decimal separator is ,.

Clinical features

Note the presence of either a


gamma-subunit or an epsilonsubunit

Age group, years

Embryonic- and adulttypes

In general, a thymoma predicts


more severe MG. Likewise, antiTitin and anti-RyR1 antibodies are
markers of a more severe course
of the disorder.
In paraneoplastic MG (thymoma),
a frequent finding is severe
weakness of the extraocular muscles. This is explicable in terms of
the multiply innervated fibres at
this location expressing embryonic (foetal) AChR at their NMJs.
From the present evidence, one
should also regard thymoma MGpatients as a group at special risk
of myocardial pathology. Accordingly, should heart symptoms occur in such patients, consider the
possibility of myocarditis (or pericarditis) related to MG and autoimmunity.
Routinely however,
and using the currently available
modalities of heart examinations,
it appears that regardless of any
thymic pathology, MG patients
should not undergo such examinations [16]

Investigations
Autoantibodies
If only MG symptoms are present,
then primarily

Anti-AChR (adult- & foetal-type)


Anti-Titin (must be determined
with an assay using the main
immunogenic region (MIR)
o Almost all MG patients
with anti-titin and onset <
50 years of age have a coexistent thymoma, the exception being acute severe
generalised MG
o MG without thymoma: antititin in 50% to 90% of MG
with age at onset > 50 years
and not a feature of earlyonset MG, see above.
Anti-MuSK (a few case histories)
and anti-AChR seronegative
Please note that apart from antiMuSK seropositive cases, thymomas
are not encountered in anti-AChR antibody seronegative MG. Moreover,
autoantibodies to various epitopes of
striated muscles are associated with
co-existent myopathy adding to the
myasthenic weakness.
Cf. Paraneoplastic myopathies, myasthenia gravis- associated.
Secondary
If in addition to anti-AChR, anti-Titin
is not a finding, then consider

Anti-Striated muscle (unspecific)


or anti-RyR1

o
o

Frequency in MG + thymoma:
80% to 90%
MG without thymoma: rare <
10%

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Positive also in MG with myositis

Anti-CASPR2 (formerly
anti-vg-K-channels)

called

These channels are located at the


neuromuscular junction and in the
CNS, and Kv1.4 are also located in
the heart & smooth and striated
muscles

Cytokine antibodies
Anti-IF alpha (interferon alpha)
(75%)
Anti-Il12 (interleukin 12)
Autoantibodies against such messenger molecules are more common
in MG patients with a thymoma than
in those without (75% versus 30%).
Typically, the titres of these autoantibodies increase substantially if a
thymoma recurs after surgery. Accordingly, these antibodies are also
valuable in the post-surgery monitoring of these patients.
Titin, also known as
connectin

In cases with findings other


than strict myasthenic weakness, then also:

Anti-GAD
Anti-CV2
Anti-vg-Ca channel (P/Q-type)
Anti-AChR (nicotinic alpha3, autonomic, ganglionic)
Please see the various syndromes
associated with these autoantibodies.

Other investigations
Follow the general guidelines for MG
and search for a thymoma in antiAChR seropositive cases. If striated
muscle autoantibodies of any specificity are a feature as well, then the
likelihood of a coexisting thymoma is
much greater, but the non-finding
does not rule out that anyhow, such
a neoplasm may be present. If furthermore, anti-Cytokine antibodies
are present, then the search for a
thymoma should be intensive.
Somewhat puzzling, thymomas may
be encountered up to several months
or years before the onset of MG, at
about the time of the MG diagnosis,
and subsequently also up to several
years hereafter. Therefore, a nonthymoma SPMG diagnosis may necessitate repeated search for this neoplasm at suitable intervals, in particular in cases with a later onset
than before 30 years of age.

Treatment
This giant muscle molecule is
a molecular spring

Ryanodine 1 receptor (RyR1)

A major cellular mediator of Ca++-release


in striated muscle

Follow the general principles in MG.


In addition
Drug to enhance RYR-related sarcoplasmic Ca++-release
Immunosuppression
Compared to SPMG without a thymoma, paraneoplastic SPMG is more
aggressive and often requiring
Early and more intensive combined immunosuppressive therapy with steroids and azathioprine
A series of plasma exchanges or
alternatively, intravenous highdose IgG in order to adequately
manage MG crises

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Surgery
Removal of the thymoma is an option
upon oncologic indications only,
since it is likely that the myasthenic
disorder in itself will substantially deteriorate soon after the surgical procedure, possibly rendering more intensive immunosuppressant control
necessary for up to several years
subsequent to operation. [2]

Risk of passive transfer MG


Comprises
Neonatal MG
Acquired arthrogryposis multiplex
The chapter: Maternal autoantibodies and passive transfer in humans
provides a detailed review of this.
The possibility of passive transfer MG
is of great concern in a myasthenic
woman planning a pregnancy or already being so. Note however, that
even though a fertile thymoma patient does not show any myasthenic
signs, the foetus may still be at risk,
since in such a case, anti-AChR to
the embryonic receptor may be present in the serum of the woman, not
causing her any harm, but being detrimental to neuromuscular transmission of a foetus.
Among thymoma-MG patients, the
relative difference in titres between
the two specificities of anti-AChR antibodies may vary substantially. This
has implications to the risk of transferring MG to an offspring.

Whether a female thymoma patient


is diagnosed with MG or not, in relation to a pregnancy consider examination of a serum sample:
Anti-AChR antibodies, preferably by using an assay with a mixture of adult- and foetal-type
human receptor from different
cell lines in a standardised ratio
o A ratio of foetal- vs. adulttype autoantibodies may provide a more useful estimate of
the actual risk, since such a
calculation results in more
emphasis of fraction of antibodies to the gamma subunit.

Monitor such a pregnancy


carefully
o Longitudinal measurements of
anti-AChR
Bad omens are:
o Decreased foetal movements
o Signs of hydramnios

Treatment during pregnancy


o Upon rising titres or ominous
signs, consider more intensive
treatment bearing in mind
that this must serve to decrease the concentration of
antibodies.
o Cf. also the chapter General
therapeutic considerations.
o If plasma exchange by any
technique is the choice, then
take extra care to avoid drastic shifts in hormone levels,
since this may result in an
unwanted abortion.

In short:

Selected references
1.
2.
3.
4.

5.

Olanow CW, Lane RJ, Hull Jr KL, Roses AD. Neonatal myasthenia gravis in the infant of an
asymptomatic thymectomized mother. Can J Neurol Sci 1982; 9 (2): 85-87.
Somnier FE. Exacerbation of myasthenia gravis after removal of thymomas. Acta Nerol Scand
1994; 90: 56-66.
Riemersma S, Vincent A, Beeson D, Newland C, Hawke S, Vernet-der Garabedian B, Eymard B,
Newsom- Davis J. Association of arthrogryposis multiplex congenita with maternal antibodies
inhibiting fetal acetylcholine receptor. J Clin Invest 1996; 98 (10): 2358-2863.
Gardnerova M, Eymard B, Morel E, Faltin M, Zajac J, Sadovsky O, Tripou P, Domergue M, Vernet
der Garabedian Bach JF. The fetal/adult acetylcholine receptor antibody ratio in mothers with
myasthenia gravis as a marker for transfer of the disease to the newborn. Neurology 1997; 48
(1): 50-54.
Skeie GO, Lunde PK, Sejersted OM, Mygland A, Aarli JA, Gilhus NE. Myasthenia gravis sera
containing anti-ryanodine receptor antibodies inhibit binding of [3H]-ryanodine to sarcoplasmic
reticulum. Muscle Nerve 1998; 21 (3): 325-335.

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6.
7.
8.
9.

10.
11.
12.

13.
14.
15.
16.
17.
18.
19.
20.
21.

Somnier FE, Skeie GO, Aarli JA, Trojaborg W. EMG evidence of myopathy and the occurrence of
titin autoantibodies in patients with myasthenia gravis. Eur J Neurol 1999; 6 (5): 555-563.
Buckley C, Newson-Davis J, Willcox N, Vincent A. Do titin antibodies in MG predict thymoma or
thymoma recurrence? Neurology 2001; 57 (9): 1579-1582.
Somnier FE, Engel PJH. The occurrence of anti-Titin antibodies and thymomas. A population
survey of MG 1970-1999. Neurology 2002; 59 (1): 92-98.
Shiono H, Wong HL, Matthews I, Liu JL, Zhang W, Sims G, Meager A, Beeson D, Vincent A,
Willcox N. Spontaneous production of anti-IFN-alpha and anti-IL-12 autoantibodies by thymoma
cells from myasthenia gravis patients suggests autoimmunization in the tumor. International
Immunology 2003; 15 (8): 903-913.
Takamori M, Motomura M, Kawaguchi N, Nemoto Y, Hattori T, Yoshikawa H, Otsuka K. Antiryanodine receptor antibodies and FK506 in myasthenia gravis. Neurology 2004; 62 (10): 18941896.
Somnier FE. Increasing incidence of late-onset anti-AChR antibody-seropositive myasthenia gravis.
Neurology 2005; 65 (6): 928-930.
Suzuki S, Satoh T, Yasuokova H, Hamaguchi Y, Tanaka K, Kawakami Y, Suzuki N, Kuwana M.
Novel autoantibodies to a voltage-gated potassium channel KV1.4 in a severe form of myasthenia
gravis. J Neuroimmunol 2005; 170 (1-2): 141-149.
Thomas S, Critchley P, Lawden M, Farooq S, Thomas A, Proudlock FA, Constantinescu CS, Gottlob I. Stiff
person syndrome with eye movement abnormality, myasthenia gravis, and thymoma. J Neurol Neurosurg
Psychiatry 2005; 76 :141-142.
Skeie GO, Aarli JA, Gilhus NE. Titin and ryanodine receptor antibodies in myasthenia gravis. Acta
Neurol Scand Suppl 2006; 183: 19-23. [Review].
Fraterman S, Khurana TS, Rubinstein NA. Identification of acetylcholine receptor subunits
differentially expressed in singly and multiply innervated fibers of extraocular muscles. Invest
Opthalmol Vis Sci 2006; 47 (9): 3828-3834.
Yoshikawa H, Sato K, Edihiro S, Furukawa Y, Maruta T, Iwasa K, Watanabe H, Takaoka S, Suzuki
Y, Takamori M, Yamada M. Elevation of IL-12 p40 and its antibody in myasthenia gravis with
thymoma. J Neuroimmunol 2006; 175 (1-2): 169-175.
Camdessanche JP, Lassabliere F, Meyronnet D, Ferraud K, Honnorat J, Antoine JC. Expression of
the onconeural CV2/CRMP5 antigen in thymus and thymoma. J Neuroimmunol 2006; 174 (1-2):
168-173.
Owe JF, Gilhus NE. Myasthenia gravis and the Heart. ACNR 2008; 8 (5): 9-10. [Review]
Vincent A, Irani SR. Caspr2 antibodies in patients with thymomas. J Thorac Oncol 2010; 5(10
Suppl 4): S277-80.
Ito A, Sasaki R, Ii Y, Nakayama S, Motomura M, Tomimoto H: [A case of thymoma-associated
myasthenia gravis with anti-MuSK antibodies].Rinsho Shinkeigaku; 2013;53(5):372-5
Choi Decroos E, Hobson-Webb LD, Juel VC, Massey JM, Sanders DB. Do acetylcholine receptor
and striated muscle antibodies predict the presence of thymoma in patients with myasthenia
gravis? Muscle Nerv 2014 Jan;49 (1) :30-4.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Paraneoplastic myopathies
In association with a variety of neoplasms, the features of these myopathies are a predominantly proximal and symmetrical muscular weakness, and maybe
also dermatologic manifestations or myasthenic fatigue.
Table 10: Currently known disorders
Category
A
B
C
D
E

Autoimmune myopathy
Dermatomyositis

Associated autoantigens
Mi2, SAE2, SAE1, Mi2, TIF1, PX2

Polymyositis
Overlap
Acute necrotizing myopathy
Inclusion body myositis
Paraneoplastic myasthenia gravis
associated myopathy
Sporadic rippling muscle syndrome

SRP, Jo-1, PL-12, PL-7, EJ, OJ


PM-Scl75, PM-Scl10, KU
HMGCR
Mup44

A. Polymyositis,
dermatomyositis
Poly- or dermatomyositis is an
idiopathic inflammatory myopathy
without or with characteristic cutaneous manifestations. The incidence of
polymyositis and dermatomyositis is
5-10 cases per 100,000 individuals.

Titin
Titin isoform N2A, ATP synthase 6, PPP1R3

Onset

Adults over 30 years of age; female-to-male ratio 2:1


Slowly progressive over weeks to
months; active 2-3 years

Polymyositis is presumed to be an
autoimmune-mediated disease secondary to defective cellular immunity,
which may be due to diverse causes
that may occur alone or in association
with viral infections, malignancies, or
connective-tissue disorders. Evidence
suggests that a T-cellmediated cytotoxic process is directed against unidentified muscle antigens.

Dermatomyositis is likely the result


of a humoral attack on the muscle capillaries and small arterioles. Complement c5b-9 membrane-attack complex
is deposited and is needed in preparing
the cell for destruction in antibodymediated disease. B-cells and CD4
(helper) cells are also present in abundance in the inflammatory reaction associated with the blood vessels.

Heliotrope rash

Clinical features
Myopathy
Muscular weakness, primarily
proximal and most often symmetrical
Skin manifestations
Heliotrope rash involving the periorbital skin
Photosensitive poikilodermatous
eruption

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Erythematous scaly plaques on


dorsal hands with periungual telangiectasia and joint eruptions
(Gottron papules)

Association with malignant disease


Dermatomyositis
SIR
95 % CI
Overall
3.0
2.5-3.6
Ovarian

10.5

6.1-18.1

Lung

5.9

3.7-9.2

Pancreatic

3.8

1.6-9.0

Stomach

3.5

1.7-7.3

Colorectal

2.5

1.4-4.4

Non-Hodgkin
3.6
1.2-11.1
lymphoma
Polymyositis
Poikilodermatous eruptions

Non-Hodgkin
lymphoma
Lung

3.7

1.7-8.2

2.8

1.8-4.4

Bladder
cancers

2.4

1.3-4.7

Hill CL et al. 2001 - 618 cases of


dermatomyositis, of whom 198 (32 %)
had cancer: 115 of the 198 (58 %)

developed cancer after diagnosis of


dermatomyositis. 137 of the 914
(15 %) cases of polymyositis had
cancer, which developed after
diagnosis of polymyositis in 95.

Laboratory markers

Gottron papules

Diagnosis
The following combination:
Typical skin changes
Muscle weakness
Elevated serum creatinine kinase
Characteristic neurophysiologic
findings
Muscle biopsy
Remarks
Typically, cancer is a finding simultaneously with the myopathy
diagnosis
In dermatomyositis, a neoplasm
is found more frequently in women than in men

Associated neoplasms

Ovarian
Lung
Pancreatic
Stomach
Colorectal
Non-Hodgkin lymphoma

Antinuclear antibody (ANA) is


frequently positive.

Irrespective of neoplasms, there is


association also with these autoantibodies:
1. Myositis-specific antibodies
(MSA)
o Jo-1 (25% seropositivity in
myositis)
o Mi-2 (25% seropositivity in
dermatomyositis)
o PL-7, PL-12
o EJ, OJ
o SRP
o Ku
o (KS, KJ, PMS1)
2.
o
o
o

Myositis-overlap antibodies
PM-Scl 75, PM-Scl 100
Ro-52
(U1-nRNP 70 k, U1-nRNP A,
U1-nRNP C)

Anti-SRP is associated with an


aggressive course of polymyositis
and unsatisfactory effect of treatment.

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Clinical features
Anti-syntethase syndrome
Symptomatology
Autoantigens
polymyositis
fever
Jo-1, EJ,
polyarthritis
OJ, PL-7,
Raynauds phenomenon
PL-12
interstitial lung disease

3. Anti-TIF1, anti-MDAS, antiNXP2


Anti-TIF1 (transcriptional intermediary
factor 1-gamma)
Cancer
Classical
Healthy
associated
DM
controls
DM
58 %
5%
0%
(n=12)
(n=39)
(n=20)
Anti-MDA5 (melanoma differentiationassociated gene 5)

All such seropositives (26 %, n= 82)


had DM
Hashino et a.. Rheumatology 2010; 49
(9): 1726-36
Anti-NXP2 (MORC3) or anti-TIF1
Cancer associated DM: 83 %
(n=213)
Fiorentino DF et al. Arthritis Rheum.
2013; 65 (11): 2954-62.

Treatment
Oncologic & immunosuppressants
Corticosteroids
Azathioprine
Intravenous administration of
high-dose IgG

B. Acute necrotizing
myopathy
This syndrome may represent a
severe form of polymyositis.

Onset

Quite rare disorder


Rapid progression over one to
three months

Symmetrical and predominantly


proximal weakness
Eventually, severe functional disability

Associated neoplasms

Lung
Bladder
Breast
Gastrointestinal tract

Investigations
Serum creatine kinase
Markedly elevated
Neurophysiology
Evident myopathic findings
Muscle biopsy
Patchy necrosis and perimysial
phosphatase staining with little
inflammation

Associated antibody

Anti-HMGCR (3-hydroxy-3methylglutaryl-coenzyme A
reductase; the rate-limiting enzyme for cholesterol synthesis

Differental-diagnoses
Statin-provoked rhabdomyolysis

Treatment
Oncologic and immunosuppressants
Corticosteroids
Azathioprine
Intravenous administration of
high-dose IgG

C. Inclusion body myositis, sporadic


This myopathy is associated with
Anti-Mup44 and rarely endometrial carcinoma of the uterus;
please see below.

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Muscle biopsy: sIBM

Onset and incidence


This sporadic form of IBM (sIBM) is
an age-related disease a type of
muscular dystrophy; and the most
frequent acquired myopathy seen in
adults aged over 50 years.
The mean age of onset is around
60 years (but with considerable variation). About 20% of cases display
symptoms before 50. It appears to
be slightly more common in men.
Prevalence is about 15 per million in
the overall population, with a prevalence of 50 per million population in
people over 50 years of age.
Hereditary - hIBM:
1. IBM1
is listed under OMIM
601419: MYOPATHY, MYOFIBRILLAR, 1;

MFM1
2.

IBM2 is listed under OMIM #


600737. INCLUSION BODY MYOPATHY
2, AUTOSOMAL RECESSIVE; IBM2

Another form of IBM2 is Nonaka


distal myopathy; see: OMIM #
605820: NONAKA MYOPATHY; NM
4. IBM
associated
with
Paget
disease of bone and dementia
(IBMPFD; see: OMIM # 167320
3.

INCLUSION
BODY
MYOPATHY
WITH
EARLY-ONSET PAGET DISEASE AND
FRONTOTEMPORAL DEMENTIA; IBMPFD
5.

IBM 3; see OMIM

# 605637

INCLUSION
BODY
MYOPATHY
AUTOSOMAL DOMINANT; IBM3

3,

and dermatomyositis, asymmetry


is common.
Early involvement of the knee extensors, ankle dorsiflexors, and
wrist/finger flexors is characteristic of s-IBM.
Weakness of the wrist and finger
flexors is often disproportionate
to that of their extensor counterparts. Hence, loss of finger dexterity and grip strength may be a
presenting or prominent symptom.
Dysphagia is common, occurring
in 40-66% of patients with wellestablished disease and in 9% of
patients at presentation. Dysphagia may manifest as a feeling of
stasis, a need to swallow repeatedly, regurgitation, or choking.
Mild facial weakness may be noted in about one third of patients.
Isolated erector spinae weakness
or "droopy neck" syndrome has
been reported with s-IBM.
Myalgias and cramping are relatively uncommon.
Sensory and autonomic dysfunction is not present except in patients with a concurrent polyneuropathy.
Cardiac disease is common; it is
most likely due to the older age
of most patients. Direct cardiac
muscle involvement by the disease has not been demonstrated.

Associated neoplasms
Uterus: endometrial carcinoma
Differental-diagnosis
Polymyositis, motor neuron disease,
myasthnia gravis

Investigations

Clinical features
Since s-IBM is an acquired myopathic
process, weakness or impairment of
muscle function in the area(s) affected is the presenting symptom. The
disease follows a slowly progressive
course.
The distribution of weakness in sIBM is variable, but both proximal
and distal muscles are usually affected and, unlike polymyositis

In most cases of s-IBM, serum CK


level is normal or elevated to a
mild-to-moderate degree. Elevation greater than 12 times normal
may occur but is rare.
Neurophysiology
Electromyography studies
display abnormalities

usually

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Muscle biopsy
May display several common findings
including;
inflammatory
cells
invading muscle cells, vacuolar
degeneration, inclusions or plaques
of abnormal proteins. sIBM is a
challenge to the pathologist and even
with a biopsy, diagnosis can be
ambiguous

Associated antibodies

Anti-Mup44 (Cytosolic 5'nucleotidase 1A)


Anti-HMGCR (3-hydroxy-3methylglutaryl-coenzyme A
reductase)

Treatment

Abbreviations: SP is anti-AChR seropositive;


MG is myasthenia gravis.

Provocation appears to be a common


denominator in both disorders: either
by a neoplasm or by environmental
factors.

Consider immunosuppressant or
myofibre regenerator
Alemtuzumab
Bimagrumab
The FDA have granted breakthrough
status for bimagrumab (stimulating
myofibre regeneration) based on the
results of a phase 2 proof-of-concept
study that showed that the drug substantially benefited patients with
sIBM compared to placebo
Severe dysphagia may require
cricopharyngeal
myotomy
or
placement of a gastrostomy tube.
Chemodenervation with botulinum
toxin A injection into the upper
esophageal sphincter has also been
shown to be of benefit

D. Myasthenia gravisassociated myopathy


This myopathy is associated with
postsynaptic disorders of the NMJ,
comprising:
Paraneoplastic-SPMG (thymoma)
Late-onset SPMG

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Onset
See figure showing the annual incidence rates of early-, late-onset &
thymoma-MG in the section Paraneoplastic SPMG with thymoma.

Associated neoplasm

Clinical features

Anti-AChR (100%, adult- and foetal-type)

Symmetrical and predominantly


proximal weakness
Myasthenic fatigue
Muscular atrophy
More or less severe muscular atrophy is a common feature in all
these cases, combined with the
finding of anti-Titin and other anti-striated antibodies.

Comments
SPMG fulfils the criteria of an autoantibody-mediated disorder. Since the
anti-Striated muscle antibodies are
for intracellular structures, it is
tempting to speculate that the myopathic component may be T-cell mediated.

Neurophysiology

Myopathic findings
In more than 20% of thymoma-MG
In more than 30% of in lateonset MG

Thymoma: a finding in about 1015 % of all MG cases

Associated antibodies

Anti-Titin: the presence of these antibodies correlates with myopathy


per se and with the overall clinical
severity of the disorder.
70% in thymoma-MG
55% in late-onset nonthymoma MG
Anti-RyR1
d. Anti-Striated muscle (by immunohistochemistry):
o This unspecific method detects
antibodies to various muscle
epitopes, for example also the
ryanodine receptor.
o Accordingly, the frequency of seropositives is higher than compared with anti-Titin results.

Treatment
Please see paraneoplastic MG.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Population-based cohort studies on the link between myositis and malignancy


Reference

Frequency of cancer (%)


Dermatomyositis

Polymyositis

Relative risk
Dermatomyositis

Sigurgeirsson
et al. 1992

61/392 (16 %)

Airio et al.
1995

31/203 (15 %)

26/336 (8 %)

3.8

1.7

Chow et al
1995

19/71 (27 %)

12/175 (7 %)

6.5

1.0

42/396 (11 %) Female 3.4

Male
2.4

Polymyositis
Female
1.7

Male
1.8

Malignancy in myositis - Waimann et. al. 2011


Cancer diagnosis
DM (n=58)
PM (n=35)
Breast
31%
20 %
Lung
17 %
12 %
Adenocarcinoma was the predominant histological
type (DM 60%, PM 39%)
Cancer diagnosis before onset: PM 57%; DM
26%.
Overall, PM or DM were concurrent with cancer diagnosis or recurrence in 40% of the cases.

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Abbreviations: CADM cancer associated dermatomyositis; DM Dermatomyositis; JDM Juvenile dermatomyositis; PM polymyositis; IBM inclusion body myositis
Selected references
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.

Brownell B, Hughes JT. Degeneration of muscle in association with carcinoma of the bronchus. J
Neurol Neurosurg Psychiatry 1975; 38: 363-70.
Barnes B. Dermatomyositis and malignancy. Ann Int Med 1976; 84: 68-76.
Emslie-Smith AM, Engel AG. Necrotizing myopathy with pipestem capillaries, microvascular
deposits of the complement membrane attack complex (MAC) and minimal cellular infiltration.
Neurology 1991; 41: 936-939.
Dalakas MC. Polymyositis, dermatomyositis and inclusion-body myositis. N Eng J Med 1991; 325:
1487-1498. [Review]
Sigurgeirsson B, Lindelf B, Edhag O, Allander E. Risk of cancer in patients with dermatomyositis
or polymyositis. N Engl J Med 1992; 326 (6): 363-367.
Somnier FE, Trojaborg W. Neurophysiological evaluation in myasthenia gravis. A comprehensive
study of a complete patient population. Electroencphalography and clinical Neurophysiology 1993;
89 (2): 73-87.
Airio A., Pukkala E., Isomaki H. Elevated cancer incidence in patients with dermatomyositis: a
population-based study. J Rheumatol. 1995; 22: 13001303.
Chow W.H., Gridley G., Mellemkjaer L., McLaughlin J.K., Olsen J.H., Fraumeni J.F., Jr. Cancer risk
following polymyositis and dermatomyositis: a nationwide cohort study in Denmark. Cancer
Causes Control. 1995; 6: 913.]
Levin MI, Mozaffar T, Taher M. et al. Paraneoplastic necrotizing myopathy. Clinical and
pathological features. Neurology 1998: 50 (3); 764-767.
Somnier FE, Skeie GO, Aarli JA, Trojaborg W. EMG evidence of myopathy and the occurrence of
titin autoantibodies in patients with myasthenia gravis. Eur J Neurol 1999; 6 (5): 555-563.
Callen, JP. Dermatomyositis. Lancet 2000; 355 (9197): 53-57.
Badrising UA, Maat-Schieman M, van Duinen SG, et al. Epidemiology of inclusion body myositis in
the Netherlands: a nationwide study. Neurology 2000; 55 (9): 1385-7.
Phillips BA, Zilko PJ, Mastaglia FL. Prevalence of sporadic inclusion body myositis in Western
Australia. Muscle Nerve. 2000; 23 (6): 970-2.
Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of specific cancer types in
dermatomyositis and polymyositis: a population-based study. Lancet 2001; 357: 96-100.
Somnier FE, Engel PJH. The occurrence of anti-Titin antibodies and thymomas. A population
survey of MG 1970-1999. Neurology 2002; 59 (1): 92-98.

81

15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

16. Bronner IM, Hoogendijk JE, Wintzen AR, et al. Necrotising myopathy, an unusual presentation of a
steroid-responsive myopathy. J Neurol 2003; 250 (4): 480-485.
17. Selcen D, Fukuda T, Shen XM, Engel AG. Are MuSK antibodies the primary cause of myasthenic
symptoms? Neurology 2004; 62 (11): 1945-1950.
18. Shiraishi H, Motomura M, Yoshimura T, Fukodome T, Fukuda T, Nakao Y, Tsujihata M, Vincent A,
Eguchi K. Acetylcholine receptors loss and postsynaptic damage in MuSK antibody-positive
myasthenia gravis. Ann Neurol 2005; 57 (2): 289-293.
19. Ohta K, Shigemoto K, Kubo S, Maruyama N, Abe Y, Ueda N, Jujinami A, Ohta M. MuSK Ab
described in seropositive MG sera found to be Ab to alkaline phosphatase. Neurology 2005; 65
(12): 1988.
20. Somnier FE. Increasing incidence of late-onset anti-AChR antibody-seropositive myasthenia gravis.
Neurology 2005; 65 (6): 928-930.
21. Benveniste O, Jacobson L, Farrugia ME, Clover L, Vincent A. MuSK antibody positive myasthenia
gravis plasma modifies MURF-1 expression in C2C12 cultures and mouse muscle in vivo. J
Neuroimmunol 2005; 170 (1-2): 41-48.
22. Farrugia ME, Robson MD, Clover L, Anslow P, Newsom-Davis J, Kenneth R, Hilton-Jones D,
Matthews PM, Vincent A. MRI and clinical studies of facial and bulbar muscle involvement in MuSK
antibody-associated myasthenia gravis. Brain 2006; 129 (Pt 6): 1481-1492.
23. Bonneva, N, Frenkien-Cuvelier M, Bidault J, Brenner T, Berrih-Aknin S. Major pathogenic effects
of anti-MuSK antibodies in myasthenia gravis. J Neuroimmunol 2006; 177 (1-2): 119-131.
24. Skeie GO, Aarli JA, Gilhus NE. Titin and ryanodine receptor antibodies in myasthenia gravis. Acta
Neurol Scand Suppl 2006; 183: 19-23. [Review].
25. Niks EH, Kuks JB, Roep BO, Haasnoot GW, Verduijn W, Ballieux BE, De Baets MH, Vincent A,
Verschuuren JJ. Strong association of MuSK antibody-positive myasthenia gravis and HLA-DR14DQ5. Neurology 2006; 66 (11): 1772-1774.
26. Fraterman S, Khurana TS, Rubinstein NA. Identification of acetylcholine receptor subunits
differentially expressed in singly and multiply innervated fibers of extraocular muscles. Invest
Opthalmol Vis Sci 2006; 47 (9): 3828-3834.
27. Romi F., Aarli JA, Gilhus NE. Myasthenia gravis patients with ryanodine receptor antibodies have
distinctive clinical features. Eur J Neurol 2007; 14 (6): 617-620.
28. Zhang W, Jiang SP, Huang L. Dermatomyositis and malignancy: a retrospective study of 115
cases. Eur Rev Med Pharmacol Sci. 2009 Mar-Apr;13(2):77-80
29. Dalakas MC, Rakocevic G, Schmidt J, Salajegheh M, McElroy B, Harris-Love MO, Shrader JA, Levy
EW, Dambrosia J, Kampen RL, Bruno DA, Kirk AD. Effect of Alemtuzumab (CAMPATH 1-H) in
patients with inclusion-body myositis. Brain 2009; 132 (Pt 6): 1536-44.
30. Hoshino K, Muro Y, Sugiura K, Tomita Y, Nakashima R, Mimori T. Anti-MDA5 and anti-TIF1gamma antibodies have clinical significance for patients with dermatomyositis. Rheumatology
(Oxford). 2010; 49 (9): 1726-33
31. Rominiyi O, Broman DM, Rajaganeshan R, Selvasekar CR. Colon cancer presenting with
polymyositisA case report. Int J Surg Case Rep. 2011; 2(7): 225227.
32. Hoshino K, Muro Y, Sugiura K, Tomita Y, Nakashima R, Mimori T. Anti-MDA5 and anti-TIF1gamma antibodies have clinical significance for patients with dermatomyositis. Rheumatology
(Oxford). 2010; 49 (9):1726-33.
33. Waimann CA, Olejeme KA, Tayar, JH, Lei X,Suarez-Almazor ME. Cancer Associated Myositis:
Temporal Relationship, Survival and Risk of Cancer Recurrence. Results From a Large Historical
Cohort in United States of America. Arthritis & Rheumatism 2011 November 04
34. Labrador-Horrillo M, Martnez MA, Selva-O'Callaghan A, Trallero-Aragus E, Balada E, VilardellTarrs M, Juarez C. Anti-TIF1 antibodies (anti-p155) in adult patients with dermatomyositis:
comparison of different diagnostic assays. Ann Rheum Dis 2012; 71 (6): 993-6
35. Acciavatti A, Avolio T, Rappuoli S, Foderi L, Soldati V, Franchi M, Volpi N, Nuti R. Paraneoplastic
necrotizing myopathy associated with adenocarcinoma of the lung - a rare entity with atypical
onset: a case report. J Med Case Rep. 2013 Apr 25;7(1):112. doi: 10.1186/1752-1947-7-112.
36. Mohassel P, Mammen AL. Statin-associated autoimmune myopathy and anti-HMGCR
autoantibodies. Muscle Nerve 2013 Mar 21. doi: 10.1002/mus.23854. [Epub ahead of print]
37. Hall JC, Casciola-Rosen L, Samedy LA, Werner J, Owoyemi K, Danoff SK, Christopher-Stine L. Anti-melanoma differentiation-associated protein 5-associated dermatomyositis: expanding the clinical spectrum. Arthritis Care Res (Hoboken). 2013; 65 (8): 1307-15
38. Pluk H, van Hoeve BJ, van Dooren SH, et al. Autoantibodies to cytosolic 5'-nucleotidase 1A in
inclusion body myositis. Ann Neurol 2013; 73 (3): 397-407.
39. Fiorentino DF et al. Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1.Arthritis Rheum. 2013; 65 (11):
2954-62.
40. Drouot L, Allenbach Y, Jouen F, et al . Exploring necrotizing autoimmune myopathies with a novel
immunoassay for anti-3-hydroxy-3-methyl-glutaryl-CoA reductase autoantibodies. Arthritis Res
Ther.2014 Feb 3;16(1):R39.
41. Jrgensen AB, Frikke-Schmidt R, Nordestgaard BG, Anne Tybjrg-Hansen A Loss-of-Function
Mutations in APOC3 and Risk of Ischemic Vascular Disease. N Engl J Med 2014; 371: 32-41

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1. Titin isoform N2A: Accordingly


and as opposed to classical
myasthenia gravis - in rippling
muscle syndrome, the immunogenic region of titin is distinct from the main immunogenic region (MIR).
2. ATP synthase 6
3. PPP1R3 (protein phosphatase
1 regulatory subunit 3)

E. Rippling muscle
syndrome, sporadic
This myopathy appears to be attributable to mechanical sensitivity
and instability due an effect of antiStriated muscle antibodies.

Onset

30 to 55 years

Clinical features

Rippling muscles
Rolling muscle contractions
Muscle stiffness
Myotonia
Cramps
o Induced by exercise or touching muscle
o Spread in transverse direction
across muscle
May be painful
Distribution: cranial, proximal,
distal
Bulbar: dysphagia and dysarthria
Normal sensation and tendon reflexes

Investigations

Serum CK: mildly elevated


Muscle biopsy: inflammation,
lymphocytic
EMG: normal with silent cramps

Antibodies

Anti-Skeletal muscle (see below for specificity): use unspecific


immunohistochemical methods to
detect these antibodies, unless a
specific method is available
There are three distinct muscle
antigens:

Anti-AChR
adult-type)

(alpha3-type

and

Although the mechanism of antibody


penetration is not known, previous
studies have shown that the autoantibodies in RMS affect the contractile
machinery of myofibres resulting in
mechanical sensitivity and instability.

Associated neoplasm

Thymoma

Associated disorders

Myasthenia gravis: rippling muscles may precede this disorder


Acquired neuromyotonia

Rule out

Hereditary rippling muscle syndromes


o dominant or recessive (genes
RMD1 and CAV3)
o quite similar features to those
of the sporadic disorder

Treatment
Immunosuppression: Prednisone or
Azathioprine
Benefit appears to set in over 2 to 4
months
Note: Pyridostigmine may exacerbate this disorder.

Selected references
1.
2.

3.

Ansevin CF, Agamanolis DP. Rippling muscles and myasthenia gravis with rippling muscles. Arch
Neurol 1996; 53 (2): 197-199.
Walker GR, Watkins T, Ansevin CF. Identification of autoantibodies associated with rippling
muscles and myasthenia gravis that recognize skeletal muscle proteins: possible relationship of
antigens and stretch-activated ion channels. Biochem Biophys Res Commun 1999; 264 (2): 430435.
Vernino S, Auger RG, Emslie-Smith AM, Harper CM, Lennon VA. Myasthenia, thymoma,
presynaptic antibodies, and a continuum of neuromuscular hyperexcitability. Neurology 1999; 53
(6):1233-1233.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

4.
5.
6.
7.

Vermino S, Lennon VA. Ion channel and striational antibodies define a continuum of autoimmune
neuromuscular hyperexcitability. Muscle Nerve 2002; 26 (5): 702-707.
Ashok MS, Day JW. Autoimmune rippling muscle. Neurology 2003; 61 (6): 869-870.
Watkins TC, Zelinka LM, Kesic M, Ansevin CF, Walker GR. Identification of skeletal muscle
autoantigens by expression library screening using sera from autoimmune rippling muscle disease
(ARMD) patients. J Cell Biochem 2006; 99 (1): 79-87.
Zelinka L, McCann S, Budde J, Sethi S, Guidos M, Giles R, Walker GR. Characterization of the in
vitro expressed autoimmune rippling muscle disease immunogenic domain of human titin encoded
by TTN exons 248-249. Biochem Biophys Res Commun 2011;411 (3): 501-5.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Symptomatic overview
Paraneoplastic ataxia
Paraneoplastic ataxia:
For specific features, please see the following:
Paraneoplastic cerebellar degeneration (PCD), including a comprehensive
Table
Paraneoplastic encephalomyelitis (PEM)
Paraneoplastic opsoclonus/myoclonus (POM): in adults, anti-Ri syndrome

Paraneoplastic epilepsy
Paraneoplastic epilepsy:
For specific features, please see the following:
Paraneoplastic limbic encephalitis (PLE)
Paraneoplastic sensory neuropathy (SSN, PSN)
Morvans fibrillary chorea
Opsoclonus / myoclonus: adults
Opsoclonus / myoclonus: Ri (ANNA2, NOVA1)
syndrome
Stiff-person syndrome (SPS)
Autoimmune encephalitis and epileptic seizures
In summary: recent studies in the field of paraneoplastic syndromes and
autoimmune encephalitides provide several clues that suggest the immune
aetiology of some types of epileptic disorders, including the acute presentation of
symptoms, the frequent detection of CSF pleocytosis and oligoclonal bands in the
context of negative viral studies, and the detection of CSF antibodies reacting
with the neuropil of hippocampus and the cell surface of neurons.
These disorders can be divided into limbic and cortical extralimbic encephalitides
and may have paraneoplastic or non-paraneoplastic aetiology.
Paraneoplastic autoimmune encephalitis with epilepsy
While there is strong evidence that the
first
four
immune
responses
are
Anti-Hu
mediated by cytotoxic T-cells responses,
Anti-CV2 (CRMP5)
there
are
studies
indicating
that
Anti-Ta (Ma2)
amphiphysin antibodies may be directly
Anti-Ri
Anti-Amphiphysin
pathogenic. Of these five immune
responses, the anti-Hu antibodies are
those most frequently described with seizures, epilepsia partialis continua, and
status epilepticus. The underlying tumours are small-cell lung cancer (all
antibodies), breast cancer (anti-Ri), germ-cell tumours of the testis (Ta/Ma2),
and thymoma (CV2/CRMP5). With the exception of the encephalitis associated
with Ta/Ma2 antibodies, in which approximately 30% of patients respond to
The associated antibodies include

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tumour removal and immunotherapy, the other disorders are rarely treatmentresponsive.
Autoimmune encephalitides that are not strictly paraneoplastic
In a context of autoimmune
The associated antibodies include
encephalitides, there is an
Extracellular
expanding group of that may
Anti-LGI1 (anti-VGKC)
Yes
occur with or without tumour
Anti-NMDAR
Yes
association, depending on the
Anti-AMPAR
Yes
type of antibody. A frequent
Anti- GABBR1
Yes
feature
of
these
immune
Anti-D1, anti-D2, anti-lyso-GM1
Yes
responses (except for GAD
Anti-GAD
No
anti-Alpha-enolase (ENO1)
No
antibodies and anti-ENO1) is
that the autoantigens are A finding of antibodies to extracellular epitopes would
a
disorder
as
autoimmune
synaptic
extracellular
and
therefore classify
encephalopathy
accessible
to
circulating
antibodies. These antigens include the excitatory glutamatergic receptors (NMDA,
AMPA), the inhibitory GABA (B) receptor (GABBR1), and the recently reported
true target antigens (LGI1 and CASPR2) of antibodies previously attributed to
voltage-gated potassium channels (VGKC). GAD antibodies usually associate with
non-paraneoplastic stiff-person syndrome and cerebellar dysfunction, but there
are increasing number of reports showing that these antibodies also occur with
subtypes of limbic encephalitis and refractory epilepsy. Antibodies to the NR1
subunit of the NMDAR associate with a characteristic syndrome that presents with
behavioural change or psychosis and usually progresses to a decline of the level
of consciousness, catatonia, seizures, dyskinesias, autonomic instability, and
frequent hypoventilation. AMPA receptor and GABA(B) receptor antibodies
associate with a clinical picture of limbic encephalitis, with early and prominent
seizures in the case of GABA(B) receptor antibodies. Recent reports indicate that
LGI1, a secreted neuronal protein, is the target antigen of limbic encephalitis
previously attributed to VGKC. Interestingly, this disorder associates with
frequent seizures (~80% of the patients) along with hyponatraemia. Moreover,
mutations of LGI1 are the cause of autosomal dominant partial epilepsy with
auditory features (ADPEAF), also called autosomal dominant lateral temporal lobe
epilepsy. In contrast, CASPR2, a protein that is expressed in brain and peripheral
nerve, clustering the VGKC at the juxtaparanodal regions of myelinated axons is
the target antigen of encephalitis and peripheral nerve hyperexcitability that may
result in Morvans syndrome.
Anti-D1, anti-D2, anti-lyso-GM1 are findings related to the post-streptococcal
neurological syndrome.
Anti-Alpha-enolase (ENO1) is associated with Hashimotos encephalitis and
autoimmune thyroiditis.
Prompt recognition of all the disorders associated with antibodies
against cell surface antigens is important
They may also affect children and young adults (typical of anti-NMDAR
encephalitis)
They are responsive to immunotherapy and/or treatment of the tumour when
appropriate
As a contrast, anti-GAD associated encephalitis is less treatment-responsive

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Paraneoplastic extrapyramidal disorders


Paraneoplastic extrapyramidal disorders:
For specific features, please see the following:
Paraneoplastic brainstem encephalitis (as a part of PEM)
Paraneoplastic cerebellar syndrome: anti-CV2/CRMP5 syndrome
Paraneoplastic choreo-athetosis (anti-CV2/CRMP5, anti-Hu)
Stiff-person syndrome (SPS)
Stiff-person syndrome, variants: suggestive features

Paraneoplastic pain
Paraneoplastic pain
For specific features, please see the following:
Stiff-person syndrome (SPS)
Paraneoplastic sensory neuronopathy (SSN, PSN)
Paraneoplastic sensory-motor neuropathy

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Maternal autoantibodies
and passive transfer in humans
Reports of vertical transmission of cancer are exceptionally rare, although maternal cells do reach the foetus
and cancer occurs in nearly one in 1000 pregnant women.
Malignant melanoma is the best-known example of a cancer that can metastasize to the foetus. Another example is
transfer to the foetus of an aggressive natural-killer-cell
lymphoma in the mother, with fatal consequences to the
infant.
It is conceivable that T-cell-mediated autoimmunity is transferable, since maternal cells may be a feature of the umbilical cord bloodstream. In theory, all autoimmune disorders, fulfilling the criteria of being antibody-mediated (Table 1),
may also occur because of passive transfer from a mother to an unborn child,
possibly leading to foetal or neonatal disorders. Another mechanism may be that
neoplasms express antigens that are cross reacting exclusively with structures of
the foetus and that later on are replaced by adult ones (for example AChRs of the
embryonic- and adult-types). In such cases, provoked antibodies may be beneficial to the mother and but potentially detrimental to the offspring.
Either such transferred PNS may resemble those of the mother or they may differ
quite substantially (Table 8), since the infant is under development. Moreover,
the severity of such a disorder may vary from transient neonatal ones, often both
self-limiting and self-repairing, over various malformations, and maybe even to
severe and permanent defects of the nervous system. The worst-case scenario is
fatalities.
leukaemias, Hodgkins disease, malignant monoclonal gammopathies,
Table 11: Foetal exposure to materetc. Moreover, women beyond the
nal autoantibodies
normal age of fertility or having reExamples
covered from a cancer are increasPNS resembling that of
ingly seeking medical assistance to
1 the mother
become pregnant.
Neonatal MG
2

Deformities

Acquired arthrogryposis
multiplex

Malformations
3

Skeletal & lung dysplasia

Neuro-developmental dis4 orders

Autism
Psychomotor retardation

General comments
Within a context of PNSs, such diseases are only potentially hazardous
to the offspring if they set in during
the period of fertility. The good bearing is that many cancers are unfortunate incidents happening later in life.
However, this argument is not valid
to thymomas, breast cancer, various

Clear messages of warning

Recurrent stillbirth
A sibling with deformities or malformations

Paraneoplastic myasthenia gravis


In thymoma-MG (occurring in about
10% of all myasthenics), the neoplasm is associated with a broad diversity of autoantibodies, some of
which may cause adverse pathology
to an unborn child and at the same
time be of benefit to the mother.
The following onconeural antibodies
are associated with thymomas:
o Anti-AChR (nicotinic adult-type)
o Anti-AChR (nicotinic foetal-type)

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Anti-AChR (nicotinic alpha3-type,


ganglionic autonomic)

o
o
o
o
o
o

Anti-vg-K channels
Anti-Titin
Anti-RyR1
Anti-CV2
Anti-GAD
Anti-Hu

Other disorders
A variety of other autoantibodies
may also be a feature, but it is beyond the scope here to elaborate
more on such topics. There are indeed publications suggesting that
maternal antibodies are responsible
for foetal deformities or other congenital disease. It has also been
suggested that some developmental
disorders (e.g. autism) may be attributable to maternal antibodies;
see the puzzling case history below.
Anti-brain antibodies and autism
spectrum of disorders (ASD)
The underlying etiology for autism
remains unknown, although genetic
and environmental factors, including
in utero environmental factors, are
thought to be involved.
There is mounting evidence that
maternal antibodies can target the
fetal brain. Several studies have
identified the presence of antibodies
that bind to human fetal brain tissue
in mothers with an ASD child. When
anti-brain antibodies from mothers of
an ASD child are administered to
pregnant mice or pregnant monkeys,
the offspring exhibit behavioral
alterations akin to those seen in ASD
children.
As reported (Brimberg et al. 2013),
several studies have linked maternal
infections or inflammation during
pregnancy to the development of
ASD in offspring, suggesting that
activation of the maternal immune
system might lead to an increased
risk of having a child with ASD.
To further examine ties between
anti-brain antibodies, autism, and
autoimmunity, Dr. Diamond and
colleagues screened plasma of 2431

mothers of an ASD child and 653


unselected women of childbearing
age for anti-brain antibodies.
Using immunohistology on mouse
brain, they found that mothers of an
ASD child were nearly 4 times more
likely to harbor anti-brain antibodies
than
unselected
women
of
childbearing age (P < .00001).
In total, 10.7 % of the plasma of
mothers of an ASD child (260/2431)
displayed strong reactivity to mouse
brain antigens compared with 2.6%
of the plasma from control women
(17/653). Only 28 % of plasma of
mothers of an ASD child showed no
binding compared with 64.7 % of
plasma from control women.
The
researchers
analyzed
an
additional 318 plasma samples of
mothers of an ASD child from a
separate cohort and found that 28
(8.8 %) displayed strong reactivity to
mouse brain antigens. Only 22.6 %
(72 samples) showed no binding.

Risk of passive transfer of


PNSs
Up until now, the publications exclusively associate such foetal disorders
with transplacental transfer of autoantibodies in relation to myasthenia
gravis. In view of the current data
therefore, it appears that the overall
risk of transferred PNSs is quite low.

Awareness is the key word, since


preventive therapy is often possible.
This may even be quite successful,
see Therapeutic considerations.
There is more specific information
about how to handle the various
PNSs in the sections addressing particular such disorders.

A puzzling case history


Possibly passive transfer of ataxia
and developmental disorder:
A mother of three children:
The first one normal
The second with autism
The third with a severe specif-

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ic language disorder
To investigate this case for passively
transferable factors, maternal serum
was injected into pregnant mice.
Subsequently, the mouse offspring
exhibited altered motor coordination,
and MRIs showed cerebellar signs.
This case history started in around
1998. However, there were no findings of any cancer during a follow-up
period of five years. Anyhow, it is
tempting to speculate in terms of
transferred autoimmunity provoked
by a neoplasm, which has escaped
detection.

Disorders
A. Myasthenia gravis
The finding of autoantibodies specific
to foetal AChR is frequent in MG patients. For further details, please see
Risk of passive transfer MG in
the chapter Paraneoplastic SPMG
(thymoma).

Summary of topics related


to myasthenia gravis
Embryonic-type AChR
The AChRs exist in a foetal and adult
form differing only by a gamma subunit versus an epsilon one.
Nicotinic acetylcholine
receptors

Embryonic- and adulttypes

Note the presence of either a


gamma-subunit or an epsilonsubunit

Location of embryonic-type AChR


Expressed during development
During the last weeks of intrauterine life in humans, adult-type
AChR replaces it.
Later in life, it is only expressed
At low levels in adult human
muscle
At multiply innervated extraocular muscle fibres
As upregulated receptor in denervated muscle
In the myoid cells of the thymus, highlighting the hazards related to thymomas

B. Transient neonatal MG
This disorder is well recognized and
due to transfer of maternal antibodies. Altogether, this form of MG is an
observation in about 20% of infants
born to myasthenic mothers.
C. Acquired arthrogryposis multiplex (AAM)
Any paralyzing agent can cause AAM,
including anti-AChR antibodies that
limit foetal movement, even to an
extent of abolishing the AChR function. Joints cannot develop normally,
unless they are regularly in i motion.
Foetal movements are mandatory
not just a sign of life.
Most infants with multiple congenital
bent joints are diagnosed with a hereditary disorder or a disease completely unrelated to autoimmunity.
Only about 2% of AAM is associated
with autoantibodies.
In a myasthenia gravis context, recurrent AAM is associated with antiAChR to the receptor of foetaltype. In some of these cases, the
mother did not show any evidence of
MG herself, but suffered recurrent

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foetal loss, stillbirth or early termination. Preventive treatment during a


pregnancy is an option, and the outcome may be a perfectly healthy
child.

concurrent thymomas has not been


reported in these studies. In Denmark, this paraneoplastic form of MG
accounts for about 10% of all myasthenics.

In Norway, it appears that about 2%


of infants to MG mothers are born
with severe skeletal anomalies, and
all these children have died. To this
percentage must be added all the
less severe cases with only a few affected joints. The frequency of co-

Conclusion
If a thymoma does not appear to coexist in a female diagnosed with seropositive MG and planning a pregnancy, then consider a new search
for this neoplasm.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Selected references:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.

19.
20.
21.
22.
23.
24.
25.
26.
27.

Drachman DB, Coulombre A. Experimental clubfoot and arthrogryposis multiplex congenita.


Lancet 1962; 2: 523-526.
Shepard MK. Arthrogryposis multiplex congenita in sibs. Birth Defects 1971; 7 (2): 127.
Keesey J, Lindstrom J, Cokely H. Anti-acetylcholine receptor antibody in neonatal myasthenia
gravis [letter]. N Engl J Med 1977; 296 (1): 55.
Olanow CW, Lane RJ, Hull Jr KL, Roses AD. Neonatal myasthenia gravis in the infant of an
asymptomatic thymectomized mother. Can J Neurol Sci 1982; 9 (2): 85-87.
Lefvert AK, Osterman PO. Newborn infants to myasthenic mothers: A clinical study and an
investigation of acetylcholine receptor antibodies in 17 children. Neurology 1983; 33 (2): 133-138.
Morel E, Eymard B, Vernet-der-Garabedian B, Pannier C, Dulac O, Bach, JF. Neonatal myasthenia
gravis: a new clinical and immunologic appraisal on 30 cases. Neurology 1988; 38 (1): 138-142.
Vogel H, Halpert D, Horoupian DS. Hypoplasia of posterior spinal roots and dorsal spinal tracts
with arthrogryposis multiplex congenita. Acta Neuropathol 1990; 79 (6): 692-696.
Stoll C, Ehret Mentre MC, Treisser A, Tranchant C. Prenatal diagnosis of congenital myasthenia
with arthrogryposis in a myasthenic mother. Prenat Diagn 1991; 11 (1): 17-22.
Giacoia GP. Transplacentally transmitted autoimmune disorders of the fetus and newborn.
Pathogenic considerations. South Med J 1992; 85 (2): 139-145.
Papazian O. Transient neonatal myasthenia gravis. J Child Neurol 1992; 7 (2): 135-141.
Dinger J, Prager, B. Arthrogryposis multiplex in a newborn of a myasthenic mother - case report
and literature. Neuromuscul Disord 1993; 3 (4): 335-339.
Vernet der Garabedian B, Lacokova M, Eymard B, Morel E, Faltin M, Zajac J, Sadovsky O,
Dommergues M, Tripon P, Bach JF. Association of neonatal myasthenia gravis with antibodies
against the fetal acetylcholine receptor. J Clin Invest 1994; 94 (2): 555-559.
Vincent A, Newland C, Brueton L, Beeson D, Riemersma S, Huson SM, Newsom-Davis J.
Arthrogryposis multiplex congenita with maternal autoantibodies specific for a fetal antigen.
Lancet 1995; 346 (8966): 24-25.
Barnes PR, Kanabar DJ, Brueton L, Newsom-Davis J, Huson SM, Mann NP, Hilton Jones D.
Recurrent congenital arthrogryposis leading to a diagnosis of myasthenia gravis in an initially
asymptomatic mother. Neuromuscul Disord 1995; 5 (1): 59-65.
Riemersma S, Vincent A, Beeson D, Newland C, Hawke S, Vernet der Garabedian B, Eymard B,
Newsom-Davis J. Association of arthrogryposis multiplex congenita with maternal antibodies
inhibiting fetal acetylcholine receptor. J Clin Invest 1996; 98 (10): 2358-2863.
Gordon N. Arthrogryposis multiplex congenita. Brain Dev 1998; 20 (7): 507-11.
Silberstein EP, Kakulas BA. Arthrogryposis multiplex congenita in Western Australia. J Paediatr
Child health 1998; 34 (6): 518-23.
Vincent A, Jacobson L, Plested P, Polizzi A, Tang T, Riemersha S, Newland C, Chorazian S, Farrar J,
MacLennan C, Wilcox N,Beeson D, Newsom-Davis J. Antibodies affecting ion channel function in
acquired neuromyotonia, in seropositive and seronegative myasthenia gravis, and in antibodymediated arthrogryposis multiplex congenita. Ann N Y Acad Sci 1998; 841: 482-496.
Jacobson L, Polizzi A, Moriss-Kay G, Vincent A. Plasma from human mothers of fetuses with
severe arthrogryposis multiplex congenita causes deformities in mice. J Clin Invest 1999; 103
(7): 1031-1038.
Vincent A, Beeson D, Lang B. Molecular targets for autoimmune and genetic disorders of
neuromuscular transmission. Eur J Biochem 2000; 267 (23): 6717-6728.
Dalton P, Deacon R, Blamire A, Pike M, McKinlay I, Stein J, Styles P, Vincent A. Maternal neuronal
antibodies associated with autism and language disorder. Ann Neurol 2003; 53 (4): 533-537.
Hoff JM, Daltveit AK, Gilhus NE. Arthrogryposis multiplex congenita - a rare fetal condition caused by maternal myasthenia gravis. Acta Neurol Scand Suppl 2006; 183: 26-27.
Fraterman S, Khurana TS, Rubinstein NA. Identification of acetylcholine receptor subunits
differentially expressed in singly and multiply innervated fibers of extraocular muscles. Invest
Opthalmol Vis Sci 2006; 47 (9): 3828-3834.
Dalton P, Clover L, Wallerstein R, Stewart H, Genzel-Boroviczeny O, Dean A, Vincent A. Fetal
Arthrogryposis and maternal antibodies. Neuromuscul Disord 2006; 16 (8): 481-491.
Brimberg L, Sadiq A, Gregersen PK, Diamond B. Brain-reactive IgG correlates with autoimmunity
in mothers of a child with an autism spectrum disorder. Molecular Psychiatry 2013; 18: 11711177
Braunschweig D, Krakowiak P, Duncanson P, Boyce R, HansenRL, Ashwood P, Hertz-Picciotto I,
Pessah IN, Van de Water J. Autism-specific maternal autoantibodies recognize critical proteins in
developing brain. Translational Psychiatry 2013; 3: e277
Bauman MD, Losif A M, Ashwood P, Braunschweig D, Lee A, Schumann CM, Van de Water J,
Amaral DG. Maternal antibodies from mothers of children with autism alter brain growth and
social behavior development in the rhesus monkey. Translational Psychiatry 2013; 3: e278

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Autoantibodies associated with PNS


For a listing of myositis-specific and overlap antibodies, please see paraneoplastic myopathies

Table 12: alphabetical listing of some paraneoplastic antibodies, also including


some that are not strictly paraneoplastic
Abbreviated
antibody name

Antibody
Alias; Anti-

Anti-AChR (adult-type)

nAChR (adult)

Anti-AChR (alpha3-type)

nAChR (3)

Anti-AChR (foetal-type)

nAChR (foetal)

Anti-AChR (M1-type)

mAChR (M1)

Anti-AGNA

SOX1

Anti-Adenylate-Kinase 5

AK5

Anti-Alpha-enolase

ENO1

Anti-AMPAR

GluR1/R2

ANNA3

neuronuclear antigen 3

Anti-ARHGAP26/GRAF)

RhoGTPase-activating protein 26

Anti-BRSK2

BR serine/threonine kinase 2

Anti-vg-Ca-channel
(P/Q-type)
Anti-vg-Ca-channel (N type)

P/Q-VGCC
N-VGCC

carbonic anhydrase-related protein 8

Anti-CASPR2

contactin-associated protein-2
CRMP5,
POP66

Anti-Gephyrin
Anti-mGluR1

GAD67,
GAD65
mGluR1

Anti-HMGCR

voltage-gated calcium channel of P/Qtype


voltage-gated calcium channel of Ntype

Anti-CARP8

Anti-GAD

Anti-Hu

Anti-vg-K-channel

Anti-LGI1
Anti-Ma1
Anti-Neurofilaments
Anti-NMDAR
Anti-PCA2
Anti-PKC gamma
Anti-Pyridoxal
phosphatase
Anti-Recoverin

alpha-enolase 1

Anti-Amphiphysin

Anti-EFA6A

nicotinic acetylcholine receptor of


adult-type
nicotinic acetylcholine receptor of
alpha3-type
nicotinic acetylcholine receptor of
embryonic-type
muscarinic acetylcholine receptor of
M1-type
SRY (sex determining region Y)-box
1, glial nuclear

-amino-3-hydroxyl-5-methyl-4isoxazole-propionate receptor
amphiphysin

Anti-CV2

Full name of antigen

Anti-Ri
Anti-RyR1

Hull, ANNA1, HuC,


HuC, HEL-N1
VGPC, VGKC, Kv1.1,
KV1.2, KV1.6

oligodendrocyte proteins, collapsin


response mediator proteins 5,
paraneoplastic oligodendrocyte
cytoplasmatic protein 66
Exchange factor for ARF6
glutamate decarboxylase I + II or
glutamic acid decarboxylase 67 and
65
metabotropic glutamate receptor 1
3-hydroxy-3-methylglutaryl-CoA reductase
neuronuclear antigen 1
voltage-gated K-channel of various
subtypes
leucine-rich, glioma inactivated 1
membrane reactive antigen 1
N-methyl-D-aspartate receptor
Purkinje cell antigen 2
protein kinase C gamma
pyridoxal phosphatase

Richards, ANNA2,
NOVA1, NOVA2

recoverin
neuronuclear antigen 2,
neurooncological ventral antigen 1and
2
ryanodine receptor 1

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Anti-Striated muscle

Anti-Ta

Ma2/PNMA2

Anti-TIF
Anti-Titin

Anti-Tr

PCA-Tr, Trotter, DNER

Anti-TULIP-1
Anti-UBE2E1

TULP1

Anti-Yo
( CDR2L)
Anti-ZIC4

Young, PCA1, CDR1


(CDR34), CDR2, CDR2L
(CDR62-1, CDR62-2),
CDR3, PCD17-SN, CZF

tumour-associated antigen
membrane reactive antigen 2
transcriptional intermediary factor 1gamma
titin
delta and notch-like epidermal growth
factor-related receptor
tubby-like protein 1
ubiquitin-conjugating enzyme E2E 1
Purkinje cell antigen 1, cerebellar
degeneration related protein 34 or 62
zinc finger protein 4

= most frequent; = extracellular (plasma membrane) location

In principle, there are at least seven categories of


autoantibodies to be recognized
1. Neuronal nuclear or nucleolar
o Hu (ANNA1), Ri (ANNA2), ANNA3, Ta (Ma2), Ma1, Zic4
2. Neuronal or muscular cytoplasmatic
o Yo (PCA1), PCA-Tr, PCA2, Gephyrin, PKC gamma, BR-Serine /
Theonine kinase 2, Adenylate-Kinase 5, CARP8, ENO1, UBE2E1,
striational (Titin, RyR1, etc.)
3. Glial
o CV2 (CRMP-5, POP66, oligodendrocytes), Bergman (AGNA, SOX-1),
astrocytes (AQP4), ENO1
4. Presynaptic vesicles
o GAD, Amphiphysin
5. Voltage- or ligand-gated CSF or plasma membrane structures
o Ionotropic channels and receptors
AChR (adult, foetal, alpha3, M1-types), NMDAR (NR1, NR2), AMPAR
(GluR1, GluR2), calcium- & potassium-channels, GlyR-alpha1
o Metabotropic channels and receptors
D1, D2, GABABR1, mGluR1, mGluR5
6. Other CSF membrane structures including accessory proteins
o AQP4, MuSK, CASPR2, gangliosides including lyso-GM1, ENO1
7. Synaptic proteins
o LGI1
The group of disorders associated with antibodies to cell surface or synaptic proteins appears to be characterised by a more promising outcome
of therapy as opposed to those associated with autoantibodies to intracellular
structures.

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CASPR2

vgKCcompl
ex
LGI1

D1, D2

GABABR1

GlyR 1

AMPAR

NMDAR

Lyso-GM1

AGNA (SOX1), Bergman

AQP4, astrpcytes

GAD (65, 67)

Amphiphysin

ENO1

Ma1, Zic4, Gephyrin

Ta (Ma2)

Tr (PCA2)

CV2 (CRMP5), POP66


oligodendrocytes
Yo (PCA1)

ANNA3

Ri (ANNA2)

Hu (ANNA1)
Nuclear

Vesicles

x x x x x
x x

Membrane

Cytoplasmatic

Channels & receptors


Tropic
Iono
Metabo

x x x x x x

Synaptic

Intracellular

x x x

Glial

Extracellular

Neuronal

Autoantibodies

Various currently known autoantibodies in association with CNS disorders

x x
x

x x

Co-occurrence of autoantibodies
Autoantibody

Anti-AMPAR
Anti-GABABR1
Anti-GAD
Anti-GlyRalpha1
Anti-CV2 (CRMP5)
Anti-VGCC
AGNA (anti-SOX1)
Anti-BRSK2
Anti-Amphiphysin
Anti-Ri
Anti-Zic4
Anti-thyreoglobulin
Anti-thyroid peroxidase
Anti-TSH receptor
Anti-M
Anti-dsDNA
ANA
Anti-Cardiolipin

Anti-AMPAR

Anti-GABABR1

Anti-GAD
X
X

Anti-ENO1

X
X

X
X
X

X
X
X

X
X
X
X

X
X
X

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Paraneoplastic antibodies targeting the nervous


system or striated muscles versus neoplasms
Abbreviations: AAS (acquired autonomic neuropathy, PAN; LEMS
(Lambert-Eaton myasthenic syndrome); MAR (melanoma-associated retinopathy); MG (myasthenia gravis); NMJ (neuromuscular junction), PCD
(paraneoplastic cerebellar degeneration); PEM (paraneoplastic encephalomyelitis); PLE (paraneoplastic limbic encephalitis); POM (paraneoplastic opsoclonus / myoclonus); PSN (paraneoplastic sensory neuronopathy, also SSN); SCLC (smallcell lung cancer); SPS (stiff-person syndrome)

Anti-AChR
There are different types of ligandgated acetylcholine receptors. With a
postsynaptic location at the NMJs,
there are the nicotinic adult- & foetal-types (paraneoplastic MG) and
presynaptic, the muscarinic AChRs of
M1-type (LEMS). At ganglia, these
receptors are of alpha3-type (autonomic neuropathy). There are no
PNS associated with AChRs of the
CNS, which also differ quite substantially from those mentioned above.
The nicotinic AChRs function as regulated ion channels, whereas the muscarinic AChRs activate other ionic
channels through a second messenger cascade.
The most frequent associated neoplasms are thymoma (MG, AAS) and
SCLC (LEMS, AAS).
Anti-AGNA (SOX1, glial nuclear)
The target is nuclear structures of
the Bergmann glia (anti glial nuclear
antibodies = AGNA) in the Purkinje
cell layer.
SOX1 (for Sex determining region Ybox 1) is a transcription factor in the
Sox protein family. SOX1 expression
is restricted to neuroectoderm in the
tetrapod embryo. SOX1 is involved in
early
central
nervous
system
development, where it is functionally
redundant with SOX3 and to a lesser
degree SOX2, and maintenance of
neural progenitor cell identity. SOX1
is expressed particularly in the
ventral striatum, and Sox1-deficient
mice have altered striatum.

PEM (limbic encephalitis) and maybe


PCD.
Anti-Alpha-enolase (ENO1)
This antibody is associated with
paraneoplastic retinopathy and Hashimoto's encephalopathy. The target
is the N-terminal region (amino terminal) of alpha-enolase. In a PNS
context, this protein is located in retinal ganglion cells and inner nuclear
layer cells.
The most frequent associated neoplasms are SCLC and melanoma
(MAR).
Anti-Adenylate Kinase 5 (AK5)
A few cases with limbic encephalitis
refractory to corticosteroids, IVIg
and plasma exchange have been
reported.
Serum/CSF antibodies
reacted with the cytoplasm of
neurons. Probing of a hippocampal
cDNA library resulted in the isolation
of adenylate kinase 5 (AK5). Human
AK5-affinity
purified
antibodies
reproduced
the
neuronal
immunolabeling
of
patients'
antibodies.
Anti-AMPAR (GluR1, GluR2)
The target
is
the
-amino-3hydroxyl-5-methyl-4-isoxazolepropionate receptor (AMPAR, a glutamate receptor of the ionic type.)
The clinical features are limbic encephalitis with seizures and more.
The associated neoplasms are SCLC,
non-SCLC, thymoma and breast cancer.

These antibodies are a feature of


SCLC and the following PNS: LEMS,

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Anti-Amphiphysin
Amphiphysin is the predominant antigen in stiff-person syndrome, PEM
and other PNS. It is a neuronal protein - an adapter molecule - highly
concentrated in nerve terminals. This
presynaptic cytoplasmatic protein
(128 kDa) is located both in the CNS
and at the NMJs, and it is abundant.
Amphiphysin as well as dynamin and
synaptojanin all have a putative role
in synaptic vesicle recycling. The two
isoforms appears to act in concert as
a heterodimer.

Such autoantibodies are associated


with the LEMS and most frequently
SCLC.

The most frequent associated neoplasms are SCLC (PEM, PLE) and
breast cancer (SPS, POM).

Anti-CASPR2
The target is contactin-associated
protein-2, a part of some votagegated potassium channel complex.

ANNA3
The neuronuclear antigen 3 (170
kDa) is located at the nuclei of
Purkinje cells, and accordingly this
autoantibody is associated with
paraneoplastic cerebellar degeneration.
The most frequent associated neoplasm is SCLC.
Anti-ARHGAP26/GRAF
The antigen is RhoGTPase-activating
protein 26.
This onconeural antibody is associated with cerebellar ataxia and ovarian
cancer.
Anti-BRSK2
The antigen is BR serine/threonine
kinase 2, a protein also known as
SAD1B kinase, and preferentially expressed in the brain and testis and
implicated in neuronal polarization as
well as synaptic development.
This onconeural antibody is associated with limbic encephalitis and SCLC.
Anti-vg-Ca-channel
There are at least five types of voltage-gated calcium-channels (all 64
kDa): N, L, P/Q, R, and T. Only the
Ca-channel of P/Q-type is of diagnostic relevance in PNS, and in this context, it is located at the presynaptic
membrane of NMJs.

Anti-CARP8
The carbonic anhydrase-related protein 8 is located in the Purkinje cell
cytoplasm & dendrites and at the lateral nuclei of thalamus. The typical
finding is a pure paraneoplastic cerebellar syndrome (PCD).
The most frequent associated neoplasm is melanoma.

Mainly, the expression of CASPR2 is


at myelinated nerves confined to the
axon at the juxtaparanodal region
and at some isolated paranodal loops.
In
the
juxtaparanodal
region,
CASPR2 precisely co-localized with
Shaker-like
potassium
channels.
CASPR2 specifically associated with
Kv1.1, Kv1.2, and their Kv-beta-2
subunit. This association involves the
C-terminal region of CASPR2. It has
been suggested that CASPR2 may
stabilize the localization of potassium
channels in the juxtaparanodal region, and that CASPR2 family members may play a role in the local differentiation of the axon into distinct
functional subdomains.
The typical clinical diagnoses are:
aquired neuromyoyonia (Morvans
syndrome) or limbic encephalitis.
The most frequent associated neoplasm is thymoma.
Anti-CV2
(CRMP5,
CRMP2-4,
POP66
There are more than 11 associated
PNS with this target, which belongs
to a family of ~66 kDa CNS proteins.
One of the names is CRMP for collapsin response mediator proteins.
The CRMP family is composed of five
cytosolic phosphoproteins and highly
expressed throughout the brain during development. CRMP5 is the main

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antigen recognized by anti-CV2 antibodies, whereas the recognition of


other members is inconsistent, such
as CRMP2, CRMP3 or CRMP4. Another name for this target is paraneoplastic oligodendrocyte cytoplasmatic protein 66. It is co-associated
with amphiphysin. It appears to be
directly or indirectly associated with
neuron survival. CV2 is a cytoplasmatic antigen of oligodendrocytes,
located in the cerebellum, basal ganglia, brainstem, spinal cord & optic
chiasm.
The most frequent associated neoplasms are SCLC (PEM, PLE, SSN,
PCD (thymoma), POM, chorea, and
optic neuritis.
Anti-EFA6A (Pleckstrin and Sec7
domain protein)
ADP-ribosylation factor 6 (ARF6) is a
small GTPase known to regulate actin
remodelling and membrane traffic.
Exchange factor for ARF6 (EFA6A) is
a protein that interacts with a member of the two-pore-domain potassium channel family and is involved in
the regulation of the dendritic development of hippocampal neurons.
The most frequent associated neoplasm is ovarian teratoma. PEM with
psychiatric symptoms, seizures and
central hypoventilation are typical
clinical features.
Anti-GAD (GAD65, GAD67)
In mammals, GAD (glutamate decarboxylase) exists in two isoforms encoded by two different genes, Gad-II
(GAD65, 585 amino acids) and Gad-I
(GAD67, 594 amino acids) and with
molecular weights of 65 and 67 kDa,
respectively. The amino acid sequence of both is with about 65 %
homology (primarily in middle and Cterminal regions). The central region,
which contains the decarboxylase
catalytic domain, appears to be highly immunoreactive.
Exclusively, the expression of GAD65
is at GABA-ergic nerve terminals,
which co-localizes with Amphiphysin
and CV2 (CRMP5) while GAD67 is

spread evenly throughout the cells.


This difference is thought to reflect a
functional difference; GAD67 synthesizes GABA for neuron activity unrelated to neurotransmission, such as
synaptogenesis and protection from
neural injury. This function requires
widespread, ubiquitous presence of
GABA. GAD65, however, synthesizes
GABA for neuro-transmission, and
therefore is only necessary at nerve
terminals and synapses.
Anti-GAD65 is also a feature of diabetes. Upon incubation of nerve cells
with serum or CSF from diabetics,
there is no inhibition of the synthesis
of GABA, whereas this happens with
serum or CSF from PNS patients, and
even in a dose-dependent manner.
Accordingly, the anti-GAD appears to
recognize different epitopes.
The antibodies are associated with
SPS and the following neoplasms:
breast, SCLC and thymoma.
Anti-Gephyrin
The target is a protein, which is associated with inhibitory neurotransmitter receptors. It is a bi-functional
protein and essential for both synaptic clustering of inhibitory neurotransmitter receptors in the CNS and
the biosynthesis of the molybdenum
cofactor in peripheral tissues. It copurifies with the inhibitory glycine receptor. Gephyrin is responsible for
clustering GlyRs to postsynaptic sites
by linking the GlyR subunit to the
cytoskeleton. Moreover, in all brain
areas containing synapses, there is a
density of this protein.
The antibody is associated with the
SPS, multiple myeloma and undifferentiated neoplasm.
Anti-HMGCR (alias 3-hydroxy-3methylglutaryl-CoA reductase)
Normally in mammalian cells this enzyme is suppressed by cholesterol
derived from the internalization and
degradation of low density lipoprotein (LDL) via the LDL receptor.
Competitive inhibitors of the reduc-

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tase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL
and lowers the plasma concentration
of cholesterol, an important determinant of atherosclerosis.

of the disease is the dorsal root ganglia, which has a robust expression
of four Hu homologues. In assays,
either recombinant full length Hu-D
sequence or peptide fragments are
used.

This autoantibody is associated with


acute necrotizing myopathy (polymyositis?); sporadic inclusion-body
myositis; polymyositis / dermatomyositis

Almost all cases of PEM with anti-Hu


antibodies are related to small-cell
lung carcinoma. The human Hu proteins are also abundant in most neuroblastomas. In fact, anti-Hu is the
most frequently encountered onconeural antibody.

Anti-mGluR1
The target is the metabotropic glutamate receptor 1 located as follows:
in the cerebral cortex (superficial
layer); the cerebellum (Purkinje cell
bodies & spines); glomeruli of olfactory bulb (neurons & neurophils);
hippocampus; thalamus; superior
colliculus; spinal trigeminal nucleus.
These antibodies are a feature of
Hodgkins disease also exhibiting
PCD.
Anti-Hu (Hull, ANNA1)
Hull was the pioneer to find this antibody. The target is called neuronuclear antigen 1 (35-40 kDa), a structure of all neurons in both the CNS
and the peripheral nervous system.
These antibodies react with a group
of 35- to 40-kilodalton neuronal
RNA-binding proteins, including HuD,
PLE21/HuC, and Hel-N1. Nuclear and
cytoplasmic staining of CNS neurons
demonstrates the presence of these
antibodies. A ubiquitous protein,
HuR, is also an antigenic target. The
neuronal proteins are homologous to
the embryonic lethal abnormal visual
(ELAV) protein in Drosophila species.
Anti-Hu antibodies may alter the
production of these proteins, which
are essential for the development,
maturation, and maintenance of the
vertebrate nervous system. Intrathecal synthesis of anti-Hu antibodies
may represent an autoimmune crossreaction with neurologic tissue, triggered by a remote carcinoma.
In about 70% of patients with the
anti-Hu syndrome, the initial target

It is associated with the following


neoplasms: SCLC, breast, ovarian,
testicular, prostate, thymoma, neuroblastoma and more. Apart from
stiff-person syndrome, this antibody
is associated with all the other PNSs,
and in particular SSN & PEM. This
antibody may also be a finding in
primary lateral sclerosis (PLS), and
associated with adenocarcinoma in
gall bladder and duodenum.
Anti-vg-K-channel (VGKC, KV1.1,
KV1.2, KV1.6)
There is an abundance of voltagegated K-channel types. There are only three members of the Shakerrelated subfamily A, and which are
relevant to PNS: Kv1.1; Kv1.2; Kv1.6.
These channels are inward rectifiers.
Within a PNS context, such channels
have previously been reported to be
targets at limbic structures, basal
ganglia and at presynaptic MNJs.
Such channels are also located at
paranodes and internodes of peripheral nerves. CASPR2 and LGI1 are
accessory proteins of such potassium-channel, together forming complexes. It appears that in a PNS
context CASPR2 is the true target.
See anti-CASPR2
The associated neoplasms are SCLC
and thymoma.
Anti-LGI1 (Leucine-rich, glioma
inactivated 1)
It is a secreted synaptic protein,
which associates with VGKCs and

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AMPA receptors via the ADAM proteins.


LGI1 is a ligand for ADAM22 that
positively
regulates
synaptic
transmission mediated by AMPA-type
glutamate receptors. The molecular
function of ADAM22 is as a receptor,
and it is highly expressed in the
brain. ADAM23 can bind to LGI1, and
is also highly expressed in the brain,
prominently
in
the
amygdala,
caudate
nucleus,
hypothalamus,
thalamus,
cerebral
cortex
and
occipital
pole.
LGI1
regulates
voltage-gated potassium channels
assembled from KCNA1, KCNA4 and
KCNAB1. LGI1 slows down channel
inactivation by precluding channel
closure mediated by the KCNAB1
subunit.
Moreover, this protein appears to
play a role in the control of
neuroblastoma
cell
survival:
expression is reduced in low-grade
brain tumours and significantly
reduced or absent in malignant
gliomas
It is associated with the following
neoplasms: thyroid, lung, thymoma,
ovarian teratoma and more. The
paraneoplastic disorder is limbic encephalitis with seizures and hyponatriaemia.
Anti-Ma1
The name of this protein is membrane reactive antigen 1. It is a
combined 37 and 40 kDa neuronal
(subnucleus) & testicular germ cell
protein with homology to Ma2 (see
anti-Ta below).
The main features of anti-Ma syndromes are brainstem dysfunction
with EOM limitation, dysphagia, cerebellar disorders with ataxia of trunk
and extremities. In addition, sensory
loss and myokymia may be other
characteristics. The associated tumours are as follows: breast, lung
(large-cell) and colon.

Anti-Neurofilaments
The targets are neurofilament proteins of the perikaryal type, which
undergo
transformation
and
transport into the axonal type. Clinically, POM is the characteristic feature.
The most common associated neoplasms are SCLC and neuroblastoma.
Anti-NMDAR (NR1)
The target is the N-methyl-Daspartate receptor (NMDAR, a glutamate receptor of the ionic type.)
The NMDA receptor is distinct in that
it is both ligand-gated and voltagedependent. Activation of NMDA receptors results in opening of an ion
channel that is non-selective to cations. This allows flow of Na+ and
small amounts of Ca2+ ions into the
cell and K+ out of the cell. Presumably, calcium flux through NMDARs
plays a critical role in synaptic plasticity, a cellular mechanism for learning
and
memory.
N-methyl-Daspartate is the name of its specific
agonist.
The associated neoplasm is a teratoma, the most common tumour in
new-borns. Mature cystic teratomas
account for 10-20% of all ovarian
neoplasms. Not only are they the
most common ovarian germ cell tumour but also the most common
ovarian neoplasm in patients younger than 20 years. The incidence of all
testicular tumours in men is 2.1-2.5
per 100,000. Germ cell tumours represent 95% of testicular tumours after puberty, but pure benign teratomas of the testis are rare, accounting
for only 3-5% of germ cell tumours.
The incidence of all testicular tumours in pre-pubertal boys is 0.5-2
per 100,000, with mature teratomas
accounting for 14-27% of these tumours. Benign teratomas of the mediastinum are rare, representing 8%
of all tumours of this region.
Anti-NMDAR is associated with a particular type of limbic encephalitis
characterised by neuropsychiatric
features, troubled memory, seizures,

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dyskinesias,
dystonia,
decreases
consciousness, sleep disorder and
more (dyskinetic encephalitis lethargica).
Anti-PCA2
The antigen is a 280 kDa neuronspecific protein, located in the cytoplasm of Purkinje cell in soma & dendrites. Typically, the associated neoplasm is SCLC, also explaining that
these autoantibodies may co-exist
with anti-vg-Ca-channel (P/Q- & Ntype) and anti-AChR (of muscle &
neuronal type).
Clinically, anti-PCA2 is associated
with PCD. Attributable to the coexisting onconeural antibodies listed
above, PLE, LEMS, AAS and a motor
syndrome may also be present.
Anti-Protein kinase C gamma
(anti-PKC gamma)
Paraneoplastic cerebellar degeneration also occurs in patients with nonSCLC and without typical onconeural
antibodies - and is associated with
immune reactions against key proteins of the Purkinje cells such as
PCK gamma.
Anti-Pyridoxal phosphatase
Pyridoxal phosphatase is a coenzyme of vitamin B6 (pyridoxine).
The antigen is located at both the
central and the peripheral nervous
system. Deficiency of vitamin B6 is
usually associated with seizures and
sensory-motor neuropathy. A seropositive finding may be a feature of
about 9% of patients with lung cancer and of 7% with other neoplasms,
for example well-differentiated thyroid cancer and of autoimmune thyroid disease.
PNS associated with this antibody are
awaiting discovery.
Anti-Ri (Richards, ANNA2, NOVA1,
NOVA2)
Richards was the first to report the
finding of these antibodies. The
names of the targets are also neuronuclear antigen 2 and neurooncological ventral antigen 1. The

CNS antigens are either a 55-kDa


protein (Nova; RNA binding) or an
80-kDa protein. There are no such
targets in the peripheral nervous
system. The characteristic clinical
features are PCD or a movement disorder with myoclonus / opsoclonus,
triggered by visual fixation.
Frequently, other onconeural antibodies are co-existing. Therefore, a
variety of other PNS is associated:
encephalopathy, myelopathy, peripheral neuropathy (sensory-motor;
polyradiculopathy; cranial neuropathy: VI; VIII [deafness or tinnitus]),
laryngospasm, dystonia (jaw opening
or neck), LEMS, visual blurring, incontinence.
The typical associated neoplasms are
located at breast or lung (both SCLC
& non-SCLC).
Anti-Recoverin
The target is a 23-kDa photoreceptor
protein in the retina. The associated
neoplasms are SCLC and melanoma.
CAR is the clinical feature.
Anti-RyR1
The target is the ryanodine receptor
1 of striated muscles. The main immunogenic regions are epitopes at
the C-terminus (AA 5019-5038) and
at the C-terminus transmembrane
(AA 4997-5017) regions. These receptors function as calcium release
channels.
The autoantibodies are associated
with paraneoplastic MG (thymoma).
Moreover, they are a feature of nonparaneoplastic late-onset MG.
Anti-Striated muscle (unspecific)
Immunohistochemistry is the method
to detect such antibodies. Accordingly, unspecific binding of IgG to various epitopes of striated muscles is
the finding.
These autoantibodies are associated
with thymoma, paraneoplastic myasthenia gravis, and rippling muscle

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syndrome. See also anti-Titin and


anti-RyR1.
Anti-Ta (Ma2, PNMA2)
The target is tumour-associated antigen or membrane-reactive antigen 2.
It is a 41.5-kDa protein located in
the subnucleus of neurons. There is
homology to Ma1.
In about 90%, the patients present
with isolated or combined limbic, diencephalic or brainstem dysfunction
(PEM). Excessive daytime sleepiness
may also be an observation, and in
such cases decreased / absent
hypocretin-1 may be a feature of the
CSF. In young male patients, the
primary tumour is in the testis. In
other patients, the most frequent
neoplasms are lung adenocarcinoma,
colon or breast cancer.
Anti-TIF (transcriptional
intermediary factor 1-gamma)
This factor plays a role in the control
of cell proliferation.
The autoantibody is associated with
polymyositis / dermatomyositis, and
in
particular
cancer
associated
dermatomyositis (CADM) with 58 %
of co-existing neoplasms in anti-Tif
seropositive cases.
Anti-Titin
The target is the giant protein titin of
striated muscles. This is the largest
molecule of the body, functioning as
a giant spring.
The autoantibodies are associated
with paraneoplastic MG (thymoma),
although they are also a frequent
finding in non-paraneoplastic lateonset MG. The titres appear to correlate with the severity of MG, possibly
attributable to a co-existing myopathy. Such autoantibodies are a feature of healthy controls in only about
0.4%, so they are of a high diagnostic value.
In myasthenic patients, the detection
of these autoantibodies should be by
a method using the main immunogenic region (MIR, for example MGT-

30-peptide). In sporadic rippling


muscle syndrome, the antibodies are
to the titin isoform N2A.
Anti-Tr (Trotter, PCA-Tr)
Trotter discovered this antibody. The
antigen is located at the cytosol and
outer surface of the endoplasmic reticulum, and typically found in
Purkinje cell cytoplasm and dendrites.
The antigen is the delta and notchlike epidermal growth factor-related
receptor (DNER).
The associated cancer is Hodgkins
lymphoma. Interestingly, the neoplasm is only rarely stained by the
antibody.
PCD is the typical neurological feature. Variant syndromes may be a
reversible limbic encephalitis and optic neuritis.
Anti-TULIP-1 (TULP1)
Tubby-like protein 1 is a photoreceptor-specific protein. It co-localises
and interacts with actin in photoreceptor cells of the retina. In humans,
there are two genes, TULP1 and
TULP2. The expression of TULP1 is
exclusively in retina, whereas TULP2
is located in both retina and testis.
Paraneoplastic retinitis is the clinical
finding.
Anti-Ubiquitin-conjugating
enzyme E2E1 (UBE2E1)
The modification of proteins with
ubiquitin is an important cellular
mechanism for targeting abnormal or
short-lived proteins for degradation.
Ubiquitination involves at least three
classes
of
enzymes:
ubiquitinactivating
enzymes,
or
E1s,
ubiquitin-conjugating enzymes, or
E2s, and ubiquitin-protein ligases, or
E3s. This gene encodes a member of
the E2 ubiquitin-conjugating enzyme
family. Three alternatively spliced
transcript variants encoding distinct
isoforms have been found for this
gene.
Paraneoplastic encephalomyelitis and
SCLC are assiciated.

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Anti-Yo (Young, CDR1 (CDR34), CDR2,


CDR2L
(CDR62-1,
PCD17-SN, CZF)

CDR62-2),

CDR3,

Young was the first to report the


finding of these antibodies. The
names of the targets are also
Purkinje cell antigen 1 and cerebellar
degeneration related proteins 34 &
62. They are proteins of the Purkinje
cell cytoplasm (ribosomes both
membrane bound & free and Golgi
apparatus) and various neoplasms:
34kDa (CDR34); 62kDa (CDR62-1,
CDR62-2, leucine zipper); CDR3
(leucine zipper); 52kDa (PCD17-SN,
leucine zipper); 58kDa (CZF, zinc
finger); CDR2L is localized to the cell
membrane
The following PNS are associated:
PCD, PLE and SPS. The most frequent neoplasm is breast cancer
(95%). Other cancers may be SCLC,
ovarian, prostatic, oesophagus, gastric, parotid.
Anti-ZIC4
The zinc finger (Zic) proteins have
important roles in the development

of the nervous system, and comprise


a family of five zinc-finger proteins
with extensive sequence homology
(range 52%-62% identity). Because
the Zic proteins are highly homologous to each other, the sera of patients with anti-Zic4 antibodies usually react with Zic1, and less frequently with Zic2. The anti-Zic4 antibodies show predominant reactivity
with the nuclei of neurons of the
granular layer of the cerebellum and
less intense reactivity with other
neurons, including in descending order Purkinje cells, and neurons of
deep cerebellar nuclei, brainstem and
brain.
SCLC is the associated neoplasm,
and PCD is the typical neurologic
finding. A combined finding of antiZIC4 and other onconeural antibodies is typical in PEM. Detection of
Zic4 antibodies often associates with
anti-Hu or CV2 (CRMP5) antibodies.
Patients with isolated Zic4 antibodies
are more likely to develop cerebellar
dysfunction than those with concurrent other autoimmunities.

Table 13: The most frequently encountered onconeural autoantibodies and their
associated neoplasms, and accounting for about 60 % of all PNS cases
Onconeural antibody
Neoplasms
by decreasing order of occurrence
Anti-Hu
SCLC, breast, ovary, testis
Anti-Yo
Breast, ovary, SCLC
Anti-CV2 (CRMP5)
SCLC, thymoma
Anti-Ta (Ma2, PNMA2)
Testis, breast
Anti-Amphiphysin
Breast (98%), SCLC
Anti-Ri
SCLC, breast, ovary

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Diagnostic criteria - Overview


Recommended diagnostic criteria for paraneoplastic
neurological syndromes.
Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold W,
Honnorat J, Smitt PS, Vedeler C, Verschuuren JJ, Vincent A, Voltz R.
J Neurol Neurosurg Psychiatry 2004; 75 (8): 1135-1140.
Comment in: J Neurol Neurosurg Psychiatry 2004; 75 (8): 1090.

BACKGROUND: Paraneoplastic neurological syndromes (PNS) are defined by


the presence of cancer and exclusion of other known causes of the neurological
symptoms, but this criterion does not separate "true" PNS from neurological
syndromes that are coincidental with a cancer. OBJECTIVE: To provide more
rigorous diagnostic criteria for PNS. METHODS: An international panel of
neurologists interested in PNS identified those defined as "classical" in previous
studies. The panel reviewed the existing diagnostic criteria and recommended
new criteria for those in whom no clinical consensus was reached in the past. The
panel reviewed all reported onconeural antibodies and established the conditions
to identify those that would be labelled as "well characterised". The antibody
information was obtained from published work and from unpublished data from
the different laboratories involved in the study.

RESULTS: The panel suggest two levels of evidence to define a neurological


syndrome as paraneoplastic: "definite" and "possible". Each level can be reached
combining a set of criteria based on the presence or absence of cancer and the
definitions of "classical" syndrome and "well characterised" onconeural antibody.

CONCLUSIONS: The proposed criteria should help clinicians in the classification


of their patients and the prospective and retrospective analysis of PNS cases.

In short
Ideally, no other possible explanation than remote effect of cancer
should be an option.
Symptoms & signs consistent with PNS.
Inclusion & exclusion criteria see Definition of PNS elsewhere in this book.
An investigation resulting in specific findings consistent with what is
referenced in the various PNS chapters of this book.

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Overview of management
See also General therapeutic considerations, page 7
For specific treatment: see the various chapters of this book

Management of paraneoplastic neurological syndromes:


report of an EFNS Task Force.
Vedeler CA, Antoine JC, Giometto B, Graus F, Grisold W, Hart IK, Honnorat
J, Sillevis Smitt PA, Verschuuren JJ, Voltz R.
Eur J Neurol 2006; 13 (7): 682-690.
Download the whole report from here:
CV2 (
Paraneoplastic Neurological Syndrome Euronetwork.
PNSEURONET: http://www.pnseuronet.org/

Summary
An overview of the management of classical PNS, i.e. paraneoplastic limbic
encephalitis, subacute sensory neuronopathy, paraneoplastic cerebellar
degeneration,
paraneoplastic
opsoclonus-myoclonus,
Lambert-Eaton
myasthenic syndrome and paraneoplastic peripheral nerve hyperexcitability
is given. Myasthenia gravis and paraproteinemic neuropathies are not
included in this report. No evidence-based recommendations were possible,
but good practice points were agreed by consensus. To allow tumour therapy
to be started early and further to prevent progressive neuronal death and
irreversible disability, urgent investigation is indicated. This is particularly
true in central nervous system (CNS) PNS syndromes,
Onconeural antibodies are of great importance in the investigation of PNS
and can be used to focus tumour search. PDG-PET is useful if the initial
radiological tumour screen is negative. Early detection and treatment of the
tumour is the approach that seems to offer the greatest chance for PNS
stabilization. Immune therapy usually has no or modest effect on many of
the CNS syndromes, whereas such therapy is beneficial for PNS affecting the
neuromuscular junction. Symptomatic therapy should be offered to all
patients with PNS.

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15 September 2014, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Listing of some books and reviews


Darnell RB, Posner JB. Paraneoplastic sydromes. Oxford University Press 2011
Abeloff, Armitage, Niederhuber, Kastan, McKenna. Abeloff's Clinical Oncology,
4th Edition. Churchill Livingstone 2008 - please see:
Dalmau, J, Rosenfeld M. Chapter 51 Paraneoplastic Neurologic Syndromes
de Beukelaar JW, Sillevis Smitt PA. Managing paraneoplastic neurological
disorders. Oncologist 2006; 11 (3): 292-305.
Dropcho EJ. Update on paraneoplastic syndromes. Curr Opin Neurol 2005; 18
(3): 331-336.
Sillevis Smitt P. Neuro-oncology: diagnosis in the spotlight. Lancet Neurol
2004; 3 (1): 14.
Llado A, Mannucci P, Carpentier AF, Paris S, Blanco Y, Saiz A, Delattre JY, Graus F.
Value of Hu antibody determinations in the follow-up of paraneoplastic
neurologic syndromes. Neurology 2004; 63 (10): 1947-1949.
Giannopoulou C. Navigating the paraneoplastic neurological syndromes.
Eur J Nucl Med Mol Imaging 2003; 30 (3): 333-338.
Benyahia B, Carpentier AF, Delattre JY. [Antineuron antibodies and
paraneoplastic neurological syndromes]. [French]. Rev Neurol (Paris) 2003;
159 (4): 463-465.
Vianello M, Tavolato B, Giometto B. Glutamic acid decarboxylase
autoantibodies and neurological disorders. Neurol Sci 2002; 23 (4): 145-151.
Giometto B, Taraloto B, Graus F. Autoimmunity in paraneoplastic
neurological syndromes. Brain Pathol 1999; 9 (2): 261-273.
Posner JB, Dalmau JO. Paraneoplastic syndromes affecting the central
nervous system. Annu Rev Med 1997; 48: 157-166.
Serratrice G, Azulay JP. [What is left of Morvan's fibrillary chorea?].
[French]. Rev Neurol (Paris) 1994; 150 (4): 257-265.
O'Neill JH, Murray NM, Newsom-Davis J. The Lambert-Eaton myasthenic
syndrome. A review of 50 cases. Brain 1988; 111: 577-596.

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Subject index
A
acute necrotizing myopathy 76
ANA 75
ANNA1 99
ANNA2 101
ANNA3 43; 97
anti-AChR
adult-type 22; 28; 43; 67; 69; 70; 79; 83; 88; 96
alpha3-type 56; 67; 83; 89; 96
foetal-type 22; 28; 43; 67; 69; 70; 79; 83; 88; 96
M1-type 64; 96
anti-Adenylate kinase 5 36; 96
anti-Alpha-enolase (ENO1) 46; 96
anti-AMPAR (GluR1/R2) 35; 96
anti-Amphiphysin 33; 35; 37; 42; 53; 97
anti-ARHGAP26 (GRAF) 30
anti-ARHGAP26/GRAF 97
antibody removal / plasma exchange 19
antibody-mediated autoimmunity
criteria 8
anti-BRSK2 35; 97
anti-Ca-channel 22; 25; 28; 30; 43; 64; 97
anti-CARP8 29; 97
anti-CASPR2 22; 35; 65; 67; 71; 97
anti-CDR32 103
anti-CDR62 103
anti-CRMP2-4 97
anti-CRMP5 97
anti-CV2 / CRMP5 25; 26; 31; 33; 35; 37; 38; 43;
44; 58; 60; 89; 97
anti-CV2/CRMP5 syndrome 26
anti-DPP5 22
anti-DPPX 22
anti-EFA6A 36; 98
anti-GabaBR1 35
anti-GAD 35; 37; 50; 51; 89; 98
anti-GAD65 98
anti-Gephyrin 52; 98
anti-GluR1/R2 (AMPAR) 35; 96
anti-GlyR alpha1 52
anti-HMGCR 76; 78; 98
anti-Hu 25; 35; 37; 39; 40; 42; 43; 57; 59; 60; 89;
99
anti-Hu syndrome 25
anti-IF-alpha (interferon) 71
anti-IL12 (interleukin) 71
anti-K-channel 89; 99
anti-Ma1 27; 100
anti-Ma1-syndrome 27
anti-Ma2, see also anti-Ta 102
anti-MDAS 76
anti-mGluR1 28; 29; 99
anti-mGluR5 35
anti-Mup44 76; 78
anti-nCMAg 36
anti-Neurofilaments 41; 100
anti-NMDAR 36; 100

anti-Pancreatic-islet-cell 52
anti-Parietal-cell 53
anti-PCA1 103
anti-PCA2 28; 35; 52; 101
anti-PCA2 syndrome 28
anti-Peripherin 56
anti-PKC gamma 30; 101
anti-POP66 97
anti-Pyridoxal-phosphatase 57; 58; 101
anti-Recoverin 46; 101
anti-Ri 25; 33; 37; 38; 42; 101
anti-RyR1 (ryanodine) 70; 79; 89; 101
anti-Striated muscle 70; 79; 83; 101
anti-Ta (Ma2) 35; 37; 42; 43; 102
anti-TIF 76
anti-Titin 22; 89; 102
anti-Tr 25; 28; 43; 44; 102
anti-Tr syndrome 28
anti-Tulip1 102
anti-UBE2E1 36; 102
anti-vg-Ca-channel 22; 25; 28; 30; 43; 97
N-type 64
P/Q-type 64
anti-vg-K-channel 71; 89; 99
anti-Yo 25; 26; 42; 103
anti-Yo syndrome 26
anti-ZIC4 25; 30; 33; 41; 103
arthrogryposis multiplex 90
ataxia 85
ataxia in cerebellar degeneration 24
ataxia with anti-CARP8 29
ataxia with anti-CV2 26
ataxia with anti-GAD 29
ataxia with anti-Hu 25
ataxia with anti-Ma1 27
ataxia with anti-mGluR1 28
ataxia with anti-PCA2 28
ataxia with anti-Ri 42
ataxia with anti-Tr 28
ataxia with anti-Yo 26
ataxia with anti-ZIC4 29
ataxia, LEMS associated 30
autonomic neuropathy 55

B
bladder cancer 56; 76
blood pressure, labile and low 33; 56
brainstem encephalitis 36
breast cancer 25; 26; 27; 35; 37; 40; 42; 51; 53;
60; 76; 88; 97; 98; 99; 100; 101; 103

C
cerebellar degeneration (PCD) 24
choreo-athetosis 31
chronic gastrointestinal pseudoobstruction 33; 56
colon cancer 27; 75

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cramp-fasciculation syndrome 65
criteria
antibody-mediated autoimmunity 8
paraneoplastic neurological syndromes 4
T-cell-mediated autoimmunity 8

D
diagnostic strategy in PNS 12
duodenum cancer 40

E
epilepsy 22; 35; 42; 51; 59; 85
extrapyramidal disorders 26; 31; 37; 50; 52; 53; 87

melanoma 29; 60
monoclonal gammopathy 58
Morvan's fibrillary chorea 22
motor neuron disease 39
motor neuropathy 57
myasthenia gravis 69
myasthenia gravis-associated myopathy 78
myeloma 40; 57
myoclonus 42; 53
myokymia 27; 66; 100
myopathies 74
myopathy
acute necrotizing myopathy 76
paraneoplastic MG-associated myopathy 78
myositis-overlap antibodies 75
myositis-specific antibodies (MSA) 75

N
G
gall bladder cancer 40
ganglioneuroblastoma 42
ganglioneuroma 42
gastric cancer 26; 75
gastrointestinal pseudoobstruction 33; 56

H
hereditary inclusion body myositis 77
high-dose IgG 19
Hodgkin's disease 25; 28; 29; 40; 44; 60; 67; 88;
96; 99; 102
hypotension, labile 33; 56

I
immunosuppression 19
Inclusion body myositis, hereditary 77
Inclusion body myositis, sporadic 76
Isaacs' syndrome 65

neuroblastoma 42
neuromyotonia (Isaacs' syndrome) 65
neuropathy
autonomic 55
motor 57
sensory 59
sensory-motor 57

O
oesophageal cancer 26; 60
Ophelia syndrome 35
opsoclonus / myoclonus (POM) 41
opsoclonus / myoclonus in adults
anti-Hu, anti-Yo, anti-Ta 42
anti-Ri 42
optic neuritis 44
ovarian cancer 25; 26; 37; 42; 60; 75; 99; 103

Lambert-Eaton myasthenic syndrome (LEMS) 63


LEMS-associated PCD 30
leukaemia 40; 57
lung cancer 5; 12; 13; 25; 27; 28; 30; 31; 33; 35;
37; 38; 42; 44; 46; 51; 53; 56; 57; 58; 59; 60; 63;
64; 67; 75; 76; 93; 96; 97; 98; 99; 100; 101; 102;
103
lymphoma 25; 28; 29; 40; 44; 46; 57; 67; 75; 96;
99; 102

pain 50; 57; 58; 59; 87


pancreas cancer 75
paraneoplastic neurological syndrome
definition 4
paraproteinaemia 57; 58
parotid cancer 26
polyneuropathy
autonomic 55
motor 57
sensory 59
sensory-motor 57
progressive encephalopathy with rigidity and reflex
myoclonus (PERM) 53
prostate cancer 60

M-components 58

rectum cancer 56; 75

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renal cancer 44; 60


retinopathy (CAR) 46
rippling muscle syndrome, sporadic 83
ROHHAD syndrome 42

S
SCLC 5; 12; 13; 25; 27; 28; 30; 31; 33; 35; 37; 38;
42; 44; 46; 53; 56; 57; 59; 60; 63; 64; 67; 75; 96;
97; 98; 99; 100; 101; 103
sensory neuropathy 59
sensory-motor neuropathy 57
sporadic inclusion body myositis 76
sporadic rippling muscle syndrome 83
stiff-person syndrome 50
stiff-person syndrome variants 52
focal SPS 52
other types 53
PERM 53
with anti-GAD 53
subaucte sensory neuronopathy (SSN) 59

T
testis cancer 27; 35; 37; 42; 60; 99; 100; 102
thymoma 9; 16; 22; 27; 35; 37; 51; 56; 60; 67;
69; 70; 71; 72; 78; 79; 88; 90; 91; 96; 98; 99;
101; 102
thyroid cancer 44; 58
transfer from mother to foetus 88

U
uterus cancer 27

W
Waldenstrom's macroglobulinaemia 40

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Autoimmune encephalitis, please see


separate compendium

Autoimmune encephalitis
History & current
knowledge
Short compendium
Version 3.2, May 2014

By
Finn E. Somnier, M.D., D.Sc. (Med.), copyright
Department of Clinical Biochemistry, Immunology & Genetics
Statens Serum Institut, Copenhagen, Denmark

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Channelopathies, receptor and


solute carriers disorders in
neurology, please see separate
compendium

Channelopathies
receptor and solute carrier
disorders in neurology
Autoantibodies and biomarkers of neurological disorders
Version 3.1, February 2014

By
Finn E. Somnier, M.D., D.Sc. (Med.), copyright
Department of Clinical Biochemistry, Immunology & Genetics
Statens Serum Institut, Copenhagen, Denmark

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Department of Clinical Biochemistry, Immunology


and Genetics
STATENS SERUM INSTITUT
Artillerivej 5 DK-2300 Copenhagen S Denmark
Tel. +45 3268 3268 Fax: +45 3268 3869
serum@ssi.dk www.ssi.dk
http://www.ssi.dk/Diagnostik/Downloads.aspx

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