Paraneoplastic neurological syndromes

Transcription

Paraneoplastic neurological
and muscular syndromes
Short compendium
Version 4.5, April 2016
By
Finn E. Somnier, M.D., D.Sc. (Med.), copyright ®
Department of Autoimmunology and Biomarkers,
Statens Serum Institut, Copenhagen, Denmark
30/01/2016, 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
MORVAN’S 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 ............................................................................................................. 29
LEMS-associated ..................................................................................................................... 30
Anti-ARHGAP26 (GRAF) ....................................................................................................... 30
Anti-PKC gamma .................................................................................................................... 30
PARANEOPLASTIC CHOREO-ATHETOSIS / STRIATAL ENCEPHALITIS ................................. 31
PARANEOPLASTIC MORE CLASSICAL CNS DISORDERS ......................................................... 33
Paraneoplastic encephalomyelitis (PEM) ....................................................................... 34
Paraneoplastic limbic encephalitis (PLE),may include other structures ............ 35
A variety of associated autoatibodies ...................................................................................................... 36
Paraneoplastic brainstem encephalitis ........................................................................... 37
Anti-Ta (Ma2) syndrome .......................................................................................................................... 38
Paraneoplastic myelitis / myelopathy ............................................................................. 38
PARANEOPLASTIC MOTOR NEURON DISEASE? ........................................................................ 40
PARANEOPLASTIC OPSOCLONUS / MYOCLONUS (POM) ..................................................... 42
POM in children ....................................................................................................................... 42
POM in adults ........................................................................................................................... 43
Anti-Hu, Yo, Ta (Ma2) syndromes ............................................................................................................ 43
Anti-Ri syndrome...................................................................................................................................... 43
PARANEOPLASTIC OPTIC NEURITIS ........................................................................................... 45
PARANEOPLASTIC RETINOPATHY (CAR, MAR) .................................................................... 47
STIFF-PERSON SPECTRUM OF SYMPTOMS (SPS AND PERM) ............................................ 51
SPS variants ............................................................................................................................. 53
SYNDROMES OF THE PERIPHERAL NERVOUS SYSTEM ........................................ 56
PARANEOPLASTIC AUTONOMIC NEUROPATHY ......................................................................... 56
CHRONIC GASTROINTESTINAL PSEUDOOBSTRUCTION .......................................................... 56
PARANEOPLASTIC MOTOR NEUROPATHY .................................................................................. 58
PARANEOPLASTIC SENSORY-MOTOR NEUROPATHY ............................................................... 58
PARANEOPLASTIC SENSORY NEURONOPATHY (SSN, PSN) ............................................... 60
SYNDROMES OF THE NEUROMUSCULAR JUNCTION .............................................. 63
LAMBERT-EATON MYASTHENIC SYNDROME ............................................................................. 64
ACQUIRED NEUROMYOTONIA, ISAACS’ SYNDROME ............................................................... 66
MORVAN’S FIBRILLARY CHOREA ................................................................................................ 66
1
PARANEOPLASTIC SEROPOSITIVE MYASTHENIA GRAVIS WITH THYMOMA ....................... 70
PARANEOPLASTIC MYOPATHIES .................................................................................... 75
POLYMYOSITIS, DERMATOMYOSITIS......................................................................................... 75
NECROTIZING MYOPATHY ............................................................................................................ 77
SPORADIC INCLUSION BODY MOSITIS ...................................................................................... 78
MYASTHENIA GRAVIS-ASSOCIATED MYOPATHY ..................................................................... 80
RIPPLING MUSCLE SYNDROME – ACQUIRED SPORADIC, AUTOIMMUNE ............................ 82
SYMPTOMATIC OVERVIEW ................................................................................................ 86
PARANEOPLASTIC ATAXIA ........................................................................................................... 86
PARANEOPLASTIC EPILEPSY........................................................................................................ 86
PARANEOPLASTIC EXTRAPYRAMIDAL DISORDERS ................................................................. 88
PARANEOPLASTIC PAIN............................................................................................................... 88
MATERNAL AUTOANTIBODIES AND PASSIVE TRANSFER IN HUMANS ........ 89
AUTOANTIBODIES ASSOCIATED WITH PNS ............................................................. 94
PARANEOPLASTIC ANTIBODIES TARGETING THE NERVOUS SYSTEM OR
STRIATED MUSCLES VERSUS NEOPLASMS ................................................................ 97
DIAGNOSTIC CRITERIA - OVERVIEW ......................................................................... 106
OVERVIEW OF MANAGEMENT ........................................................................................ 107
LISTING OF SOME BOOKS AND REVIEWS ................................................................ 108
SUBJECT INDEX ..................................................................................................................... 109
AUTOIMMUNE ENCEPHALITIS, PLEASE SEE SEPARATE COMPENDIUM .... 112
CHANNELOPATHIES, RECEPTOR AND SOLUTE CARRIERS DISORDERS IN
NEUROLOGY, PLEASE SEE SEPARATE COMPENDIUM ......................................... 113
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
2
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
3
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 lung cancer
(SCLC) and anti-Hu (Hull) antibodies.
The seropositive incidence is about
17% in SCLC patients. Accordingly,
4
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., antiNMDAR, 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 T-cell 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
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
5
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.
6
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 Freund’s 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.
In analogy with other autoimmune
disorders, a useful categorization of
the PNSs is:
1. Antibody (humoral)-mediated
7
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
or 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)
Morvan’s fibrillary chorea
Paraneoplastic limbic encephalitis
Acquired neuromyotonia (Isaacs’
syndrome)
Paraneoplastic ataxia
Stiff-person syndrome?
Paraneoplastic opsoclonus,
myoclonus?
to satisfy these criteria, either totally
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
8
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:
1822–1830]
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]
o
2010: passive transfer of anti-NMDAR [J Neurosci. 2010 April 28; 30(17): 5866–5875 ]
2012: Lewis rat animal model of Sydenham chorea and related
neuropsychiatric disorders
o
[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
(1983)
 Immunization with cholinergic
synaptosomes (1990)
Neuromyotonia
(2003)
Autoimmune autonomic neuropathy
(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”
(Matzinger’s hypothesis), which in a
9
PNS context would mean a neoplasm.
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, crossreactive 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 humoral-mediated
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 Freund’s 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





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
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 non-finding
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 passway at some step. The breaches of
barriers are supposedly symmetric
and located at the most vulnerable
sites.
12
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 anti-Hu 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-vg-Ca-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.
13
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.
14
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 on-going 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 nonspecific (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 anti-CV2
(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.
15
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 syndrome
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 36.
16
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
1
2
3
4
5
6
7
8
9
10 11 12
Months after onset
17
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
Enumera- Modality
tion
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.
18
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 4-8
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 Guillain-Barré 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 therapy must
be kept at an efficient level and as
19
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.
Another concern in relation
to PNS

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.
Other modalities of therapy
Also in relation to PNSs, such symptomatic treatment (Table 2, 1 - 3) follows the usual procedures.
Newer options for treatment

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-cell-mediated
disorders.
Therapeutic keywords in T-cell
mediated autoimmunity:
 Often a medical emergency

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
The legitimacy of immunosuppression in a patient with cancer
20
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
21
Syndromes of the central nervous system
Morvan’s 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 contactin-associated
protein-2 (CASPR2), accessory proteins and integrated in vgKC complexes. This disorder appears to fulfil the criteria of an
antibody-mediated autoimmunity.
Anti-CASPR2 disorders:
Acquired neuromyotonia
Peripheral nerve hyperexcitability
Morvan’s 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 chorée fibrillaire. Gazette hebdomadaire de médecine 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.
22
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, synapseorganizing 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): 2417-26.
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. Löscher 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: 1570–1584.
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, Morvan’s syndrome and acquired
neuromyotonia. Brain 2010; 133 (9): 2734-2748.
23
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
24
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
 Hodgkin’s 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
Table3:
Listing
A
B
C
D
E
F
G
H
I
J
K
L







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).
25
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
26
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 gastro-intestinal;
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
Associated
neoplasms
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
(espe-
cially in the chest)
 Small-cell lung (80%)
27
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 antiYo syndromes
Clinical features


Ataxia, moderate to severe
Variant syndromes
o Limbic encephalitis (7%): reversible
o Optic neuritis
Associated neoplasm


Hodgkin’s 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
28
criteria of an antibody-mediated autoimmunity.
Course: progressive ataxia
Onset
Months
(80%)
to
years
after
neoplasm
Course
Persistent or monophasic
Clinical features



Onset: 3 years after neoplasm
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
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
I. Syndrome with
anti-GAD antibodies
Neoplasm
Hodgkin's lymphoma, during remission
Treatment
Please see stiff-person syndrome:
variants
Immunosuppression may be of value.
J. Syndrome with
anti-ZIC4 antibodies
H. Ataxia with antiCARP8 antibodies
Ataxia associated with antibodies
to carbonic anhydrase-related protein
8.
Epidemiology: only one patient reported a 77-year-old female
Clinical features



Ataxia, moderate to severe
Slurred speech
Vertigo
Neoplasm: small-cell lung (SCLC)
Antibodies
29
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.
Antibodies
 Anti-vg-Ca channels (P/Q- & N-
In short, detection of Zic4 antibodies
often associates with
 Anti-Hu or CV2 (CRMP5) antibodies
Treatment


type)
Increased incidence in
syndromes
anti-Hu
Neoplasm: small-cell lung
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
Ataxia associated with LambertEaton myasthenic syndrome.

Anti-ARHGAP26 (GRAF), anti-Protein kinase C gamma (PKC gamma))
Neoplasm


ovarian (anti-GRAF)
non-SCLC (anti-PCK gamma)
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, Aguirre‐Cruz ML, Saiz A, Benyahia B, Dalmau J, Graus F .
Protein kinase Cγ autoimmunity in paraneoplastic cerebellar degeneration and non‐small‐cell lung
cancer. J Neurol Neurosurg Psychiatry 2006; 77 (12): 1359–1362.
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, Martínez-García, P, Hernandez AL, et al. Two new cases of anti-Ca (anti-ARHGAP26/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.
30
Paraneoplastic choreo-athetosis / striatal encephalitis
Paraneoplastic choreo-athetosis is a rare encephalopathy characterized by extrapyramidal features such as chorea & athetosis. Most frequently, this disorder is associated with anti-CV2
(CRMP5) antibodies, rarely with anti-Hu. The diagnosis is only justified, if chorea is the single or predominant sign in association with
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.
However, if the clinical appearance is that of a multifocal paraneoplastic 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.
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

Anti-CV2 (CRMP5) is the finding
in most cases. Sometimes, antiHu, anti-Amphiphysin, anti-Ri,
and anti-Zic4 are features as well.
Associated neoplasm
Small-cell lung cancer (SCLC)
Some differential diagnoses







Hereditary disorders with chorea,
such as Huntington’s disease, neuroacanthocytosis. Metabolic disorders
such as Wilson disease and others
Immunologic disorders, for example
SLE
Paraneoplastic: Morvan’s 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.
3.
4.
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.
Croteau D, Owainati A, Dalmau J, Rogers LR. Response to cancer therapy in a patient with a
paraneoplastic choreiform disorder. Neurology. 2001; 57: 719-22.
Oguma T, Kobayashi H, Katada S, Onodera O, Tanaka K, Tsuji S, Uno T, Ishida T, Kagamu H, Gejyo
F, Motomura M. Paraneoplastic striatal encephalitis. Neurology 2001; 57 (12): 2326.
Vernino S, Tuite P, Adler CH, Meschia JF, Boeve BF, Boasberg P, Parisi JE, Lennon VA.
Paraneoplastic chorea associated with CRMP-5 neuronal antibody and lung carcinoma. Ann Neurol
2002; 51 (5): 625-30.
31
5.
6.
7.
8.
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.
Vigliani MC, Honnorat J, Antoine JC, Vitaliani R, Giometto B, Psimaras D, Franchino F, Rossi C, Graus
F; PNS EuroNetwork. Chorea and related movement disorders of paraneoplastic origin: the PNS
EuroNetwork experience. J Neurol. 2011 Nov;258(11):2058-68.
Crespo-Burillo JA, Hernando-Quintana N, Ruiz-Palomino P, Martín-Martínez J.Chorea secondary to
striatal encephalitis due to anti-CV2/CRMP5 antibodies. Case description and review of the
literature. [Article in English, Spanish]. Neurologia 2015; 30(7):451-453.
Aydin D, Somnier F. Lassen L.H. Paraneoplastic Choreoathetosis in a Patient with Small Cell Lung
Carcinoma and Anti-CRMP5/CV2: A Case Report. Case Rep Neurol 2016; 8: 16-19.
32
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
A
B
C
D
Additional
of disorders
Paraneoplastic
Paraneoplastic
Paraneoplastic
Paraneoplastic
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: antiPrimary Associated neoplasms
(alphabetical order)
analysis
SCLC
Anti-AGNA
SOX1
SCLC, non-SCLC, thymoma, breast
Anti-AMPAR
GluR1/2
Breast, SCLC
AntiYes
Amphiphysin
SCLC
Anti-BRSK2
Thymoma
Anti-CASPR2
SCLC, thymoma
Anti-CV2
CRMP5,POP66
Yes
Ovarian
Anti-EFA6A
SCLC, thymoma, breast, renal,
Anti-GAD
Yes
Anti-GabaBR1
Anti-Hu
*Anti-K-channel
Anti-LGI1
Anti-mGluR1
Anti-mGluR5
Anti-NMDAR
Anti-PCA-2
Anti-Ri
Anti-Ta
Anti-Tr
Anti-Yo
GABBR1
ANNA-1
VGKC, VGPC
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-
SCLC, non-SCLC, breast, ovarian
Yes
Yes
Testicular, ovarian
Yes
Breast, ovarian, SCLC
Morbus Hodgkin
33
62
* LGI1 and CASPR2 are accessory proteins at VGKCs, and are the true targets
30% of these patients. The most
common symptoms are
o orthostatic hypotension
o urinary retention
o pupillary abnormalities,
o impotence
o dry mouth
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
The dorsal root ganglia are affected. This is a feature of about
Occasionally, there is also chronic
intestinal pseudo-obstruction due
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.
Small-cell lung cancer (SCLC) in
about 75%
 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.
34
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 neuro-oncological 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 memory (85%)
 Cognitive disturbance (15%)
35








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 Morvan’s 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 non-paraneoplastic anti-NMDAR encephalitis (idiotypic or SLE with CNS
involvement)
EEG
Cerebrospinal fluid
Pleocytosis and oligoclonal bands (in
about 60%)









Small-cell lung cancer (50%)
Testicular tumour (20%)
Ovarian
Breast cancer (8%)
Thymoma
Hodgkin’s disease
Prostate
Teratoma
Thyroid

Renal cancer (anti-GAD)
Lung cancer
 Anti-Hu
 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
Hodgkin’s 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
36

Anti-NMDAR (NR1)
Types of autoimmune antiNMDAR encephalitis
o Of unknown cause (post-infectious?)
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 cell-membrane
antigens) which is highly expressed in hippocampus and cerebellum)
 Anti-Adenylate kinase 5)
 Anti-UBE2E1

About 40% are seronegative, and
the absence of onconeural antibodies 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 anti-Ta
(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
37
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 – and in such cases,
decreased / absent hypocretin1 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
38
Clinical features
Motor
 Patchy weakness: arms > legs
May progress to neck
 Fasciculations
 Eventually, respiratory failure
Sensory
 Associated ganglionopathy

Lung (small-cell)
Other options


Anti-CV2 (CRMP5) syndrome,
see ‘Paraneoplastic cerebellar syndrome (PCD)’
Anti-Ri (ANNA2) syndrome,
see ‘Opsoclonus / myoclonus’
Associated neoplasm
Selected references
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
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, Reñé 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: 1481-94.
Graus F, Keime-Guibert F, Reñé 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, Reñé 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): 1831-1844.
Sabater L, Gómez-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): 1319–1335.
Kleopa KA, Elman LB, Lang B, Vincent A, Scherer SS. Neuromyotonia and limbic encephalitis sera
Brain 2006; 129: 1570–1584.
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;
39
23. 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.
24. Tüzün 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): 177–180.
25. Sansing LH, Tüzün 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): 424–434.
30. Irani SR, Sian Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, Peles E, Buckley C, Lang
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
40
slower in patients with concomitant ALS.
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)
o
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
Weakness, occasionally accompanied by minor sensory symptoms
Subacute often asymmetrical
Progressive
o Hodgkin’s disease
o Non-Hodgkin’s 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
 Waldestrom’s
macroglobulinaemia
 Multiple myeloma
 Chronic lymphocytic leukaemia
 Follicular cell lymphoma
 Hodgkin’s 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.
41
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
A
B
C
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
42

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
43
Other associated antibodies
(75%):
 Anti-Hu
 Anti-Ta (Ma2)
 Anti-Tr
 ANNA3
 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: 1009.
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.
44
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
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
Onset
Rule out: neuromyelitis optica (NMO)
(Devic’s 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.
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 (Hodgkin’s disease)
Swollen optic discs and field defects
Vascular leakage, evident at and
remote from the disc




Small-cell lung cancer
Lung adenocarcinoma
Renal or thyroid carcinoma
Hodgkin’s 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.
45
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): 164-167.
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. Devic’s syndrome-like phenotype associated with thymoma and anti-CV2/CRMP5 antibodies. J
Neurol Neurosurg Psychiatry 2007; 78: 325-327
46
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-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




Small-cell lung cancer
Melanoma
Gynaecologic
Colon, lymphoma
47
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":
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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, Tausjø 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.
48
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: 5767.
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): 927–928.
43. Hartmann TB, Bazhin AV, Schadendorf D, Eichmüller 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: 1568.
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.
49
54. Pföhler 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. Arés-Luque A, García-Tuñón 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; 22:11913
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 melanomaassociated retinopathy treated with intravenous immunoglobulin. J Neuroophthalmol 2008; 28: 236.
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.
50
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 antibody-mediated autoimmunity. Anti-Amphiphysin, anti-Gephyrin and / or antiCV2 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"
51
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


Breast
Other: lung, thymoma, Hodgkin's
and non-Hodgkin’s lymphoma,
myeloma, renal cell carcinoma
Epilepsy treated with anti-GABA
agents, suggests PERM variant.
Diabetes mellitus, type I (30- 60 %).
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: DRβ1 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
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
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.
Anti-GlyR alpha1 antibodies
52
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 and spasms of lower limbs
53
Stimuli: especially voluntary movement; also reflex stimuli
 Asymmetric
 Posturing of feet
 Trunk spared
Treatment (partial benefit)
Baclofen, Diazepam
2. Jerking SPS
Pathology



Perivascular inflammation
Gliosis in spinal cord, pons and
medulla
Neuronal loss: spinal gray
4. SPS in cerebellar syndrome with anti-GAD
Clinical features
Epidemiology
Stiffness: axial and lower limb
Later features
 Brainstem myoclonus
 Upper motor neuron signs
 PERM, see below
Clinical features
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
Onset age: females 20 to 75 years
The onset is slowly progressive.
Ataxia: limb and trunk
Nystagmus
Dysarthria (50%)
Stiffness (15%)
No brainstem involvement



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
54
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: 2219-2223.
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, O’Riordan 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): 1–7.
55
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”.
Clinical features

Orthostatic hypotension without
compensatory tachycardia
56







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 α3-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


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
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)
57
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
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 sensory-motor
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-Barré
syndrome.
58


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 well-differentiated 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; 67:714.
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; 74:507–9.
59
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-Hu-seronegative 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 (40-70%)
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
60
Autonomic (30%)
 Blood pressure: labile, hypotension (20%)
 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, Hodgkin’s
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.
 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%
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, HelN2, ple21
Other antibodies
 Anti-CV2 (CRMP5) in about
15%
 Serum M-protein: not reported

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)
Toxic: cis-platinum
Pyridoxine deficiency
Sjögren's syndrome
61
Treatment
Physical therapy may be of value in
cases with sensory ataxia.
Unfortunately, it is rare to observe
any effect on the neurologic syndromes
Oncologic
 Usually, the anti-Hu titre is reduced after tumour treatment
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, René 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.
Camdessanché 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)
62
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
63
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.
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-vg-Ca
channel antibodies, but without clinical signs or symptoms of myasthenic
muscle weakness.
Maybe it is related to anti-SOX1 (anti-Glial
nuclear antibodies, AGNA), the target being the Bergman glia in the Purkinje cell
layer.
See
also: “Cerebellar syndromes
with anti-PCA2 antibodies”.
Associated neoplasm
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
In more than 50 % LEMS cases smallcell lung cancer (SCLC) is co-existent,
64
Hz) or preferably maximal 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 Ca-influx
channel. It appears that this autoantibody is a feature of all anti-vgCa 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-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.
65
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 Morvan’s syndrome. Moreover, see sporadic rippling
muscle syndrome.
66
Anti-CASPR2 disorders:
Peripheral nerve hyper-excitability
Morvan’s 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

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.
Voltage-gated-K+-channel
Course
Fluctuations, but no spontaneous remissions
Neurophysiology
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.
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.
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.
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.
Distribution: limbs > trunk & face
Myokymia
This feature is absent in some patients, and may develop on subsequent study, often as a mild continuous spontaneous activity.
67
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 Fwaves.




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 (contactin-associated 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 contactinassociated protein-2 in limbic encephalitis.
Therefore, this assay is not specific to antiVGPC.


Myasthenia gravis (seropositive,
anti-AChR antibodies)
The over activity begins with or after MG. The frequency of Isaac’s
syndrome in myasthenics is estimated at about 10 to 20% and observed with a thymoma in patients
> 40 years
 Penicillamine treatment
CSF may occasionally show abnormality
 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
68
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. Morvan’s 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
Brain 2006; 129: 1570–1584.
Irani SR, Sian Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, Peles E, Buckley C, Lang
69
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 co-occurrence 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)
thymomas (cortical type?). 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
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%)
 Coomb’s (10%)
70
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 rates of
myasthenia gravis in EasternDenmark 1970-99.
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
1
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 co-existent 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 early-onset
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 gravisassociated.
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%
71
o

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.
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 non-thymoma 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
72
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.
In short:
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. adult-type
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.
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.
73
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.
74
Paraneoplastic myopathies
In association with a variety of neoplasms, the features of these myopathies are a predominantly proximal
and symmetrical muscular weakness, and maybe arthralgias, dermatologic manifestations or myasthenic
fatigue.
Table 10: Some currently known disorders
Category
A
B
C
D
E
Other
Autoimmune myopathy
Dermatomyositis
Associated autoantigens
Mi2β, SAE2, SAE1, Mi2α, TIF1γ, PX2
Polymyositis
Overlap
Acute necrotizing myopathy
Inclusion body myositis
Severe autoimmune myopathy (IIM)
Paraneoplastic myasthenia gravis
associated myopathy
Sporadic rippling muscle syndrome
Giant cell myositis
Eosinophilic myositis
Granulomatous myositis
Macrophagic myofasciitis
Pipestem capillary disease
Myositis related to other connective
tissue diseases
SRP, Jo-1, PL-12, PL-7, EJ, OJ
PM-Scl75, PM-Scl10, KU
HMGCR
cN1A (Mup44)
FHL1
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.
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 connectivetissue disorders. Evidence suggests that
a T-cell–mediated cytotoxic process is
directed against unidentified muscle antigens.
Onset


Adults over 30 years of age; female-to-male ratio 2:1
Slowly progressive over weeks to
months; active 2-3 years
Titin
Titin isoform N2A, ATP synthase 6, PPP1R3
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
antibody-mediated disease. B-cells and
CD4 (helper) cells are also present in
abundance in the inflammatory reaction
associated with the blood vessels.
Clinical features
Myopathy
 Muscular weakness, primarily
proximal and most often symmetrical
Skin manifestations
 Heliotrope rash involving the
periorbital skin
 Photosensitive poikilodermatous
eruption
 Erythematous scaly plaques on
dorsal hands with periungual
telangiectasia and joint eruptions
(Gottron papules)
75
Association with malignant disease
Dermatomyositis
SIR
95 % CI
Heliotrope rash
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
lymphoma
3.6
1.2-11.1
Polymyositis
Gottron papules
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.
Poikilodermatous eruptions
Laboratory markers

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






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.
76
Anti-syntethase syndrome
Symptomatology
Autoantigens
polymyositis
fever
Jo-1, EJ,
polyarthritis
OJ, PL-7,
Raynaud’s phenomenon
PL-12
interstitial lung disease
3. Anti-TIF1γ, anti-MDAS, antiNXP2
Anti-TIF1γ (transcriptional
intermediary factor 1-gamma) – alias anti155/140
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 antiTIF1γ
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. Necrotizing
myopathy
Onset


Quite rare disorder
Rapid progression over one to
three months
Clinical features




Symmetrical and predominantly
proximal weakness
May also include dysphagia
(60 %)
Arthragias (50 %)
Eventually, severe functional disability
Associated neoplasms (13 %)




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
Tissue type
 Increased frequency of HLADR11 (70-90 % vs. about 20 %
in controls)
 Protective: DQA1; DQB6
Associated antibody
This autoimmune disorder may
represent a severe form of polymyositis.

Anti-HMGCR
(3-hydroxy-3-methylglutarylcoenzyme A reductase) - the ratelimiting enzyme for cholesterol
synthesis. Serum from such patients specifically recognizes the
intracellular catalytic domain of
HMGCR.
77
Differental-diagnoses
 Statin-provoked rhabdomyolysis
Interestingly, it appears that the
frequencies of statin use differ in antiHMGCR
seropositives
versus
dermatomyositis and polymyositis
cases
(83 %, 25 % and 37 %,
repectively) – and using the chi2-test,
this is significant.
Statins may cause diffuse or multifocal up-regulation of MHC-I expression
even in non-necrotic fibres.


C. Inclusion body myositis, sporadic
This myopathy is associated with
anti-cN1A
(anti-Mup44)
and
rarely endometrial carcinoma of
the uterus; please see below.
Statins are among the most commonly prescribed medications that
significantly reduce cardiovascular
risk in selected individuals. However,
these drugs can also be associated
with muscle symptoms ranging from
mild myalgias to severe rhabdomyolysis.
While statin myotoxicity is usually
self-limited, in some instances statinexposed subjects can develop an autoimmune myopathy typically characterized by progressive weakness,
muscle enzyme elevations, a necrotizing myopathy on muscle biopsy, and
autoantibodies that recognize HMGCR
(3-hydroxy-3-methylglutaryl-coenzyme A reductase), the pharmacologic target of statins.
These antibodies are also found in
some autoimmune myopathy patients
without statin exposure. Importantly,
anti-HMGCR antibodies are not found
in the vast majority of statin-exposed
subjects without autoimmune myopathy, including those with self-limited
statin intolerance.
Thus, testing for these antibodies may
help differentiate those with self-limited statin myopathy who recover after statin discontinuation from those
with a progressive statin-associated
autoimmune myopathy who typically
require immune-suppressive therapy.
Treatment
Oncologic and immunosuppressants
 Corticosteroids
Azathioprine
Intravenous administration of
high-dose IgG
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 INCLUSION
3.
BODY MYOPATHY WITH EARLY-ONSET
PAGET DISEASE AND FRONTOTEMPORAL
DEMENTIA; IBMPFD
78
5.
IBM 3; see OMIM
# 605637
INCLUSION
BODY
MYOPATHY
AUTOSOMAL DOMINANT; IBM3
3,
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
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 a feature 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.
Uterus: endometrial carcinoma
Differental-diagnosis
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 usually display abnormalities
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


Anti-cN1A (Cytosolic 5'nucleotidase 1A) – alias antiMup44
Anti-HMGCR (3-hydroxy-3methylglutaryl-coenzyme A
reductase)
Treatment
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
79
This myopathy is associated with
postsynaptic disorders of the NMJ,
comprising:
 Paraneoplastic-SPMG (thymoma)
 Late-onset SPMG
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.
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
Associated neoplasm

Thymoma: a finding in about 1015 % of all MG cases
Anti-AChR (100%, adult- and foetal-type)
Onset
See figure showing the annual incidence rates of early-, late-onset &
thymoma-MG in the section “Paraneoplastic SPMG with thymoma”.
Clinical features



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 antistriated 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 non-thymoma 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.
Comments
SPMG fulfils the criteria of an autoantibody-mediated disorder. Since the
80
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.
81
Abbreviations: CADM cancer associated dermatomyositis; DM Dermatomyositis; JDM Juvenile dermatomyositis; PM polymyositis; IBM inclusion body myositis
E. Rippling muscle
syndrome, sporadic –
autoimmune




This myopathy appears to be attributable to mechanical sensitivity
and instability due an effect of antiStriated muscle antibodies.
Onset
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
30 to 55 years

Clinical features
Antibodies





Rippling muscles
Rolling muscle contractions
Muscle stiffness
Myotonia
Cramps
o Induced by exercise or touching muscle

Anti-Skeletal muscle (see below
for specificity): use unspecific immunohistochemical methods to
detect these antibodies, unless a
specific method is available
82
There are three associated and
distinct muscle antigens:
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)

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


Myasthenia gravis: rippling muscles may precede this disorder
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.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
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30. Skeie GO, Aarli JA, Gilhus NE. [Review].Titin and ryanodine receptor antibodies in myasthenia gravis.
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31. Niks EH, Kuks JB, Roep BO, Haasnoot GW, Verduijn W, Ballieux BE, De Baets MH, Vincent A,
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32. Fraterman S, Khurana TS, Rubinstein NA. Identification of acetylcholine receptor subunits
33. Christopher-Stine L. Statin myopathy: an update. Curr Opin Rheumatol 200618 (6): 647-53
34. Needham M, Fabian V, Knezevic W, Panegyres P, Zilko P, Mastaglia FL. Progressive myopathy
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35. Romi F., Aarli JA, Gilhus NE. Myasthenia gravis patients with ryanodine receptor antibodies have
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37. Dalakas MC, Rakocevic G, Schmidt J, Salajegheh M, McElroy B, Harris-Love MO, Shrader JA, Levy
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38. Hoshino K, Muro Y, Sugiura K, Tomita Y, Nakashima R, Mimori T. Anti-MDA5 and anti-TIF1-gamma
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85
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:
 Paraneoplastic limbic encephalitis (PLE)
 Paraneoplastic sensory neuropathy (SSN, PSN)
 Morvan’s 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
The associated antibodies include
86
Ta/Ma2 antibodies, in which approximately 30% of patients respond to tumour
removal and immunotherapy, the other disorders are rarely treatment-responsive.
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 voltagegated potassium channels (VGKC). GAD antibodies usually associate with nonparaneoplastic 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 Morvan’s syndrome.
Anti-D1, anti-D2, anti-lyso-GM1 are findings related to the post-streptococcal
neurological syndrome.
Anti-Alpha-enolase (ENO1) is associated with Hashimoto’s 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
87
Paraneoplastic extrapyramidal disorders
Paraneoplastic extrapyramidal disorders:
 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, variants: suggestive features
Paraneoplastic pain
Paraneoplastic pain
 Paraneoplastic sensory neuronopathy (SSN, PSN)
 Paraneoplastic sensory-motor neuropathy
88
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 selflimiting and self-repairing, over various malformations, and maybe even to severe
and permanent defects of the nervous system. The worst-case scenario is fatalities.
Moreover, women beyond the normal
age of fertility or having recovered
Table 11: Foetal exposure to materfrom a cancer are increasingly seeking
nal autoantibodies
medical assistance to become pregExamples
nant.
1
PNS resembling that of
the mother

2
3
Neonatal MG
Deformities

Acquired arthrogryposis
multiplex
Malformations

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
leukaemias, Hodgkin’s disease, malignant monoclonal gammopathies, etc.
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)
o Anti-AChR (nicotinic alpha3-type,
ganglionic autonomic)
o
o
o
Anti-vg-K channels
Anti-Titin
Anti-RyR1
89
o
o
o
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 antibrain
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 specific
language disorder
To investigate this case for passively
transferable factors, maternal serum
90
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.
‘Risk of passive transfer MG’ in the
chapter “Paraneoplastic SPMG (thymoma)”.
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
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
to myasthenic mothers.
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
Disorders
A. Myasthenia gravis
The finding of autoantibodies specific
to foetal AChR is frequent in MG patients. For further details, please see
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
foetal loss, stillbirth or early termination. Preventive treatment during a
pregnancy is an option, and the outcome may be a perfectly healthy child.
91
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-concurrent
thymomas has not been reported in
these studies. In Denmark, this paraneoplastic form of MG accounts for
about 10% of all myasthenics.
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.
92
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24.
25.
26.
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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): 10311038.
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
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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
Dalton P, Clover L, Wallerstein R, Stewart H, Genzel-Boroviczeny O, Dean A, Vincent A. Fetal
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93
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 (α3)
♪
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
alpha3-type
embryonic-type
muscarinic acetylcholine receptor of
M1-type
SRY (sex determining region Y)-box
1, glial nuclear
α-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
94
Anti-Striated muscle
☼
Anti-Ta
Ma2/PNMA2
Anti-TIFγ
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.
95
CASPR2
vgKCcompl
ex
LGI1
D1, D2
GABABR1
GlyR α1
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
x
Vesicles
x x x x x
x x
Membrane
Cytoplasmatic
Channels & receptors
Tropic
Iono
Metabo
x
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 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
X
Anti-GABABR1
Anti-GAD
X
X
Anti-ENO1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
96
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 (small-cell 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- & foetaltypes (paraneoplastic MG) and presynaptic, the muscarinic AChRs of M1type (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 α-amino-3-hydroxyl5-methyl-4-isoxazole-propionate receptor (AMPAR, a glutamate receptor
of the ionic type.)
The clinical features are limbic encephalitis with seizures and more. The
associated neoplasms are SCLC, nonSCLC, thymoma and breast cancer.
These antibodies are a feature of
SCLC and the following PNS: LEMS,
97
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 voætagegated 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 (Morvan’s
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
98
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 co-purifies
with the inhibitory glycine receptor.
Gephyrin is responsible for clustering
GlyRs to postsynaptic sites by linking
the GlyRβ 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 reductase induce
the expression of LDL receptors in the
99
liver, which in turn increases the catabolism of plasma LDL and lowers
the plasma concentration of cholesterol, an important determinant of
atherosclerosis.
This autoantibody is associated with
acute necrotizing myopathy (polymyositis?); sporadic inclusion-body
myositis; polymyositis / dermatomyositis
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
Hodgkin’s 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 RNAbinding 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 cross-reaction with neurologic tissue, triggered
by a remote carcinoma.
In about 70% of patients with the
anti-Hu syndrome, the initial target 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.
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.
It is associated with the following neoplasms: SCLC, breast, ovarian, testicular, prostate, thymoma, neuroblastoma and more. Apart from stiffperson 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 Shaker-related
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 antiCASPR2
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
AMPA receptors via the ADAM proteins.
LGI1 is a ligand for ADAM22 that
positively
regulates
synaptic
100
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-D-aspartate receptor (NMDAR, a glutamate
receptor of the ionic type.) The NMDA
receptor is distinct in that it is both
ligand-gated and voltage-dependent.
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 prepubertal 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,
101
dyskinesias, dystonia, decreases consciousness, sleep disorder and more
(dyskinetic encephalitis lethargica).
Anti-PCA2
The antigen is a 280 kDa neuron-specific 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-vgCa-channel (P/Q- & N-type) and antiAChR (of muscle & neuronal type).
Clinically, anti-PCA2 is associated with
PCD. Attributable to the co-existing
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 co-enzyme
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 welldifferentiated 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 neuro-oncological 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 Cterminus (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
syndrome. See also anti-Titin and
anti-RyR1.
Anti-Ta (Ma2, PNMA2)
102
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.
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.
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.
The antigen is the delta and notch-like
epidermal growth factor-related receptor (DNER).
Anti-TIFγ (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-Tifγ
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 late-onset 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 MGT30-peptide). In sporadic rippling muscle syndrome, the antibodies are to
the titin isoform N2A.
The associated cancer is Hodgkin’s
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, ubiquitinconjugating 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.
Anti-Yo (Young, CDR1 (CDR34), CDR2,
CDR2L
(CDR62-1,
PCD17-SN, CZF)
CDR62-2),
CDR3,
Anti-Tr (Trotter, PCA-Tr)
103
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
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.
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.
SCLC is the associated neoplasm, and
PCD is the typical neurologic finding.
A combined finding of anti-ZIC4 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.
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
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
104
105
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.
106
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.
107
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): 145151.
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.
108
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 · 77; 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 · 77; 78
anti-nCMAg · 36
anti-Neurofilaments · 41; 101
anti-NMDAR · 36; 101
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; 102
anti-Ri · 25; 33; 37; 38; 42; 101
anti-RyR1 (ryanodine) · 70; 79; 89; 102
anti-Striated muscle · 70; 79; 83; 102
anti-Ta (Ma2) · 35; 37; 42; 43; 102
anti-TIF γ · 76
anti-Titin · 22; 89; 102
anti-Tr · 25; 28; 43; 44; 103
anti-Tr syndrome · 28
anti-Tulip1 · 103
anti-UBE2E1 · 36; 103
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; 102; 103
C
cerebellar degeneration (PCD) · 24
choreo-athetosis · 31
109
chronic gastrointestinal pseudoobstruction · 33; 56
colon cancer · 27; 75
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 · 27; 31; 37; 50; 52; 53; 87
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; 103
hypotension, labile · 33; 56
I
immunosuppression · 19
Inclusion body myositis, hereditary · 77
Inclusion body myositis, sporadic · 77
Isaacs' syndrome · 65
L
Lambert-Eaton myasthenic syndrome (LEMS) · 63
LEMS-associated PCD · 30
leukaemia · 40; 57
lung cancer · 5; 12; 13; 25; 26; 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; 103
M
M-components · 58
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 · 79
myeloma · 40; 57
myoclonus · 42; 53
myokymia · 27; 66; 100
myopathies · 74
myopathy
paraneoplastic MG-associated myopathy · 79
myositis-overlap antibodies · 76
myositis-specific antibodies (MSA) · 75
N
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
P
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
110
R
rectum cancer · 56; 75
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; 102; 103
sensory neuropathy · 59
sensory-motor neuropathy · 57
sporadic inclusion body myositis · 77
sporadic rippling muscle syndrome · 83
statin-provoked rhabdomyolysis · 77
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; 79; 88; 90; 91; 96; 98; 99; 100;
102
thyroid cancer · 44; 58
transfer from mother to foetus · 88
U
uterus cancer · 27
W
Waldenstrom's macroglobulinaemia · 40
111
Autoimmune encephalitis, please see
separate compendium
Autoimmune encephalitis
History & current
knowledge
Short compendium
Version 3.2, May 2014
By
Department of Clinical Biochemistry, Immunology & Genetics
112
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
Department of Clinical Biochemistry, Immunology & Genetics
113
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
[email protected] – www.ssi.dk
http://www.ssi.dk/Diagnostik/Downloads.aspx
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Paraneoplastic neurological syndromes

Transcription

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