Paraneoplastic Neurological and Muscular Syndromes

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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

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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 printed in blue Treatment printed in green

Underlined text is hyperlinked

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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

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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 Often quite disabling neurologic cancer” signifies that PNSs per features definition cannot be attributable Another characteristic is that the neu- to: rologic features in themselves may be  Mechanical, inflammatory or much more disabling that the other neoplastic effects in continuity effects of the cancer. Although rela- with neoplasms, including me- tively uncommon, the PNSs therefore tastasis and meningeal carci- are important causes of severe and nomatosis permanent neurologic disability. Early  Cancer-related cachexia and diagnosis of the neurologic disorder anorexia and prompt initiation of tumour treat-  Neurotoxicity from chemother- ment probably increase the likelihood apy of neurologic improvement.  Adverse effects of radiation therapy  Vascular or metabolic disorders Occurrence of onconeural anti-  Infections bodies  All other not cancer-related Several autoantibodies have a syn- causes dromic association, although none of them appears to predict a specific neurological syndrome. Conversely, a Adhering to this definition, mild or positive autoantibody profile has 80% subclinical muscular weakness or pe- to 90% predictive value for a specific ripheral neuropathies are features in cancer. It is not uncommon for more up to 20% of patients with cancer. than 1 paraneoplastic autoantibody to However, a clinically significant PNS be detected, each predictive of the occurs in less than 1% of such pa- same cancer. tients. The great majority (>90%) of patients with PNSs have circulating on- PNSs are heralding neoplasms coneural antibodies which can be use- As a rule, such syndromes are early ful in identifying the neurologic disor- symptoms (or set of symptoms) that der as paraneoplastic and in finding might indicate the start of a neoplastic the associated neoplasm. However, disease before specific symptoms oc- such autoantibodies can also be a fea- cur (prodromes). The symptoms and ture of some patients with cancer and signs may even precede the diagnosis without neurological symptoms. The of a neoplasm by several months and strongest association between neo- sometimes years. This may also be plasia and neurological disorders is true even after an intensive search for that between small-cell lung cancer a tumour. In such a case, consider (SCLC) and anti-Hu (Hull) antibodies. one or more follow-up examinations The seropositive incidence is about at appropriate intervals. 17% in SCLC patients. Accordingly,

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these autoantibodies are important across membranes. The internaliza- markers of PNS and neoplasms. tion of proteins located in membranes is normally a process of endocytosis As a rule: the ‘classical’ onconeural as part of a recycling process. Pre- antibodies (anti-Hu, Yo, Ma2, CV2 sumably, “internalizing” antibodies (CRMP-5), amphiphysin and Ri) are enter cells by the same mode, alt- directed against intracellular antigens hough various other similar mecha- and are strongly associated with un- nisms may be operational as well. derlying malignancy. By contrast, onconeural antibodies directed against Onconeural antibodies are organ spe- cell surface antigens (e.g., anti- cific. For example, anti-Hu and anti-Ri NMDAR, VGKC, AChR) have a weaker (Richards) antibodies are both immu- tumour association. noreactive with nuclear structures of the central nervous system, but in Discussion contrast to anti-Hu, anti-Ri antibodies It is tempting to speculate that PNSs do not bind to nuclei of neurons in the may be attributable to immune re- peripheral nervous system. Therefore, sponses against tumours that express anti-Hu and anti-Ri are also known as neural antigens. The majority of the anti-neuronuclear antibodies type one onconeural antibodies are specific for & two (ANNA1, ANNA2), respectively. intracellular antigens, and only a Likewise, the occurrence of anti-Ri is minor fraction of them is exposed to not associated with any peripheral extracellular structures, such as re- PNS, while an anti-Hu finding is asso- ceptors and channels (Table 9). ciated with PNS of both locations. It is also noteworthy that more than nine The central and peripheral nervous onconeural antibodies recognize in- systems are usually considered im- tracellular structures of the Purkinje mune privileged sites, so the parane- cells, which are some of the largest oplastic immune response must be neurons in the brain. However, pas- capable of breaching the blood-brain sive or more direct transfer models or the blood-nerve barrier in order to with purified IgG from such patients cause neurological pathology. The have failed to produce any PNS in an- neuromuscular junction (NMJ) is an imals, apart from anti-mGluR1. On exception, since no barrier is protect- the other hand, reports have shown ing this location. It is quite uncertain that transfer of specific T-cells pro- to which extent intrathecal synthesis vokes neurological disorders in animal of onconeural antibodies may account models. Therefore, it appears that in- for pathology. The intracellular locali- tracellular antigen related PNSs also zation of many paraneoplastic anti- involve an autoimmune T-cell compo- gens adds further to the difficulty in nent. Accordingly, it is possible that understanding the putative pathologi- merely, neuronal autoantibodies are cal role of onconeural antibodies. Ac- markers of a destructive process, or cordingly, these antibodies may be else may signify direct toxicity of the important diagnostic tools but are not activated immune system. necessarily causing the manifestations of PNS, at least not alone. Associated both with and without neoplasms, it is now possible to The value of antibodies is to protect diagnose autoimmune synaptic against foreign agents. They should encephalitis. The targets may be cell gain access wherever required, in- membrane proteins (receptors and cluded in the cerebrospinal fluid (CSF) channels), a protein within a synapse and inside cells. Onconeural antibod- (e.g. LGI1) or structures that are ies are indeed a feature of both the expressed presynaptically (e.g. an NMJ and CSF in PNS. As one may ex- enzyme necessary for the synthesis of pect, there is strong evidence to sug- a neurotransmitter). Currently known gest that active mechanisms are facil- such autoantibodies are directed to itating the passage of antibodies NMDAR, AMPAR, GABABR1, GlyR

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alpha1, AQP4, LGI1, CASPR2, and Hypothesis GAD. It appears that intrathecal A dynamic hypothesis may therefore synthesis of specific autoantibodies be that PNSs either develop depend- and CNS infiltration of plasma cells ent on the synthesis and local influx of are features of some of these autoantibodies or as T-cell mediated disorders. autoimmunity, and in many cases maybe combined. As related to autoantibodies to exposed extracellular structures, it is a Knowledge is lacking about a variety different story. There is clear evidence of co-factors. Genetics may also play to show that such associated antibod- a major role. Further studies of PNSs ies play a direct role in autoimmune may provide clues to a better under- disorders of the NMJ and other synap- standing of tumour immunology and ses. Using purified IgG (or monoclonal of how the nervous system becomes antibodies) directed to exposed involved. epitopes, passive transfer models have been quite successful in produc- ing direct pathology. There are three Various other aspects major mechanisms. Modulating anti- Since we know the location and func- bodies appear to signal that a struction of many of the involved structure is already “outdated”, i.e. it is tures of the nervous system, a finding time to replace it. This may be a factor of specific autoantibodies provides an causing endocytosis ahead of time. important clue to directly linking such Alternatively, the autoantibodies may a feature to one or more specific loca- provoke complement-mediated de- tions of the nervous system. Con- struction. The result is a scarcity of versely, the clinical findings may sug- antigenic targets. The antibodies may gest one or more specific autoanti- also act as competitive inhibitors of bodies to look for. In short, knowl- such receptors or channels. Alto- edgeable and skilful neurologists are gether, this autoimmune pathology is able to recognize the clinical manifes- quite detrimental to the transmission. tations 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.

30/01/2016, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Short introduction to the immune system

favourable that the immune system is The innate immune system there to protect against neoplasms, • This is what we are born with but it is unfortunate when this also and it is non-specific implies the nervous system to become • All antigens are attacked pretty malfunctioned. Clearly, the immune much equally system is not perfect. • It is genetically based and we pass it on to our offspring Model disease The immunopathogenesis of PNSs is The adaptive or acquired im- very complex. In order to discover mune system various mechanisms therefore, the • Cell-mediated immunity study of experimental disorders are • Humoral-mediated immunity important. If a structure is not protected by any Overall classification barriers (BBB = the blood brain bar- The innate immune system provides rier; BNB = blood nerve barrier) and essential protection already from birth. the antigen is an exposed extracellu- The adaptive immune system is there lar molecule, then it is technically to provide additional protection more simple to create models. Con- against various hazards that may versely, there are also sequestered happen later in life. structures in existence, i.e. they are invisible to the immune system due to The immune system within a PNS a BBB or BNB or an intracellular loca- context tion. In such latter cases, special The current concept is that the ex- measures are necessary in order to pression of neuronal proteins by the circumvent these hindrances. A first cancer triggers an immune response step may be transfer of encephalitis- against the tumour and that is misdi- inducing T-cells to make the barrier rected against the nervous system, leaky. This may also happen by an im- resulting in the paraneoplastic disor- munization using Freund’s adjuvant. der. This immune response is charac- Having solved these obstacles, the fi- terized by high titer of serum antibod- nal steps consist in either immuniza- ies (often accompanied by cytotoxic tion with a purified antigen or transfer T-cell responses) that specifically re- of disease-provoking agents such as act with proteins exclusively ex- specific T-cells or antibodies (for expressed by neurons and the cancer ample purified immunoglobulin or cells (onconeuronal antigens). Detec- specific monoclonals). tion of these serum antibodies allows for a major step as a part of the diag- Unprotected locations are at the NMJs. nosis of these neurologic disorders as In the peripheral nervous system, paraneoplastic. there are also less protected areas as follows: distal nerve terminals, nodes Such autoimmunity often involves of Ranvier, areas close to the cell body, pathological mechanisms of the in- and ganglia. In such cases with more nate immune system and in particular or less easy accessibility, a transfer by toll-like receptors. Conceivably, how- various direct routes may be possible: ever, PNSs may arise either as inade- intravenous, intraperitoneal, intrathe- quate innate immunity, as inappropri- cal, or by local injection. ate adaptive or acquired immunity, or as combined and even more complex In analogy with other autoimmune autoimmunity. Metaphorically, the oc- disorders, a useful categorization of currence of PNSs may be looked upon the PNSs is: as an “own goal”. It is of course quite 1. Antibody (humoral)-mediated

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

Criteria to be satisfied to accept a disorder as autoantibody mediated

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

Table 1a: The following disorders appear to satisfy these criteria, either totally or to a lesser extent Disorder Autoantibodies Seropositive myasthenia gravis (SPMG)  Paraneoplastic SPMG (thymoma) Anti-AChR to the nicotinic receptor of  Early-onset SPMG adult- and embryonic type  Late-onset SPMG  Neonatal SPMG  Acquired arthrogryposis multiplex in SPMG Autoimmune autonomic neuropathy Anti-AChR to the nicotinic receptor of (AAN) alpha3-type Anti-vg-Ca-channel of P/Q- and N- Lambert-Eaton myasthenic syn- type, anti-AChR to the muscarinic re- drome (LEMS) ceptor of M1-type Anti-Accessory proteins at vg-K- Morvan’s fibrillary chorea channels Anti-Acessory proteins at vg-K- Paraneoplastic limbic encephalitis channels, anti-NMDAR, anti-mGluR1, anti-mGluR5, anti-Amphiphysin? Acquired neuromyotonia (Isaacs’ Anti-Accessory proteins at vg-K- syndrome) channels Paraneoplastic ataxia Anti-mGluR1 Stiff-person syndrome? Anti-Amphiphysin Paraneoplastic opsoclonus, Anti-Amphiphysin myoclonus?

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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 ] o 2012: Lewis rat animal model of Sydenham chorea and related neuropsychiatric disorders [http://www.nature.com/npp/journal/v37/n9/abs/npp201256a.html]

Milestones in experimental The role of onconeural autoanti- disease, including PNSs bodies A. Without a barrier of protec- Such autoantibodies are a feature of tion the serum in more than 90% of pa-  Myasthenia gravis tients with PNSs. The finding in itself  Immunization with purified is strong evidence of a coexisting ne- ACHR (rabbit model 1975) oplasm, which currently may even es-  Transfer of purified IgG cape detection by other means due to (1975) a too small size or a location, which is  Transfer of monoclonals unfavourable to diagnostics. (1981)  Immunization with peptide The breakdown of tolerance appears sequences of ACHR (1994) to be quite selective, since there is an  LEMS almost exclusive finding of highly or-  Transfer of purified IgG gan-specific onconeural antibodies in (1983) PNSs.  Immunization with cholinergic synaptosomes (1990) An illustrative example:  Neuromyotonia Polymyositis is associated with coex-  Transfer of purified IgG isting cancer. Due to binding of all the (2003) myositis specific and overlap antibod-  Autoimmune autonomic neu- ies, there are lesions and repair ropathy mechanisms, including local infiltra-  Transfer of purified IgG tions with lymphocytes. Accordingly, (2004) the immune system is exposed to titin, the largest molecule in the body. An- B. With barriers of protection yhow, anti-Titin antibodies are never  Presumed humoral mediated a feature of this disorder. On the other  Pioneer CNS model 2003: hand, anti-Titin antibodies are indeed passive transfer of mGluR1 markers of postsynaptic NMJ disor- antibodies ders associated with myopathy, for  Presumed T-cell mediated example in paraneoplastic myasthe-  Pioneer CNS model 2004: nia gravis (thymoma). transfer of T-cells specific for the onconeural antigen Ma1 A lesson learned is that an already tol-  Passive transfer in rats by erated structure that becomes ex- means of IgG to amphiphysin posed does not provoke autoimmun- (2005, 2010) ity in itself. To doing so, it may have to be located within a “danger zone” (Matzinger’s hypothesis), which in a

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PNS context would mean a neoplasm. “danger zone” somewhere in the body Although still controversial and also in and even remote from the location of contrast to “classical” immunology, the auto-attack. this theory deals with an extra step - costimulation on peripheral sites - Another mechanism in autoimmunity saying that the cells of the body must may be epitope spreading (ES), asso- signal distress (“danger”) prior to ciating such pathology with chronic vi- awakening the immune system, and rus infections or neoplasia. The term that the mere presence of a foreign ES means the development of im- antigen is not enough for any action mune responses to epitopes distinct to be taken. In short, the danger met- from and non-cross-reactive with the aphor involves the use of the innate dominant primary epitope. In autoim- immune system to break peripheral munity, the process of ES may begin tolerance possibly leading to activa- with molecular mimicry which then tion of the adaptive immune system. spread to different epitopes (secondary epitopes) on one protein (intra- Bypass of T cell tolerance: some molecular ES), or to epitopes on other initial steps into autoimmunity proteins (intermolecular ES). Accord- Foreign epitopes do provoke useful ingly, the secondary epitopes, which immune defences. They may come are often cryptic epitopes on the same into the body from the environment or molecule or dominant epitopes on arise as neo-antigens. Modification of neighbouring molecules, are those to an already tolerated structure may be which responses arise later. Theoreti- an adverse effect of drugs or other en- cally, individuals harbouring mutated vironmental agents. The T-cells are gene products are more likely to be on the alert and ready to recognise exposed to cross-reacting autoanti- them upon proper presentation, and a bodies due to molecular mimicry or to “counterattack” may set in. ES than controls without. The theories about autoimmunity also Cross-reacting epitopes on the other comprise bystander activation, and hand, are targets shared by neo- superantigens that activate polyclonal plasms or invading microorganisms groups of T-cells. In particular, activa- and existent structures of the body tion of cytotoxic T-cells may be an im- (molecular mimicry). Mimicry be- portant mechanism. There are two tween epitopes of the body and an in- major groups of autoimmune disor- vader or neoplasm can be classified as ders: T-cell- and humoral-mediated “similar” or “dissimilar” dependant on ones. the extent of identity from a biochem- ical point of view. Accordingly, cross- Summary reactive antibodies, which recognize In short, it appears that in-host toler- dissimilar epitopes - comparing that ated targets are in jeopardy, if special of the provoking invader to the tar- conditions present similar epitopes to geted one of the body, may be a case the immune system. Such an expo- of a structural 3-D configuration in it- sure could be in conjunction with ne- self being sufficient for binding. oplasia or certain infections, thereby giving rise to a “danger zone”. Im- If targets are located intracellularly or munization with a purified substance protected by barriers, such as the in Freund’s adjuvant also creates such blood-brain/nerve barrier, then sup- an area. posedly they are invisible (“sequestered”) to the immune system. In It is far beyond the scope of this text such a situation, no autoimmunity but to go into all the details. The precise only useful immunoprotection sets in. mechanisms are complex and quite Unfortunately, if the immune system often largely unknown. eventually gains access to such epitopes, then autoimmunity is at play. The triggering event could be a

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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 becom- ing antigenic  The extent of protection against provoked complement attack may vary considerably on various surfaces

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Diagnostic strategy

A PNS diagnosis requires Furthermore, in such a case, the clin- combined clinical and serological ical severity of the PNS is likely to be findings proportional to the titre of the auto- In relation to PNSs, four situations antibody, enabling a performance of may exist; please see the following longitudinal monitoring of the disor- paragraphs A to D below. In all these der also by means of serum samples. instances, there is strong evidence in favour of the existence of a cancer un- D. Onconeural antibodies are der development. found in the serum, and a T-cell- mediated PNS is likely A. No onconeural antibodies are A relevant seropositive finding is found in the serum, even though available, but a broader spectrum of a PNS is likely the immune defence must be in oper-  The sensitivity of the autoantibody ation to cause any neurological disor- assay is too low der such as T-cells, cytokines & chem-  The autoantibody may only be okines, and other co-factors. found in the cerebrospinal fluid  It is a case of not circulating but Accordingly, serological evidence sup- sequestered autoantibody, i.e. it is ports the diagnosis, but the fulfilment only present in situ at the various of additional criteria is desirable. Once lesions again, “failure” to detect an autoanti-  A relevant autoantibody has not body does not exclude the diagnosis; yet been discovered see alternative A.  It is a case of a T-cell-mediated disorder with no particular role of The starting point any circulating autoantibodies The typical PNS-diagnostic procedure Clearly, the fulfilment of other diag- begins by a patient seeking medical nostic criteria is desirable. assistance for symptoms evolving at a chronology consistent with such a dis- B. Onconeural antibodies are order. found in the serum, although there are no symptoms or signs With only few exceptions, the clinical consistent with a PNS findings should be explicable in terms This is a common situation. Anti-Hu of a bilateral and symmetrical neuro- antibodies are a finding in more than logical disorder. This follows by sev- 15% of patients with SCLC, but only eral features. The remote effects are about 1% does exhibit a significant due to malfunction of antigenic struc- PNS. A diagnosis always requires clin- tures wherever they are located in the ical manifestations, and serological nervous system, and thus character- findings in themselves are not diag- ized by being bilateral and symmetric. nostic of any PNS. The onconeural antibodies and the pathological T-cells are organ-specific. C. Onconeural antibodies are The bloodstream is a common pass- found in the serum, and a hu- way at some step. The breaches of moral-mediated PNS is likely barriers are supposedly symmetric Assuming that the antibody is an as- and located at the most vulnerable sociated one rather than irrelevant, sites. 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.

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Step one versus onconeural antibodies’, which A focused clinical neurological may be useful in choosing an ade- examination quate serological screening. The spe- Perform a thorough neurological scru- cific findings of this step may point di- tiny and go as far as possible to doc- rectly to one or only a few significant ument that the findings are bilateral, first-line tests (cf. also the chapter symmetric and most likely also lo- ‘Onconeural antibody targets …..’ for cated to one or more foci as outlined additional clues), or alternatively, above. Furthermore, take care not to choose a ”package” covering more mistake any single element of the than 60% of the spectrum (Table 9). findings for another. Multifocal clinical findings are quite likely associated with anti-Hu antibod-  Cognition, personality changes, ies. other mental symptoms: mimick- ing a psychiatric disorder or more It is also worth bearing in mind a pos- likely of a neurologic nature? sible co-existence of more than one of  Mapping ataxia, coordination of these autoantibodies, so consider an movements inclusion of all relevant ones. A typical  Striated muscles: central or pe- example is anti-Hu together with any ripheral pattern of paresis; muscle of the following: anti-CV2, anti-Am- tonus; atrophy; myokymia; neu- phiphysin, anti-Ri, anti-vg-Ca-chan- romyotonia; chorea; athetosis; nel and anti-Zic4. In such cases, SCLC opsoclonus; myoclonus. Does rest is the expected underlying finding. or exercise influence muscular Optionally, consider postponement of symptoms? What may provoke or supplemental tests to a second-line relieve involuntary movements? procedure. However, if you are plan- Consider observations during ning a treatment with high-dose IgG, sleep, etc. then the infusion of such antibodies  Polyneuropathy is the most com- may seriously hamper the interpreta- mon paraneoplastic neurological tion of subsequent antibody analyses disorder, so a very detailed exam- for a long period. Circumvention of ination is called for this situation is possible by storage of  Examination of reflexes a sufficient number of serum samples  Look for signs of autonomic neu- on beforehand. ropathy  Video recordings of neurological In diagnosing a humoral-mediated signs may also be useful – and in PNS, the finding of a relevant on- particular when viewed by a coneural autoantibody is providing knowledgeable neurologist quite strong evidence in favour of the supposed disorder. This is in contrast to T-cell-mediated ones, in which an Step two onconeural marker is only providing The finding of onconeural indirect evidence of the diagnosis. antibodies in serum or CSF Moreover, it is not rare to encounter a Several autoantibodies have a syn- seropositive patient without any fea- dromic association, but no autoanti- tures of a PNS, which is explicable in body predicts a specific neurological terms of the immune system trying to syndrome. Conversely, a positive au- combat a neoplasm somewhere in the toantibody profile has 80% to 90% body, although without causing any predictive value for a specific cancer. harm to the nervous system. With few It is not uncommon for more than 1 exceptions therefore, the onconeural paraneoplastic autoantibody to be de- antibodies are valuable markers of tected, each predictive of the same neoplasm, which may even escape cancer. other means of detection at an unfavourable point in time. By the end of this textbook, please find a categorized table showing ‘PNS

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Step three High definition magnetic reso- Diagnostics by imagery nance imaging (HD MRI) captures CT provides rapid, non-invasive imag- images at a much higher resolution ing of the CNS. than ever seen before. With this new technique, radiologists can shorten MRI offers better resolution of neural scan times and see highly detailed structures than that of CT. Currently, pictures. Although the true value of MRI is the preferred first-line choice this new technology of imaging still is for detection of autoimmune inflam- unknown, it may turn out to be signif- matory areas, demyelinising plaques, icant also in the diagnostics of PNSs. neoplasms, metastases, early infarc- tion, subclinical brain oedema, and much more. For example, visualiza- Positron emission tomography tion of inflammatory, demyelinising, (PET) or neoplastic lesions may require en- PET neuroimaging is based on an as- hancement with intravenous para- sumption that areas of high radioac- magnetic contrast agents, such as tivity are associated with brain activ- gadolinium. The use of diffusion- ity. The technology is using radioiso- weighted MRI allows rapid and early topes with a very short half-life, so a detection of the various disorders. cyclotron must be available not too far away in delivery-time to the PET scan- As related to MRI, the expected find- ner. PET uses isotopes incorporated ing in PNSs of the CNS is a bilateral, into compounds normally used by the symmetric and somewhat diffuse pa- organ under examination, for exam- thology. It may be bi-focal such as in ple glucose. Such labelled compounds a “pure” syndrome of limbic encepha- are known as radiotracers. In neurol- litis, cerebellar degeneration, chorea ogy, fluorodeoxyglucose (FDG) is a or athetosis (basal ganglia). Alterna- common tracer, and the abbreviation tively, it could also be multifocal alt- for this imaging is FDG-PET. hough still symmetrical. This is the expected finding in two situations: the existence of multiple sites of a tar- Single photon emission computed geted specific epitope; in cases with tomography (SPECT) more than one onconeural antibody, This imaging technique is using there is a situation of different tar- gamma rays, and it is providing true geted epitopes. 3D information. Brain SPECT is using technetium-99m. Be aware that in paraneoplastic cerebellar degeneration, MRI typically In relation to paraneoplastic CNS dis- does not reveal any pathology at the orders, PET or SPECT may be useful, onset or even long time during the when ‘classic’ MRI fails to reveal any course, although it may eventually findings, although they are suppos- show atrophy. edly there.

In short: in a context of PNSs, MRI Some paraneoplastic CNS disorders often serves to exclude that there are are truly multifocal or showing clinical unilateral findings such as signs of continuity with a pattern that may brain tumour, metastasis, stroke, vary among patients. In such in- vasculitis, etc. Asymmetrical bilateral stances PET, SPECT or MRI combined findings would point towards glioblas- may result in a much more precise toma, metastases, inflammatory de- mapping of the pathology. myelinising disorder, vascular disease etc., rendering a paraneoplastic diagnosis more unlikely.

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Step four next chapter. Key word may be a Find intrathecal evidence in fa- medical urgency. vour of on-going immunological processes and exclude meningeal carcinomatosis Step five (neurophysiology) Lumbar puncture can be a helpful tool, EEG, evoked potentials, EMG, since CSF inflammation is a common nerve conduction velocity stud- feature of PNS patients. The likelihood ies, repetitive nerve stimulation, of pathological findings is gradually single-fibre EMG decreasing by time after onset of neu- EEG is a method to detect electrical rological symptoms. pathology associated with seizure disorders, sleep disorders, and metabolic Presence of a mass that could precip- or structural encephalopathies. Ab- itate transtentorial or cerebellar her- normal wave patterns may be non- niation constitutes a risk. As a rule specific (for example paraneoplastic therefore, consider CT or MRI prior to epilepsy with epileptiform sharp any examination of the cerebrospinal waves) or diagnostic (e.g. in Creutz- fluid (CSF). feldt-Jakob disease as a differential diagnosis to paraneoplastic chorea). Table 2 provides a summarization of the findings Measurement of evoked poten-  Increased total protein (hyperpro- tials is a method using visual, audi- teinorachia) is a sensitive but non- tory, or tactile stimuli to activate cor- specific measure of disease. responding areas of the cerebral cor-  Elevated immunoglobulin and oli- tex, resulting in measurable and dis- goclonal banding are also frequent tinct focal cortical electrical activity. findings, although unspecific and a Computer processing cancels out feature in a variety of other disor- noise to allow detection of abnormal ders, such as demyelinising ones waveforms. Evoked responses are and various infections of the CNS. particularly useful for detecting clini-  Pleiocytosis - with not too many cally unapparent deficits, which may lymphocytes (usually < 25) - is an also be of interest in the diagnosis of expected early finding in about PNSs. For example, consider such an 50%. However, depending on the examination in an anti-Hu or anti-CV2 specific nature of the disorder, (CRMP5) seropositive patient. Such pleocytosis may be present for cases are likely to have a multifocal longer periods. A cell count above disorder including areas, which may for example > 100 should alert escape detection by other examina- you to look for other diseases. tions. Per definition, a finding of malignant cells in the CSF excludes the possibil- Electromyography and nerve con- ity of a PNS. Sometimes the search for duction velocity studies are both of malignant cells may involve consecu- great value to identify affected nerves tive lumbar punctures over time, and muscles. It may be clinically diffi- since the initial ones could be falsely cult to make out whether a muscular negative. weakness is due to nerve, muscle, or neuromuscular junctional disorder. CSF findings are a reflection of on-go- Neurophysiology also enables a more ing immune processes in the CNS. precise location of sensory dysfunc- They fade away along with the eradi- tions. In addition, neuropathies can cation of antigenic structures. If im- be classified into demyelinising and munosuppressive treatment is under axonal ones, which has important im- consideration, then current CSF pa- plications to both a proper diagnosis thology is an argument in favour of and adequate treatment. such a treatment. Please also see the arguments for early treatment in the

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In addition, more precise detection  Moreover, all neoplasms associ- and correct identification of my- ated with any particular syndrome okymia, neuromyotonia and myoclo- are listed in the various chapters nus are tasks for a neurophysiologist. of this textbook dealing with any specific disorder. Repetitive nerve stimulation is a good method to diagnose myasthenia  If an onconeural antibody is un- gravis (paraneoplastic, thymoma) mistakably present and currently, and the Lambert-Eaton myasthenic a neoplasm cannot be found, then syndrome (LEMS). Single-fibre EMG consider supplementary search may also be of value. procedures at suitable intervals. A non-finding of cancer does not Step six rule out a PNS diagnosis, since an Search for a neoplasm autopsy may reveal a relevant ne-  By the end of this textbook, please oplasm for the first time. find a categorized table showing ‘Neoplasms versus onconeural an- Step seven tibodies’, which may be useful in Systematically, exclude all rele- searching for the most common vant differential diagnoses cancers associated with any par- An important criterion of a PNS is the ticular autoantibody. exclusion of all known other disorders with similar symptoms. The finding of  The chapter ‘Onconeural antibody onconeural antibodies may be a pre- targets in the nervous system and text to somewhat restricting the neoplasms’ may provide other search for other diagnoses, and this clues. argument may be either supported or weakened by the outcome of steps 3- 6.

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Table 2: Cerebrospinal fluid findings in patients with paraneoplastic neurologic syndromes: study of n = 295 such patient Anti-Hu Anti-Yo Anti-CV2 Anti-Ma/Ta Anti-Ri Anti-Tr 58% 20% 8% 6% 5% 3% Within a Relative to time of onset of An exclusive few Later Irrespectively of time neurological symptoms feature months Hyperproteinorachia (protein 67% level) Presence of oligoclonal 63% bands Pleiocytosis 47% 28% 10% Pleiocytosis without More frequent early in evolution than later-on hyperptroteinorachia 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

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 Arbitraryincreasing scale Months after onset

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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 com- 6 bined; various other agents

General therapeutic consider- at suitable intervals. This allows for ations timely adjustments of the treatment. Myasthenia gravis is the prototype of antibody-mediated autoimmunity in Unfortunately, T-cell-mediated auto- neurology. The experience related to immunity is not proportionate to se- the remedy of this disorder has been rum titres of antibodies. developed over decades and should at least be applicable to the PNSs listed Choice of therapy in Table 1. Table 2 proposes some principles of a rational and efficient treatment of Longitudinal monitoring of a dis- PNSs. Oncologic therapy serves a order by antibody measurements double purpose. Evidently, a treatable It is possible to monitor the severity cancer should undergo an expert- of the disorders of Table 1 both effi- choice of treatment with documented ciently and conveniently by means of effect. In addition, any removal / re- consecutive measurements of the rel- duction of neoplastic tissue may help evant titres of serum autoantibodies to stop or at least diminish the impact of such provoked autoimmunity.

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Antibody removal weeks of lasting effect, where after it In T-cell mediated disorders, treat- tapers off. ment option 5 (Table 2) is not really having any spectacular effect, whereas it may be quite efficient in High-dose IgG the autoantibody-mediated ones. The prevailing theory about the effect Therefore, this may be a proper of high-dose IgG (IVIG) is that an in- choice in cases of rapidly increasing fusion of anti-idiotypic antibodies re- severity or crises in such PNSs (Table sults in a neutralization of autoanti- 1). bodies.

Since steroids and for example azathi- Since only a minor fraction of the sub- oprine may take many weeks and stances is thought to have any effect, sometimes months to reach their and the remaining compounds to be maximum capacity of benefit, ses- either superfluous or to cause adverse sions of plasma exchanges may also effects, technical improvements of be an important remedy during the this method are warranted. This may waiting time for an accomplishment of happen by purification, safely and ad- such an effect. Likewise, if sufficient equately eliminating unwanted parts. control is unlikely to occur following On the other hand, the benefit of treatment option 6 (Table 2), then high-dose IgG may also be attributa- maintenance removals at suitable in- ble to a somewhat broader spectrum tervals are to be considered. Unfortu- of substances. Currently therefore, nately, this may also be the proper one is left with a treatment using the (only?) choice in cases with bad toler- whole mixture of IgG. In the treat- ance to immunosuppressants. ment of PNSs, this theoretical aspect of a broader mode of action may be of A treatment of one plasma volume a particular significance. Unfortu- during each session often results in an nately, high-dose IgG treatment is about 75% removal of the circulating quite expensive. pool of autoantibodies. Subsequently of course, antibodies from the extra- If IVIG proves to be of benefit, the du- vascular compartments gradually fil- ration of the effect will probably only ter back into the bloodstream. A se- last weeks or a few months, where af- ries of removals with one or a few ter a relapse is expected to occur. This days in between each session is there- may call for a repeated intravenous fore often the method of choice. There high-dose IgG session and probably appears to be a remarkable tolerance on a full scale, rather than a booster to the original plasma exchange pro- like in the Guillain-Barré syndrome, cedure with replacement of only albu- the rationale being an on-going can- min and water as well as to the newer cer and not a past infection. immunosorption techniques.

Usually, repair of the affected struc- Immunosuppression tures sets in right after the start of The experience from long-term treat- such treatment, and benefit is often ment of myasthenics makes it clear observable within days or weeks. The that every effort must be made not to so-called “Lazarus effect”, i.e. a se- lose immunosuppressant control by verely paralyzed patient is able to an administration of a too low dose, walk immediately after the first since once lost it may be quite difficult plasma exchange, is attributable to the immediate removal of blocking to achieve stable remission again. Un- fortunately, all of the currently avail- antibodies. Unfortunately, the synthe- able immunosuppressive drugs are sis of autoantibodies continues in symptomatic, so such therapy must spite treatment option 5. As a rule of thumb therefore, one may expect 4-8 be kept at an efficient level and as

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long as needed. The principle – or dif- Another concern in relation ficulty – is to find an optimal balance to PNS between the required minimal dose and  The legitimacy of immunosup- the risk of serious adverse effects. pression in a patient with cancer Furthermore, this must be worked out in a long-term perspective.

The experience with steroids and Az- Other modalities of therapy athioprine is long. Methotrexate, Cy- Also in relation to PNSs, such sympto- closporine and Cyclophosphamide are matic treatment (Table 2, 1 - 3) fol- other drugs with documented benefit, lows the usual procedures. although also with a substantially higher risk of adverse effects. Tacroli- mus is a newer and maybe promising Newer options for treatment drug, although the experience with  A chimeric monoclonal IgG1- this substance is somewhat more lim- kappa antibody, Rituximab, that ited in neurology. binds specifically to the CD20 antigen and mediates B cell lysis, Immunosuppression is the primary may be beneficial to temporarily treatment of choice in T-cell-mediated decrease synthesis of harmful au- disorders. toantibodies Therapeutic keywords in T-cell  Protection against harmful effects mediated autoimmunity: of the membrane attack com-  Often a medical emergency plexes (MAC) may be a promising new remedy. Humanized mono-  Early destruction of the microenvi- clonal antibodies are appearing on ronment around neurons or neu- the scene. Eculizumab is a new ronal death such drug, which is directed to the complement protein C5, and  Do not hesitate too long before of- thereby inhibiting terminal com- fering such therapy plement activation  A patient may sooner or later be  Treatment targeting cytokines or left with no therapeutic remedy chemokines alternatively using antisense suppression of various

enzymes may be other options.

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

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

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Syndromes of the central nervous system

Morvan’s fibrillary chorea Morvan’s fibrillary chorea is a rare autoimmune synaptic encephalopathy characterized by chorea and sometimes combined with limbic features, myotonia, neuropathy, and perspira- tion. 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 vg- KC complexes. This disorder appears to fulfil the criteria of an antibody-mediated autoimmunity.

Associated disorders Anti-CASPR2 disorders: . Anti-AChR antibody seropositive Acquired neuromyotonia Peripheral nerve hyperexcitability myasthenia gravis (SPMG) Morvan’s syndrome . LEMS Neuromyotonia with autonomic and CNS involvement Autoantibodies

Limbic encephalitis  Anti-LGI1 (leucine-rich, glioma CNS manifestations without periph- inactivated 1 protein) eral involvement  Anti-CASPR2 (contactin-associated protein-2) Clinical features  (Anti-voltage-gated K-channels) . Attacks of involuntary fibrillary The targets are located at the dentate gyrus of contraction (chorea) in mus- hippocampus and at the neuromuscular junction. In RIAs, using 2 % digitonin extract of cles at rest radio-labelled dendrotoxin, antibodies to o Involving the muscles of the Shaker types Kv1.1, 1.2, 1.6 are detectable, calves, the posterior parts of although not differentiated. Moreover, such the thighs, and rarely the VGKC extract are complexed with two other channel-complex proteins, leucine-rich, glioma trunk inactivated 1 protein and contactin-associated . Other CNS dysfunction protein-2 in limbic encephalitis. Therefore, this o Limbic encephalitis with loss assay is not specific to anti-VGPC. of memory  Anti-DPPX (DPP5) o Insomnia (agrypnia) o Hallucinations MG, LEMS laboratory: o Disorientation  Anti-AChR (adult-type, foetal- o Seizures type) . Neuromyotonia  Anti-Titin . Hyperhidrosis  Anti-voltage-gated-Ca-channel . Polyneuropathy (P/Q-, N-type)

Course Some differential diagnoses May improve spontaneously or with See examples under paraneoplastic immunosuppression choreo-athetosis.

Associated neoplasm Treatment Thymoma High-dose IgG or plasma exchange Immunosuppression

Selected references 1. Morvan AM. De la chorée fibrillaire. Gazette hebdomadaire de médecine et de chirurgie, Paris, 1890; 27: 173-176, 186-189, 200-202. 2. Roger H, Alliez J, Roger J. [Morvan's fibrillary chorea; 70 observations with 30 personal cases.] Rev Neurol (Paris) 1953; 88 (3):164-73.

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3. Madrid A, Gil-Peralta A, Gil-Neciga E, Gonzalez JR, Jarrin S. Morvan's fibrillary chorea: remission after plasmapheresis. J Neurol 1996; 243 (4): 350-3. 4. Maselli RA, Agius M, Lee EK, Bakshi N, Mandler RN, Ellis W. Morvan's fibrillary chorea. Electrodiagnostic and in vitro microelectrode findings. Ann N Y Acad Sci 1998; 841: 497-500. 5. Agius MA, Zhu S, Lee EK, Aarli JA, Kirvan C, Fairclough RH, Maselli R. Antibodies to AChR, synapse- organizing proteins, titin, and other muscle proteins in Morvan's fibrillary chorea. Ann N Y Acad Sci 1998; 841: 522-4. 6. Lee EK, Maselli RA, Ellis WG, Agius MA. Morvan's fibrillary chorea: a paraneoplastic manifestation of thymoma. J Neurol Neurosurg Psychiatry 1998; 65 (6): 857-62. 7. Liguori R, Vincent A, Clover L, Avoni P, Plazzi G, Cortelli P, Baruzzi A, Carey T, Gambetti P, Lugaresi E, Montagna P. Morvan's syndrome: peripheral and central nervous system and cardiac involvement with antibodies to voltage-gated potassium channels. Brain 2001; 124 (Pt 12): 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.

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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 Predominant syndrome Associated cancer associated with PCD

Breast , small-cell lung (SCLC), Anti-Yo (PCA-1) antibodies PCD ovarian, prostatic

PCD (+occasionally: limbic encephali- Anti-Tr antibodies Hodgkin's lymphoma tis, optic neuritis)

Anti-mGluR1 antibodies PCD Hodgkin's lymphoma, ovarian

Anti-ZIC4 antibodies PCD SCLC , lung adenocarcinoma

Anti- ARHGAP26 (GRAF) PCD Ovarian

PCD with ataxia, headache, nausea, Anti-HOMER3 None confusion

Sometimes Associated With Ataxia and other findings PCD

Encephalomyelitis, PCD, sensory neu- SCLC, lung adenocarcinoma, Anti-Hu (ANNA-1) antibodies ronopathy other cancers

PCD, brain-stem encephalitis, parane- Anti-Ri (ANNA-2) antibodies Breast, SCLC, gynaecologic oplastic opsoclonus-myoclonus

Encephalomyelitis, PCD, chorea, pe- Anti-CV2/CRMP5 antibodies SCLC, thymoma, other cancers ripheral neuropathy, uveitis

Anti-PCA2 Encephalomyelitis, PCD SCLC

Anti-Ta (Ma2), Ma1 protein Limbic, hypothalamic, brain-stem en- Breast, lung adenocarcinoma, antibodies cephalitis, infrequently PCD testis, ovarian, other cancers

Stiff-person syndrome, encephalomy- Anti-Amphiphysin antibodies Breast, SCLC elitis, PCD

Anti-VGCC antibodies Eaton-Lambert syndrome, PCD SCLC, lymphoma

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Overview of paraneoplastic ataxia Associated neoplasms and onconeural antibodies Onset (Only the most common) Although varying, PCD often sets in  SCLC: anti-Hu, anti-CV2, anti-Ca- before the diagnosis of a neoplasm. channel (P/Q-, N-type), anti-ZIC4  Ovary (epithelial): anti-Yo Evolution  Breast: anti-Yo, anti-Ri Usually, this disorder rapidly pro-  Hodgkin’s disease: anti-Hu, gresses over weeks to months, then anti-Tr stabilization. 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 moder- ately 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 pro-  Alcohol related ataxia gressive cerebellar atrophy  Gluten associated ataxia (anti- TG6) General clinical features  Autosomal dominant cerebellar ataxias (ADCA) Symmetric pancerebellar syndrome  Familial or sporadic ataxia with vertigo  Idiopathic late-onset cerebellar atrophy (ILOCA) Pathology  Multiple system atrophy (MSA), Loss of Purkinje cells cerebellar subtype  Epstein-Barr virus associated cer- Table3: ebellar encephalitis List- PCD-associated autoan-  Primary autoimmune cerebellar ing tibody ataxia (PACA) A Anti-Hu B Anti-Yo C Anti-CV2 / CRMP5 A. Anti-Hu syndrome D Anti-Ma1 E Anti-PCA2 F Anti-Tr (PCA-Tr) Clinical features G Anti-mGluR1  Ataxia H Anti-CARP8  Associated with a variety of other I Anti-GAD PNS in the central and peripheral J Anti-ZIC4 nerve system Please see elsewhere and in par- LEMS-associated, anti-vg- K ticular paraneoplastic encepha- Ca-channel lomyelitis (PEM) and sensory L Other autoantibodies neuronopathy (SSN).

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Causes of death Neoplasm: small-cell lung.  Progression of neoplasm in 55%  Neurologic in 35% Onset: before detection of cancer Associated neoplasms Treatment  Breast Oncologic  Ovary: epithelial Significant tumour reduction may sta-  Male patients: gastric, parotid, bilize the neurological features oesophageal adenocarcinoma  Metastases: invasion of regional Immunotherapy lymph nodes common (85%) Is rarely effective  No neoplasm found in 10%

Investigations Mammography Pelvic examination and imaging B. Anti-Yo syndrome Serum

o Anti-Yo antibody Gender o Carcinoembryonic antigen  Females in most of the cases (CEA) and cancer antigen (CA)  Males, only three patients are re- 125 ported, two with gynaecomastia o Titre may decrease after tumour resection CSF Onset o Protein: mildly elevated Mean 60 years of age o Cells: mild mononuclear pleo- Related to cancer cytosis  Before cancer: 60% o Anti-Yo antibody present  After start of tumour treatment:

25%  May begin with tumour relapse: Treatment 15% Oncologic Such therapy does only rarely result in improvement of the ataxia Clinical features Immunotherapy Ataxia Cyclophosphamide may possibly be of  Severe, pancerebellar some benefit  Located to trunk and limbs

 Dysarthria, oculomotor

 Nystagmus, including down beat-

ing  Oscillopsia and diplopia C. Anti-CV2 / CRMP5 Usually, other CNS & PNS sys- syndrome tems are not involved. Ataxia with antibodies to col- Progression lapsin response-mediator protein 5 The symptoms aggravate over weeks to months, mean two to three months. Clinical features Eventually, the outcome is non-ambu- The symptoms are quite varied latory in 95%. Cerebellar (50%)  Ataxia Survival  Nystagmus Mean two to six years  Dysarthria Dependent on tumour type Limbic encephalopathy (30%)  Breast: 100 months  Dementia  Gynaecological: 22 months  Mental status and mood changes  Seizures 26

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Opsoclonus/myoclonus (5%)  Thymoma (5%) Movement disorders (15%)  Other: uterine sarcoma  Basal ganglia: chorea Cranial nerve disorders (15%) Treatment  Optic neuropathy Tumour removal may result in some  Abnormal olfaction or taste improvement Myelopathy (16%) Peripheral nervous system  Sensory or sensory-motor disorders (45%)

 Autonomic dysfunction (30%), es- D. Anti-Ma1 syndrome pecially isolated gastro-intestinal; also multiple systems  Polyradiculopathy (5%) Typically, in this syndrome there o Sensory-motor is a combination of cerebellar and o Legs > arms brainstem disorders. o Symmetric o Onset: subacute Age at onset o Pathology: axonal loss; in-  55-65 years flammation (50%)  Either up to one year before de- Neuromuscular junction (10%) tection of the neoplasms or con-  LEMS current with the cancer diagnosis Other associated syndromes  Optic neuritis Clinical features: not uniform  Uveitis  Cerebellar: trunk and extremities  Intestinal pseudo-obstruction  Brainstem: EOM limitation, dysphagia Anti-CV2 / CRMP5 antibody  Other: sensory loss, myokymia Antigen  A 66 kDa neural specific protein with homology to UNC-33 and ULIP Prognosis: death in about 50%

Cellular distribution Antigen  Synapse-rich regions of brain and  Ma1 protein gut o 37 and 40 kDa proteins located  Small DRG neurons to neuronal & testicular germ  Small-cell neoplasms cell  Oligodendrocytes: cytoplasm o Homology to Ma2 (Ta) and  Cerebellum, brainstem, spinal Ma3 cord and optic chiasm Tumours: not uniform Please note that in some patients,  Testis anti-Hu, or anti-amphiphysin, anti-RI,  Breast and anti-ZIC4 are features as well.  Lung (large-cell)

 Colon Investigations . CSF Pathology o Pleocytosis (lymphocytes) Gliosis of brainstem and cerebellar o High protein nuclei; inflammation . Anti-CV2 / CRMP5 antibodies

(IgG)

 Present in both serum and CSF

Associated neoplasms (especially in the chest)  Small-cell lung (80%)

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E. Syndrome with Course: subacute anti-PCA2 antibodies  Usually irreversible Spontaneous disappearance may

Gender occur in cases with no tumour  Remissions (15%): more com-  Females in 70% mon in younger than after 40 years of age Onset  Survival  40-85 years of age o Mean > 9 years o Longer than in anti-Hu or anti- Clinical features Yo syndromes Quite varied syndromes  Limbic encephalitis: 50% Clinical features  Cerebellar ataxia: 30%  Ataxia, moderate to severe  Lambert-Eaton myasthenic syn-  Variant syndromes drome: 20% o Limbic encephalitis (7%): re-  Autonomic neuropathy: 10% versible  Motor syndrome: 10% o Optic neuritis  Stiff-person syndrome  No neurologic syndrome: 10% Associated neoplasm

 Hodgkin’s lymphoma (90%), es- Associations pecially nodular sclerosis  Smokers  No neoplasm (10%)  Lung cancer (small-cell) Anti-PCA-Tr antibody Antigen Antigen  Protein: 280 kDa Delta/Notch-like Epidermal Growth  Location: neuron-specific. Factor-Related Receptor (DNER) Purkinje cell cytoplasm in soma Tissue staining and dendrites  Cerebellum o Purkinje cell cytoplasm and Associated antibodies dendrites  Anti-PCA2 (IgG): serum + low o Dotted pattern in molecular titres in CSF cerebellar molecular layer  Anti-vg-Ca-Channel (P/Q- & N-  Neoplasm: only rarely stained type)  Tr cell localization  Anti-AChR (nicotinic adult- and o Cytosol and outer surface of foetal-types) endoplasmic reticulum  Anti-AChR (nicotinic alpha3-type,  Location autonomic) o Usually present in serum and CSF, maybe only in CSF

Cerebellar pathology F. Anti-Tr (PCA-Tr)  Loss of Purkinje cells  No inflammation syndrome

Gender Males > females (3:1) G. Ataxia with anti-

Onset mGluR1 antibodies

 Age: median 61 years; range 15 to 75 years Ataxia associated with antibodies  Before (70%) or after cancer; also to metabotropic glutamate receptor during remission R1. This disorder appears to fulfil the 28

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criteria of an antibody-mediated auto- Onset: 3 years after neoplasm immunity. Course: progressive ataxia Onset Months to years after neoplasm Clinical features: Pure cerebellar (80%) syndrome

 Ataxia: limb, truncal, gait, dysar- Course thria Persistent or monophasic  Ocular: horizontal nystagmus  Mental status: normal Clinical features  Ataxia: truncal and gait Investigations  Intention tremor Antibodies  Mental status: normal  Anti-CARP8 o Tissue staining Investigations  Cerebellum: Purkinje cell Antibodies cytoplasm and dendrites  Anti-mGluR1  Weaker staining o Tissue staining  Lateral nuclei of thalamus  Cerebellum: Purkinje cell  Bronchial epithelial cells bodies (punctuate) and  Melanomas: one of seven spines tested  Glomeruli of olfactory bulb:  Location: serum and CSF neurons and neurophils  Cerebral cortex: superficial Other laboratory layer CSF  Other: hippocampus (CA3),  Lymphocytosis thalamus, superior collicu-  Oligoclonal bands lus, spinal trigeminal nucleus Neoplasm: melanoma o Location: serum and CSF

Other laboratory Treatment: none  CSF: high total IgG and IgG index  MRI: normal I. Syndrome with Neoplasm anti-GAD antibodies Hodgkin's lymphoma, during remission Please see stiff-person syndrome: variants Treatment Immunosuppression may be of value.

J. Syndrome with H. Ataxia with anti- anti-ZIC4 antibodies CARP8 antibodies

Clinical features Ataxia associated with antibodies  Ataxia, moderate to severe to carbonic anhydrase-related protein  Slurred speech 8.  Vertigo

Epidemiology: only one patient re- Neoplasm: small-cell lung (SCLC) ported a 77-year-old female Antibodies 29

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 Anti-ZIC4 Antibodies Bearing in mind that SCLC is the as-  Anti-vg-Ca channels (P/Q- & N- sociated neoplasm, consider looking type) for other onconeuronal antibodies as  Increased incidence in anti-Hu well. PEM rather than PCD is the most syndromes likely diagnosis, should such antibodies also be a feature. Neoplasm: small-cell lung

In short, detection of Zic4 antibodies Treatment often associates with See the Lambert-Eaton myasthenic

 Anti-Hu or CV2 (CRMP5) antibod- syndrome. ies On the other hand, patients with iso- L. Ataxia with other lated Zic4 antibodies are more likely autoantibodies to develop isolated cerebellar dysfunction than those with concurrent immunities. Antibodies  Anti-ARHGAP26 (GRAF), anti-Pro- K. LEMS-associated tein kinase C gamma (PKC gamma))

Neoplasm Ataxia associated with Lambert-  ovarian (anti-GRAF) Eaton myasthenic syndrome.  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.

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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 jus- tified, 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 unjusti- fiable, see PCD, anti-CV2 (CRMP5) syndrome.

Associated neoplasm MRI through the basal ganglia Small-cell lung cancer (SCLC) (A), reduced intensity is evident in the T1 weighted image of the bilateral caudate head. (B), markedly increased Some differential diagnoses intensity is evident in the T2 weighted  Hereditary disorders with chorea, image such as Huntington’s disease, neu- roacanthocytosis. Metabolic disorders

such as Wilson disease and others Clinical features  Immunologic disorders, for example  Chorea, i.e. involuntary brief, ir- SLE regular, unpredictable, purpose-  Paraneoplastic: Morvan’s fibrillary less movements that flow from chorea one body part to another without  Post-infectious: chorea (subsequent a rhythmic pattern and involving to group-A streptococci) movements over joints  Infectious: Creutzfeldt-Jacob disease  Stroke  Athetosis, i.e. involuntary writh-  Senile chorea ing movements particularly of the

arms and hands Treatment High-dose IgG Associated antibodies Immunosuppression  Anti-CV2 (CRMP5) is the finding Oncologic in most cases. Sometimes, anti- Possibly, Carboplatin-etoposid cycles Hu, anti-Amphiphysin, anti-Ri, or similar drugs to treat the SCLC and anti-Zic4 are features as well.

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

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5. 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. 6. 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. 7. 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. 8. 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.

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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:

Cate- of disorders gory A Paraneoplastic encephalomyelitis (PEM) B Paraneoplastic limbic encephalitis (PLE) C Paraneoplastic brainstem encephalitis D Paraneoplastic myelitis Additional 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-ob-

struction

Table 5: Overview of paraneoplastic encephalitides: autoantibodies vs. neoplasms Short name Alias: anti- Primary Associated neoplasms (alphabetical order) analysis Anti-AGNA SOX1 SCLC Anti-AMPAR GluR1/2 SCLC, non-SCLC, thymoma, breast Anti- Yes Breast, SCLC Amphiphysin Anti-BRSK2 SCLC Anti-CASPR2 Thymoma Anti-CV2 CRMP5,POP66 Yes SCLC, thymoma Anti-EFA6A Ovarian Anti-GAD Yes SCLC, thymoma, breast, renal, Hodgkin Anti-GabaBR1 GABBR1 SCLC Anti-Hu ANNA-1 Yes SCLC, non-SCLC, *Anti-K-channel VGKC, VGPC Yes SCLC, thymoma Anti-LGI1 Thyroidea, kidney, thymus, ovarian teratoma lung Anti-mGluR1 Ovarian, morbus Hodgkin Anti-mGluR5 Morbus Hodgkin Anti-NMDAR NR1 / NR2 Yes Teratoma Anti-PCA-2 SCLC Anti-Ri ANNA-2, Nova-1 SCLC, non-SCLC, breast, ovarian Anti-Ta Ma2, PNMA2 Yes Testicular, ovarian Anti-Tr Purkinje cell Yes Morbus Hodgkin (Tr) Anti-Yo APCA-1, CDR- Yes Breast, ovarian, SCLC

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

30% of these patients. The most A. Paraneoplastic common symptoms are encephalomyelitis o orthostatic hypotension (PEM) o urinary retention o pupillary abnormalities, o impotence o dry mouth The term paraneoplastic encephalomyelitis (PEM) comprises several Occasionally, there is also chronic syndromes characterized by neuronal intestinal pseudo-obstruction due loss, microglial proliferation, inflam- to damage of the neurons of the matory infiltrates in the CNS and the myenteric plexus. co-existence mainly of anti-Hu antibodies. Although some patients may  Subacute sensory neu- have clinical involvement of only one ronopathy (SSN, PSN) location throughout the complete clin- This is the most common clinical ical course, 75% of them present with syndrome. In about 20% of the a multifocal disorder. patients, SSN is the only clinical evidence of paraneoplastic dis- Overview of the general ease. clinical features The symptoms and signs reflect the Associated neoplasms variable anatomic involvement and Small-cell lung cancer (SCLC) in include about 75%

 Encephalopathy (limbic en- Associated antibodies cephalitis)  Anti-Hu (most frequent) This is the second most common Particularly in cases presenting with clinical syndrome, and it may re- isolated limbic encephalitis through- main isolated throughout the clin- out the complete clinical course: ical evolution.  Anti-CV2 (CRMP5)  Anti-Amphiphysin  Brainstem syndromes  Anti-Ri (bulbar encephalitis)  Anti-PCA2 These features reflect a predomi-  Anti-Yo nant involvement of the floor of  Anti-ZIC4, less frequent the fourth ventricle and the infe-  other antibodies, see Table 5 rior olives, resulting in vertigo, and below nystagmus, oscillopsia, ataxia, diplopia, dysarthria, and dysphagia. Treatment Oncologic  Myelitis Significant tumour reduction may stabilize the neurological features.  Autonomic dysfunction The dorsal root ganglia are af- Immunotherapy fected. This is a feature of about Rarely effective Anyhow, intravenous high-dose IgG, steroids or plasmapheresis may be worth trying, since a few patients do improve.

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b. MRI demonstrating tem- B. Paraneoplastic lim- poral lobe abnormalities c. EEG showing epileptic ac- bic encephalitis (PLE) tivity in the temporal lobes – may include non-

limbic structures 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

Onset PLE is a rare disorder characterized by Most frequently (85%), there is a sub- personality changes (autoimmune acute onset of confusion and marked psychosis), irritability, depression, reduction of short-term memory. Sei- seizures, memory loss and sometimes zures are frequent, and they may an- dementia. The diagnosis is difficult tedate by months the onset of the because clinical markers are often cognitive deficits. lacking, and symptoms usually precede the diagnosis of cancer or mimic Other patients (15%) have a more in- other complications. sidious onset with depression or hal-

lucinations, which can confuse the di- The diagnosis of PLE required neuro- agnosis with that of a psychiatric ill- pathological examination or the pres- ness. ence of the four following criteria

1. A compatible clinical picture

2. An interval of <4 years between Clinical features the development of neurological This disorder presents with a di- symptoms and tumour diagnosis versity of symptoms including: Do also consider autoimmune syn- Accordingly and in many cases, the aptic encephalitis with no underly- symptoms are not restricted to limbic ing neoplasm structures. Short-term memory loss 3. Exclusion of other neuro-oncolog- or amnesia, disorientation, confusion, ical complications depression, agitation, anxiety are typ- 4. At least one of the following ical features. a. CSF with inflammatory

changes but no evidence of Typical findings infection  Loss of short-term memory (85%)  Cognitive disturbance (15%)

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 Epileptic seizures (50%)  Renal cancer (anti-GAD)  Acute confusional syndrome (45%) Associated antibodies  Additional psychiatric symptoms Lung cancer (40%)  Anti-Hu  Personality change, hallucinations,  Anti-CV2 (CRMP5) depression  Anti-Amphiphysin  Brainstem symptoms (25%)  Anti-GAD  Signs of hypothalamic involve-  AGNA (anti-SOX1) ment (20%)  Anti-PCA2  Involvement of other neurological  Anti-AMPAR (GluR1/R2)) structures (about 40%)  Anti-BRSK2  Anti-GabaBR1  See also cerebellar syndromes with anti-GAD & anti-PCA2 an- Breast tibodies and Morvan’s fibril-  Anti-AMPAR (GluR1/R2) lary chorea. Thymoma Diagnostic criteria  Anti-LGI1  Typical clinical symptoms  Anti-CASPR2  Less than four years to tumour di-  Anti-AMPAR (GluR1/R2) agnosis  Brain MRI, SPECT or PET showing Testis cancer the typical involvement of hippo-  Anti-Ta (Ma2) antibodies are a campus feature in the great majority of  Exclusion of other diagnoses patients. Usually, these cases o In particular, the more com- also present with diencephalic mon non-paraneoplastic auto- and upper brainstem symptoms immune limbic encephalitis as- that identify a characteristic syn- sociated with autoantibodies drome. This antibody may also be to vg-K-channels and which a finding in patients with other disorder, apart from the neo- neoplasms, such as prostate, plasm is clinically indistin- ovarian teratoma, breast, and guishable from PLE with a thy- pulmonary adenocarcinoma moma. o Also exclusion of non-parane- Ovarian cancer oplastic anti-NMDAR encepha-  Anti-mGluR1 litis (idiotypic or SLE with CNS  Anti-LGI1 involvement) Prostate or breast cancer Other investigations  Anti-Yo EEG Cerebrospinal fluid Hodgkin’s lymphoma Pleocytosis and oligoclonal bands (in  Anti-Tr about 60%)  Anti.mGkuR1  Anti-mGluR5 (Ophelia syndrome) Associated neoplasms  Anti-GAD  Small-cell lung cancer (50%)  Testicular tumour (20%) Teratoma  Ovarian Acute psychiatric symptoms, pro-  Breast cancer (8%) longed disturbance of conscious-  Thymoma ness, seizures (refractory status  Hodgkin’s disease epilepticus), autonomic instability,  Prostate central hypoventilation and vari-  Teratoma ous involuntary movements, dys-  Thyroid kinesias, dystonia

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 Anti-NMDAR (NR1)  About 40% are seronegative, and Types of autoimmune anti- the absence of onconeural anti- NMDAR encephalitis bodies does not rule out the diag- o Of unknown cause (post-in- nosis fectious?) o Paraneoplastic Treatment In general (anti-Hu), this disorder Epidemiology of anti-NMDAR rarely improves with treatment. seropositives Oncologic  Recent research suggests that Removal of the tumour may result in non-paraneoplastic encephali- a certain degree of reversal. tis may be the most frequent Symptomatic  Anti-NMDAR encephalitis is in- Consider drug therapy of epilepsy and creasingly recognized in chil- psychiatric symptoms. dren, comprising 40% of all

cases with encephalitis of pre- Immunotherapy vious unknown origin  In particular, patients with anti-Ta  In male patients, it appears (Ma2) antibodies or those without that teratomas are not a fea- detectable onconeural antibodies ture. This is consistent with may benefit the rare incidence in the testes  Probably, a finding of anti-vg-K- of pure benign teratomas, ac- channels or anti-NMDAR also sug- counting for only 3-5% of gests a good response to immuno- germ cell tumours. Accordingly therapy and anyhow, they should be  Vice versa, the presence of anti- searched for Hu antibodies appears to predict a  Female patients: decreasing poor response to such treatment frequency of teratomas by age Options

o Intravenous high-dose IgG Table 6 o Plasmapheresis, which is an obvi- Female patients Age group, Frequency of ous choice, if anti-vg-K-channel years teratomas or anti-NMDAR antibodies are de- Older than 18 55% tected 14.1 – 18 30% o Steroids or other immunosup- Up to 14 10% pressants

Particular additional clinical feature C. Paraneoplastic  Maybe also excessive daytime sleepiness brainstem encephali- In such cases, decreased / absent tis hypocretin-1 may be a feature of the CSF Paraneoplastic brainstem encephalitis Various Most frequently, this disorder is a  Anti-EFA6A (a guanine nucleotide part of multifocal pathology: exchange factor) Please look elsewhere for the  Anti-nCMAg (novel cell-membrane specific features of the various antigens) which is highly ex- syndromes pressed in hippocampus and cere-  Paraneoplastic opsoclonus / bellum) myoclonus (POM)  Anti-Adenylate kinase 5)  Paraneoplastic sensory neu-  Anti-UBE2E1 ropathy (SSN, PSN)  Stiff-person syndrome: variants, PERM

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Schematic representation

 Atypical parkinsonism with severe akinesia, facial masking, rigidity, and tremor  Maybe, excessive daytime sleepiness – and in such cases, decreased / absent hypocretin- 1 may be a feature of the CSF

 MRI may reveal hyperintense T2-weighted images in the up-

per brainstem, hypothalamus, thalamus, hippocampus, which are rarely enhanced by contrast

Short summary Associated antibodies and 1. Association with small-cell lung cancer cancer (SCLC)  Anti-Hu: SCLC The brainstem encephalitis usually  Anti-CV2 (CRMP5): SCLC, thy- also involves other locations of the moma nervous system (encephalomyeli-  Anti-Amphiphysin: breast tis).  Anti-Ri: breast  Anti-Ta (Ma2): testis, breast, 2. Association with breast or gy- colon, lung adenocarcinoma naecological cancer  Anti-GAD: SCLC, breast, thy- In about 75%, there is also opso- moma, Hodgkin and non- clonus. Hodgkin lymphoma, renal cell If not so, then: carcinoma  Oculomotor abnormalities, including gaze paresis, nystagmus, ab- Treatment normal visual tracking, blepharo- The syndrome may stabilize or im- spasm, and abnormal vestibulo- prove subsequent to a successful on- ocular reflexes cological treatment (e.g. anti-Ta  Truncal ataxia may predominate (Ma2)). and cause severe gait difficulty

and frequent falls Immunotherapy  Limb ataxia is usually mild and Although a few patients may benefit, most patients retain the ability to such therapy rarely is effective. In write and to feed themselves particular however, patients with a  Nausea, dizziness, dysarthria, finding of anti-Ta antibodies and no dysphagia, diplopia, rigidity, par- findings of other paraneoplastic auto- kinsonism antibodies are the most likely to im-

prove.  MRI brain scans are usually o Steroids or other immunosuppres- normal. sants

o Intravenous high-dose IgG 3. Association with testis cancer o Plasmapheresis and other neoplasms (anti-Ta

(Ma2) syndrome) Usually combined with limbic en- D. Paraneoplastic cephalitis or diencephalic symptoms myelitis/myelopathy

 Vertical gaze paresis or paraly- sis Paraneoplastic myelitis / myelop-  Mild to moderate dysarthria, athy, which may also be a part of dysphagia, facial weakness more multifocal pathology (PEM)

Anti-Hu-associated 38

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Clinical features  Lung (small-cell) Motor  Patchy weakness: arms > legs May progress to neck Other options  Fasciculations  Anti-CV2 (CRMP5) syndrome,  Eventually, respiratory failure see ‘Paraneoplastic cerebellar syndrome (PCD)’ Sensory  Anti-Ri (ANNA2) syndrome,  Associated ganglionopathy see ‘Opsoclonus / myoclonus’

Associated neoplasm

Selected references 1. Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine 1992; 71: 59- 72. 2. 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. 3. 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. 4. Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear antibodies. Neurology 1998; 50: 652-72. 5. 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. 6. 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. 7. Graus F, Keime-Guibert F, Reñé R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001; 124: 1138-48. 8. 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. 9. Graus F, Keime-Guibert F, Reñé R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001; 124: 1138-48. 10. Rosenfeld MR, Eichen JG, Wade DF, et al. Molecular and clinical diversity in paraneoplastic immunity to Ma proteins. Ann Neurol 2001; 50: 339-48. 11. Sutton IJ, Barnett MH, Watson JDG, et al. Paraneoplastic brainstem encephalitis and anti-Ri antibodies. J Neurol 2002; 249: 1597-8. 12. 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. 13. Pozo-Rosich P, Clover L, Saiz A, et al. Voltage-gated potassium channel antibodies in limbic encephalitis. Ann Neurol 2003; 54: 530-3. 14. 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. 15. 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. 16. 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. 17. 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. 18. 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. 19. 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. 20. 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. 21. 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. 22. 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;

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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 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. 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 To date, the World Neurological Asso- anti-Hu syndrome ciation does not recognize the exist- In up to 20% of paraneoplastic en- ence of paraneoplastic ALS (EL Esco- rial Criteria for ALS, 1998). cephalomyelitis (PEM), MND is

also a feature. This MND involves Oncological patients with ALS do both upper and lower motor neu- not differ from individuals with ron, and such neurology may even sporadic ALS. be an early manifestation. Other-  No other anti-neuronal anti- wise, these patients do not differ bodies apart from anti-Hu to any other aspect of PEM without  Cause of death: motor neuron MND. defiance

 Comparable survival  Amyotrophic lateral sclerosis  Cancer treatment usually does (ALS) not improve neurological sta- ALS may be a feature of oncologic tus. patients, although this is a rare  On the contrary, though, tu- event. mour progression might be

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slower in patients with con- o Weakness, occasionally ac- comitant ALS. companied by minor sensory symptoms  Primary lateral sclerosis (PLS) o Subacute often asymmet-  Pure involvement of the upper rical motor neurons o Progressive  Rare disease observed in women with a breast cancer Associated neoplasms  Also associated with adenocar- o Hodgkin’s disease cinoma in gall bladder and du- o Non-Hodgkin’s lymphoma odenum (anti-Hu positive) Course Accordingly, PLS is the most likely Independent from the cancer candidate in MND, which is attributable to a paraneoplastic Note that the World Association of origin. Neurology does not recognize the existence of a paraneoplastic PMA. Course o Chronic and progressive  Motor neuron diseases and o May eventually turn into a lymphoproliferative disorders fully expressed ALS (LPD) o The coexistent cancer does MND (ALS, PLS and PMA) has been not modify PLS progression. observed in relation to  Waldestrom’s macroglobuli- Investigations naemia o Consider mammography  Multiple myeloma in a female patient with  Chronic lymphocytic leukae- PLS mia o Possibly also anti-Hu in  Follicular cell lymphoma MND  Hodgkin’s disease

 Progressive muscular atrophy Summary (PMA)  It is unclear, if the association Also called: Subacute motor is coincidental or of signifi- neuronopathy cance in LPD  MND in LPD patients implies a Clinical features poor prognosis due to MND o Painless lower motor neu- progression ron  Unfortunately, the treatment of the LPD is unlikely to affect the coexisting MND.

Selected references 1. 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. 2. Forsyth PS, Dalmau J, Graus F, Cwik V, Rosemblum MK, Posner JB: Motor neuron syndromes in cancer patients. Ann Neurol 1997; 41: 722-730. 3. Rowland LP: Paraneoplastic Primary Lateral Sclerosis and Amyotrophic Lateral Sclerosis. Ann Neurol 1997; 41: 703-705. 4. 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. 5. Criteria for the diagnosis of ALS.

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Paraneoplastic opsoclonus / myoclonus (POM)

Paraneoplastic opsoclonus / myoclonus: This disorder is within the group of classical PNS. Involuntary movements of the eyes and other striated muscles in any direction char- acterize it. POM is associated with a variety of neoplasms and onconeural antibodies.

Table 7: Neurologic clinical features The following paraneoplastic clonus Opsoclonus: conjugate saccades. disorders are known  Involuntary  Multidirectional Cate- Paraneoplastic opso-,  Arrhythmic gory myoclonus (POM)  Nearly continuous  High amplitude A POM in children  Persist when the eyes are closed and during sleep POM in adults  Associated with blinking, myoclo- B  Anti-Hu, anti-Yo, anti- nus Ta (Ma2) syndromes  Increases with visual pursuit and POM in adults voluntary refixation C  Anti-Ri syndrome Myoclonus (brief involuntary twitching of a muscle or of a group of muscles)

Cerebellar ataxia A. Opsoclonus / myo- Dysphagia and more clonus in children 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  Encephalitis: post-viral syndrome, post-infectious autoimmunity e.g. after group-A strep- Neuroblastoma tococci  Toxic: thallium, lithium, amitrip- Clinical Syndrome tyline Age at onset: mean about 18  Diabetic hyperosmolar coma months. Most before the age of five,  Intracranial lesions: other tu- and rare in children older than 10 mours, hydrocephalus, thalamic years haemorrhage Gender: males slightly more often than females Differential diagnoses in chil- Onset: before or after cancer dren with neuroblastic tumours

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 Neuroblastoma, ganglioneuro- Epidemiology blastoma, ganglioneuroma Onset age: 35 to 85 years Rapid-onset obesity with hypotha- Male/female rate 1:2 lamic dysfunction, hypoventilation, and autonomic dysregulation Clinical features (ROHHAD syndrome) Movement disorder  Opsoclonus (30%), triggered by Treatment visual fixation Corticosteroids  Myoclonus Residua: CNS signs are frequent  Laryngospasm; dystonia (jaw opening or neck) Cerebellar: ataxia B. Opsoclonus /  The most common feature of an myoclonus in adults: anti-Ri-syndrome (50%)  Truncal ataxia and gait disorder anti-Hu, Yo, Ta (Ma2)  Nystagmus: 35% syndromes  Dysarthria: rare Other associated disorders in

some patients

 Peripheral neuropathy (25%), Clinical features sensory-motor with subacute on- Opsoclonus and myoclonus set Associated features  Myelopathy (20%)  Encephalopathy  Encephalopathy with confusion  Seizures and seizures  Syndrome of SIADH (inappropri-  Cranial neuropathy: VI; VIII ate antidiuretic hormone secre- (deafness or tinnitus) tion)  Visual blurring  Polyradiculopathy Associated antibodies and ne-  LEMS oplasms  Incontinence  Anti-Hu, anti-amphiphysin: small- cell lung Course  Anti-Yo: breast, ovarian  Quite variable  Anti-Ta (Ma2): testis  About 30% become wheelchair-  See also anti-Ri syndrome below bound one month after the onset  Less long-term disability than Other associations compared with the anti-Yo and  Post-viral syndrome anti-Hu syndromes  Longer survival than in the anti- Treatment Yo and anti-Hu syndromes Symptomatic Thiamine Associated neoplasms (85%) Clonazepam  Breast Immunosuppression  Lung (SCLC & non-SCLC) High-dose IgG, prednisone  Neoplasm discovered before neurological disorder: 15% Remissions: May occur spontane-  Distant metastases: 10% ously Anti-Ri (ANNA2, NOVA1) antibodies C. Opsoclonus / myo- CNS antigens: 55 kDa (NOVA; RNA binding) and 80 kDa proteins clonus in adults: anti- Immunohistochemistry: antibodies Ri syndrome bind to CNS, but not to peripheral neurons

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 Pleocytosis (40%) Other associated antibodies (75%): CNS imaging  Anti-Hu Normal in 65%, else there may be  Anti-Ta (Ma2) findings in cortex, brainstem or cauda  Anti-Tr equina.  ANNA3  Anti-CV2 (CRMP5) Treatment  Anti-AChR Most patients experience neurological  Anti-vg-Ca channel (P/Q- & N- improvement after tumour-directed type) or immunomodulatory therapy. Immunosuppression Investigations Corticosteroids CSF Intravenous high-dose IgG  High protein (35%)

Selected references 1. Anderson NE, Budde-Steffen C, Rosenblum MK, et al. Opsoclonus, myoclonus, ataxia and encephalopathy in adults with cancer: A distinct paraneoplastic syndrome. Medicine 1988; 67: 100- 9. 2. 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. 3. Pranzatelli MR. The neurobiology of the opsoclonus-myoclonus syndrome. Clin Neuropharmacol 1992; 15: 186-228. 4. Bataller, L.; Graus, F.; Saiz, F. et al. Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus- myoclonus. Brain 2001; 124: 437- 43. 5. Sutton IJ, Barnett MH, Watson JDG, et al. Paraneoplastic brainstem encephalitis and anti-Ri antibodies. J Neurol 2002; 249:1597-8.

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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.

 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 MRI from an optic neuritis case. T1-weighted and fat-suppressed Rule out: neuromyelitis optica (NMO) spin echo coronal through the (Devic’s disease) / optic spinal orbits. multiple sclerosis (OSMS), for Arrows: Enlargement and contrast example by testing for anti- enhancement of the left optic nerve in Aquaporin4 (AQP4) antibodies. the retrobulbar portion Consider testing for anti-MOG to diagnose anti-AQP4 seronegative Onset recurrent opticus neuritis. Subacute in patients aged 50-75 years and typically in smokers Associated neoplasms  Small-cell lung cancer Clinical features  Lung adenocarcinoma  Vision loss  Renal or thyroid carcinoma  Co-existing retinitis with vitre-  Hodgkin’s disease ous inflammatory cells in about 30% Autopsy / biopsy  Multifocal neurological accom- . Full-length CRMP5 protein is iden- paniments with superficially re- tifiable in normal retina and optic semblance to Devic's disease at nerve by Western blot analyses. presentation (myelopathy) . Photoreceptor cells, retinal ganglion cells, and nerve fibres exhibit Investigations immunoreactivity specific to  Serum: anti-CV2 (SCLC); anti- CRMP5. Tr (Hodgkin’s disease)  Swollen optic discs and field defects See also: Paraneoplastic cerebellar  Vascular leakage, evident at and degeneration with anti-CV2 (CRMP5) remote from the disc syndrome.

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Selected references 1. Pillay N, Gilbert JJ, Ebers GC, Brown JD. Internuclear ophthalmoplegia and "optic neuritis": paraneoplastic effects of bronchial carcinoma. Neurology 1984; 34 (6):788-91. 2. Waterston JA, Gilligan BS. Paraneoplastic optic neuritis and external ophthalmoplegia. Aust N Z J Med 1986; 16 (5):703-4. 3. 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. 4. 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. 5. 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. 6. Bataller L, Dalmau J. Neuro-ophthalmology and paraneoplastic syndromes. [Review]. Curr Opin Neurol 2004; 17 (1):3-8. 7. 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. 8. Thirkill CE. Cancer-induced, immune-mediated ocular degenerations. [Review]. Ocul Immunol Inflamm 2005; 13 (2-3): 119-31. 9. 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

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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 Additional info  Visual loss with unilateral onset,  The sensitivity of these antibody- often before detection of the tests is as follows: 60% of patients tumour with autoimmune retinopathy  Scotomas, initially, peripheral (AR); in 40% of CAR cases and ring, later-on central  The anti-Photoreceptor is directed to nuclear steroid receptors in the Course outer layer of retina and other Fluctuating and rapidly progressive protein bands  The anti-Rod is a particular Investigations feature of (MAR) as well as of CSF: normal colon cancer-associated retinopathy Electrophysiology: ERG abnormal,  The alpha-Enolase target is at the VER normal N-terminal region (amino terminal), located in retinal Antibodies ganglion cells and inner nuclear  Anti-Recoverin (23 kDa, calcium- layer cells binding protein)  Anti-ENO1 is also a feature of  Anti-Heat Shock Cognate Protein Hashimoto's encephalopathy and HSC 70 some gastrointestinal disorders  Anti-CV2 (CRMP5)  Anti-Alpha-Enolase (ENO1) Associated neoplasms  Anti-Arrestin  Small-cell lung cancer  Anti-TULIP-1  Melanoma  Anti-Photoreceptor cell-specific  Gynaecologic nuclear receptor  Colon, lymphoma  Anti-Rod bipolar cell  Anti-Carbonic anhydrase  Anti-Trasducin B

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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 (sub- photopsias; 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. Pillay N, Gilbert JJ, Ebers GC, Brown JD. Internuclear ophthalmoplegia and "optic neuritis": paraneoplastic effects of bronchial carcinoma. Neurology 1984; 34:788. 2. Berson EL, Lessell S. Paraneoplastic night blindness with malignant melanoma. Am J Ophthalmol 1988; 106: 307. 3. 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.. 4. Jacobson DM, Thirkill CE, Tipping SJ. A clinical triad to diagnose paraneoplastic retinopathy. Ann Neurol 1990; 28:162-7. 5. Keltner JL, Thirkill CE, Tyler NK, Roth AM. Management and monitoring of cancer-associated retinopathy. Arch Ophthalmol 1992; 110: 48. 6. Malik S, Furlan AJ, Sweeney PJ, et al. Optic neuropathy: a rare paraneoplastic syndrome. J Clin Neuroophthalmol 1992; 12:137. 7. 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. 8. 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 9. 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 10. 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. 11. 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 12. 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. 13. 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 14. 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. 15. 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. 16. Guy J, Aptsiauri N. Treatment of paraneoplastic visual loss with intravenous immunoglobulin: report of 3 cases. Arch Ophthalmol 1999; 117: 471-7. 17. Heckenlively JR, Fawzi AA, Oversier J, et al. Autoimmune retinopathy: patients with antirecoverin immunoreactivity and panretinal degeneration. Arch Ophthalmol 2000; 118: 1525-33. 18. Ritland JS, Eide N, Tausjø J. Bilateral diffuse uveal melanocytic proliferation and uterine cancer. A case report. Acta Ophthalmol Scand 2000; 78: 366-8. 19. 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. 20. 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. 21. Eichen JG, Dalmau J, Demopoulos A, et al. The photoreceptor cell-specific nuclear receptor is an autoantigen of paraneoplastic retinopathy. J Neuroophthalmol 2001; 21: 168-72.

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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 melanoma- associated 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 melanoma- associated retinopathy: effect on visual acuity and electrophysiologic findings. Arch Dermatol 2004; 140: 1258-61. 37. Ohguro H, Yokoi Y, Ohguro I, et al. Clinical and immunologic aspects of cancer-associated retinopathy. Am J Ophthalmol 2004; 137: 1117-19. 38. Chang PY, Yang CH, Yang CM. Cancer-associated retinopathy in a patient with hepatocellular carcinoma: case report and literature review. Retina 2005; 25:1093. 39. Damek DM. Paraneoplastic Retinopathy/Optic Neuropathy. Curr Treat Options Neurol 2005; 7: 57- 67. 40. Weleber RG, Watzke RC, Shults WT, Trzupek KM, Egan RA, Heckenlively J, Adamus G. “Clinical and electrophysiologic characterization of paraneoplastic and autoimmune retinopathies associated with anti-enolase antibodies”. Am J Ophthal 2005; 139: 780-794. 41. Dot C, Guigay J, Adamus G. “Anti-alpha-enolase Antibodies in Cancer-associated Retinopathy with Small Cell Carcinoma of the Lung” Am J Ophthal 2005; 139: 746-747. 42. Sharan S, Thirkill CE, Grigg JR. Autoimmune retinopathy associated with intravesical BCG therapy. Br J Ophthalmol. 2005 ; 89(7): 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: 156- 8. 50. Sheorajpanday R, Slabbynck H, Van De Sompel W, et al. Small cell lung carcinoma presenting as collapsin response-mediating protein (CRMP) -5 paraneoplastic optic neuropathy. J Neuroophthalmol 2006; 26: 168-72. 51. Duong HV, McLean IW, Beahm DE. Bilateral diffuse melanocytic proliferation associated with ovarian carcinoma and metastatic malignant amelanotic melanoma. Am J Ophthalmol 2006; 142: 693-5. 52. Espandar L, O'Brien S, Thirkill C, et al. Successful treatment of cancer-associated retinopathy with alemtuzumab. J Neurooncol 2007; 83: 295-302. 53. Magrys A, Anekonda T, Ren G, Adamus G. The role of anti-alpha-enolase autoantibodies in pathogenicity of autoimmune-mediated retinopathy. J Clin Immunol 2007; 27: 181-92.

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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; 22:1191- 3 60. Ko MW, Dalmau J, Galetta SL. Neuro-ophthalmologic manifestations of paraneoplastic syndromes. J Neuroophthalmol 2008; 28: 58-68. 61. Subhadra C, Dudek AZ, Rath PP, Lee MS. Improvement in visual fields in a patient with melanoma- associated retinopathy treated with intravenous immunoglobulin. J Neuroophthalmol 2008; 28: 23- 6. 62. Adamus G. Autoantibody targets and their cancer relationship in the pathogenicity of paraneoplastic retinopathy. Autoimmun Rev 2009; 8: 410-4. 63. Bazhin AV, Dalke C, Willner N, et al. Cancer-retina antigens as potential paraneoplastic antigens in melanoma-associated retinopathy. Int J Cancer 2009; 124:140-9. 64. Lu Y, Jia L, He S, et al. Melanoma-associated retinopathy: a paraneoplastic autoimmune complication. Arch Ophthalmol 2009; 127: 1572-80. 65. Moss HE, Liu GT, Dalmau J. Glazed (vision) and confused. Surv Ophthalmol 2010; 55: 169-73. 66. Kiratli H, Erkan K. Loss of Retinal Pigment Epithelium Associated with Bilateral Diffuse Uveal Melanocytic Proliferation. Ophthalmic Surg Lasers Imaging 2010; 5: 1-4 67. Besirli CG, Comer GM. High-resolution OCT imaging of RPE degeneration in bilateral diffuse uveal melanocytic proliferation. Ophthalmic Surg Lasers Imaging 2010; 41 Suppl:S96-S100.

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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 anti- CV2 may be additional findings.

Epidemiology Muscle spasms  Females (70%) May occur spontaneously or are triggered by Age at onset  Stretching  Childhood or adult  Emotion  Anti-GAD antibody positive:  Sensory stimulation o Most common 3rd to 5th dec-  Fear of open spaces ades, mean 40 years Typical cause o Sudden myoclonic jerks that Course may produce falling  Usually, SPS is slowly progressive o This is followed by tonic activ- (insidious) or static over years ity that subsides over seconds  Occasionally, the onset is rapid Location of spasms  Focal syndromes may progress to  Arms: extension and pronation more generalized involvement  Trunk: extension  In occasional patients, sudden  Legs: extension and mild abduc- death may occur due to tion; foot inversion o Cardiac arrhythmias  Co-contraction of agonist and an- o Restrictive respiratory arrest tagonists o Rapid tapering of intrathecal  Abdominal and thoracic parasp- baclofen inous muscles  Spasms may produce little move- Prodromes ment due to co-contraction Episodic stiffness or falling, pains and around joints tightness in axial muscles Consequences and disability  May be associated with severe Clinical features pain  May also be severe enough to Stiffness cause fractures Especially, the distribution is in axial  Due to frequent falls, a cane or and proximal limb muscles. Fre- walker is commonly needed quently, it is also asymmetric or Relaxation of spasms prominent in one leg. The involve-  Sleep & benzodiazepines ment of limbs impairs walking. There may be lumbar hyperlordosis, limiting Reflexes truncal flexion.  Tendon reflexes: normal or in-

creased These features are reduced in sleep,  Abdominal cutaneous: may be lost and do usually fluctuate over time as  Startle responses: increased well.

Gait: "Tin soldier"

Autonomic dysfunction

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 Normal: 40% in SPS; 10% in Extraocular movements: (only PERM variant. some patients)  Anti-GAD antibodies, although  Gaze-holding nystagmus usually lower titre than in serum  limited abduction  Intrathecal anti-GAD synthesis  Vertical and horizontal ocular mis- may occur alignment  Deficient smooth pursuit MRI of the CNS: non-diagnostic  Impaired saccade initiation EMG Otherwise, normal neurologic ex- Continuous action potentials amination in most SPS patients  Indistinguishable from voluntary activity: normal motor units Associated neoplasms  Persist during attempts at  Breast relaxation  Other: lung, thymoma, Hodgkin's  Most prominent in axial muscles and non-Hodgkin’s lymphoma,  Rhythmic and synchronous myeloma, renal cell carcinoma persistent 5 - 6 Hz bursts of 50 to 60 ms duration Associated disorders  Interruption of bursts by spasms Epilepsy treated with anti-GABA with rapid activity; full agents, suggests PERM variant. interference pattern; > 4 sec Diabetes mellitus, type I (30- 60 %).  Activity reduced by intravenous Immune disorders diazepam.  Thyroiditis (15%)  No fibrillations or grouped  Pernicious anaemia (10%) rhythmic discharges  Myasthenia gravis  Poor relaxation after contraction  Ovarian or adrenal failure, vitiligo  Similar immune disorders may oc- Serum antibodies cur in family members Apart from the pancreas, GAD65 is More common with anti-GAD anti- only expressed at GABA-ergic nerve bodies terminals, which co-localizes with Am- HLA: DRβ1 0301 (40-70 %) phiphysin and CV2 (CRMP5) while GAD67 is spread evenly throughout CNS pathology the cells. This difference is thought to Perivascular inflammation reflect a functional difference; GAD67 Spinal cord: neuronal loss synthesizes GABA for neuron activity Lateral vestibular nucleus: loss of unrelated to neurotransmission, such neurons as synaptogenesis and protection from neural injury. This function re- Differential diagnosis quires widespread, ubiquitous pres- Hyperekplexia (Stiff-baby syndrome) ence of GABA. GAD65, however, syn- o Childhood onset: DYT1 gene thesizes GABA for neurotransmission, mutations and therefore is only necessary at Rule out associated pernicious anae- nerve terminals and synapses. mia Anti-GAD65 antibodies Investigations Prevalence in SPS: 50-90 %. Serum CK: transiently elevated Anti-GAD67 antibodies ANA (30%). The prevalence of anti-GAD67 is un- CSF known, so currently, the significance  Oligoclonal bands (60%) of anti-GAD65 versus anti-GAD67 is  Protein high (20%) relatively unexplored.  Pleocytosis: 10% in SPS; 60% in PERM variant

Anti-GlyR alpha1 antibodies 52

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About 10 % of patients with SPS spec- Therapy trum of symptoms (with or without Unfortunately, treatment is rarely associated GAD antibodies) completely effective. Symptomatic Anti-CV2 (CRMP5)  Diazepam (very high doses; 20 mg to 300 mg/day) Anti-Amphiphysin  Clonazepam Anti-Gephyrin, rarely  Baclofen Oral: adjunct medication Tissue staining pattern Pump (intrathecal)  GABA nerve terminals Indication: severe syndromes  Co-localizes with amphiphysin and Warning: acute withdrawal has CRMP5 been fatal Valproate The levels of anti-GAD antibody titres Tiagabine: 6 mg qd vary with clinical syndromes  High in Stiff-man syndrome Immunomodulatory therapies  Usually much higher than in CSF  Corticosteroids: high dose solumedrol with tapering Specificity: more with higher anti- Improvement over months GAD antibody titres  Intravenous high-dose IgG  Plasma exchange Anti-GAD antibodies may also be  Rituximab a finding in other syndromes 1. Palatal myoclonus 2. Epilepsy (autoimmune encephalitis) Stiff-person  Therapy-resistant, localiza- syndrome (SPS), tion-related variants  Frequency: 15%.  Anti-GAD antibody titres: high or moderate The associated autoantibody is 3. Cerebellar ataxia  Anti-GAD in all the variant syn- 4. Insulin-dependent diabetes dromes mellitus (IDDM)  Age spectrum: Childhood & Table 8: adolescence Enumera- SSPS, variants  Anti-GAD antibody titres: low tion to moderate titre 1 Focal SPS 5. In association with 2 Jerking SPS Antibodies to tyrosine phos-  3 PERM phatase IA-2 In PCD, also with  T-cell immunity 4 anti-GAD 6. Autoimmune polyendocrine 5 Other SPS syndrome II

Other antibodies associated 1. Focal SPS with SPS Most frequently, this is a stiff-leg syn-  Anti-Pancreatic islet cell (60%) drome or alternatively, a stiff-arm Also found in type I diabetes, alt- syndrome. hough with lower titre and a different staining pattern Onset 35 to 60 years  Anti-PCA2 Clinical features Stiffness and spasms of lower limbs

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Stimuli: especially voluntary move- Pathology ment; also reflex stimuli  Perivascular inflammation  Asymmetric  Gliosis in spinal cord, pons and  Posturing of feet medulla  Trunk spared  Neuronal loss: spinal gray

Treatment (partial benefit) Baclofen, Diazepam 4. SPS in cerebellar syndrome with anti-GAD

2. Jerking SPS Clinical features Epidemiology Stiffness: axial and lower limb Onset age: females 20 to 75 years Later features  Brainstem myoclonus Clinical features  Upper motor neuron signs The onset is slowly progressive.  PERM, see below Ataxia: limb and trunk Nystagmus Progression over decade Dysarthria (50%) Stiffness (15%) No brainstem involvement 3. Progressive encephalopathy with rigidity and re- Associated disorders flex myoclonus (PERM)  Late-onset insulin-dependent diabetes mellitus Thyroiditis Onset: subacute (weeks)   Poly-endocrine syndrome Clinical features

Stiffness Additional antibodies  Distal > proximal at disease onset  Anti-Parietal cell Rigidity

Spasms: episodic MRI: non-diagnostic. Muscle wasting & weakness

Autonomic  Hyperhidrosis associated with Treatment: not described spasms Cranial nerves 5. Other paraneoplastic  EOM: nystagmus and ophthal- SPS moplegia  Blindness Suggestive features  Deafness, dysarthria SPS confined to upper limbs. Other CNS  Long tract Rapid disease progression to  Vertigo fixed joint deformities  Preserved intellect Also associated Progression  Sensory ganglionopathy  Over months and usually, death within one to 39 months Neoplasms  Some cases remain mild  Breast  Lung (small-cell) Investigations Neurophysiology: similar to SPS Additional antibodies and brainstem myoclonus  Anti-Amphiphysin Serum: anti-GAD, anti-Glycine receptor Treatment: Not described CSF: inflammatory

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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.

30/01/2016, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Syndromes of the peripheral nervous system

The autonomic nervous system

Paraneoplastic autonomic neuropathy (AAN)

Paraneoplastic autonomic neuropathy: Paraneoplastic autonomic dysfunction of the ganglions and para- sympatic & 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 Clinical features (AAN) appears to fulfil the criteria of an  Orthostatic hypotension without antibody-mediated autoimmunity. This compensatory tachycardia disorder has also been nicknamed “autonomic myasthenia gravis”.

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 Gastrointestinal dysmotility Associated neoplasms (80%)  Thymoma  Anhidrosis (60%)  SCLC  Dry eyes and mouth  Bladder  Pupillary response reduced (30%)  Rectum  GU: urinary or erectile dysfunction (30%) Differential diagnosis  Sensory paraesthesia in extremi-  Multiple system atrophy (MSA) ties (25%) with predominant autonomic fail-  Cough. ure (former term: Shy-Drager syndrome) Investigations  Anti-Peripherin seropositive neu- CSF ropathy with endocrinopathy  Elevated protein in 60%  Typically, there are no cells Treatment  Oncological therapy of associ- Antibody ated neoplasm  Anti AChR (alpha3-type)  Intravenous high-dose IgG, The nicotinic α3-AChR is located early after onset or at progress- at autonomic ganglions ing disability

This autoantibody may be a feature 2. The following syndromes of other disorders: may also exhibit autonomic  Isaacs’ syndrome (50%) dysfunction:  Lambert-Eaton myasthenic syndrome (10%)  Paraneoplastic cerebellar syn-  Myasthenia gravis (a few dromes: with anti-PCA2 anti- patients) bodies; with CV2 (CRMP5) antibodies See also autonomic features of the  Paraneoplastic sensory-motor anti-Hu and anti-CV2 (CRMP5) syn- neuropathy with anti-CV2 dromes: subacute sensory neu- (CRMP5) antibodies ronopathy (SSN), chronic gastro-  Morvan’s fibrillary chorea intestinal pseudo obstruction.  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)

30/01/2016, Copyright, Finn E. Somnier, MD., D.S. (Med.)

Paraneoplastic motor neuropathy

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

Onset Course: progressive then stabiliza- After diagnosis of tumour tion or improvement

Epidemiology Associated neoplasms Majority male & > 50 years  Non-Hodgkin Lymphoma  Also other lymphomas & myelo- Clinical features proliferative disorders Weakness  Ductal adenocarcinoma of breast  Asymmetric; arms > legs  Mild and sometimes only lower Investigations motor neuron CSF: No cells; mildly increased  Normal bulbar protein Cramps: painful MRI: Spinal cord normal Painless in some patients ? 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 about 15%-30% of these patients  Associated with anti-Hu or anti-  Subacute sensory neuronopathy CV2 antibodies and in some pa- (SSN) tients both autoantibodies  Motor symptoms usually resulting  Possibly, anti-Pyridoxal phospha- from motor neurone degeneration tase  In about 30%, there is an equal  Paraproteinaemic disorders proportion of sensory and motor involvement Clinical features  Frequently, the distribution is asymmetrical or multifocal Electrophysiology  Showing axonal and or demye- Note: Both mononeuritis multiplex linising processes and polyradiculopathy may resemble this disorder. Moreover, an Antibodies acute severe evolution in the four  Anti-Hu seropositive patients limbs may mimic the Guillain-Barré Sensory or motor neuropathy in syndrome.

30/01/2016, Copyright, Finn E. Somnier, MD., D.S. (Med.)

 Anti-Pyridoxal phosphatase  Anti-CV2 seropositive patients may also be a finding Polyneuropathy in about 60% This autoantibody is a finding in sera of pa-  Most frequently, this is a sen- tients with lung cancer and well-differentiated thyroid cancer. They may also be a sory-motor neuropathy prefer- feature of an autoimmune thyroid disorder. entially affecting the lower Pyridoxal phosphatase is a co-enzyme of limbs vitamin B6 (pyridoxine). Theoretically  Pain is less frequent than with therefore, such antibodies may cause seizures and in particular a sensory-motor a finding of anti-Hu antibodies neuropathy with burning paraesthesias and eventually motor deficits. However, Other features (in about 65%) there are no reports about PNS related to  Central nervous system disor- anti-Pyridoxal, so such a disorder awaits discovery. der  Autonomic neuropathy  Eye involvement Please, also see

 Paraneoplastic cerebellar syndro-  Paraproteinaemias (monoclonal gammopathies) mes: CV2 (CRMP5) syndrome  M-components (IgA, IgG, IgM)  Opsoclonus / myoclonus: anti-Ri syndrome (due to other antibodies than anti-Ri)

Selected references 1. Vincent D, Dubas F, Haw JJ, et al. Nerve and muscle microvasculitis. J Neurol Neurosurg Psychiatry 1986; 49:1007-10. 2. Younger DS, Dalmau J, Inghirami G, ET AL. Anti-Hu-associated peripheral nerve and muscle microvasculitis. Neurology 1994; 44: 181-3. 3. Oh SJ. Paraneoplastic vasculitis of the peripheral nervous system. Vasculitis and the nervous system. Neurologic Clinics 1997; 15 (4): 849-63. 4. 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. 5. Antoine JC, Mosnier JF, Absi L, et al. Carcinoma associated paraneoplastic peripheral neuropathies in patients with and without anti-onconeural antibodies. J Neurol Neurosurg Psychiatry 1999; 67:7- 14. 6. Rudnicki SA, Dalmau J. Paraneoplastic syndromes of the spinal cord, nerve, and muscle. Muscle Nerve 2000; 23:1800-18. 7. 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. 8. 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.

30/01/2016, Copyright, Finn E. Somnier, MD., D.S. (Med.)

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.

 Subsequently, plateau with little Epidemiology improvement  Males in about 20-85% (US & Eu-  Occasional improvement with ropean study, respectively). The treatment-induced remission of difference may be attributable to the neoplasm varied smoking patterns.  Age of onset Favourable PNS prognosis is as- o Mean 60's (range 35-85 years sociated with of age)  Variable survival data: similar to  Tobacco smoking: > 95 % or better than in anti-Hu-seronegative patients Clinical features  Significant response, related to Painful paraesthesias and dysaes- oncologic treatment thesias (80%)  Limited disease at time of diagno-  Asymmetric, distal or proximal sis Sensory loss (95%), all modalities  Initial metastases tend to spare are involved nervous system  Proprioceptive loss: prominent  Ataxia: sensory Less common outcomes  Pseudoathetosis  Mild course Distribution  Acute (< 24 hrs. in about 3%)  Proximal and distal  Chronic (> six months in about  Asymmetric (35%) or symmetric 15-40%)  Upper limb only (25%)  Lower limb only (45%) Survival: mean 28 months (6 Motor months to 8 years)  Normal (75%)  Occasional sensory-motor in- Associated syndromes (40-70%) volvement (25%), possibly sub- Limbic encephalitis ± seizures clinical (10%)  The weakness may be proximal or Epilepsy partialis continua distal Cerebellar: ataxia and nystagmus  In rare cases (5%), amyotrophy Brainstem encephalitis or fasciculations  Vestibular disorders  Oculomotor paresis Course  Bulbar palsy  Initial localized pain or sensory  Hearing loss loss Myelitis: patchy weakness with arms  Then progression over days to six > legs months LEMS

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Autonomic (30%)  Diffusely absent or reduced.  Blood pressure: labile, hypoten-  May be variable among nerves sion (20%) Motor studies show variable involve-  Oesophageal achalasia ment  Gastro-paresis  Often normal  Pseudo-obstruction  Occasionally, there is axonal loss,  Constipation (10%) which may occur without associ-  Intestinal obstruction (10%) ated weakness.  Urinary dysfunction (10%)  IADHS (inappropriate ADH syn- CSF drome)  Cells: in about 50%, the number  Maybe primary lateral sclerosis of mononuclear cells is elevated (2 (PLS) to 26/mm3).  Protein: high (20 to 190) in 70% Patients may also have a multifocal  Oligoclonal bands CNS disorder: paraneoplastic encephalomyelitis Autoantibodies (PEM), please see specific chapter. IgG versus Hu (ANNA1).  Cell targets: selective staining of

nuclei Associated neoplasms (in 88%, Neurons (PNS & CNS), and often small & slow growing) adenohypophysis, adrenal cortex,  Small-cell lung cancer: strong- retina est neoplasm association Clinical correlations  Frequency: 80% of Hu posi-  Low titres are associated with tive serums neoplasm not provoking neuro-  Prevalence: 17% of SCLC. logic symptoms  Others (rare)  High titres are associated with  Breast, ovary, renal, testis, neoplasm and SSN prostate, oesophagus, mela- Antibody location: serum and CSF noma, thymoma, Hodgkin’s Antibody type disease  All subtypes of IgG, although pre-  These neoplasms may coexist dominantly IgG1 with small-cell lung cancer Hu antigens Investigations  RNA binding proteins Note. SCLC may escape the initial de- Hu is a family of 35 to 40 kDa neu- tection and only be disclosed upon fol- ronal nuclear proteins. The pro- low-up testing (30%). teins are HuD, HuC, Hel-N1, Hel- N2, ple21 MRI, PET. Other antibodies Surgical examinations  Anti-CV2 (CRMP5) in about Bronchoscopy, mediastinoscopy, 15% thoracotomy  Serum M-protein: not reported Electrodiagnostic Sensory nerve action potentials  Intra-lesional lymphocytes of CD45RO-type (memory cells) Pathology  Patchy dorsal root ganglion in- Differential diagnosis flammation and neuronal loss Toxic: cis-platinum  About 50% with inflammation Pyridoxine deficiency elsewhere in spinal cord or brain Sjögren's syndrome  Spinal cord with loss of axons in posterior columns

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Physical therapy may be of value in Treatment 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. Chinn JS and Schuffler MD. Paraneoplastic visceral neuropathy as a cause of severe gastrointestinal motor dysfunction. Gastroenterology 1988; 95: 1279-86. 2. Lennon VA, Sas DF, Busk MF, et al. Enteric neuronal antibodies in pseudoobstruction with small- cell lung carcinoma. Gastroenterology 1991; 100: 137-42. 3. Chalk CH, Windebank AJ, Kimmel DW, et al. The distinctive clinical features of paraneoplastic sensory neuronopathy. Can J Neurol Sci 1992; 19:346-51. 4. Graus F, Bonaventura I, Uchuya M, et al. Indolent anti-Hu-associated paraneoplastic sensory neuropathy. Neurology 1994; 44: 2258-61. 5. 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. 6. Graus F, Keime-Guibert F, René R, et al. Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain 2001; 124:1138-48. 7. Lee HR, Lennon VA, Camilleri M, et al. Paraneoplastic gastrointestinal motor dysfunction: clinical and laboratory characteristics. Am J Gastroenterol 2001; 96: 373-9. 8. 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. 9. J W Meeusen; K E Haselkorn; J P Fryer; T J Kryzer; S J Gibbons; Y Xiao; V A Lennon. Gastrointestinal hypomotility with loss of enteric nicotinic acetylcholine receptors: active immunization model in mice. Neurogastroenterol. Motil. 25, (2013)

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Syndromes of the neuromuscular junction

In contrast to the central and peripheral nervous system, the NMJ is not protected by any barrier, leaving it relatively unhindered exposed to toxins, chemical agents, and autoantibodies. The neuromuscular transmission is known in details (Figure 2), including the composi- tion and function of many structures. Ac- cordingly, 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

30/01/2016, Copyright, Finn E. Somnier, MD., D.S. (Med.)

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 and most frequently found within two Muscle weakness years after the diagnosis of LEMS. Typically, the chronology of the distribution of the weakness is the reverse Pro-GRP (gastrin-releasing peptide) of that of myasthenia gravis. In more and SOX1 antibodies both appear to than 90%, the weakness starts proxi- be highly associated SCLC markers, mally in the legs. The paresis can then also without a co-existent parane- spread to other striated muscles in a oplastic syndrome. caudo-cranial order. In some patients, this might lead to a need for artificial Anti-SOX seropositivity is a feature of respiration. Ptosis and ophthalmople- about 60% of SCLC cases with LEMS. gia can be present, but tend to be milder than in autoimmune myasthe- Table 9 nia gravis. LEMS associated neoplasms % Autonomic dysfunction Dry mouth, dryness of the eyes, (n = 141) blurred vision, impotence, constipa- Pulmonary malignancies 79 tion, impaired sweating, or orthostatic (Small cell lung carcinoma) 67 hypotension. The autonomic dysfunc- Lymphoma 5 tion is mostly mild to moderate, in Leukaemia 4 contrast to the severe disabling auto- Miscellaneous 11 nomic dysfunction in the anti-Hu syn- Prostate carcinoma 2 drome. Laryngeal carcinoma 2 Lymph metastasis, unknown primary 3 Cerebellar degeneration Breast carcinoma 1 Gall bladder carcinoma 0.7 In rare cases, patients with LEMS and Rectal adenocarcinoma 0.7 SCLC develop such features. In some Carcinoma of maxillary glandule 0.7 patients, cerebellar degeneration is Malignant thymoma 0.7 present together with anti-vg-Ca Ameloblastoma 0.7 channel antibodies, but without clinical signs or symptoms of myasthenic muscle weakness. Diagnostic criteria

A typical history and clinical findings Maybe it is related to anti-SOX1 (anti-Glial nuclear antibodies, AGNA), the target be- with in addition at least one of the fol- ing the Bergman glia in the Purkinje cell lowing: layer. 1. Low compound muscle action potential after nerve stimulation with See also: “Cerebellar syndromes decrement at low frequency stim- with anti-PCA2 antibodies”. ulation (3 Hz) of more than 10%, and increment after high fre- Associated neoplasm quency stimulation (more than 20 In more than 50 % LEMS cases small- cell lung cancer (SCLC) is co-existent,

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Hz) or preferably maximal voluntary contraction) of more than Voltage-gated-Ca++-channel 100%. 2. Anti-vg-Ca channel (P/Q- type) 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 M1- type) antibodies in about 80 % These are directed to the presynaptic muscarinic AChR, which is associated with the TRPC3 channel Small cell lung cancer (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-vg- Ca channel seronegative LEMS patients.

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 nu- Treatment clear antibodies) Symptomatic Autoantibodies against cerebellar  3, 4-diaminopyridine, possibly Bergmann glia are a feature of LEMS combined with pyridostigmine sera in about 65% of the patients

(sensitivity). Vice versa, SOX antibod- Immunotherapy ies has a specificity of 95% to discrim-  Steroids inate between LEMS with SCLC and  Plasma exchange non-tumour LEMS.  High-dose intravenous IgG

 Rituximab  Azathioprine Additional autoantibodies  Cyclophosphamide In cases with SCLC and symptoms other than muscle weakness Specific tumour treatment  Anti-Hu In SCLC local resection, radiotherapy,  Anti-PCA2 or chemotherapy may result in a re-  Anti-CV2 markable recovery of the LEMS.  Anti-Amphiphysin  Anti-GAD  Anti-Ri  Anti-AChR (alpha3) Please see the various syndromes associated with these autoantibodies.

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Selected references 1. O'Neill JH, Murray NM, Newsom-Davis J. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain 1988; 111: 577-96. 2. 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. 3. 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. 4. O'Suilleabhain P, Low PA, Lennon VA. Autonomic dysfunction in the Lambert-Eaton myasthenic syndrome: serologic and clinical correlates. Neurology 1998; 50: 88-93. 5. 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. 6. 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. 7. 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. 8. Takamori M, Motomura M, Fukodome T, Yoshikawa H. Autoantibodies against M1 muscarinic receptor in myasthenia gravis. Eur J Neurol 2007; 14 (11): 1230-1235. 9. 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.

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Mental disturbances (25%) Anti-CASPR2 disorders: Morvan's syndrome, limbic encephali- Acquired neuromyotonia tis with personality change, insomnia, Peripheral nerve hyper-excitability irritability Morvan’s syndrome

Neuromyotonia with autonomic and Other features CNS involvement Limbic encephalitis Sensory symptoms (30%), paraes- CNS manifestations without periph- thesias and numbness, hyperhidrosis eral involvement (35% to 55%) Tendon reflexes are often normal.

Onset  With an onset, usually in late childhood or early adulthood, familial and acquired (primarily autoimmune) forms have been reported  Most frequently < 60 years (mean 46 years)  All origins: nine to 80 years

Differential diagnosis  Paraneoplastic opsoclonus / myoclonus (POM) Voltage-gated-K+-channel

Clinical features Course The symptoms may fluctuate in se- Fluctuations, but no spontaneous re- verity over periods of months. Typi- missions cally, exercise or muscle contractions are factors of precipitation. Neurophysiology

Muscle twitching EMG Visible myokymia or neuromyotonia is Spontaneous axonal action poten- symptomatic in 10 to 40%. The inter- tials mittent cramps and stiffness occur at In general, there is peripheral nerve rest, and may be induced or exacer- hyperexcitability due to potentials bated by exercise. The predominant arising along the course of motor ax- distribution of these features is dis- ons and increased excitability of the tally in the arms and legs. Face, nodal membrane. The potentials per- tongue and pharyngeal muscles may sist during general anaesthesia. NMJ be involved. Moreover, an observation blockade eliminates the abnormal is delayed muscle relaxation and no muscle activity. percussion-induced contraction. The muscle activity continues during sleep. Distribution: limbs > trunk & face

Fatigue, hypertrophy Fasciculations may be the only sign If existing, the weakness is absent or of disease and may occur without my- mild in about 30%, especially in over- okymia. This may be clinically con- active muscles. Muscle hypertrophy fused in the early stages with amyo- may occur in 20%. These features do trophic lateral sclerosis. not predict co-existence of MG or pol- Myokymia yneuropathy. This feature is absent in some pa-

tients, and may develop on subsequent study, often as a mild continuous spontaneous activity.

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These are spontaneous bursts of mo-  Morvan's fibrillary chorea tor unit potentials of a brief duration,  Polyneuropathy: sensory-motor less than one second. They consist of with M-protein two to five potentials per burst, with a  HIV infection frequency of 5-70 Hz. They recur reg-  Other associated immune disor- ularly or irregularly (0.1 to 3 per sec- ders ond) and may persist after treatment o Thyroid o Diabetes Neuromyotonia More persistent activity and muscle Investigations contraction. These are spontaneous Serum CK: Elevated in 50% bursts of single motor unit potentials, prolonged (several seconds) and of a Autoantibodies frequency of 40 - 300 Hz. The bursts  Anti-CASPR2 (contactin-asso- are very irregular and associated with ciated protein-2) in more than persistent muscle contraction. Treat- 50 % ment may be able to reduce them.  (Anti-voltage-gated K-channels) Another observation is repetitive F- The targets are located at the dentate gyrus of waves. hippocampus, at neural juxtaparanodes, and at the neuromuscular junction. In RIAs, using 2 % digitonin extract of radio-labelled dendrotoxin, Associated neoplasms antibodies to Shaker types Kv1.1, 1.2, 1.6 are Neoplasms detectable, although not differentiated. Moreo-  Lung ver, such VGKC extract are complexed with two  Thymus other channel-complex proteins, leucine-rich, glioma inactivated 1 protein and contactin-  Hodgkin's disease associated protein-2 in limbic encephalitis. Isaacs’ syndrome often predates the Therefore, this assay is not specific to anti- diagnosis of these neoplasms. VGPC.

Associated disorders  Anti-AChR (autonomic alpha3-  Myasthenia gravis (seropositive, type, 50%) anti-AChR antibodies)  Anti-AChR (adult-type, foetal- The over activity begins with or af- type), in co-existing parane- ter MG. The frequency of Isaac’s oplastic MG syndrome in myasthenics is esti- mated at about 10 to 20% and ob- Nerve conduction studies are usu- served with a thymoma in patients ally normal. > 40 years  Penicillamine treatment CSF may occasionally show abnormality Treatment  Oligoclonal bands Symptomatic  Slightly increased protein  Carbamazepine (200 to 600 mg/day) Muscle biopsy: fibre hypertrophy of  Phenytoin (200 to 400 mg/day) type-I predominance  Mexiletine

Other disorders with K+-chan- Immunosuppression nel antibodies:  Plasma exchange (short-term  Cramp-fasciculation syndrome benefit).  Limbic encephalitis  Prednisone  Morvan's fibrillary chorea  KCNA1 mutations in episodic ataxia 1 (hereditary Isaacs- Mertens syndrome, myokymia 1)

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Selected references 1. Newsom-Davis J, Mills KR. Immunological associations of acquired neuromyotonia (Isaacs' Syndrome). Report of five cases and literature review. Brain 1993; 116: 453-469. 2. Hart IK, Waters C, Vincent A, et al. Autoantibodies detected to expressed potassium channels are implicated in neuromyotonia. Ann Neurology 1997; 41: 238-246. 3. 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. 4. 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. 5. Buckley C, Oger J, Clover L, et al. Potassium channel antibodies in two patients with reversible limbic encephalitis. Ann Neurol 2001 50: 74-79. 6. 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. 7. 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. 8. 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. 9. 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.

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Paraneoplastic seropositive myasthenia gravis with thymoma

Paraneoplastic seropositive* myasthenia gravis (SPMG with a thymoma): An autoimmune postsynaptic disorder of the neuromuscular junction, characterized by the 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 myasthenia- Mixed epithelial / lymphocytic- gravis-associated myopathy and sporadic rippling cortical thymoma muscle syndrome. (*Seropositive = anti-AChR antibodies seropositive)

thymomas (cortical type?). Presuma- bly, this neoplasm therefore provokes a synthesis of such autoantibodies and maybe to other targets as well under such conditions.

SPMG is co-existent in about 50% of patients with a thymoma. Otherwise, this neoplasm is associated with a va- Chest x-ray: thymoma riety of other autoimmune disorders and corresponding autoantibodies.

Thymomas vs. autoimmunity Frequently, thymoma patients are The normal job of the thymus is to ed- diagnosed with more than one such ucate and export T-cells to the rest of disorder. the body, in order to help B-cells to make antibodies and stimulate other Unrelated to a thymoma, MG is in it- cells to protect against infections and self associated with other antibodies, neoplasms. apart from maybe ANA  Anti-Lymphocyte (60%) Unfortunately, the emergence of a  Anti-Nuclear (ANA, 30%) thymoma often results in a vast ex-  Anti-Thyroid (microsomal & thy- cess of harmful T-cells, provoking var- roglobulin), 30% ious autoimmune disorders. It ap-  Rheumatoid factor (25%) pears that a ‘dangerous’ tumour mi-  Anti-Platelet (25%) croenvironment is created with both  Anti-Parietal cell (15%) pre-activation and antibodies to cyto-  Anti-Smooth muscle (10%) kines (IF-alpha, IL-12). Normally,  Coomb’s (10%) 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

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Epidemiology in MG Nicotinic acetylcholine The frequency of this neoplasm is receptors about 10% of all myasthenics. The Embryonic- and adult- peak age at onset of thymoma-SPMG types is in-between early- and late-onset MG (dichotomy by 50 years of age). For more details, see the adjacent figure.

18 1,4 Non-thymoma 16 1,2 14 Thymoma-MG 1 Note the presence of either a 12 gamma-subunit or an epsilon- 10 0,8 subunit 8 0,6 6 0,4 Rate x 10-6 4 Investigations 2 0,2 0 0 Autoantibodies

0-9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 If only MG symptoms are present, then primarily Age group, years  Anti-AChR (adult- & foetal-type) Trimodal occurrence  Anti-Titin (must be determined Mean annual incidence rates of with an assay using the main im- myasthenia gravis in Eastern- munogenic region (MIR) Denmark 1970-99. o Almost all MG patients with The rates are per million population and by anti-titin and onset < 50 age group. Note the different scales of the value axes, the right one is for years of age have a co-ex- paraneoplastic SPMG, and that the decimal istent thymoma, the excep- separator is “,”. tion being acute severe generalised MG Clinical features o MG without thymoma: anti-  In general, a thymoma predicts titin in 50% to 90% of MG with more severe MG. Likewise, anti- age at onset > 50 years and Titin and anti-RyR1 antibodies are not a feature of early-onset markers of a more severe course MG, see above. of the disorder.  Anti-MuSK (a few case histories)  In paraneoplastic MG (thymoma), – and anti-AChR seronegative a frequent finding is severe weakness of the extraocular muscles. Please note that apart from anti- This is explicable in terms of the MuSK seropositive cases, thymomas multiply innervated fibres at this are not encountered in anti-AChR an- location expressing embryonic tibody seronegative MG. Moreover, (foetal) AChR at their NMJs. autoantibodies to various epitopes of  From the present evidence, one striated muscles are associated with should also regard thymoma MG- co-existent myopathy adding to the patients as a group at special risk myasthenic weakness. of myocardial pathology. Accord- Cf. “Paraneoplastic myopathies”, my- ingly, should heart symptoms oc- asthenia gravis- associated. cur in such patients, consider the possibility of myocarditis (or peri- Secondary carditis) related to MG and auto- If in addition to anti-AChR, anti-Titin immunity. Routinely however, is not a finding, then consider and using the currently available  Anti-Striated muscle (unspecific) modalities of heart examinations, or anti-RyR1 it appears that regardless of any o Frequency in MG + thymoma: thymic pathology, MG patients 80% to 90% should not undergo such examina- o MG without thymoma: rare < tions [16] 10%

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o Positive also in MG with myositis In cases with findings other  Anti-CASPR2 (formerly called than strict myasthenic weak- anti-vg-K-channels) These channels are located at the ness, then also: neuromuscular junction and in the  Anti-GAD CNS, and Kv1.4 are also located in the  Anti-CV2 heart & smooth and striated muscles  Anti-vg-Ca channel (P/Q-type)  Anti-AChR (nicotinic alpha3, au- Cytokine antibodies tonomic, ganglionic)  Anti-IF alpha (interferon alpha) Please see the various syndromes as- (75%) sociated with these autoantibodies.  Anti-Il12 (interleukin 12) Autoantibodies against such “messen- Other investigations ger molecules” are more common in Follow the general guidelines for MG MG patients with a thymoma than in and search for a thymoma in anti- those without (75% versus 30%). AChR seropositive cases. If striated Typically, the titres of these autoanti- muscle autoantibodies of any specific- bodies increase substantially if a thy- ity are a feature as well, then the like- moma recurs after surgery. Accord- lihood of a coexisting thymoma is ingly, these antibodies are also valua- much greater, but the non-finding ble in the post-surgery monitoring of does not rule out that anyhow, such a these patients. neoplasm may be present. If furthermore, anti-Cytokine antibodies are Titin, also known as present, then the search for a thy- connectin moma 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 necessi- tate repeated search for this neoplasm at suitable intervals, in particular in cases with a later onset than before 30 years of age.

Treatment Follow the general principles in MG. This giant muscle molecule is In addition a molecular spring  Drug to enhance RYR-related sar-

coplasmic Ca++-release Ryanodine 1 receptor (RyR1) 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 high- ++ A major cellular mediator of Ca -re- dose IgG in order to adequately lease in striated muscle manage MG crises

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Surgery In short: Removal of the thymoma is an option Whether a female thymoma patient is upon oncologic indications only, diagnosed with MG or not, in relation since it is likely that the myasthenic to a pregnancy consider examination disorder in itself will substantially de- of a serum sample: teriorate soon after the surgical pro-  Anti-AChR antibodies, prefera- cedure, possibly rendering more in- bly by using an assay with a mix- tensive immunosuppressant control ture of adult- and foetal-type hu- necessary for up to several years sub- man receptor from different cell sequent to operation. [2] lines in a standardised ratio o A ratio of foetal- vs. adult-type autoantibodies may provide a Risk of passive transfer MG more useful estimate of the Comprises actual risk, since such a calcu-  Neonatal MG lation results in more empha-  Acquired arthrogryposis multi- sis of fraction of antibodies to plex the gamma subunit. The chapter: “Maternal autoantibodies and passive transfer in humans”  Monitor such a pregnancy provides a detailed review of this. carefully o Longitudinal measurements of The possibility of passive transfer MG anti-AChR is of great concern in a myasthenic Bad omens are: woman planning a pregnancy or al- o Decreased foetal movements ready being so. Note however, that o Signs of hydramnios even though a fertile thymoma patient does not show any myasthenic  Treatment during pregnancy signs, the foetus may still be at risk, o Upon rising titres or ominous since – in such a case, anti-AChR to signs, consider more intensive the embryonic receptor may be pre- treatment bearing in mind that sent in the serum of the woman, not this must serve to decrease causing her any harm, but being det- the concentration of antibodies. rimental to neuromuscular transmis- o Cf. also the chapter “General sion of a foetus. therapeutic considerations”. o If plasma exchange by any Among thymoma-MG patients, the technique is the choice, then relative difference in titres between take extra care to avoid drastic the two specificities of anti-AChR an- shifts in hormone levels, since tibodies may vary substantially. This this may result in an unwanted has implications to the risk of trans- abortion. ferring MG to an offspring.

Selected references 1. 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. 2. Somnier FE. Exacerbation of myasthenia gravis after removal of thymomas. Acta Nerol Scand 1994; 90: 56-66. 3. 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. 4. 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. 5. 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

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6. 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. 7. 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. 8. 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. 9. 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. 10. Takamori M, Motomura M, Kawaguchi N, Nemoto Y, Hattori T, Yoshikawa H, Otsuka K. Anti- ryanodine receptor antibodies and FK506 in myasthenia gravis. Neurology 2004; 62 (10): 1894- 1896. 11. Somnier FE. Increasing incidence of late-onset anti-AChR antibody-seropositive myasthenia gravis. Neurology 2005; 65 (6): 928-930. 12. 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. 13. 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. 14. Skeie GO, Aarli JA, Gilhus NE. Titin and ryanodine receptor antibodies in myasthenia gravis. Acta Neurol Scand Suppl 2006; 183: 19-23. [Review]. 15. 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. 16. 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. 17. 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. 18. Owe JF, Gilhus NE. Myasthenia gravis and the Heart. ACNR 2008; 8 (5): 9-10. [Review] 19. Vincent A, Irani SR. Caspr2 antibodies in patients with thymomas. J Thorac Oncol 2010; 5(10 Suppl 4): S277-80. 20. 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 21. Choi Decroos E, Hobson-Webb LD, Juel VC, Massey JM, Sanders DB. Do acetylcholine receptor and striated muscle antibodies predict the presence of thymoma in patients with myasthenia gravis? Muscle Nerv 2014 Jan;49 (1) :30-4.

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Paraneoplastic myopathies

In association with a variety of neoplasms, the features of these myopathies are a predominantly proximal and symmetrical muscular weakness, and maybe ar- thralgias, dermatologic manifestations or myasthenic fatigue.

Table 10: Some currently known disorders

Category Autoimmune myopathy Associated autoantigens Dermatomyositis Mi2β, SAE2, SAE1, Mi2α, TIF1γ, PX2 A Polymyositis SRP, Jo-1, PL-12, PL-7, EJ, OJ Overlap PM-Scl75, PM-Scl10, KU B Acute necrotizing myopathy HMGCR C Inclusion body myositis cN1A (Mup44) Severe autoimmune myopathy (IIM) FHL1 Paraneoplastic myasthenia gravis D Titin associated myopathy E Sporadic rippling muscle syndrome Titin isoform N2A, ATP synthase 6, PPP1R3 Giant cell myositis Eosinophilic myositis Granulomatous myositis Other Macrophagic myofasciitis Pipestem capillary disease Myositis related to other connective tissue diseases

Dermatomyositis is likely the result A. Polymyositis, of a humoral attack on the muscle capillaries and small arterioles. dermatomyositis Complement c5b-9 membrane-attack complex is deposited and is needed in Poly- or dermatomyositis is an id- preparing the cell for destruction in iopathic inflammatory myopathy with- antibody-mediated disease. B-cells and out or with characteristic cutaneous CD4 (helper) cells are also present in manifestations. The incidence of poly- abundance in the inflammatory reaction associated with the blood vessels. myositis and dermatomyositis is 5-10 cases per 100,000 individuals.

Polymyositis is presumed to be an Clinical features autoimmune-mediated disease second- Myopathy ary to defective cellular immunity, which  Muscular weakness, primarily may be due to diverse causes that may proximal and most often sym- occur alone or in association with viral metrical infections, malignancies, or connective-

tissue disorders. Evidence suggests that Skin manifestations

a T-cell–mediated cytotoxic process is  Heliotrope rash involving the directed against unidentified muscle an- periorbital skin tigens.  Photosensitive poikilodermatous eruption Onset  Erythematous scaly plaques on  Adults over 30 years of age; fe- dorsal hands with periungual male-to-male ratio 2:1 telangiectasia and joint eruptions  Slowly progressive over weeks to (Gottron papules) months; active 2-3 years

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Heliotrope rash Association with malignant disease Dermatomyositis SIR 95 % CI Overall 3.0 2.5-3.6 Ovarian 10.5 6.1-18.1 Lung 5.9 3.7-9.2 Pancreatic 3.8 1.6-9.0 Stomach 3.5 1.7-7.3 Colorectal 2.5 1.4-4.4 Non-Hodgkin 3.6 1.2-11.1 lymphoma Polymyositis Gottron papules Non-Hodgkin 3.7 1.7-8.2 lymphoma Lung 2.8 1.8-4.4 Bladder 2.4 1.3-4.7 cancers 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 Poikilodermatous eruptions cancer, which developed after diagnosis of polymyositis in 95.

Laboratory markers  Antinuclear antibody (ANA) is frequently positive.

Irrespective of neoplasms, there is association also with these autoanti- Diagnosis bodies: The following combination: 1. Myositis-specific antibodies  Typical skin changes (MSA)  Muscle weakness o Jo-1 (25% seropositivity in  Elevated serum creatinine kinase myositis)  Characteristic neurophysiologic o Mi-2 (25% seropositivity in findings dermatomyositis)  Muscle biopsy o PL-7, PL-12 o EJ, OJ Remarks o SRP  Typically, cancer is a finding sim- o Ku ultaneously with the myopathy di- o (KS, KJ, PMS1) agnosis  In dermatomyositis, a neoplasm is 2. Myositis-overlap antibodies found more frequently in women o PM-Scl 75, PM-Scl 100 than in men o Ro-52 o (U1-nRNP 70 k, U1-nRNP A, Associated neoplasms U1-nRNP C)  Ovarian  Lung Anti-SRP is associated with an ag-  Pancreatic gressive course of polymyositis and  Stomach unsatisfactory effect of treatment.  Colorectal  Non-Hodgkin lymphoma

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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, anti- NXP2 Onset Anti-TIF1γ (transcriptional  Quite rare disorder intermediary factor 1-gamma) – alias anti-  Rapid progression over one to 155/140 three months Cancer Classical Healthy associated DM controls Clinical features DM  Symmetrical and predominantly 58 % 5 % 0 % proximal weakness (n=12) (n=39) (n=20)  May also include dysphagia Anti-MDA5 (melanoma differentiation- (60 %) associated gene 5)  Arthragias (50 %) All such seropositives (26 %, n= 82)  Eventually, severe functional dis- had DM ability Hashino et a.. Rheumatology 2010; 49 (9): 1726-36 Associated neoplasms (13 %) Anti-NXP2 (MORC3) or anti-  Lung TIF1γ  Bladder Cancer associated DM: 83 %  Breast (n=213)  Gastrointestinal tract Fiorentino DF et al. Arthritis Rheum. 2013; 65 (11): 2954-62. Investigations Serum creatine kinase Treatment  Markedly elevated Oncologic & immunosuppres- Neurophysiology sants  Evident myopathic findings  Corticosteroids Muscle biopsy  Azathioprine  Patchy necrosis and perimysial  Intravenous administration of phosphatase staining with little high-dose IgG inflammation Tissue type  Increased frequency of HLA- DR11 (70-90 % vs. about 20 % B. Necrotizing in controls)  Protective: DQA1; DQB6 myopathy Associated antibody This autoimmune disorder may  Anti-HMGCR represent a severe form of polymyo- (3-hydroxy-3-methylglutaryl- sitis. coenzyme A reductase) - the rate- limiting enzyme for cholesterol synthesis. Serum from such patients specifically recognizes the intracellular catalytic domain of HMGCR.

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Differental-diagnoses  Azathioprine  Statin-provoked rhabdomyolysis  Intravenous administration of Interestingly, it appears that the high-dose IgG frequencies of statin use differ in anti- HMGCR seropositives versus dermatomyositis and polymyositis C. Inclusion body my- cases (83 %, 25 % and 37 %, ositis, sporadic repectively) – and using the chi2-test, this is significant. This myopathy is associated with Statins may cause diffuse or multifo- anti-cN1A (anti-Mup44) and cal up-regulation of MHC-I expression rarely endometrial carcinoma of even in non-necrotic fibres. the uterus; please see below.

Statins are among the most commonly prescribed medications that Muscle biopsy: sIBM 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 statin- Onset and incidence exposed subjects can develop an au- This sporadic form of IBM (sIBM) is an toimmune myopathy typically charac- age-related disease – a type of mus- terized by progressive weakness, cular dystrophy; and the most fre- muscle enzyme elevations, a necrotiz- quent acquired myopathy seen in ing myopathy on muscle biopsy, and adults aged over 50 years. autoantibodies that recognize HMGCR (3-hydroxy-3-methylglutaryl-coen- The mean age of onset is around zyme A reductase), the pharmaco- 60 years (but with considerable var- logic target of statins. iation). About 20% of cases display symptoms before 50. It appears to be These antibodies are also found in slightly more common in men. some autoimmune myopathy patients Prevalence is about 15 per million in without statin exposure. Importantly, the overall population, with a preva- anti-HMGCR antibodies are not found lence of 50 per million population in in the vast majority of statin-exposed people over 50 years of age. subjects without autoimmune myopathy, including those with self-limited Hereditary - hIBM: statin intolerance. 1. IBM1 is listed under OMIM 601419: MYOPATHY, MYOFIBRILLAR, 1; MFM1 Thus, testing for these antibodies may 2. IBM2 is listed under OMIM # help differentiate those with self-lim- 600737. INCLUSION BODY MYOPATHY 2, ited statin myopathy who recover af- AUTOSOMAL RECESSIVE; IBM2 ter statin discontinuation from those 3. Another form of IBM2 is Nonaka with a progressive statin-associated distal myopathy; see: OMIM # autoimmune myopathy who typically 605820: NONAKA MYOPATHY; NM require immune-suppressive therapy. 4. IBM associated with Paget disease of bone and dementia (IBMPFD; Treatment see: OMIM # 167320 INCLUSION Oncologic and immunosuppres- BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL sants DEMENTIA; IBMPFD  Corticosteroids

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5. IBM 3; see OMIM # 605637 Polymyositis, motor neuron disease, INCLUSION BODY MYOPATHY 3, myasthnia gravis AUTOSOMAL DOMINANT; IBM3 Investigations

In most cases of s-IBM, serum CK Clinical features level is normal or elevated to a Since s-IBM is an acquired myopathic mild-to-moderate degree. Eleva- process, weakness or impairment of tion greater than 12 times normal muscle function in the area(s) af- may occur but is rare. fected is the presenting symptom. The disease follows a slowly progres- Neurophysiology sive course. Electromyography studies usually dis-  The distribution of weakness in s- play abnormalities IBM is variable, but both proximal and distal muscles are usually af- Muscle biopsy fected and, unlike polymyositis May display several common findings and dermatomyositis, asymmetry including; inflammatory cells is common. invading muscle cells, vacuolar  Early involvement of the knee ex- degeneration, inclusions or plaques tensors, ankle dorsiflexors, and of abnormal proteins. sIBM is a wrist/finger flexors is characteris- challenge to the pathologist and even tic of s-IBM. with a biopsy, diagnosis can be  Weakness of the wrist and finger ambiguous flexors is often disproportionate to that of their extensor counter- Associated antibodies parts. Hence, loss of finger dexter-  Anti-cN1A (Cytosolic 5'- ity and grip strength may be a nucleotidase 1A) – alias anti- presenting or prominent symp- Mup44 tom.  Anti-HMGCR (3-hydroxy-3- Dysphagia is common, occurring  methylglutaryl-coenzyme A in 40-66% of patients with well- reductase) established disease and in 9% of patients at presentation. Dyspha- Treatment gia may manifest as a feeling of Consider immunosuppressant or stasis, a need to swallow repeat- myofibre regenerator edly, regurgitation, or choking.  Alemtuzumab Mild facial weakness may be a fea-  Bimagrumab ture in about one third of patients. The FDA have granted breakthrough  Isolated erector spinae weakness status for bimagrumab (stimulating or "droopy neck" syndrome has myofibre regeneration) based on the been reported with s-IBM. results of a phase 2 proof-of-concept  Myalgias and cramping are rela- study that showed that the drug sub- tively uncommon. stantially benefited patients with sIBM  Sensory and autonomic dysfunc- compared to placebo tion is not present except in patients with a concurrent polyneu- Severe dysphagia may require ropathy. cricopharyngeal myotomy or  Cardiac disease is common; it is placement of a gastrostomy tube. most likely due to the older age of Chemodenervation with botulinum most patients. Direct cardiac mus- toxin A injection into the upper cle involvement by the disease has esophageal sphincter has also been not been demonstrated. shown to be of benefit Associated neoplasms Uterus: endometrial carcinoma D. Myasthenia gravis- associated myopathy Differental-diagnosis 79

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anti-Striated muscle antibodies are This myopathy is associated with for intracellular structures, it is tempt- postsynaptic disorders of the NMJ, ing to speculate that the myopathic comprising: component may be T-cell mediated.  Paraneoplastic-SPMG (thymoma)  Late-onset SPMG Neurophysiology Abbreviations: SP is anti-AChR seropositive; MG is myasthenia gravis.  Myopathic findings  In more than 20% of thy- Provocation appears to be a common moma-MG denominator in both disorders: either  In more than 30% of in late- by a neoplasm or by environmental onset MG factors. Associated neoplasm  Thymoma: a finding in about 10- 15 % of all MG cases

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

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-thy-

moma MG Onset See figure showing the annual inci- Anti-RyR1 dence rates of early-, late-onset & d. Anti-Striated muscle (by immuno- thymoma-MG in the section “Parane- histochemistry): oplastic SPMG with thymoma”. o This unspecific method detects an-

tibodies to various muscle Clinical features epitopes, for example also the  Symmetrical and predominantly ryanodine receptor. proximal weakness o Accordingly, the frequency of se-  Myasthenic fatigue ropositives is higher than com-  Muscular atrophy pared with anti-Titin results. More or less severe muscular atrophy is a common feature in all Treatment these cases, combined with the Please see paraneoplastic MG. finding of anti-Titin and other anti- striated antibodies.

Comments SPMG fulfils the criteria of an autoantibody-mediated disorder. Since the

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

Reference Frequency of cancer (%) Relative risk

Dermatomyositis Polymyositis Dermatomyositis Polymyositis Sigurgeirsson Male Female Male 61/392 (16 %) 42/396 (11 %) Female 3.4 et al. 1992 2.4 1.7 1.8 Airio et al. 31/203 (15 %) 26/336 (8 %) 3.8 1.7 1995 Chow et al 19/71 (27 %) 12/175 (7 %) 6.5 1.0 1995

Malignancy in myositis - Waimann et. al. 2011 Cancer diagnosis DM (n=58) PM (n=35) Breast 31% 20 % Lung 17 % 12 % Adenocarcinoma was the predominant histological type (DM 60%, PM 39%) Cancer diagnosis before onset: PM 57%; DM 26%. Overall, PM or DM were concurrent with cancer diagnosis or recurrence in 40% of the cases.

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Abbreviations: CADM cancer associated dermatomyositis; DM Dermatomyositis; JDM Ju- venile dermatomyositis; PM polymyositis; IBM inclusion body myositis

o Spread in transverse direction E. Rippling muscle across muscle syndrome, sporadic –  May be painful  Distribution: cranial, proximal, autoimmune distal  Bulbar: dysphagia and dysarthria

 Normal sensation and tendon re- This myopathy appears to be at- flexes tributable to mechanical sensitivity and instability due an effect of anti- Investigations Striated muscle antibodies.  Serum CK: mildly elevated  Muscle biopsy: inflammation, Onset lymphocytic 30 to 55 years  EMG: normal with silent cramps

Clinical features Antibodies  Rippling muscles  Anti-Skeletal muscle (see below  Rolling muscle contractions for specificity): use unspecific im-  Muscle stiffness munohistochemical methods to  Myotonia detect these antibodies, unless a  Cramps specific method is available o Induced by exercise or touch- ing muscle

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There are three associated and  Thymoma distinct muscle antigens: 1. Titin isoform N2A: Accordingly Associated disorders and as opposed to classical  Myasthenia gravis: rippling mus- myasthenia gravis - in rippling cles may precede this disorder muscle syndrome, the immu-  Acquired neuromyotonia nogenic region of titin is distinct from the main immuno- Rule out genic region (MIR).  Hereditary rippling muscle syn- 2. ATP synthase 6 dromes 3. PPP1R3 (protein phosphatase o dominant or recessive (genes 1 regulatory subunit 3) RMD1 and CAV3) o quite similar features to those  Anti-AChR (alpha3-type and of the sporadic disorder adult-type) Treatment Although the mechanism of antibody Immunosuppression: Prednisone or penetration is not known, previous Azathioprine studies have shown that the autoanti- Benefit appears to set in over 2 to 4 bodies in RMS affect the contractile months machinery of myofibres resulting in mechanical sensitivity and instability. Note: Pyridostigmine may exacer- bate this disorder. Associated neoplasm Selected references 1. Brownell B, Hughes JT. Degeneration of muscle in association with carcinoma of the bronchus. J Neurol Neurosurg Psychiatry 1975; 38: 363-70. 2. Barnes B. Dermatomyositis and malignancy. Ann Int Med 1976; 84: 68-76. 3. Emslie-Smith AM, Engel AG. Necrotizing myopathy with pipestem capillaries, microvascular deposits of the complement membrane attack complex (MAC) and minimal cellular infiltration. Neurology 1991; 41: 936-939. 4. Dalakas MC. Polymyositis, dermatomyositis and inclusion-body myositis. N Eng J Med 1991; 325: 1487-1498. 5. [Review]Sigurgeirsson B, Lindelöf B, Edhag O, Allander E. Risk of cancer in patients with dermatomyositis or polymyositis. N Engl J Med 1992; 326 (6): 363-367. 6. Somnier FE, Trojaborg W. Neurophysiological evaluation in myasthenia gravis. A comprehensive study of a complete patient population. Electroencphalography and clinical Neurophysiology 1993; 89 (2): 73-87. 7. Airio A., Pukkala E., Isomaki H. Elevated cancer incidence in patients with dermatomyositis: a population-based study. J Rheumatol. 1995; 22: 1300–1303. 8. Chow W.H., Gridley G., Mellemkjaer L., McLaughlin J.K., Olsen J.H., Fraumeni J.F., Jr. Cancer risk following polymyositis and dermatomyositis: a nationwide cohort study in Denmark. Cancer Causes Control. 1995; 6: 9–13. 9. Ansevin CF, Agamanolis DP. Rippling muscles and myasthenia gravis with rippling muscles. Arch Neurol 1996; 53 (2): 197-199. 10. Levin MI, Mozaffar T, Taher M. et al. Paraneoplastic necrotizing myopathy. Clinical and pathological features. Neurology 1998: 50 (3); 764-767. 11. 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. 12. Walker GR, Watkins T, Ansevin CF. Identification of autoantibodies associated with rippling muscles and myasthenia gravis that recognize skeletal muscle proteins: possible relationship of antigens and stretch-activated ion channels. Biochem Biophys Res Commun 1999; 264 (2): 430-435. 13. Vernino S, Auger RG, Emslie-Smith AM, Harper CM, Lennon VA. Myasthenia, thymoma, presynaptic antibodies, and a continuum of neuromuscular hyperexcitability. Neurology 1999; 53 (6):1233- 1233. 14. Callen, JP. Dermatomyositis. Lancet 2000; 355 (9197): 53-57. 15. Badrising UA, Maat-Schieman M, van Duinen SG, et al. Epidemiology of inclusion body myositis in the Netherlands: a nationwide study. Neurology 2000; 55 (9): 1385-7. 16. Phillips BA, Zilko PJ, Mastaglia FL. Prevalence of sporadic inclusion body myositis in Western Australia. Muscle Nerve. 2000; 23 (6): 970-2. 17. Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study. Lancet 2001; 357: 96-100. 18. 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.

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19. Vermino S, Lennon VA. Ion channel and striational antibodies define a continuum of autoimmune neuromuscular hyperexcitability. Muscle Nerve 2002; 26 (5): 702-707. 20. Bronner IM, Hoogendijk JE, Wintzen AR, et al. Necrotising myopathy, an unusual presentation of a steroid-responsive myopathy. J Neurol 2003; 250 (4): 480-485. 21. Ashok MS, Day JW. Autoimmune rippling muscle. Neurology 2003; 61 (6): 860-70 22. Selcen D, Fukuda T, Shen XM, Engel AG. Are MuSK antibodies the primary cause of myasthenic symptoms? Neurology 2004; 62 (11): 1945-1950. 23. Shiraishi H, Motomura M, Yoshimura T, Fukodome T, Fukuda T, Nakao Y, Tsujihata M, Vincent A, Eguchi K. Acetylcholine receptors loss and postsynaptic damage in MuSK antibody-positive myasthenia gravis. Ann Neurol 2005; 57 (2): 289-293. 24. Ohta K, Shigemoto K, Kubo S, Maruyama N, Abe Y, Ueda N, Jujinami A, Ohta M. MuSK Ab described in seropositive MG sera found to be Ab to alkaline phosphatase. Neurology 2005; 65 (12): 1988. 25. Somnier FE. Increasing incidence of late-onset anti-AChR antibody-seropositive myasthenia gravis. Neurology 2005; 65 (6): 928-930. 26. Benveniste O, Jacobson L, Farrugia ME, Clover L, Vincent A. MuSK antibody positive myasthenia gravis plasma modifies MURF-1 expression in C2C12 cultures and mouse muscle in vivo. J Neuroimmunol 2005; 170 (1-2): 41-48. 27. Farrugia ME, Robson MD, Clover L, Anslow P, Newsom-Davis J, Kenneth R, Hilton-Jones D, Matthews PM, Vincent A. MRI and clinical studies of facial and bulbar muscle involvement in MuSK antibody- associated myasthenia gravis. Brain 2006; 129 (Pt 6): 1481-1492. 28. Watkins TC, Zelinka LM, Kesic M, Ansevin CF, Walker GR. Identification of skeletal muscle autoantigens by expression library screening using sera from autoimmune rippling muscle disease (ARMD) patients. J Cell Biochem 2006; 99 (1): 79-87. 29. Bonneva, N, Frenkien-Cuvelier M, Bidault J, Brenner T, Berrih-Aknin S. Major pathogenic effects of anti-MuSK antibodies in myasthenia gravis. J Neuroimmunol 2006; 177 (1-2): 119-131. 30. Skeie GO, Aarli JA, Gilhus NE. [Review].Titin and ryanodine receptor antibodies in myasthenia gravis. Acta Neurol Scand Suppl 2006; 183: 19-23. 31. Niks EH, Kuks JB, Roep BO, Haasnoot GW, Verduijn W, Ballieux BE, De Baets MH, Vincent A, Verschuuren JJ. Strong association of MuSK antibody-positive myasthenia gravis and HLA-DR14- DQ5. Neurology 2006; 66 (11): 1772-1774. 32. 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. 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 with up-regulation of MHC-I associated with statin therapy. Neuromuscul Disord 2007; 17 (2):194-200. 35. Romi F., Aarli JA, Gilhus NE. Myasthenia gravis patients with ryanodine receptor antibodies have distinctive clinical features. Eur J Neurol 2007; 14 (6): 617-620. 36. Zhang W, Jiang SP, Huang L. Dermatomyositis and malignancy: a retrospective study of 115 cases. Eur Rev Med Pharmacol Sci. 2009;13(2):77-80 37. Dalakas MC, Rakocevic G, Schmidt J, Salajegheh M, McElroy B, Harris-Love MO, Shrader JA, Levy EW, Dambrosia J, Kampen RL, Bruno DA, Kirk AD. Effect of Alemtuzumab (CAMPATH 1-H) in patients with inclusion-body myositis. Brain 2009; 132 (Pt 6): 1536-44. 38. Hoshino K, Muro Y, Sugiura K, Tomita Y, Nakashima R, Mimori T. Anti-MDA5 and anti-TIF1-gamma antibodies have clinical significance for patients with dermatomyositis. Rheumatology (Oxford). 2010; 49 (9): 1726-33 39. Rominiyi O, Broman DM, Rajaganeshan R, Selvasekar CR. Colon cancer presenting with polymyositis—A case report. Int J Surg Case Rep. 2011; 2(7): 225–227. 40. Hoshino K, Muro Y, Sugiura K, Tomita Y, Nakashima R, Mimori T. Anti-MDA5 and anti-TIF1-gamma antibodies have clinical significance for patients with dermatomyositis. Rheumatology (Oxford). 2010; 49 (9):1726-33. 41. Mammen AL, Tae Chung T , Christopher-Stine L, Rosen P, Rosen A, Casciola-Rosen LA. Autoantibodies against 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase (HMGCR) in Patients with Statin-Associated Autoimmune Myopathy. Arthritis Rheum. 2011; 63(3): 713–721. 42. Waimann CA, Olejeme KA, Tayar, JH, Lei X,Suarez-Almazor ME. Cancer Associated Myositis: Temporal Relationship, Survival and Risk of Cancer Recurrence. Results From a Large Historical Cohort in United States of America. Arthritis & Rheumatism 2011 - Abstract 43. Mammen AL, Chung T, Christopher-Stine L, Rosen P, Rosen A, Doering KR, Casciola-Rosen LA. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin- associated autoimmune myopathy. Arthritis Rheum. 2011; 63(3): 713-21. 44. Zelinka L, McCann S, Budde J, Sethi S, Guidos M, Giles R, Walker GR. Characterization of the in vitro expressed autoimmune rippling muscle disease immunogenic domain of human titin encoded by TTN exons 248-249. Biochem Biophys Res Commun 2011;411 (3): 501-5. 45. Labrador-Horrillo M, Martínez MA, Selva-O'Callaghan A, Trallero-Araguás E, Balada E, Vilardell- Tarrés M, Juarez C. Anti-TIF1γ antibodies (anti-p155) in adult patients with dermatomyositis: comparison of different diagnostic assays. Ann Rheum Dis 2012; 71 (6): 993-6 46. Mammen AL, Gaudet D, Brisson D, Christopher-Stine L, Lloyd TE, Leffell MS, Zachary AA. Increased Frequency of DRB1*11:01 in Anti-HMG-CoA Reductase-Associated Autoimmune Myopathy.Arthritis Care Res (Hoboken) 2012; 64 (8): 1233–1237.

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47. Acciavatti A, Avolio T, Rappuoli S, Foderi L, Soldati V, Franchi M, Volpi N, Nuti R. Paraneoplastic necrotizing myopathy associated with adenocarcinoma of the lung - a rare entity with atypical onset: a case report. J Med Case Rep. 2013; 7(1): 112. doi: 10.1186/1752-1947-7-112. 48. Mohassel P, Mammen AL. Statin-associated autoimmune myopathy and anti-HMGCR autoantibodies. Muscle Nerve; 48(4): 477-83. 49. Hall JC, Casciola-Rosen L, Samedy LA, Werner J, Owoyemi K, Danoff SK, Christopher-Stine L. Anti- melanoma differentiation-associated protein 5-associated dermatomyositis: expanding the clinical spectrum. Arthritis Care Res (Hoboken). 2013; 65 (8): 1307-15 50. Pluk H, van Hoeve BJ, van Dooren SH, et al. Autoantibodies to cytosolic 5'-nucleotidase 1A in inclusion body myositis. Ann Neurol 2013; 73 (3): 397-407. 51. Fiorentino DF et al. Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1γ.Arthritis Rheum. 2013; 65 (11): 2954-62. 52. Drouot L, Allenbach Y, Jouen F, et al . Exploring necrotizing autoimmune myopathies with a novel immunoassay for anti-3-hydroxy-3-methyl-glutaryl-CoA reductase autoantibodies. Arthritis Res Ther.2014; 16(1): R39. 53. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Anne Tybjærg-Hansen A Loss-of-Function Mutations in APOC3 and Risk of Ischemic Vascular Disease. N Engl J Med 2014; 371: 32-41 54. Albrecht I, Wick C, Hallgren Å, et al. Development of autoantibodies against muscle-specific FHL1 in severe inflammatory myopathies. J Clin Invest 2015; 125 (12): 4612-24 55. Ramanathan S, Langguth D, Hardy TA, Garg N, Bundell C, Rojana-Udomsart A, Dale RC, Robertson T, Mammen AL, Reddel SW. Clinical course and treatment of anti-HMGCR antibody-associated necrotizing autoimmune myopathy. Neurol Neuroimmunol Neuroinflamm. 2015; 2(3): e96.

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Symptomatic overview

Paraneoplastic ataxia

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

Paraneoplastic epilepsy

Paraneoplastic epilepsy: For specific features, please see the following:  Paraneoplastic limbic encephalitis (PLE)  Paraneoplastic sensory neuropathy (SSN, PSN)  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

The associated antibodies include While there is strong evidence that the Anti-Hu first four immune responses are Anti-CV2 (CRMP5) mediated by cytotoxic T-cells responses, Anti-Ta (Ma2) there are studies indicating that Anti-Ri amphiphysin antibodies may be directly 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

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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 antibodies and anti-ENO1) is anti-Alpha-enolase (ENO1) No that the autoantigens are A finding of antibodies to extracellular epitopes would extracellular and therefore classify a disorder as autoimmune synaptic encephalopathy accessible to circulating antibodies. These antigens include the excitatory glutamatergic receptors (NMDA, AMPA), the inhibitory GABA (B) receptor (GABBR1), and the recently reported true target antigens (LGI1 and CASPR2) of antibodies previously attributed to voltage- gated potassium channels (VGKC). GAD antibodies usually associate with non- paraneoplastic stiff-person syndrome and cerebellar dysfunction, but there are increasing number of reports showing that these antibodies also occur with subtypes of limbic encephalitis and refractory epilepsy. Antibodies to the NR1 subunit of the NMDAR associate with a characteristic syndrome that presents with behavioural change or psychosis and usually progresses to a decline of the level of consciousness, catatonia, seizures, dyskinesias, autonomic instability, and frequent hypoventilation. AMPA receptor and GABA(B) receptor antibodies associate with a clinical picture of limbic encephalitis, with early and prominent seizures in the case of GABA(B) receptor antibodies. Recent reports indicate that LGI1, a secreted neuronal protein, is the target antigen of limbic encephalitis previously attributed to VGKC. Interestingly, this disorder associates with frequent seizures (~80% of the patients) along with hyponatraemia. Moreover, mutations of LGI1 are the cause of autosomal dominant partial epilepsy with auditory features (ADPEAF), also called autosomal dominant lateral temporal lobe epilepsy. In contrast, CASPR2, a protein that is expressed in brain and peripheral nerve, clustering the VGKC at the juxtaparanodal regions of myelinated axons is the target antigen of encephalitis and peripheral nerve hyperexcitability that may result in 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

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Paraneoplastic extrapyramidal disorders

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

Paraneoplastic pain

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

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Maternal autoantibodies

and passive transfer in humans

Reports of vertical transmission of cancer are exception- ally rare, although maternal cells do reach the foetus and cancer occurs in nearly one in 1000 pregnant women. Malig- nant melanoma is the best-known example of a cancer that can metastasize to the foetus. Another example is transfer to the foetus of an aggressive natural-killer-cell lymphoma in the mother, with fatal consequences to the infant.

It is conceivable that T-cell-mediated autoimmunity is transferable, since maternal cells may be a feature of the umbilical cord bloodstream. In theory, all autoimmune disorders, fulfilling the criteria of being antibody-mediated (Table 1), may also occur because of passive transfer from a mother to an unborn child, possibly leading to foetal or neonatal disorders. Another mechanism may be that neoplasms express antigens that are cross reacting exclusively with structures of the foetus and that later on are replaced by adult ones (for example AChRs of the embryonic- and adult-types). In such cases, provoked antibodies may be beneficial to the mother and but potentially detrimental to the offspring.

Either such transferred PNS may resemble those of the mother or they may differ quite substantially (Table 8), since the infant is under development. Moreover, the severity of such a disorder may vary from transient neonatal ones, often both self- limiting and self-repairing, over various malformations, and maybe even to severe and permanent defects of the nervous system. The worst-case scenario is fatalities. Moreover, women beyond the normal Table 11: Foetal exposure to mater- age of fertility or having recovered nal autoantibodies from a cancer are increasingly seeking Examples medical assistance to become preg- PNS resembling that of nant.

1 the mother Clear messages of warning  Neonatal MG  Recurrent stillbirth Deformities  A sibling with deformities or mal- 2  Acquired arthrogryposis formations multiplex

3 Malformations Paraneoplastic myasthenia gravis  Skeletal & lung dysplasia In thymoma-MG (occurring in about Neuro-developmental dis- 10% of all myasthenics), the neo- orders plasm is associated with a broad di- 4 versity of autoantibodies, some of  Autism which may cause adverse pathology  Psychomotor retardation to an unborn child and at the same time be of benefit to the mother. General comments Within a context of PNSs, such dis- The following onconeural antibodies eases are only potentially hazardous are associated with thymomas: to the offspring if they set in during o Anti-AChR (nicotinic adult-type) the period of fertility. The good bear- o Anti-AChR (nicotinic foetal-type) ing is that many cancers are unfortu- o Anti-AChR (nicotinic alpha3-type, nate incidents happening later in life. ganglionic autonomic) However, this argument is not valid to o Anti-vg-K channels thymomas, breast cancer, various o Anti-Titin leukaemias, Hodgkin’s disease, malig- o Anti-RyR1 nant monoclonal gammopathies, etc. 89

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o Anti-CV2 Using immunohistology on mouse o Anti-GAD brain, they found that mothers of an o Anti-Hu ASD child were nearly 4 times more likely to harbor anti-brain antibodies Other disorders than unselected women of A variety of other autoantibodies may childbearing age (P < .00001). also be a feature, but it is beyond the scope here to elaborate more on such In total, 10.7 % of the plasma of topics. There are indeed publications mothers of an ASD child (260/2431) suggesting that maternal antibodies displayed strong reactivity to mouse are responsible for foetal deformities brain antigens compared with 2.6% of or other congenital disease. It has the plasma from control women also been suggested that some devel- (17/653). Only 28 % of plasma of opmental disorders (e.g. autism) may mothers of an ASD child showed no be attributable to maternal antibod- binding compared with 64.7 % of ies; see the puzzling case history be- plasma from control women. low. The researchers analyzed an Anti-brain antibodies and autism additional 318 plasma samples of spectrum of disorders (ASD) mothers of an ASD child from a The underlying etiology for autism separate cohort and found that 28 remains unknown, although genetic (8.8 %) displayed strong reactivity to and environmental factors, including mouse brain antigens. Only 22.6 % in utero environmental factors, are (72 samples) showed no binding. thought to be involved.

There is mounting evidence that Risk of passive transfer of maternal antibodies can target the PNSs fetal brain. Several studies have Up until now, the publications exclu- identified the presence of antibodies sively associate such foetal disorders that bind to human fetal brain tissue with transplacental transfer of auto- in mothers with an ASD child. When antibodies in relation to myasthenia anti-brain antibodies from mothers of gravis. In view of the current data an ASD child are administered to therefore, it appears that the overall pregnant mice or pregnant monkeys, risk of transferred PNSs is quite low. the offspring exhibit behavioral alterations akin to those seen in ASD Awareness is the key word, since children. preventive therapy is often possible. This may even be quite successful, As reported (Brimberg et al. 2013), see “Therapeutic considerations”. several studies have linked maternal There is more specific information infections or inflammation during about how to handle the various PNSs pregnancy to the development of ASD in the sections addressing particular in offspring, suggesting that such disorders. activation of the maternal immune system might lead to an increased risk of having a child with ASD. A puzzling case history Possibly passive transfer of ataxia and To further examine ties between anti- developmental disorder: brain antibodies, autism, and A mother of three children: autoimmunity, Dr. Diamond and  The first one normal colleagues screened plasma of 2431  The second with autism mothers of an ASD child and 653  The third with a severe specific unselected women of childbearing age language disorder for anti-brain antibodies. To investigate this case for passively transferable factors, maternal serum

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was injected into pregnant mice. Sub- ‘Risk of passive transfer MG’ in the sequently, the mouse offspring exhib- chapter “Paraneoplastic SPMG (thy- ited altered motor coordination, and moma)”. MRIs showed cerebellar signs. This case history started in around 1998. B. Transient neonatal MG However, there were no findings of This disorder is well recognized and any cancer during a follow-up period due to transfer of maternal antibodies. of five years. Anyhow, it is tempting Altogether, this form of MG is an ob- to speculate in terms of transferred servation in about 20% of infants born autoimmunity provoked by a neoplasm, which has escaped detection.

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 adult- types

to myasthenic mothers.

C. Acquired arthrogryposis multiplex (AAM) Any paralyzing agent can cause AAM, Note the presence of either a including anti-AChR antibodies that gamma-subunit or an epsilon- limit foetal movement, even to an ex- subunit tent of abolishing the AChR function. Joints cannot develop normally, unless they are regularly in i motion. Location of embryonic-type AChR Foetal movements are mandatory –  Expressed during development not just a sign of life.  During the last weeks of intrauter- ine life in humans, adult-type Most infants with multiple congenital AChR replaces it. bent joints are diagnosed with a he- Later in life, it is only expressed reditary disorder or a disease com-  At low levels in adult human mus- pletely unrelated to autoimmunity. cle Only about 2% of AAM is associated  At multiply innervated extraocular with autoantibodies. muscle fibres  As upregulated receptor in dener- In a myasthenia gravis context, recur- vated muscle rent AAM is associated with anti-  In the myoid cells of the thy- AChR to the receptor of foetal- mus, highlighting the hazards re- type. In some of these cases, the lated to thymomas mother did not show any evidence of MG herself, but suffered recurrent Disorders foetal loss, stillbirth or early termina- A. Myasthenia gravis tion. Preventive treatment during a The finding of autoantibodies specific pregnancy is an option, and the out- to foetal AChR is frequent in MG pa- come may be a perfectly healthy child. tients. For further details, please see

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In Norway, it appears that about 2% about 10% of all myasthenics. of infants to MG mothers are born with severe skeletal anomalies, and Conclusion all these children have died. To this If a thymoma does not appear to co- percentage must be added all the less exist in a female diagnosed with sero- severe cases with only a few affected positive MG and planning a pregnancy, joints. The frequency of co-concurrent then consider a new search for this thymomas has not been reported in neoplasm. these studies. In Denmark, this paraneoplastic form of MG accounts for

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Selected references: 1. Drachman DB, Coulombre A. Experimental clubfoot and arthrogryposis multiplex congenita. Lancet 1962; 2: 523-526. 2. Shepard MK. Arthrogryposis multiplex congenita in sibs. Birth Defects 1971; 7 (2): 127. 3. Keesey J, Lindstrom J, Cokely H. Anti-acetylcholine receptor antibody in neonatal myasthenia gravis [letter]. N Engl J Med 1977; 296 (1): 55. 4. 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. 5. 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. 6. 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. 7. 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. 8. 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. 9. Giacoia GP. Transplacentally transmitted autoimmune disorders of the fetus and newborn. Pathogenic considerations. South Med J 1992; 85 (2): 139-145. 10. Papazian O. Transient neonatal myasthenia gravis. J Child Neurol 1992; 7 (2): 135-141. 11. Dinger J, Prager, B. Arthrogryposis multiplex in a newborn of a myasthenic mother - case report and literature. Neuromuscul Disord 1993; 3 (4): 335-339. 12. 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. 13. 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. 14. 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. 15. 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. 16. Gordon N. Arthrogryposis multiplex congenita. Brain Dev 1998; 20 (7): 507-11. 17. Silberstein EP, Kakulas BA. Arthrogryposis multiplex congenita in Western Australia. J Paediatr Child health 1998; 34 (6): 518-23. 18. 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 antibody- mediated arthrogryposis multiplex congenita. Ann N Y Acad Sci 1998; 841: 482-496. 19. Jacobson L, Polizzi A, Moriss-Kay G, Vincent A. Plasma from human mothers of fetuses with severe arthrogryposis multiplex congenita causes deformities in mice. J Clin Invest 1999; 103 (7): 1031- 1038. 20. Vincent A, Beeson D, Lang B. Molecular targets for autoimmune and genetic disorders of neuromuscular transmission. Eur J Biochem 2000; 267 (23): 6717-6728. 21. Dalton P, Deacon R, Blamire A, Pike M, McKinlay I, Stein J, Styles P, Vincent A. Maternal neuronal antibodies associated with autism and language disorder. Ann Neurol 2003; 53 (4): 533-537. 22. 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. 23. 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. 24. Dalton P, Clover L, Wallerstein R, Stewart H, Genzel-Boroviczeny O, Dean A, Vincent A. Fetal Arthrogryposis and maternal antibodies. Neuromuscul Disord 2006; 16 (8): 481-491. 25. Brimberg L, Sadiq A, Gregersen PK, Diamond B. Brain-reactive IgG correlates with autoimmunity in mothers of a child with an autism spectrum disorder. Molecular Psychiatry 2013; 18: 1171-1177 26. Braunschweig D, Krakowiak P, Duncanson P, Boyce R, HansenRL, Ashwood P, Hertz-Picciotto I, Pessah IN, Van de Water J. Autism-specific maternal autoantibodies recognize critical proteins in developing brain. Translational Psychiatry 2013; 3: e277 27. Bauman MD, Losif A M, Ashwood P, Braunschweig D, Lee A, Schumann CM, Van de Water J, Amaral DG. Maternal antibodies from mothers of children with autism alter brain growth and social behavior development in the rhesus monkey. Translational Psychiatry 2013; 3: e278

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Autoantibodies associated with PNS For a listing of myositis-specific and –overlap antibodies, please see paraneoplastic myopathies

Table 12: alphabetical listing of some paraneoplastic antibodies, also including some that are not strictly paraneoplastic Abbreviated Antibody Full name of antigen antibody name Alias; Anti- nicotinic acetylcholine receptor of ♪ Anti-AChR (adult-type) nAChR (adult) adult-type nicotinic acetylcholine receptor of ♪ Anti-AChR (alpha3-type) nAChR (α3) alpha3-type nicotinic acetylcholine receptor of ♪ Anti-AChR (foetal-type) nAChR (foetal) embryonic-type muscarinic acetylcholine receptor of ♪ Anti-AChR (M1-type) mAChR (M1) M1-type SRY (sex determining region Y)-box Anti-AGNA SOX1 1, glial nuclear Anti-Adenylate-Kinase 5 AK5 Anti-Alpha-enolase ENO1 alpha-enolase 1 α-amino-3-hydroxyl-5-methyl-4- ♪ Anti-AMPAR GluR1/R2 isoxazole-propionate receptor ☼ Anti-Amphiphysin amphiphysin ANNA3 neuronuclear antigen 3 Anti-ARHGAP26/GRAF) RhoGTPase-activating protein 26 Anti-BRSK2 BR serine/threonine kinase 2 Anti-vg-Ca-channel voltage-gated calcium channel of P/Q- ♪ P/Q-VGCC (P/Q-type) type Anti-vg-Ca-channel (N - voltage-gated calcium channel of N- ♪ N-VGCC type) type Anti-CARP8 carbonic anhydrase-related protein 8 ♪ Anti-CASPR2 contactin-associated protein-2 oligodendrocyte proteins, collapsin

response mediator proteins 5, ☼ Anti-CV2 CRMP5, paraneoplastic oligodendrocyte POP66 cytoplasmatic protein 66 Anti-EFA6A Exchange factor for ARF6 glutamate decarboxylase I + II or GAD67, Anti-GAD glutamic acid decarboxylase 67 and GAD65 65 Anti-Gephyrin ♪ Anti-mGluR1 mGluR1 metabotropic glutamate receptor 1 3-hydroxy-3-methylglutaryl-CoA re- Anti-HMGCR ductase Hull, ANNA1, HuC, ☼ Anti-Hu neuronuclear antigen 1 HuC, HEL-N1

VGPC, VGKC, Kv1.1, voltage-gated K-channel of various ♪ Anti-vg-K-channel KV1.2, KV1.6 subtypes ♪ Anti-LGI1 leucine-rich, glioma inactivated 1 Anti-Ma1 membrane reactive antigen 1 Anti-Neurofilaments ♪ Anti-NMDAR N-methyl-D-aspartate receptor Anti-PCA2 Purkinje cell antigen 2 Anti-PKC gamma protein kinase C gamma Anti-Pyridoxal pyridoxal phosphatase phosphatase Anti-Recoverin recoverin neuronuclear antigen 2, Richards, ANNA2, ☼ Anti-Ri neurooncological ventral antigen 1and NOVA1, NOVA2 2 Anti-RyR1 ryanodine receptor 1

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Anti-Striated muscle tumour-associated antigen ☼ Anti-Ta Ma2/PNMA2 membrane reactive antigen 2 transcriptional intermediary factor 1- Anti-TIFγ gamma Anti-Titin titin delta and notch-like epidermal growth Anti-Tr PCA-Tr, Trotter, DNER factor-related receptor Anti-TULIP-1 TULP1 tubby-like protein 1 Anti-UBE2E1 ubiquitin-conjugating enzyme E2E 1 Young, PCA1, CDR1 Anti-Yo (CDR34), CDR2, CDR2L Purkinje cell antigen 1, cerebellar ☼ (♪ CDR2L) (CDR62-1, CDR62-2), degeneration related protein 34 or 62 CDR3, PCD17-SN, CZF Anti-ZIC4 zinc finger protein 4 ☼ = most frequent; ♪ = extracellular (plasma membrane) location

In principle, there are at least seven categories of autoantibodies to be recognized 1. Neuronal nuclear or nucleolar o Hu (ANNA1), Ri (ANNA2), ANNA3, Ta (Ma2), Ma1, Zic4 2. Neuronal or muscular cytoplasmatic o Yo (PCA1), PCA-Tr, PCA2, Gephyrin, PKC gamma, BR-Serine / Theonine kinase 2, Adenylate-Kinase 5, CARP8, ENO1, UBE2E1, striational (Titin, RyR1, etc.) 3. Glial o CV2 (CRMP-5, POP66, oligodendrocytes), Bergman (AGNA, SOX-1), astrocytes (AQP4), ENO1 4. Presynaptic vesicles o GAD, Amphiphysin 5. Voltage- or ligand-gated CSF or plasma membrane structures o Ionotropic channels and receptors  AChR (adult, foetal, alpha3, M1-types), NMDAR (NR1, NR2), AMPAR (GluR1, GluR2), calcium- & potassium-channels, GlyR-alpha1 o Metabotropic channels and receptors

 D1, D2, GABABR1, mGluR1, mGluR5 6. Other CSF membrane structures including accessory proteins o AQP4, MuSK, CASPR2, gangliosides including lyso-GM1, ENO1 7. Synaptic proteins o LGI1

The group of disorders associated with antibodies to cell surface or synaptic proteins appears to be characterised by a more promising outcome of therapy – as opposed to those associated with autoantibodies to intracellular structures.

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Various currently known autoantibodies in association with CNS disorders Channels & receptors

Tropic ex

vgKC

Iono Metabo compl

GM1

Hu (ANNA1) Hu (ANNA2) Ri ANNA3 POP66 CV2 (CRMP5), oligodendrocytes Yo (PCA1) (PCA2) Tr Ta(Ma2) Gephyrin Zic4, Ma1, ENO1 Amphiphysin 67) (65, GAD astrpcytes AQP4, Bergman (SOX1), AGNA Lyso NMDAR AMPAR α1 GlyR GABA D1, D2 LGI1 CASPR2

Autoantibodies

x x x x

Nuclear

x x x x x

Intracellular x x

Cytoplasmatic

Vesicles

Neuronal

x x x x x x x

Membrane

Extracellular x x

Synaptic

x x x x

Glial

Co-occurrence of autoantibodies Autoantibody Anti-AMPAR Anti-GABABR1 Anti-GAD Anti-ENO1 Anti-AMPAR X Anti-GABABR1 X Anti-GAD X X Anti-GlyRalpha1 X Anti-CV2 (CRMP5) X Anti-VGCC X X AGNA (anti-SOX1) X X Anti-BRSK2 X Anti-Amphiphysin Anti-Ri Anti-Zic4 Anti-thyreoglobulin X Anti-thyroid peroxidase X X Anti-TSH receptor X Anti-M X Anti-dsDNA X ANA X Anti-Cardiolipin X

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Paraneoplastic antibodies targeting the nervous system or striated muscles versus neoplasms

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

Anti-AChR PEM (limbic encephalitis) and maybe There are different types of ligand- PCD. gated acetylcholine receptors. With a postsynaptic location at the NMJs, Anti-Alpha-enolase (ENO1) there are the nicotinic adult- & foetal- This antibody is associated with para- types (paraneoplastic MG) and pre- neoplastic retinopathy and Hashimo- synaptic, the muscarinic AChRs of M1- to's encephalopathy. The target is the type (LEMS). At ganglia, these recep- N-terminal region (amino terminal) of tors are of alpha3-type (autonomic alpha-enolase. In a PNS context, this neuropathy). There are no PNS asso- protein is located in retinal ganglion ciated with AChRs of the CNS, which cells and inner nuclear layer cells. also differ quite substantially from those mentioned above. The nicotinic The most frequent associated neo- AChRs function as regulated ion chan- plasms are SCLC and melanoma nels, whereas the muscarinic AChRs (MAR). activate other ionic channels through a second messenger cascade. Anti-Adenylate Kinase 5 (AK5) A few cases with limbic encephalitis The most frequent associated neo- refractory to corticosteroids, IVIg and plasms are thymoma (MG, AAS) and plasma exchange have been reported. SCLC (LEMS, AAS). Serum/CSF antibodies reacted with the cytoplasm of neurons. Probing of Anti-AGNA (SOX1, glial nuclear) a hippocampal cDNA library resulted The target is nuclear structures of the in the isolation of adenylate kinase 5 Bergmann glia (anti glial nuclear (AK5). Human AK5-affinity purified antibodies = AGNA) in the Purkinje antibodies reproduced the neuronal cell layer. immunolabeling of patients' antibodies. SOX1 (for Sex determining region Y- box 1) is a transcription factor in the Anti-AMPAR (GluR1, GluR2) Sox protein family. SOX1 expression The target is the α-amino-3-hydroxyl- is restricted to neuroectoderm in the 5-methyl-4-isoxazole-propionate re- tetrapod embryo. SOX1 is involved in ceptor (AMPAR, a glutamate receptor early central nervous system of the ionic type.) development, where it is functionally redundant with SOX3 and to a lesser The clinical features are limbic en- degree SOX2, and maintenance of cephalitis with seizures and more. The neural progenitor cell identity. SOX1 associated neoplasms are SCLC, non- is expressed particularly in the ventral SCLC, thymoma and breast cancer. striatum, and Sox1-deficient mice have altered striatum.

These antibodies are a feature of SCLC and the following PNS: LEMS,

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Anti-Amphiphysin Such autoantibodies are associated Amphiphysin is the predominant anti- with the LEMS and most frequently gen in stiff-person syndrome, PEM SCLC. and other PNS. It is a neuronal protein - an adapter molecule - highly con- Anti-CARP8 centrated in nerve terminals. This The carbonic anhydrase-related pro- presynaptic cytoplasmatic protein tein 8 is located in the Purkinje cell cy- (128 kDa) is located both in the CNS toplasm & dendrites and at the lateral and at the NMJs, and it is abundant. nuclei of thalamus. The typical finding Amphiphysin as well as dynamin and is a pure paraneoplastic cerebellar synaptojanin all have a putative role syndrome (PCD). in synaptic vesicle recycling. The two isoforms appears to act in concert as The most frequent associated neo- a heterodimer. plasm is melanoma.

The most frequent associated neo- Anti-CASPR2 plasms are SCLC (PEM, PLE) and The target is contactin-associated breast cancer (SPS, POM). protein-2, a part of some voætage- gated potassium channel complex. ANNA3 The neuronuclear antigen 3 (170 kDa) Mainly, the expression of CASPR2 is at is located at the nuclei of Purkinje myelinated nerves confined to the cells, and accordingly this autoanti- axon at the juxtaparanodal region and body is associated with paraneoplastic at some isolated paranodal loops. In cerebellar degeneration. the juxtaparanodal region, CASPR2 precisely co-localized with Shaker-like The most frequent associated neo- potassium channels. CASPR2 specifi- plasm is SCLC. cally associated with Kv1.1, Kv1.2, and their Kv-beta-2 subunit. This as- Anti-ARHGAP26/GRAF sociation involves the C-terminal re- The antigen is RhoGTPase-activating gion of CASPR2. It has been sug- protein 26. gested that CASPR2 may stabilize the localization of potassium channels in This onconeural antibody is associ- the juxtaparanodal region, and that ated with cerebellar ataxia and ovar- CASPR2 family members may play a ian cancer. role in the local differentiation of the axon into distinct functional subdo- Anti-BRSK2 mains. The antigen is BR serine/threonine kinase 2, a protein also known as The typical clinical diagnoses are: SAD1B kinase, and preferentially ex- aquired neuromyoyonia (Morvan’s pressed in the brain and testis and im- syndrome) or limbic encephalitis. plicated in neuronal polarization as well as synaptic development. The most frequent associated neoplasm is thymoma. This onconeural antibody is associated with limbic encephalitis and Anti-CV2 (CRMP5, CRMP2-4, SCLC. POP66 There are more than 11 associated Anti-vg-Ca-channel PNS with this target, which belongs to There are at least five types of volt- a family of ~66 kDa CNS proteins. age-gated calcium-channels (all 64 One of the names is CRMP for col- kDa): N, L, P/Q, R, and T. Only the lapsin response mediator proteins. Ca-channel of P/Q-type is of diagnos- The CRMP family is composed of five tic relevance in PNS, and in this con- cytosolic phosphoproteins and highly text, it is located at the presynaptic expressed throughout the brain dur- membrane of NMJs. ing development. CRMP5 is the main

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antigen recognized by anti-CV2 anti- This difference is thought to reflect a bodies, whereas the recognition of functional difference; GAD67 synthe- other members is inconsistent, such sizes GABA for neuron activity unre- as CRMP2, CRMP3 or CRMP4. Another lated to neurotransmission, such as name for this target is paraneoplastic synaptogenesis and protection from oligodendrocyte cytoplasmatic protein neural injury. This function requires 66. It is co-associated with amphiphy- widespread, ubiquitous presence of sin. It appears to be directly or indi- GABA. GAD65, however, synthesizes rectly associated with neuron survival. GABA for neuro-transmission, and CV2 is a cytoplasmatic antigen of oli- therefore is only necessary at nerve godendrocytes, located in the cere- terminals and synapses. bellum, basal ganglia, brainstem, spinal cord & optic chiasm. Anti-GAD65 is also a feature of diabetes. Upon incubation of nerve cells The most frequent associated neo- with serum or CSF from diabetics, plasms are SCLC (PEM, PLE, SSN, PCD there is no inhibition of the synthesis (thymoma), POM, chorea, and optic of GABA, whereas this happens with neuritis. serum or CSF from PNS patients, and even in a dose-dependent manner. Anti-EFA6A (Pleckstrin and Sec7 Accordingly, the anti-GAD appears to domain protein) recognize different epitopes. ADP-ribosylation factor 6 (ARF6) is a small GTPase known to regulate actin The antibodies are associated with remodelling and membrane traffic. SPS and the following neoplasms: Exchange factor for ARF6 (EFA6A) is a breast, SCLC and thymoma. protein that interacts with a member of the two-pore-domain potassium Anti-Gephyrin channel family and is involved in the The target is a protein, which is asso- regulation of the dendritic develop- ciated with inhibitory neurotransmit- ment of hippocampal neurons. ter receptors. It is a bi-functional protein and essential for both synaptic The most frequent associated neo- clustering of inhibitory neurotransmit- plasm is ovarian teratoma. PEM with ter receptors in the CNS and the bio- psychiatric symptoms, seizures and synthesis of the molybdenum cofactor central hypoventilation are typical in peripheral tissues. It co-purifies clinical features. with the inhibitory glycine receptor. Gephyrin is responsible for clustering Anti-GAD (GAD65, GAD67) GlyRs to postsynaptic sites by linking In mammals, GAD (glutamate decar- the GlyRβ subunit to the cytoskeleton. boxylase) exists in two isoforms en- Moreover, in all brain areas containing coded by two different genes, Gad-II synapses, there is a density of this (GAD65, 585 amino acids) and Gad-I protein. (GAD67, 594 amino acids) and with molecular weights of 65 and 67 kDa, The antibody is associated with the respectively. The amino acid se- SPS, multiple myeloma and undiffer- quence of both is with about 65 % ho- entiated neoplasm. mology (primarily in middle and C- terminal regions). The central region, Anti-HMGCR (alias 3-hydroxy-3- which contains the decarboxylase cat- methylglutaryl-CoA reductase) alytic domain, appears to be highly immunoreactive. Normally in mammalian cells this enzyme is suppressed by cholesterol de- Exclusively, the expression of GAD65 rived from the internalization and is at GABA-ergic nerve terminals, degradation of low density lipoprotein which co-localizes with Amphiphysin (LDL) via the LDL receptor. Competi- and CV2 (CRMP5) while GAD67 is tive inhibitors of the reductase induce spread evenly throughout the cells. the expression of LDL receptors in the

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liver, which in turn increases the ca- Hu homologues. In assays, either re- tabolism of plasma LDL and lowers combinant full length Hu-D sequence the plasma concentration of choles- or peptide fragments are used. terol, an important determinant of atherosclerosis. Almost all cases of PEM with anti-Hu antibodies are related to small-cell This autoantibody is associated with lung carcinoma. The human Hu pro- acute necrotizing myopathy (poly- teins are also abundant in most neu- myositis?); sporadic inclusion-body roblastomas. In fact, anti-Hu is the myositis; polymyositis / dermatomy- most frequently encountered on- ositis coneural antibody.

Anti-mGluR1 It is associated with the following ne- The target is the metabotropic gluta- oplasms: SCLC, breast, ovarian, tes- mate receptor 1 located as follows: in ticular, prostate, thymoma, neuro- the cerebral cortex (superficial layer); blastoma and more. Apart from stiff- the cerebellum (Purkinje cell bodies & person syndrome, this antibody is as- spines); glomeruli of olfactory bulb sociated with all the other PNSs, and (neurons & neurophils); hippocam- in particular SSN & PEM. This antibody pus; thalamus; superior colliculus; may also be a finding in primary lat- spinal trigeminal nucleus. eral sclerosis (PLS), and associated with adenocarcinoma in gall bladder These antibodies are a feature of and duodenum. Hodgkin’s disease also exhibiting PCD. Anti-vg-K-channel (VGKC, KV1.1, Anti-Hu (Hull, ANNA1) KV1.2, KV1.6) Hull was the pioneer to find this anti- There is an abundance of voltage- body. The target is called neuronu- gated K-channel types. There are only clear antigen 1 (35-40 kDa), a struc- three members of the Shaker-related ture of all neurons in both the CNS subfamily A, and which are relevant to and the peripheral nervous system. PNS: Kv1.1; Kv1.2; Kv1.6. These channels are inward rectifiers. These antibodies react with a group of 35- to 40-kilodalton neuronal RNA- Within a PNS context, such channels binding proteins, including HuD, have previously been reported to be PLE21/HuC, and Hel-N1. Nuclear and targets at limbic structures, basal cytoplasmic staining of CNS neurons ganglia and at presynaptic MNJs. Such demonstrates the presence of these channels are also located at para- antibodies. A ubiquitous protein, HuR, nodes and internodes of peripheral is also an antigenic target. The neu- nerves. CASPR2 and LGI1 are acces- ronal proteins are homologous to the sory proteins of such potassium-chan- embryonic lethal abnormal visual nel, together forming complexes. It (ELAV) protein in Drosophila species. appears that – in a PNS context – Anti-Hu antibodies may alter the pro- CASPR2 is the true target. See anti- duction of these proteins, which are CASPR2 essential for the development, matu- ration, and maintenance of the verte- The associated neoplasms are SCLC brate nervous system. Intrathecal and thymoma. synthesis of anti-Hu antibodies may represent an autoimmune cross-reac- Anti-LGI1 (Leucine-rich, glioma tion with neurologic tissue, triggered inactivated 1) by a remote carcinoma. It is a secreted synaptic protein, which associates with VGKCs and In about 70% of patients with the AMPA receptors via the ADAM proteins. anti-Hu syndrome, the initial target of the disease is the dorsal root ganglia, LGI1 is a ligand for ADAM22 that which has a robust expression of four positively regulates synaptic

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transmission mediated by AMPA-type Anti-Neurofilaments glutamate receptors. The molecular The targets are neurofilament pro- function of ADAM22 is as a receptor, teins of the perikaryal type, which un- and it is highly expressed in the brain. dergo transformation and transport ADAM23 can bind to LGI1, and is also into the axonal type. Clinically, POM is highly expressed in the brain, the characteristic feature. prominently in the amygdala, caudate nucleus, hypothalamus, thalamus, The most common associated neo- cerebral cortex and occipital pole. plasms are SCLC and neuroblastoma. LGI1 regulates voltage-gated potassium channels assembled from Anti-NMDAR (NR1) KCNA1, KCNA4 and KCNAB1. LGI1 The target is the N-methyl-D-aspar- slows down channel inactivation by tate receptor (NMDAR, a glutamate precluding channel closure mediated receptor of the ionic type.) The NMDA by the KCNAB1 subunit. receptor is distinct in that it is both ligand-gated and voltage-dependent. Moreover, this protein appears to play Activation of NMDA receptors results a role in the control of neuroblastoma in opening of an ion channel that is cell survival: expression is reduced in non-selective to cations. This allows low-grade brain tumours and flow of Na+ and small amounts of Ca2+ significantly reduced or absent in ions into the cell and K+ out of the cell. malignant gliomas Presumably, calcium flux through NMDARs plays a critical role in synap- It is associated with the following ne- tic plasticity, a cellular mechanism for oplasms: thyroid, lung, thymoma, learning and memory. N-methyl-D- ovarian teratoma and more. The aspartate is the name of its specific paraneoplastic disorder is limbic en- agonist. cephalitis with seizures and hypo- natriaemia. The associated neoplasm is a teratoma, the most common tumour in Anti-Ma1 new-borns. Mature cystic teratomas The name of this protein is membrane account for 10-20% of all ovarian ne- reactive antigen 1. It is a combined 37 oplasms. Not only are they the most and 40 kDa neuronal (subnucleus) & common ovarian germ cell tumour but testicular germ cell protein with ho- also the most common ovarian neo- mology to Ma2 (see anti-Ta below). plasm in patients younger than 20 years. The incidence of all testicular The main features of anti-Ma syn- tumours in men is 2.1-2.5 per dromes are brainstem dysfunction 100,000. Germ cell tumours repre- with EOM limitation, dysphagia, cere- sent 95% of testicular tumours after bellar disorders with ataxia of trunk puberty, but pure benign teratomas of and extremities. In addition, sensory the testis are rare, accounting for only loss and myokymia may be other 3-5% of germ cell tumours. The inci- characteristics. The associated tu- dence of all testicular tumours in pre- mours are as follows: breast, lung pubertal boys is 0.5-2 per 100,000, (large-cell) and colon. with mature teratomas accounting for 14-27% of these tumours. Benign teratomas of the mediastinum are rare, representing 8% of all tumours of this region.

Anti-NMDAR is associated with a particular type of limbic encephalitis characterised by neuropsychiatric features, troubled memory, seizures,

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dyskinesias, dystonia, decreases con- the peripheral nervous system. The sciousness, sleep disorder and more characteristic clinical features are PCD (dyskinetic encephalitis lethargica). or a movement disorder with myoclonus / opsoclonus, triggered by visual Anti-PCA2 fixation. The antigen is a 280 kDa neuron-specific protein, located in the cytoplasm Frequently, other onconeural antibod- of Purkinje cell in soma & dendrites. ies are co-existing. Therefore, a vari- Typically, the associated neoplasm is ety of other PNS is associated: en- SCLC, also explaining that these auto- cephalopathy, myelopathy, peripheral antibodies may co-exist with anti-vg- neuropathy (sensory-motor; poly- Ca-channel (P/Q- & N-type) and anti- radiculopathy; cranial neuropathy: AChR (of muscle & neuronal type). VI; VIII [deafness or tinnitus]), laryngospasm, dystonia (jaw opening or Clinically, anti-PCA2 is associated with neck), LEMS, visual blurring, inconti- PCD. Attributable to the co-existing nence. onconeural antibodies listed above, PLE, LEMS, AAS and a motor syn- The typical associated neoplasms are drome may also be present. located at breast or lung (both SCLC & non-SCLC). Anti-Protein kinase C gamma (anti-PKC gamma) Anti-Recoverin Paraneoplastic cerebellar degenera- The target is a 23-kDa photoreceptor tion also occurs in patients with non- protein in the retina. The associated SCLC and without typical onconeural neoplasms are SCLC and melanoma. antibodies - and is associated with im- CAR is the clinical feature. mune reactions against key proteins of the Purkinje cells – such as PCK gamma. Anti-RyR1 The target is the ryanodine receptor 1 Anti-Pyridoxal phosphatase of striated muscles. The main immu- Pyridoxal phosphatase is a co-enzyme nogenic regions are epitopes at the C- of vitamin B6 (pyridoxine). The anti- terminus (AA 5019-5038) and at the gen is located at both the central and C-terminus transmembrane (AA the peripheral nervous system. Defi- 4997-5017) regions. These receptors ciency of vitamin B6 is usually associ- function as calcium release channels. ated with seizures and sensory-motor neuropathy. A seropositive finding The autoantibodies are associated may be a feature of about 9% of pa- with paraneoplastic MG (thymoma). tients with lung cancer and of 7% with Moreover, they are a feature of non- other neoplasms, for example well- paraneoplastic late-onset MG. differentiated thyroid cancer and of autoimmune thyroid disease. Anti-Striated muscle (unspecific) Immunohistochemistry is the method PNS associated with this antibody are to detect such antibodies. Accordingly, awaiting discovery. unspecific binding of IgG to various epitopes of striated muscles is the Anti-Ri (Richards, ANNA2, NOVA1, finding. NOVA2) Richards was the first to report the These autoantibodies are associated finding of these antibodies. The with thymoma, paraneoplastic myas- names of the targets are also neu- thenia gravis, and rippling muscle ronuclear antigen 2 and neuro-onco- syndrome. See also anti-Titin and logical ventral antigen 1. The CNS an- anti-RyR1. tigens are either a 55-kDa protein (Nova; RNA binding) or an 80-kDa Anti-Ta (Ma2, PNMA2) protein. There are no such targets in

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The target is tumour-associated anti- Trotter discovered this antibody. The gen or membrane-reactive antigen 2. antigen is located at the cytosol and It is a 41.5-kDa protein located in the outer surface of the endoplasmic re- subnucleus of neurons. There is ho- ticulum, and typically found in mology to Ma1. Purkinje cell cytoplasm and dendrites.

In about 90%, the patients present The antigen is the delta and notch-like with isolated or combined limbic, di- epidermal growth factor-related re- encephalic or brainstem dysfunction ceptor (DNER). (PEM). Excessive daytime sleepiness may also be an observation, and in The associated cancer is Hodgkin’s such cases decreased / absent lymphoma. Interestingly, the neo- hypocretin-1 may be a feature of the plasm is only rarely stained by the an- CSF. In young male patients, the pri- tibody. mary tumour is in the testis. In other patients, the most frequent neo- PCD is the typical neurological feature. plasms are lung adenocarcinoma, co- Variant syndromes may be a reversi- lon or breast cancer. ble limbic encephalitis and optic neuritis. Anti-TIFγ (transcriptional intermediary factor 1-gamma) Anti-TULIP-1 (TULP1) This factor plays a role in the control Tubby-like protein 1 is a photorecep- of cell proliferation. tor-specific protein. It co-localises and interacts with actin in photoreceptor The autoantibody is associated with cells of the retina. In humans, there polymyositis / dermatomyositis, and are two genes, TULP1 and TULP2. The in particular cancer associated expression of TULP1 is exclusively in dermatomyositis (CADM) with 58 % retina, whereas TULP2 is located in of co-existing neoplasms in anti-Tifγ both retina and testis. seropositive cases. Paraneoplastic retinitis is the clinical Anti-Titin finding. The target is the giant protein titin of striated muscles. This is the largest Anti-Ubiquitin-conjugating en- molecule of the body, functioning as a zyme E2E1 (UBE2E1) giant spring. The modification of proteins with ubiquitin is an important cellular The autoantibodies are associated mechanism for targeting abnormal or with paraneoplastic MG (thymoma), short-lived proteins for degradation. although they are also a frequent Ubiquitination involves at least three finding in non-paraneoplastic late-on- classes of enzymes: ubiquitin- set MG. The titres appear to correlate activating enzymes, or E1s, ubiquitin- with the severity of MG, possibly at- conjugating enzymes, or E2s, and tributable to a co-existing myopathy. ubiquitin-protein ligases, or E3s. This Such autoantibodies are a feature of gene encodes a member of the E2 healthy controls in only about 0.4%, ubiquitin-conjugating enzyme family. so they are of a high diagnostic value. Three alternatively spliced transcript variants encoding distinct isoforms In myasthenic patients, the detection have been found for this gene. of these autoantibodies should be by Paraneoplastic encephalomyelitis and a method using the main immuno- SCLC are assiciated. genic region (MIR, for example MGT- 30-peptide). In sporadic rippling muscle syndrome, the antibodies are to Anti-Yo (Young, CDR1 (CDR34), CDR2, the titin isoform N2A. CDR2L (CDR62-1, CDR62-2), CDR3, PCD17-SN, CZF) Anti-Tr (Trotter, PCA-Tr)

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Young was the first to report the find- extensive sequence homology (range ing of these antibodies. The names of 52%-62% identity). Because the Zic the targets are also Purkinje cell anti- proteins are highly homologous to gen 1 and cerebellar degeneration re- each other, the sera of patients with lated proteins 34 & 62. They are pro- anti-Zic4 antibodies usually react with teins of the Purkinje cell cytoplasm Zic1, and less frequently with Zic2. (ribosomes – both membrane bound The anti-Zic4 antibodies show pre- & free – and Golgi apparatus) and var- dominant reactivity with the nuclei of ious neoplasms: 34kDa (CDR34); neurons of the granular layer of the 62kDa (CDR62-1, CDR62-2, leucine cerebellum and less intense reactivity zipper); CDR3 (leucine zipper); with other neurons, including in de- 52kDa (PCD17-SN, leucine zipper); scending order Purkinje cells, and 58kDa (CZF, zinc finger); CDR2L is lo- neurons of deep cerebellar nuclei, calized to the cell membrane brainstem and brain.

The following PNS are associated: SCLC is the associated neoplasm, and PCD, PLE and SPS. The most frequent PCD is the typical neurologic finding. neoplasm is breast cancer (95%). A combined finding of anti-ZIC4 and Other cancers may be SCLC, ovarian, other onconeural antibodies is typical prostatic, oesophagus, gastric, pain PEM. Detection of Zic4 antibodies rotid. often associates with anti-Hu or CV2 (CRMP5) antibodies. Patients with iso- Anti-ZIC4 lated Zic4 antibodies are more likely The zinc finger (Zic) proteins have im- to develop cerebellar dysfunction than portant roles in the development of those with concurrent other autoim- the nervous system, and comprise a munities. 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

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Diagnostic criteria - Overview

Recommended diagnostic criteria for paraneoplastic neurological syndromes.

Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold W, Honnorat J, Smitt PS, Vedeler C, Verschuuren JJ, Vincent A, Voltz R.

J Neurol Neurosurg Psychiatry 2004; 75 (8): 1135-1140. Comment in: J Neurol Neurosurg Psychiatry 2004; 75 (8): 1090.

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

RESULTS: The panel suggest two levels of evidence to define a neurological syndrome as paraneoplastic: "definite" and "possible". Each level can be reached combining a set of criteria based on the presence or absence of cancer and the definitions of "classical" syndrome and "well characterised" onconeural antibody.

CONCLUSIONS: The proposed criteria should help clinicians in the classification of their patients and the prospective and retrospective analysis of PNS cases.

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

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

Management of paraneoplastic neurological syndromes: report of an EFNS Task Force.

 Vedeler CA, Antoine JC, Giometto B, Graus F, Grisold W, Hart IK, Honnorat J, Sillevis Smitt PA, Verschuuren JJ, Voltz R.

Eur J Neurol 2006; 13 (7): 682-690.

Download the whole report from here: CV2 (

Paraneoplastic Neurological Syndrome Euronetwork. PNSEURONET: http://www.pnseuronet.org/

Summary An overview of the management of classical PNS, i.e. paraneoplastic limbic encephalitis, subacute sensory neuronopathy, paraneoplastic cerebellar degeneration, paraneoplastic opsoclonus-myoclonus, Lambert-Eaton myasthenic syndrome and paraneoplastic peripheral nerve hyperexcitability is given. Myasthenia gravis and paraproteinemic neuropathies are not included in this report. No evidence-based recommendations were possible, but good practice points were agreed by consensus. To allow tumour therapy to be started early and further to prevent progressive neuronal death and irreversible disability, urgent investigation is indicated. This is particularly true in central nervous system (CNS) PNS syndromes,

Onconeural antibodies are of great importance in the investigation of PNS and can be used to focus tumour search. PDG-PET is useful if the initial radiological tumour screen is negative. Early detection and treatment of the tumour is the approach that seems to offer the greatest chance for PNS stabilization. Immune therapy usually has no or modest effect on many of the CNS syndromes, whereas such therapy is beneficial for PNS affecting the neuromuscular junction. Symptomatic therapy should be offered to all patients with PNS.

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Listing of some books and reviews

Darnell RB, Posner JB. Paraneoplastic sydromes. Oxford University Press 2011

Abeloff, Armitage, Niederhuber, Kastan, McKenna. Abeloff's Clinical Oncology, 4th Edition. Churchill Livingstone 2008 - please see: Dalmau, J, Rosenfeld M. Chapter 51 – Paraneoplastic Neurologic Syndromes de Beukelaar JW, Sillevis Smitt PA. Managing paraneoplastic neurological disorders. Oncologist 2006; 11 (3): 292-305.

Dropcho EJ. Update on paraneoplastic syndromes. Curr Opin Neurol 2005; 18 (3): 331-336.

Sillevis Smitt P. Neuro-oncology: diagnosis in the spotlight. Lancet Neurol 2004; 3 (1): 14.

Llado A, Mannucci P, Carpentier AF, Paris S, Blanco Y, Saiz A, Delattre JY, Graus F. Value of Hu antibody determinations in the follow-up of paraneoplastic neurologic syndromes. Neurology 2004; 63 (10): 1947-1949.

Giannopoulou C. Navigating the paraneoplastic neurological syndromes. Eur J Nucl Med Mol Imaging 2003; 30 (3): 333-338.

Benyahia B, Carpentier AF, Delattre JY. [Antineuron antibodies and paraneoplastic neurological syndromes]. [French]. Rev Neurol (Paris) 2003; 159 (4): 463-465.

Vianello M, Tavolato B, Giometto B. Glutamic acid decarboxylase autoantibodies and neurological disorders. Neurol Sci 2002; 23 (4): 145- 151.

Giometto B, Taraloto B, Graus F. Autoimmunity in paraneoplastic neurological syndromes. Brain Pathol 1999; 9 (2): 261-273.

Posner JB, Dalmau JO. Paraneoplastic syndromes affecting the central nervous system. Annu Rev Med 1997; 48: 157-166.

Serratrice G, Azulay JP. [What is left of Morvan's fibrillary chorea?]. [French]. Rev Neurol (Paris) 1994; 150 (4): 257-265.

O'Neill JH, Murray NM, Newsom-Davis J. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain 1988; 111: 577-596.

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Subject index

anti-NMDAR · 36; 101 anti-Pancreatic-islet-cell · 52 A anti-Parietal-cell · 53 anti-PCA1 · 103 acute necrotizing myopathy · 76 anti-PCA2 · 28; 35; 52; 101 ANA · 75 anti-PCA2 syndrome · 28 ANNA1 · 99 anti-Peripherin · 56 ANNA2 · 101 anti-PKC gamma · 30; 101 ANNA3 · 43; 97 anti-POP66 · 97 anti-AChR anti-Pyridoxal-phosphatase · 57; 58; 101 adult-type · 22; 28; 43; 67; 69; 70; 79; 83; 88; 96 anti-Recoverin · 46; 102 alpha3-type · 56; 67; 83; 89; 96 anti-Ri · 25; 33; 37; 38; 42; 101 foetal-type · 22; 28; 43; 67; 69; 70; 79; 83; 88; 96 anti-RyR1 (ryanodine) · 70; 79; 89; 102 M1-type · 64; 96 anti-Striated muscle · 70; 79; 83; 102 anti-Adenylate kinase 5 · 36; 96 anti-Ta (Ma2) · 35; 37; 42; 43; 102 anti-Alpha-enolase (ENO1) · 46; 96 anti-TIF γ · 76 anti-AMPAR (GluR1/R2) · 35; 96 anti-Titin · 22; 89; 102 anti-Amphiphysin · 33; 35; 37; 42; 53; 97 anti-Tr · 25; 28; 43; 44; 103 anti-ARHGAP26 (GRAF) · 30 anti-Tr syndrome · 28 anti-ARHGAP26/GRAF · 97 anti-Tulip1 · 103 antibody removal / plasma exchange · 19 anti-UBE2E1 · 36; 103 antibody-mediated autoimmunity anti-vg-Ca-channel · 22; 25; 28; 30; 43; 97 criteria · 8 N-type · 64 anti-BRSK2 · 35; 97 P/Q-type · 64 anti-Ca-channel · 22; 25; 28; 30; 43; 64; 97 anti-vg-K-channel · 71; 89; 99 anti-CARP8 · 29; 97 anti-Yo · 25; 26; 42; 103 anti-CASPR2 · 22; 35; 65; 67; 71; 97 anti-Yo syndrome · 26 anti-CDR32 · 103 anti-ZIC4 · 25; 30; 33; 41; 103 anti-CDR62 · 103 arthrogryposis multiplex · 90 ataxia · 85 anti-CRMP2-4 · 97 ataxia in cerebellar degeneration · 24 anti-CRMP5 · 97 ataxia with anti-CARP8 · 29 anti-CV2 / CRMP5 · 25; 26; 31; 33; 35; 37; 38; 43; ataxia with anti-CV2 · 26 44; 58; 60; 89; 97 ataxia with anti-GAD · 29 anti-CV2/CRMP5 syndrome · 26 ataxia with anti-Hu · 25 anti-DPP5 · 22 ataxia with anti-Ma1 · 27 anti-DPPX · 22 ataxia with anti-mGluR1 · 28 anti-EFA6A · 36; 98 ataxia with anti-PCA2 · 28 anti-GabaBR1 · 35 ataxia with anti-Ri · 42 anti-GAD · 35; 37; 50; 51; 89; 98 ataxia with anti-Tr · 28 anti-GAD65 · 98 ataxia with anti-Yo · 26 anti-Gephyrin · 52; 98 ataxia with anti-ZIC4 · 29 anti-GluR1/R2 (AMPAR) · 35; 96 ataxia, LEMS associated · 30 anti-GlyR alpha1 · 52 autonomic neuropathy · 55 anti-HMGCR · 77; 78; 98 anti-Hu · 25; 35; 37; 39; 40; 42; 43; 57; 59; 60; 89; 99 B anti-Hu syndrome · 25 anti-IF-alpha (interferon) · 71 bladder cancer · 56; 76 anti-IL12 (interleukin) · 71 blood pressure, labile and low · 33; 56 anti-K-channel · 89; 99 brainstem encephalitis anti-Ma1 · 27; 100 · 36 anti-Ma1-syndrome · 27 breast cancer · 25; 26; 27; 35; 37; 40; 42; 51; 53; anti-Ma2, see also anti-Ta · 102 60; 76; 88; 97; 98; 99; 100; 102; 103 anti-MDAS · 76 anti-mGluR1 · 28; 29; 99 anti-mGluR5 · 35 C anti-Mup44 · 77; 78 anti-nCMAg · 36 cerebellar degeneration (PCD) · 24 anti-Neurofilaments · 41; 101 choreo-athetosis · 31

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chronic gastrointestinal pseudoobstruction · 33; 56 M colon cancer · 27; 75 cramp-fasciculation syndrome · 65 criteria M-components · 58 antibody-mediated autoimmunity · 8 melanoma · 29; 60 paraneoplastic neurological syndromes · 4 monoclonal gammopathy · 58 T-cell-mediated autoimmunity · 8 Morvan's fibrillary chorea · 22 motor neuron disease · 39 motor neuropathy · 57 D myasthenia gravis · 69 myasthenia gravis-associated myopathy · 79 myeloma · 40; 57 diagnostic strategy in PNS · 12 myoclonus · 42; 53 duodenum cancer · 40 myokymia · 27; 66; 100 myopathies · 74 myopathy E paraneoplastic MG-associated myopathy · 79 myositis-overlap antibodies · 76 epilepsy · 22; 35; 42; 51; 59; 85 myositis-specific antibodies (MSA) · 75 extrapyramidal disorders · 27; 31; 37; 50; 52; 53; 87 N G neuroblastoma · 42 gall bladder cancer · 40 neuromyotonia (Isaacs' syndrome) · 65 ganglioneuroblastoma · 42 neuropathy ganglioneuroma · 42 autonomic · 55 gastric cancer · 26; 75 motor · 57 gastrointestinal pseudoobstruction · 33; 56 sensory · 59 sensory-motor · 57 H O hereditary inclusion body myositis · 77 high-dose IgG · 19 oesophageal cancer · 26; 60 Hodgkin's disease · 25; 28; 29; 40; 44; 60; 67; 88; Ophelia syndrome · 35 96; 99; 103 opsoclonus / myoclonus (POM) · 41 hypotension, labile · 33; 56 opsoclonus / myoclonus in adults anti-Hu, anti-Yo, anti-Ta · 42 anti-Ri · 42 I optic neuritis · 44 ovarian cancer · 25; 26; 37; 42; 60; 75; 99; 103 immunosuppression · 19 Inclusion body myositis, hereditary · 77 Inclusion body myositis, sporadic · 77 P Isaacs' syndrome · 65 pain · 50; 57; 58; 59; 87 pancreas cancer · 75 L paraneoplastic neurological syndrome definition · 4 Lambert-Eaton myasthenic syndrome (LEMS) · 63 paraproteinaemia · 57; 58 LEMS-associated PCD · 30 parotid cancer · 26 leukaemia · 40; 57 polyneuropathy lung cancer · 5; 12; 13; 25; 26; 27; 28; 30; 31; 33; autonomic · 55 35; 37; 38; 42; 44; 46; 51; 53; 56; 57; 58; 59; 60; motor · 57 63; 64; 67; 75; 76; 93; 96; 97; 98; 99; 100; 101; sensory · 59 102; 103 sensory-motor · 57 lymphoma · 25; 28; 29; 40; 44; 46; 57; 67; 75; 96; progressive encephalopathy with rigidity and reflex 99; 103 myoclonus (PERM) · 53 prostate cancer · 60

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R with anti-GAD · 53 subaucte sensory neuronopathy (SSN) · 59 rectum cancer · 56; 75 renal cancer · 44; 60 T retinopathy (CAR) · 46 rippling muscle syndrome, sporadic · 83 ROHHAD syndrome · 42 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; S 102 thyroid cancer · 44; 58 transfer from mother to foetus · 88 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 U sensory neuropathy · 59 sensory-motor neuropathy · 57 sporadic inclusion body myositis · 77 uterus cancer · 27 sporadic rippling muscle syndrome · 83 statin-provoked rhabdomyolysis · 77 stiff-person syndrome · 50 W stiff-person syndrome variants · 52 focal SPS · 52 Waldenstrom's macroglobulinaemia · 40 other types · 53 PERM · 53

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Autoimmune encephalitis, please see separate compendium

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

By Finn E. Somnier, M.D., D.Sc. (Med.), copyright ®

Department of Clinical Biochemistry, Immunology & Genetics Statens Serum Institut, Copenhagen, Denmark

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Channelopathies, receptor and solute carriers disorders in neurology, please see separate compendium Channelopathies receptor and solute carrier disorders in neurology Autoantibodies and biomarkers of neurological disorders

Version 3.1, February 2014

By Finn E. Somnier, M.D., D.Sc. (Med.), copyright ®

Department of Clinical Biochemistry, Immunology & Genetics Statens Serum Institut, Copenhagen, Denmark

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Department of Clinical Biochemistry, Immunology and Genetics

STATENS SERUM INSTITUT

Artillerivej 5 – DK-2300 Copenhagen S – Denmark

Tel. +45 3268 3268 – Fax: +45 3268 3869

[email protected] – www.ssi.dk

http://www.ssi.dk/Diagnostik/Downloads.aspx

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