Management of patients with known or suspected paraneoplastic syndromes includes the following components:
| (1) verification that the disorder is, in fact, paraneoplastic;
(2) diagnosis of the associated tumor;
(3) treatment of the tumor;
(4) suppression of the autoimmune effectors causing neuronal injury. |
Several neurologic syndromes are considered "classical" paraneoplastic syndromes in that they are strongly associated with cancer (13). These include multifocal encephalomyelitis, limbic encephalitis, subacute cerebellar degeneration, opsoclonus-myoclonus, subacute sensory neuronopathy, chronic gastrointestinal pseudo-obstruction, Lambert-Eaton myasthenic syndrome, and dermatomyositis. Patients presenting with any of these syndromes should be thoroughly investigated for an associated neoplasm, regardless of the presence or absence of onconeural antibodies.
The workup to find an associated tumor should be guided by the known associations between particular clinical syndromes and tumor types and by the type of autoantibodies, if present.
When the tumor is definitely diagnosed, it should be treated with the appropriate surgical, chemotherapeutic, or radiation measures. For at least some patients with CNS paraneoplastic disorders, successful tumor treatment is associated with better neurologic outcome (38). Patients with some syndromes, most notably limbic encephalitis and opsoclonus-myoclonus in adults or children, often show neurologic improvement solely with successful tumor therapy. Some patients with cerebellar degeneration and Hodgkin lymphoma, and exceptional patients with carcinoma, improve neurologically after successful tumor treatment. Some patients with peripheral nervous system paraneoplastic disorders also show neurologic improvement with successful tumor treatment. This includes Lambert-Eaton syndrome, neuromyotonia, and probably vasculitic neuropathy and polymyositis as well.
If paraneoplastic disorders are truly autoimmune diseases, they should theoretically respond to immunosuppressive or immunomodulatory treatment. Several factors make it difficult to interpret the published literature regarding immunotherapy for paraneoplastic disorders:
| • These syndromes are relatively rare. For some of the syndromes, only a handful of well-characterized published cases can be found. |
| • Most reports are anecdotal, and nearly all published series are retrospective. |
| • A reporting bias exists, in that patients who respond to treatment are more likely to be published than those who do not respond. |
| • For some syndromes, pharmacologic treatments can improve neurologic symptoms independent of tumor treatment or immunotherapy; examples include Lambert-Eaton syndrome (pyridostigmine, 3,4-diaminopyridine, or guanidine), limbic encephalitis (psychoactive and antiepileptic drugs), neuromyotonia (phenytoin and carbamazepine), stiff-person syndrome (diazepam and baclofen), and opsoclonus-myoclonus (clonazepam or valproate). |
| • Paraneoplastic cerebellar degeneration, sensory neuronopathy or encephalomyelitis, and other syndromes often stabilize spontaneously (although at a level of severe disability) so that it is difficult to interpret reports of "disease stabilization" with immunotherapy. |
| • Perhaps the greatest difficulty in evaluating immunotherapy for paraneoplastic disorders is the confounding effect of tumor treatment. When patients receive concomitant tumor treatment and immunotherapy, it becomes difficult to discern the impact of each therapy on the neurologic outcome. For many syndromes, increasing evidence shows that immunotherapy is more likely to be effective when the tumor is also treated successfully. |
Factors that interact in influencing the response to immunotherapy include the neuroanatomic site (central vs. peripheral), the cellular location of the onconeural target antigens (neuronal cell surface vs. intracellular), and the proven or presumed mechanisms of neuronal injury (antibody-mediated vs. cell-mediated). In general, syndromes affecting the peripheral nervous system are more likely to improve with tumor treatment or immunosuppressive treatment than are CNS syndromes. Syndromes caused by autoantibodies reacting with neuronal cell surface receptors or ion channels are more likely to respond to immunotherapy, probably because the antibodies do not usually cause axonal degeneration or neuronal cell death. Prime examples of this are the Lambert-Eaton myasthenic syndrome and neuromyotonia. Patients with encephalitis associated with anti-NMDAR antibodies, anti-GABABR antibodies, or antibodies against the voltage-gated potassium channel complex (anti LGI1 or anti-Caspr2) generally have a good neurologic outcome after immunotherapy (23; 19; 06; 22). Sensory neuronopathy and autonomic insufficiency involve the peripheral nervous system, but patients generally do not respond to therapy, which is probably because neuronal cell bodies in the dorsal root ganglia and autonomic ganglia are irreversibly injured or killed by the autoimmune response.
Unfortunately, the 2 most prevalent paraneoplastic CNS syndromes in adults, ie, encephalomyelitis or sensory neuronopathy associated with anti-Hu antibodies and cerebellar degeneration associated with anti-Yo antibodies, usually have a poor neurologic prognosis despite aggressive tumor treatment and a variety of immunosuppressive therapies (38). Patients with other CNS syndromes, including opsoclonus-myoclonus, limbic encephalitis, and stiff-person syndrome, have a somewhat higher likelihood of neurologic improvement, suggesting that the immune-mediated neuronal dysfunction or injury is less severe or of a sort more likely to be reversible. Even for the "unfavorable" syndromes, such as encephalomyelitis and cerebellar degeneration, a few patients do show a meaningful neurologic response to immunotherapy. For these few responders, the only factors that sometimes correlate with neurologic improvement are successful tumor treatment and the duration and severity of neurologic deficits prior to diagnosis and initiation of therapy. For patients who have already stabilized at a plateau of severe neurologic disability for more than several weeks, subsequent improvement with any intervention is not impossible but extremely unlikely. Therefore, the decision whether to try immunosuppressive therapies must be based on the particular syndrome and on the individual patient's circumstances.
Corticosteroids or IVIg are the most commonly used immunotherapies for paraneoplastic disorders. Patients generally receive an initially high dose of intravenous or oral steroid (prednisone, methylprednisolone, dexamethasone) followed by a slow, cautious taper. No clear evidence indicates the optimal drug, dose, route of administration, or schedule of corticosteroids. IVIG may be tried alone or in combination with corticosteroids. Plasma exchange could arguably be reserved for syndromes that are definitely antibody-mediated, but reports have been made of improvement in patients with other syndromes as well (39).
Some paraneoplastic disorders may respond better to repeated plasma exchanges, whereas others may have a better record at responding to IVIg. In addition, when the antibody specificity is not yet available, many clinicians will choose to proceed with 5 plasma exchange sessions approximately every other day for a rapid antibody removal and then administer intravenous immunoglobulins for a more extended immune modulation. Chronic oral or pulsed intravenous cyclophosphamide has also been used for a variety of paraneoplastic disorders, with no definite evidence establishing an optimal schedule or dose. Azathioprine or cyclosporine has been used with benefit in some patients with Lambert-Eaton syndrome, with little published information regarding their efficacy in other paraneoplastic disorders. The monoclonal antibody rituximab, which depletes B lymphocytes, produced neurologic improvement in children with neuroblastoma and opsoclonus-myoclonus and in young people with anti-NMDAR encephalitis (32; 04). Rituximab and/or cyclophosphamide have been used as second-line therapy for adult patients with multifocal or limbic encephalitis who do not respond well to corticosteroids, IVIg, or plasma exchange (23). There are studies of tacrolimus plus prednisone or of sirolimus, which are agents that specifically inhibit activated T-lymphocytes in patients with anti-Hu or anti-Yo-associated syndromes (31; 08).
Several potential explanations exist for the disappointingly poor response to immunotherapy in many patients. The continuing presence of even a small tumor burden seems to provide an "antigenic drive" for further neuronal injury. It is also likely that current immunotherapies do not adequately gain access to the central nervous system and do not effectively abrogate an ongoing autoimmune response that is "sequestered" in the central nervous system. Unfortunately, for many central syndromes, it is likely that patients have already suffered neuronal death or irreversible injury by the time the diagnosis of a paraneoplastic disorder is made.
Theoretical concern exists that if paraneoplastic disorders arise from an immune response directed against the tumor, attempts to treat the neurologic disorder with immunosuppression may adversely affect the evolution of the tumor. At this time, no definite evidence shows that patients given immunosuppressive treatment have a worse tumor outcome.
