Paraneoplastic neurological disorder syndromes

Introduction

Paraneoplastic neurological disorder (PND) syndromes are immune-mediated disorders that affect the central, peripheral, or autonomic nervous system in the setting of a cancer. These disorders are not caused by a direct tissue invasion of cancer; instead, they are associated with cancer-induced immune responses directed toward neuronal proteins. They are extremely rare, estimated to affect less than 0.1% of patients with cancer. This, however, is likely an underestimate. The recognition of PND syndromes is crucial given that they often occur before the diagnosis of a cancer or a cancer recurrence, offering an opportunity to diagnose and treat cancer earlier and with associated improved outcomes.

PND syndromes may be related to benign tumors, such as thymoma, or malignant tumors, such as small-cell carcinoma of the lung (SCLC) and breast cancer. SCLC is the most frequent malignancy associated with PND syndromes. The most commonly accepted theory is that the immune system reacts against proteins expressed by tumors, which are similar to neuronal proteins, allowing for a response to cancer as well as a mistaken response against the brain, spinal cord, nerves, neuromuscular junction, or muscle individually as well as in combination. Several antibodies have been described since the first report in 1949 (e.g., anti-Hu, anti-CV2/collapsing response mediator protein 5 [CRMP5/CV2], anti– N -methyl- d -aspartate receptor [NMDAR] and anti-Yo). ^, These antibodies can recognize intracellular as well as cell-surface antigens, and their associated syndromes differ in terms of clinical profile, pathogenesis, and outcome.

In this chapter, we will present case-based discussions of the classic PND syndromes as well as paraneoplastic mononeuritis multiplex (MM), with special attention paid to their respective clinical presentations, treatments, and prognoses. We begin with a brief discussion of the classification, pathophysiology, clinical presentation, general diagnostic approach, and treatments. This is followed by a case-based presentation of the common and clinically relevant PND syndromes.

Classification

Broadly, PND syndromes can be classified by the location of the antibody target and, specifically, whether the target is an intracellular antigen or an antigen found on the neuronal cell surface.

Intracellular antigen syndromes . Antibodies to intracellular antigens are associated with subacute onset, progressive illness, and poor outcomes, given that they result from rapid and irreversible neuronal damage. These antibodies can recognize any area of the neuroaxis in isolation or combination, leading to characteristic syndromes such as paraneoplastic cerebellar degeneration (PCD), limbic encephalitis, and sensory neuronopathy. PND syndromes have been associated with anti-Hu, anti-Yo, anti-CRMP5/CV2, anti-Ri, anti-Ma1, anti-Ma2, anti-amphiphysin, anti-Purkinje cell antibody type 2 (PCA-2), and anti-neuronal nuclear antibody type 3 (ANNA-3), among others. Detection of these antibodies should be followed by screening for an occult neoplasm. Their pathophysiology is thought to be primarily mediated by CD8+ T lymphocytes that induce cell death through cytotoxic activity. As a consequence, motor and sensory functions are markedly affected in these patients. ^, For instance, in anti-Yo PCD, 90% of patients become non-ambulatory. ^, Tumor treatment is related to the stabilization of neurological syndrome, rather than improvement.

Cell surface antigen syndromes . There are also syndromes associated with antibodies against cell-surface antigens targeting membrane receptors, ion channels, and synaptic proteins that occur less commonly in the setting of cancer ( Table 20.1 ). The past decade has seen a rise in the number of newly described syndromes. They are typically associated with better response to immunotherapy and thus better outcomes. Some of these antibodies include anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), anti-gamma-aminobutyric acid type B receptor (GABA _B ), anti-GABA _A receptor, anti-NMDAR, anti-dipeptidyl-peptidase-like protein 6 (DPPX), anti-voltage gated calcium channel (VGCC; associated with malignant tumors), anti-leucine-rich glioma inactivated 1 (LGI1), and anti-contactin-associated protein 2 (CASPR2). In some instances, the antibodies against cell-surface proteins appear to be related directly with the disease pathophysiology. For instance, antibodies to the NMDA receptor crosslink the receptor, leading to receptor internalization, whereas antibodies against LGI1 interfere with protein-protein interactions. ^, Clinical presentation varies from limbic encephalitis to, more rarely, cerebellar ataxia and dysautonomia.

Pathophysiology

Although the pathophysiology of PND syndromes is incompletely understood, autoimmune responses are believed to be involved, with patients developing T-cells and antibodies that are directed against antigens of the central nervous system (CNS), peripheral nervous system (PNS), or autonomic nervous system. When the body surveys for and attempts to eliminate tumor cells, an immune reaction is triggered against tumor antigens. This immune reaction mistakenly cross-reacts with similar proteins on neural tissues. In other cases, the cause is not identified; however, a previous viral infection or a family history of autoimmune diseases may play a role. In addition, cancer treatments such as immunologic checkpoint inhibitors may also provoke autoimmune reactions leading to neurological immune-related adverse events similar in many respects to PND syndromes (also see Chapter 30 for discussion of neurological syndromes associated with immune checkpoint inhibitors).

These anti-cancer immune responses often yield antineuronal antibodies that can be measured in the cerebrospinal fluid (CSF), as well as the serum. Antibodies facilitate the localization of an occult neoplasm associated with the PND syndrome and, in some cases, can narrow the search to a few associated organs. Seronegative cases appear to be mediated by cellular immune effectors or may reflect yet to be described syndromes. Further studies are necessary to clarify this mechanism.

Tumor prognosis is believed to be better among patients with PND syndromes as often the neoplasm is asymptomatic or undetectable at the time of presentation. However, a review of large series of patients has demonstrated that the oncologic outcome of patients with PND syndromes is not different from those patients who do not have antibodies against neural tissues.

Clinical presentation

PND syndromes may manifest in different ways such as encephalitis (inflammation of the brain), myelitis (inflammation of the spinal cord), cerebellar degeneration (ataxia, dysarthria), neuropathy (progressive numbness and weakness in lower and upper extremities), myoclonus/opsoclonus (involuntary, rapid, irregular body jerks and multidirectional eye movements), Lambert-Eaton myasthenic syndrome (LEMS; weakness of several muscle groups), and dermatomyositis (DM; proximal weakness and skin lesions). Clinical presentations may develop acutely over the course of a few days or subacutely over the course of weeks or months.

General diagnostic approach

The diagnostic evaluation for a PND syndrome should begin with a complete medical examination, including palpation of lymph nodes, breasts and testes, rectal and pelvis, and neurological examination. Diagnostic testing of the CNS includes: (1) lumbar puncture with CSF analysis (e.g., white blood cell [WBC], glucose, protein, oligoclonal bands, immunoglobulin G [IgG] index, molecular and immunologic testing, cultures, and flow cytometry), (2) MRI of the brain and/or spinal cord, and (3) electroencephalography (EEG). Paraneoplastic antibody panel testing in both serum and CSF helps to identify autoimmune markers and paraneoplastic etiologies. Electromyographic and nerve conduction studies (EMG and NCS) should be performed if neuropathy, myasthenia, or myopathy raise suspicion for PNS involvement. Serum paraneoplastic autoantibody testing alone is appropriate for evaluation of these peripheral syndromes. Serum tumor markers are also useful as part of the malignancy screen, for instance, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), cancer antigen 125 (CA-125), and prostate-specific antigen (PSA). CT of the chest, abdomen, and pelvis are helpful in evaluating for an occult malignancy, as are testicular and vaginal ultrasounds and mammography. Other tests that should be included are complete blood cell count with platelets (to assess for infection and immunosuppression), prothrombin time and activated partial thromboplastin time, electrolytes and osmolarity, toxicology screen, vitamin levels, liver function tests, and infectious tests. In the event that initial tumor screening is not revealing, repeat screening 3–6 months after the initial evaluation, and every 6 months up until 4 years is advised for patients with a diagnosis of a PND syndrome.

Typical findings in a PND syndrome involving the CNS include CSF pleocytosis, hyperproteinorachie (i.e., elevated spinal fluid protein), intensification of intrathecal immunoglobulin synthesis and presence of oligoclonal bands. MRI of the brain may reveal T2-weighted hyperintense signals or atrophy in different parts of the brain or spinal cord, depending of the neurological syndrome. EEG may demonstrate focal slowing, focal or diffuse paroxysmal sharp waves, or electrographic seizures.