Introduction

Paraneoplastic neurologic syndromes (PNS) may be the presenting symptom of cancer [Tuzun and Dalmau, 2007]. The disorders may also occur in patients with known cancer and can be mistaken for treatment effects, opportunistic infections, or the results of other causes. Neurologic complications occur in approximately 20 percent of patients treated for cancer. Direct effects of the primary tumor and/or metastases are the most common cause, while treatment-related complications are secondary causes.

The focus of this chapter is PNS, a constellation of rare but well-described syndromes associated with cancer. The chapter will provide a brief overview of the history of PNS, describe the most common syndromes, and discuss the diagnosis, treatment, and management of several syndromes that specifically affect pediatric patients. For ease of reference, the clinically relevant aspects of PNS are summarized in Table 84-1.

Table 84-1 Paraneoplastic Syndromes and Associated Tumors and Antibodies

AMPAR, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ANNA, antineuronal nuclear antibody; CRMP, collapsin response mediator protein; GABA_B, gamma-aminobutyric acid type B receptors; GAD, glutamic acid decarboxylase; MAG, myelin-associated glycoprotein; NR, N-methyl-d-aspartate (NMDA) receptor; PCA, Purkinje cell autoantibody; PTB, polypyrimidine tract binding; SCLC, small-cell lung cancer; SGPS, sulfated glucuronic acid paragloboside; TULP1, tubby-like protein 1; VGCC, voltage-gated calcium channels; VGKC, voltage-gated potassium channel.

* Well-characterized onconeural antibodies are shown in bold.

(Adapted with permission from Toothaker TB, Rubin M. Paraneoplastic neurological syndromes: a review. Neurologist Jan 2009;15[1]:21–33.)

History of Paraneoplastic Syndromes

The 19th-century French physician, Armand Trousseau, is credited with describing the first paraneoplastic syndrome in 1865, when he made the association between cancer and thromboses [Trousseau, 1865]. In 1948, Derek Denny-Brown published a paper describing two patients with sensory neuronopathy and lung cancer [Denny-Brown, 1948]. Henson and Urich described the first case of encephalomyelitis and carcinoma in 1965 [Henson et al., 1965]. The term “paraneoplastic syndrome” was first used in the 1956 by Cabanne and colleagues, who reported on three patients with paraneoplastic polyneuritis in the setting of cancer [Cabanne et al., 1956]. Graus and colleagues identified the first antibody associated with PNS in 1985 [Graus et al., 1985]. In the past two decades, 16 identifiable syndromes and at least 10 paraneoplastic antibodies have been described. Neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome was the first PNS identified in children in 1968 by Solomon and Chutorian (see below). More recently, anti-N-methyl-d-aspartate (NMDA) antibodies have been associated with an encephalomyelitis that may be paraneoplastic in adults but is only rarely associated with an identifiable neoplasm in pediatric patients.

Definition

PNS are defined as illnesses resulting from the indirect effects of cancer. There are five groups of neurologic paraneoplastic disorders: vascular, infectious, metabolic, treatment-related, and remote effects of cancer on the nervous system [DeAngelis and Posner, 2009]. This chapter will focus on the remote effects of cancer on the nervous system. PNS affect less than 0.01 percent of cancer patients. Exceptions include Lambert–Eaton myasthenic syndrome (LEMS), which affects about 3 percent of patients with small-cell lung cancer (SCLC) [Payne et al., 2010]; and myasthenia gravis, which is associated with thymoma in about 5 percent of cases [Wirtz et al., 2003].

PNS may cause injury anywhere along the neuraxis. Paraneoplastic and/or limbic encephalitis (LE) can affect the supratentorial compartment of the brain, while the cerebellum is involved in paraneoplastic cerebellar degeneration and opsoclonus-myoclonus-ataxia syndrome. The visual pathway is affected in cancer-associated retinopathy, while the spinal cord can be injured in subacute motor neuronopathy. Sensory neuronopathy involves the sensory nerves and, in LEMS, the neuromuscular junction is the target. Finally, inflammatory myopathies, including dermatomyositis, polymyositis, and inclusion body myositis, are PNS that affect the muscle. Dermatomyositis and polymyositis may be PNS, but no more than 10 percent of patients with these neuromuscular disorders have cancer; immunosuppressive treatment is often effective [Darnell and Posner, 2006].

The PNS are divided into two major categories: classical syndromes that strongly suggest an associated malignancy, and nonclassical ones that are only occasionally associated with malignancy. In 2004, Graus and colleagues published official diagnostic criteria developed by a panel of neurologists [Graus et al., 2004]. They defined classic syndromes and nonclassic syndromes (Box 84-1). Classic syndromes include encephalomyelitis, cerebellar degeneration and sensory neuronopathy. In addition, Graus and colleagues distinguished between definite PNS and possible ones (Box 84-2) [Graus et al., 2004]. The neurologic symptoms of paraneoplastic syndromes typically present before the tumor is diagnosed. The tumors are often small and difficult to detect, and may spontaneously regress. Patients often survive the tumor but with persistent neurologic effects. The hypothesis is that patients develop neurologic symptoms because the tumor expresses onconeural antigens that cause a cellular and/or humoral response; this then cross-reacts with specific antigens in varied regions of the nervous system.

Box 84-1 Paraneoplastic Syndromes of the Nervous System

Central Nervous System

Limbic encephalitis*

Encephalomyelitis*

Cerebellar degeneration*

Opsoclonus-myoclonus*

Optic neuropathy/retinopathy

Brainstem encephalitis

Stiff person syndrome

Motor neuron disease

Necrotizing myelopathy

Peripheral Nervous System

Sensory neuronopathy*

Acute sensorimotor neuropathy

Chronic sensorimotor neuropathy

Gastrointestinal pseudo-obstruction/autonomic neuropathy*

Lambert–Eaton myasthenic syndrome*

Myasthenia gravis

Inflammatory myopathy*

^* Indicates a classical paraneoplastic neurological syndrome, as defined by [Graus et al., 2004].

Lambert–Eaton Myasthenic Syndrome

Several neurologic paraneoplastic disorders may affect the neuromuscular junction: LEMS, myasthenia gravis, and neuromyotonia. LEMS is considered one of the classical neurologic PNS and is a disorder of presynaptic neuromuscular transmission; this is in contradistinction to myasthenia gravis, which is a postsynaptic disorder. Initially, patients complain of weakness and fatigue, followed by sleepiness, autonomic dysfunction, muscle weakness, and diminished deep tendon reflexes. Electromyography is helpful in distinguishing between LEMS and myasthenia gravis; patients with LEMS have an incremental response to repetitive muscle stimulation, while those with myasthenia gravis have a decremental response. The Tensilon test may also be helpful in distinguishing LEMS from myasthenia gravis. As edrophonium chloride blocks acetylcholinesterase, patients with myasthenia gravis will have a positive response to the Tensilon test, while LEMS patients have antibodies against the presynaptic receptor and thus do not respond to Tensilon. Between 40 and 60 percent of patients with LEMS harbor a malignancy, and, as in the other PNS, neurologic symptoms often precede tumor diagnosis. The most common malignancy associated with LEMS is SCLC. Recently, Payne and colleagues examined 63 patients with the diagnosis of SCLC and found that 5 (8 percent) had high titers of antibodies to voltage-gated calcium channels present in the serum, with 2 (3 percent) patients exhibiting clinical and electrophysiologic evidence of LEMS [Payne et al., 2010]. In pediatric patients, there have been several reports of neuroblastoma-associated LEMS [Bosdure et al., 2006; de Buys Roessingh et al., 2009]. In adults, both myasthenia gravis (thymoma) and LEMS (SCLC) may be the presenting complaint in a patient with an underlying cancer. Both illnesses respond to treatment [Darnell and Posner, 2006].

Paraneoplastic Cerebellar Degeneration

Paraneoplastic cerebellar degeneration (PCD) was actually the first paraneoplastic syndrome to be described and, as such, is the best described and most easily recognized. In 1919, Brouwer et al., described a patient with rapid onset of a cerebellar syndrome [Brouwer, 1919]. At autopsy, the patient had Purkinje cell loss in the cerebellum and a pelvic tumor, most likely ovarian carcinoma. In 1938, Brouwer went on to postulate the association between PCD and cancer [Brouwer, 1938]. PCD may occur in isolation but may be associated with other PNS, including LE and LEMS.