Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 22

Neurologic complications of lung cancer EDWARD J. DROPCHO* Department of Neurology, Indiana University Medical Center, Indianapolis, IN, USA

INTRODUCTION

LUNG CANCER METASTASES

Lung cancer is the leading cause of cancer-related mortality worldwide. In many countries the incidence of lung cancer is increasing. Regional differences in lung cancer incidence largely reflect the prevalence of cigarette smoking. In the US, the overall incidence of lung cancer is decreasing, but there are still more than 160 000 deaths yearly. The two major clinicopathologic subtypes of lung cancer are non-small cell lung cancers (NSCLC) and small cell lung carcinoma (SCLC), accounting for 85% and 15% of total cases, respectively (Goldstraw et al., 2011; van Meerbeeck et al., 2011). The major histologic subtypes of NSCLC are squamous cell carcinoma, adenocarcinoma, and large cell carcinoma; many tumors are histologically heterogeneous. Squamous cell carcinoma and SCLC are strongly linked to cigarette smoking. Treatment of lung cancer is determined by the tumor stage at diagnosis. NSCLC is staged by the TNM (tumornodes-metastasis) system. Approximately two-thirds of patients with NSCLC have locally advanced or metastatic disease at initial diagnosis. SCLCs were generally dichotomized at diagnosis as either limited-stage or extensive-stage. Limited-stage patients were those in whom all tumor was confined to one hemithorax and could be encompassed by a single radiation therapy port. All other SCLC patients, about two-thirds of the total, had extensive-stage disease at diagnosis. More recently, a TNM staging scheme has been adopted for SCLC, since limited-stage patients could be subdivided for overall survival based on lymph node status and/or pleural effusion at diagnosis. The overall 5 year survival is approximately 15% for patients with NSCLC, and only about 2% for patients with SCLC.

Brain metastases INCIDENCE Parenchymal brain metastases are by far the most common neurologic complication of lung cancer. Lung cancer is the single most common source of brain metastases in adults, accounting for 40–50% of all cases. Lung carcinoma is the primary tumor most likely to metastasize to the brain in the absence of other systemic metastases, and is the tumor most often found in patients for whom brain metastases are the presenting feature of the neoplasm (Giordana et al., 2000; Mavrakis et al., 2005). In two large series of patients with SCLC, the lifetime incidence of symptomatic brain metastases was 25% and 40% (Sculier et al., 1987; Seute et al., 2004) (Table 22.1). Synchronous brain metastases are present in up to 25% of patients with newly diagnosed SCLC. In one-third of these patients the brain metastases are the sole site of metastatic tumor. In up to one-half of patients the brain metastases are asymptomatic and are discovered only by “staging” magnetic resonance imaging (MRI) (Seute et al., 2008). The overall incidence of brain metastases in NSCLC patients is lower than for SCLC, but NSCLC accounts for at least two-thirds of the total cases of symptomatic brain metastases from lung cancer. Among patients with NSCLC, about one-half of brain metastases are discovered at the time of initial tumor diagnosis (synchronous metastases) and half occur subsequently (metachronous) (Rodrigus et al., 2001). Up to 20% of patients with NSCLC have synchronous brain metastases (Shi et al., 2006). There has been an increasing incidence of metachronous brain metastases from NSCLC with

*Correspondence to: Edward J. Dropcho, M.D., Department of Neurology, GH 4700, Indiana University Medical Center, 355 W. 16th St., Indianapolis, IN 46202, USA. Tel: þ1-317-963-7404, Fax: þ1-317-274-4239, E-mail: [email protected]

336

E.J. DROPCHO

Table 22.1 Neurologic complications of small cell lung carcinoma

Study

No. patients

Years accrued

BM

SEM

ISCM

LM

LEMS

Sculier et al., 1987 Seute et al., 2004

641 432

1976–1983 1980–2001

24.8% 40.5%

3.6% 5.6%

0.8% 1.2%

2.2% 8.6%

0.3% 2.3%

BM, brain metastases; SEM, spinal epidural metastases; ISCM, intramedullary spinal cord metastases; LM, leptomeningeal metastases; LEMS, Lambert–Eaton myasthenic syndrome.

improvements in multimodality treatment of newly diagnosed patients. Among NSCLC patients with stage III (locally advanced) disease who receive modern treatment, 20–40% subsequently develop brain metastases as the sole site of tumor relapse (Robnett et al., 2001; Gaspar et al., 2005; Mamon et al., 2005; Chen et al., 2007a). In most series younger patient age or adenocarcinoma (versus other NSCLC histologies) are associated with a higher risk for developing brain metastases.

CLINICAL FEATURES Lung carcinomas metastasize to the brain by hematogenous spread. Brain metastases most commonly arise in the area directly beneath the gray–white junction, and also tend to be more common at the terminal “watershed areas” of arterial circulation (the zones on the border of, or between, the territories of the major cerebral vessels). The distribution of brain metastases roughly follows the relative weight of, and blood flow to, each area: approximately 80% are located in the cerebral hemispheres, 15% in the cerebellum, and 5% in the brainstem. Recent studies are beginning to elucidate the molecular basis of the differing “neurotropism” among various systemic tumors (Nathoo et al., 2005). To successfully form brain metastases, tumor cells must attach to and penetrate microvessel endothelium, degrade the extracellular matrix, and respond to autocrine and brain-derived survival and growth factors (Eichler et al., 2011). The clinical presentation of brain metastases is similar to that of other subacute mass lesions in the brain, and is determined by the size, location, and number of lesions. Most patients have a combination of generalized symptoms (e.g., headache, altered mental status, cognitive impairment) and focal signs and symptoms determined by the anatomic location. Generalized symptoms occur in patients with mass effect and increased intracranial pressure or in patients with multiple bilateral metastases. Approximately 15% of patients have seizures as a presenting symptom of the metastasis, and another 10% of patients developing seizures

subsequently. Patients occasionally present with acute neurologic symptoms caused by hemorrhage into, or sudden expansion of, the metastasis. The best diagnostic test for brain metastases is contrast-enhanced MRI, showing more than one lesion in about two-thirds of patients (Fig. 22.1). Findings that favor metastases include multiplicity of lesions, a gray–white junction location, a lesion in the border zone between two major arterial distributions, and a small tumor nidus with a large amount of associated vasogenic edema. Contrast-enhanced MRI is more sensitive than either enhanced computed tomography (CT) scanning or unenhanced MRI in detecting lesions.

TREATMENT Treatment options for patients with brain metastases include surgical resection, whole brain radiotherapy, stereotactic radiosurgery, chemotherapy, and supportive measures including anticonvulsants and corticosteroids. Several factors must be considered when determining the ideal treatment for each patient, including the primary tumor histology, extent of systemic disease, anticipated survival, neurologic status at diagnosis, and the location, number, and size of metastases. There are several possible measures of treatment efficacy for patients with brain metastases, including improvement in neurologic signs and symptoms, improvement or maintenance of functional performance status, corticosteroid requirements, and radiographic tumor response. Using survival as an end point after treatment of brain metastases is confounded by the fact that most patients with lung cancer die from progression of the systemic tumor, and not directly from the brain metastases. Measuring survival is, therefore, more meaningful when the cause of death is determined to be “neurologic” or “nonneurologic.” The goal of treatment is not necessarily to eradicate the brain lesions. Rather, treatment should be aimed at improving neurologic symptoms, controlling the brain lesions, and maintaining patients’ neurologic function for as long as possible.

NEUROLOGIC COMPLICATIONS OF LUNG CANCER

337

A B

Fig. 22.1. Axial (A) and coronal (B) T1-weighted MRI scan from a patient with poorly differentiated non-small cell cancer (NSCLC), showing multiple contrast-enhancing brain metastases.

Corticosteroids. Dexamethasone at doses of 4–24 mg per day brings about rapid and sometimes dramatic clinical improvement in patients with brain metastases, especially those with large or multiple lesions. In many patients dexamethasone can be tapered and discontinued after treatment, while others continue to be dependent on a certain dose to maximize neurologic function. Anticonvulsants. There is no definite evidence that any particular antiepileptic drug is differentially effective for tumor-related seizures versus epilepsy caused by other structural brain lesions. In addition to their direct sideeffects, anticonvulsants may cause unfavorable drug interactions with dexamethasone and several chemotherapy agents (van Breemen et al., 2007). For patients taking dexamethasone or receiving chemotherapy agents metabolized by the liver, the nonenzyme-inducing antiepileptic drugs (e.g., levetiracetam or lamotrigine) may offer fewer drug interactions than enzyme-inducing drugs (e.g., phenytoin or carbamazepine). Valproate inhibits the hepatic metabolism of some chemotherapy agents. For patients who do not have seizures when brain metastases are discovered, current limited information indicates that prophylactic anticonvulsants do not reduce the incidence of subsequent seizures. Whole brain radiation therapy (RT). Is the most common treatment for patients with brain metastases, usually given as 30–40 Gy in 10–15 daily fractions. Studies over the past 30 years have shown no clear difference in response rates, local tumor control, or patient outcomes after whole brain RT doses ranging from 20 Gy

given over 1 week to 50 Gy over 4 weeks (Gaspar et al., 2010). There is no clear evidence that giving a boost dose to the tumor site is better than whole brain RT alone in preventing neurologic recurrences or prolonging survival. At least 75% of patients with brain metastases from SCLC show a partial or complete radiographic response to whole brain RT (Nieder et al., 1997). Approximately 50% of patients with NSCLC show a radiographic response, usually less dramatic than with SCLC. For any tumor histology, smaller metastases are more likely to regress after whole brain RT than larger lesions. About two-thirds of patients show clinical improvement. Overall median survival of patients with SCLC or NSCLC following whole brain RT is 3–6 months (Lagerwaard et al., 1999; Rodrigus et al., 2001; Videtic et al., 2007, 2009). Most lung cancer patients treated with whole brain RT ultimately die of progressive systemic cancer, though recurrent or uncontrolled brain metastases can certainly be the proximate cause of death. Surgical resection. Is not an option for most patients with brain metastases because of the presence of multiple brain lesions or of extensive systemic cancer. For patients with NSCLC and a single brain metastasis, with minimal or stable extraneural tumor burden, a randomized prospective study has shown that surgical resection followed by whole brain RT leads to significantly longer time to recurrence of brain metastases, longer duration of functional independence, and lower risk of death due to neurologic causes compared to patients treated with

338 E.J. DROPCHO RT alone (Patchell et al., 1990). The benefit of resection subtypes of NSCLC. Larger metastases generally have of single brain metastases from SCLC is less clear, given lower radiographic control rates than smaller lesions the greater sensitivity of SCLC than NSCLC to RT. Brain (Sheehan et al., 2002; Pan et al., 2005; Vogelbaum metastases may recur at the margin of a gross total et al., 2006). This is at least partly related to the fact that resection (see below). metastases smaller than 2 cm generally receive a tumor Surgical resection is generally not recommended for margin dose of up to 24 Gy, whereas the margin dose patients with more than one brain metastasis, especially for larger lesions is usually reduced to 18 Gy. For patients since the advent of stereotactic radiosurgery. Some with multiple metastases, the local control rate is probably patients with multiple metastases have one lesion that is related more to the total volume of treated tumor than to large or is in a life-threatening location (e.g., in the postethe number of metastases (Bhatnagar et al., 2006). rior fossa). For these patients, resection of the dominant The low risk of complications associated with lesion can improve neurologic function and buy time for stereotactic radiosurgery and its outpatient basis offer therapy of the other metastases. Another approach is to potential cost savings and safety advantages over actually resect more than one brain metastasis, either as conventional surgical resection. The available nona single operation or as a staged procedure. It is not known randomized retrospective comparisons indicate that how this treatment approach compares to standard whole radiosurgery produces local tumor control rates generbrain RT or to stereotactic radiosurgery. ally equivalent to those seen after surgical resection Surgical resection of recurrent brain metastases is an (O’Neill et al., 2003). Surgical resection does offer option for selected patients with a single site of brain the advantage of immediate debulking and relief of recurrence, relatively little systemic disease, and fairly symptoms due to mass effect, and can deal with metasgood performance status. This includes patients who tases too large to be suitable for radiosurgery. received prior resection, whole brain RT, or radiosurgery Another approach is to resect a single brain metasta(Arbit et al., 1995; Vecil et al., 2005; Kano et al., 2009). sis, and then give stereotactic radiosurgery to the margins of the resection cavity. In several small series Stereotactic radiosurgery. Delivers a highly focused including patients with NSCLC this combined treatment single dose of radiation (usually 10–24 Gy) to a circumresulted in 1 year local control rates of 70–90% (Prabhu scribed target. Brain metastases are theoretically well et al., 2012). Local control rates after radiosurgery may suited for radiosurgery because they are usually be lower if the resection cavity is large, or its margins are roughly spherical and well circumscribed. In most indistinct (Jagannathan et al., 2009). Specific patient centers the maximum size of each treatable lesion is selection criteria and treatment dosimetry are not well 3–4 cm. There is no theoretical limit to the number established (Roberge et al., 2012). of targets that can be treated at a single session. A large multicenter study randomized patients with Radiosurgery may also be “hypofractionated” to deliver three or fewer brain metastases to receive either whole 30–40 Gy in 3–5 daily fractions (Kwon et al., 2009). brain RT (37.5 Gy) plus radiosurgery or whole brain RT Hypofractionated radiosurgery may have a theoretical alone (Andrews et al., 2004). Nearly two-thirds of patients radiobiological advantage over single-fraction radiosurhad lung cancer. The whole brain RT plus radiosurgery gery, and can treat tumors too large for single-fraction group had a higher radiographic response rate and a treatment. Radiosurgery has been administered to a higher local tumor control rate. Despite this, there was large number of patients with brain metastases in a numno difference in the overall survival or the neurologic ber of settings: as primary treatment of single metastadeath rates between the two treatment groups. Subgroup ses instead of surgical resection; as the sole treatment of analysis showed a marginally significant survival benefit newly diagnosed single or multiple brain metastases; in for patients with a single metastasis, or those with combination with whole brain RT for newly diagnosed NSCLC, who received the radiosurgery boost. metastases; and as treatment of recurrent brain metastaThere is continuing controversy whether all patients ses (Linskey et al., 2010). with newly diagnosed single or multiple brain metastases Multiple published series of stereotactic radiosurgery treated with local therapy (i.e., surgical resection or for brain metastases from lung cancer have reported radiosurgery) should also have upfront whole brain 12 month local control rates around 90%, i.e., radioRT, or whether it is reasonable to defer whole brain graphic shrinkage or stabilization of treated lesion(s) RT and use further radiosurgery or whole brain RT as for at least 1 year after treatment (Serizawa et al., salvage therapy if brain metastases recur. The rationale 2002; Sheehan et al., 2002; Gerosa et al., 2005; Pan for upfront whole brain RT is to treat residual tumor at et al., 2005; Wegner et al., 2011). The response rates the primary site and/or distant microscopic sites elseand local control rates do not differ between metastases where in the brain. In one retrospective study, the addifrom NSCLC and SCLC, nor among various histologic tion of whole brain RT to radiosurgery provided better

NEUROLOGIC COMPLICATIONS OF LUNG CANCER 339 local control for patients with NSCLC (Varlotto et al., Chemotherapy. Cytotoxic chemotherapy has gener2005). Within 12 months after radiosurgery of brain ally not been highly successful in treating brain metastametastases, 30–60% of surviving patients develop new ses. Among patients with newly diagnosed SCLC and brain metastases distant from the initial site. Retrospecsynchronous brain metastases treated with chemothertive studies have consistently shown that upfront whole apy and no brain RT, the systemic tumor response is genbrain RT reduces the incidence of distant brain metastaerally much better than the radiographic response in the ses outside the radiosurgery treatment volume (Sneed brain (Hochstenbag et al., 2000; Seute et al., 2006). The et al., 2002). relative resistance of lung cancer brain metastases to This issue has been addressed in three prospective chemotherapy is probably multifactorial: (1) many studies in which patients who had surgical resection of patients who develop brain metastases have a single brain metastasis, or who had radiosurgery for already received one or more chemotherapy regimens; one to four brain metastases, were then randomized to (2) subclones of tumor cells that metastasize may be receive upfront whole brain RT or to observation only inherently less chemosensitive than the cells in the pri(Patchell et al., 1998; Aoyama et al., 2006; Kocher mary tumor; (3) the blood–brain barrier limits penetraet al., 2011). Overall, 57% of patients in these studies tion of water-soluble agents and macromolecules into had NSCLC; patients with SCLC were not eligible. In brain metastases. all three studies, upfront whole brain RT was associated Despite these serious limitations, chemotherapy may with a significant reduction in the incidence of local have a role in the treatment of selected patients. Some tumor recurrence at the site of surgery or radiosurgery, patients with SCLC respond to systemic chemotherapy, and a significant reduction in the incidence of distant either as initial therapy for previously untreated brain brain metastases. Two of the studies also showed signifmetastases or for recurrence of brain metastases after icantly fewer neurologic deaths in the upfront whole prior whole brain RT (Franciosi et al., 1999; Chen brain RT group (Patchell et al., 1998; Kocher et al., et al., 2008). Carboplatin plus pemetrexed has shown 2011). None of the studies showed an overall survival activity against brain metastases from lung adenocarciadvantage for upfront whole brain RT. The studies did noma (Bailon et al., 2012). Temozolomide is an alkylatnot include detailed serial assessment of neurocognitive ing agent that is taken orally, crosses the blood–brain function. There is concern over adverse neurocognitive barrier, and is generally well tolerated by patients. In effects of whole brain RT in long-term survivors, but phase II studies of recurrent or progressive brain metasthe bulk of current evidence indicates that recurrence tases from NSCLC, single-agent temozolomide showed or progression of brain metastases is a more common a 5–10% rate of partial radiographic response, and a cause of neurologic and neurocognitive deterioration median time-to-brain-tumor progression of about 2 than is toxicity of whole brain RT (Regine et al., 2002; months (Abrey et al., 2001; Giorgio et al., 2005; Siena Aoyama et al., 2007; Li et al., 2007). et al., 2010). In a small randomized study of patients with For patients with lung cancer brain metastases which newly diagnosed brain metastases (82% with lung canprogress or recur after whole brain RT, stereotactic cer) the combination of whole brain RT plus temozoloradiosurgery produces local control rates roughly equivmide during and after RT yielded a higher radiographic alent to those of previously untreated metastases response rate than RT alone (Antonadou et al., 2002). (Sheehan et al., 2002, 2005; Chao et al., 2008; Another randomized study of patients (half with lung Karlsson et al., 2009; Caballero et al., 2012). cancer) showed no difference in the radiographic response rate but a slightly longer time to intracranial Interstitial brachytherapy. Is the surgical placement tumor progression in patients given temozolomide plus of radioactive iodine pellets into the tumor bed or resecwhole brain RT compared to patients irradiated without tion cavity. Another form of brachytherapy is the surgichemotherapy (Verger et al., 2005). Further studies of cal placement of a spherical balloon into the resection temozolomide are underway; at this time there is insufcavity of a single resected brain metastasis, and then fillficient evidence to warrant its use as a standard treating the balloon with an iodine-125 solution which remains ment for patients with brain metastases. in the cavity for several days. Brachytherapy delivers a high dose of radiation to a narrow rim around the cavity, Molecular targeted agents. Gefitinib and erlotinib with a rapid drop off in the dose to the surrounding are inhibitors of epidermal growth factor receptorbrain. Brachytherapy is best suited for relatively small, associated tyrosine kinase, which have produced objecunilateral, single metastases in surgically accessible locative radiographic response or stabilization in some tions (Rogers et al., 2006; Huang et al., 2009). The relapatients with brain metastases from NSCLC (Kim tive efficacy and safety of brachytherapy versus et al., 2009; Grommes et al., 2011; Jamal-Hanjani and stereotactic radiosurgery is not clearly known. Spicer, 2011). There are anecdotal reports of response

340 E.J. DROPCHO of brain metastases from NSCLC to bevacizumab, a tumor most often found in patients for whom spinal epimonoclonal antibody against vascular endothelial dural metastasis is the presenting feature of a previously growth factor. undiagnosed neoplasm (Schiff et al., 1997). The location of spinal metastases is evenly distributed Prophylactic whole brain RT. For prevention of along the length of the spinal column, so that overall brain metastases has mainly been used for patients with about 60–70% occur in the thoracic region (Bach SCLC, because of the high prevalence of brain metastaet al., 1992). In some but not all series spinal metastases ses after systemic treatment and the high degree of senfrom lung cancer were disproportionately common in sitivity of this tumor to RT (Blanchard and Le Pechoux, the thoracic spine. Epidural spinal metastases generally 2010). For patients with limited-stage SCLC who achieve extend over one or two spinal segments, but more extena complete remission after initial systemic therapy, sive lesions are not rare. Up to 30% of patients have one several randomized studies have shown that prophylactic or more additional noncontiguous epidural lesions at whole brain RT significantly reduces the cumulative presentation, which may or may not be symptomatic. incidence of brain metastases (from 50–60% to At least 90% of spinal epidural metastases from lung 25–30%), and significantly improves overall survival cancer arise by direct extension of hematogenous verte(Gregor et al., 1997; Auperin et al., 1999; Arriagada bral bone metastases, usually in the vertebral body. Paraet al., 2002). Prophylactic RT may also benefit the subset vertebral apical (Pancoast) lung tumors may directly of patients with initially extensive SCLC who have a invade the adjacent vertebrae, or grow through the neural good response to initial chemotherapy (Slotman et al., foramina to enter epidural space. Although tumor cells 2007). The most common prophylactic whole brain RT occasionally transgress the dura to produce intradural regimen is 25 Gy given in 10 fractions. Higher RT doses extramedullary or leptomeningeal metastases, more than are not more effective (Le Pechoux et al., 2009). Patients 90% of spinal metastases remain in the epidural space. who receive prophylactic whole brain RT after compleThe production of signs and symptoms in patients tion of induction chemotherapy are not at increased risk with spinal metastases is usually multifactorial. In addifor developing subsequent neurocognitive dysfunction tion to the direct compression by epidural tumor, the spi(Gregor et al., 1997; Grosshans et al., 2008). nal cord or nerve roots can be damaged by bony Better therapies for newly diagnosed NSCLC and compression from pathologic vertebral fracture, kypholonger patient survival have led to increasing incidence sis, or spinal instability. Animal models of epidural spiof brain metastases as a site of tumor relapse. Several nal metastases have demonstrated early vasogenic studies have shown that prophylactic whole brain RT sigedema and venous congestion in the cord, followed nificantly reduces the overall incidence of brain metaseventually by spinal cord ischemia. Vascular insuffitases and the occurrence of brain metastases as the ciency may be responsible for the precipitous neurologic sole site of tumor relapse, but does not prolong overall deterioration occurring in some patients after a prodrosurvival (P€ ottgen et al., 2007; Blanchard and Le Pechoux, mal period of relatively minor symptoms. 2010; Gore et al., 2011). Prophylactic whole brain RT is The clinical presentation of epidural spinal metastanot currently considered standard care for patients with ses is remarkably stereotyped. At least 90% of patients NSCLC. Efforts are underway to identify subsets of have pain as their initial complaint, which is most often NSCLC patients who are at especially high risk for devellocalized to involved spinal segments. The local pain is oping brain metastases, and who would therefore be characteristically constant, worse at night, and relentmore likely to benefit from prophylactic whole brain RT. lessly progressive; one-third of patients have local spine tenderness. In addition to the local pain, 50–75% of Spinal epidural metastases patients also develop radicular pain; this is more common with cervical or lumbosacral than with thoracic INCIDENCE AND CLINICAL FEATURES lesions. If untreated, patients then inevitably develop Spinal epidural metastases which compress the spinal other neurologic symptoms after an interval varying cord or cauda equina are a frequent and often devastatfrom a few days to several weeks. In most large series ing complication of lung cancer. In large series of of epidural spinal metastases, by the time the diagnosis patients with metastatic spinal cord compression, the is made, at least two-thirds of patients have sensory loss most common primary tumors arise from the lung, and/or weakness, one-half are not independently ambubreast, or prostate, with each tumor type comprising latory, and at least one-third have bowel or bladder dys20–25% of the total cases. The cumulative incidence function. Of the patients who are nonambulatory at of symptomatic spinal epidural metastases is approxidiagnosis, up to one-half have deteriorated acutely over mately 3–6% for patients with SCLC or with NSCLC 24–48 hours after a variable period of pain, with or with(Seute et al., 2004) (Table 22.1). Lung carcinoma is the out mild neurologic symptoms.

NEUROLOGIC COMPLICATIONS OF LUNG CANCER The strongest predictor of functional neurologic outcome after treatment for spinal epidural metastases is patients’ pretreatment level of function. It is therefore imperative for physicians to have a high index of suspicion for the possibility of spinal metastases in cancer patients, and to have a sense of time urgency in their evaluation and treatment. Spine MRI scanning with and without gadolinium enhancement is the procedure of choice for diagnosing spinal epidural metastases. MRI scans provide multiplanar images and good delineation of epidural and paravertebral tumor extension (Fig. 22.2). In addition, MRI can visualize intramedullary cord lesions, multiple epidural lesions, and leptomeningeal tumor. MRI should be performed expeditiously in lung cancer patients with new onset neck or back pain, and/or neurologic symptoms referable to the spinal cord or cauda equina. MRI should be performed emergently for patients with signs of myelopathy, or acute neurologic deterioration. If the initial MRI scan of the symptomatic region of the spine shows epidural metastasis, it is important to then

Fig. 22.2. Sagittal T1-weighted MRI scan from a patient with lung adenocarcinoma, showing a cervical spine epidural metastasis enveloping the spinal cord and involving the posterior bony elements (upper arrow), and a thoracic spine pathologic compression fracture with adjacent epidural tumor compressing the spinal cord (lower arrow).

341

image the entire spinal column to detect asymptomatic noncontiguous multiple lesions which may affect treatment decisions.

TREATMENT The intertwined goals of treatment for patients with epidural spinal metastases are to alleviate pain, maintain or restore stability of the spinal column, and improve or maintain patients’ ambulation and neurologic function. Treatment options include best supportive care, analgesia, dexamethasone, radiation therapy, and surgical resection. Treatment needs to be individualized based on patients’ tumor histology, systemic tumor status, neurologic function, anatomic distribution of epidural spinal metastases, and anticipated survival. Spinal cord compression from epidural spinal metastasis is a true medical emergency. Dexamethasone or another corticosteroid alleviates pain and partially improves neurologic symptoms in most patients with epidural spinal metastasis. Dexamethasone is generally begun as soon as the diagnosis is made clinically or radiographically, before initiation of radiation therapy or surgery. Patients receive an initial dose of 10–100 mg and daily doses of 8–100 mg. There is no clear evidence to indicate the optimum dose or schedule. The dose should be tapered quickly, as clinically tolerated, once definitive treatment is begun. Long-term use of dexamethasone is seldom necessary or beneficial. Fractionated radiation therapy (RT) is the most common treatment for epidural spinal metastases, generally 30–40 Gy in 10–15 days to a target encompassing one or two normal vertebral bodies above and below the full extent of the epidural lesion(s). Patients with clinical signs of myelopathy should begin RT emergently. Higher doses of RT or different fractionation schemes have not yielded convincingly better results (Maranzano et al., 2005). Shorter courses of RT (e.g., 20 Gy in five fractions) in patients with NSCLC produce short-term results equivalent to longer courses of RT, but are associated with a higher rate of local tumor recurrence in patients surviving more than 6 months (Rades et al., 2011). Corticosteroids and conventional fractionated RT bring about pain relief in 70–80% of patients, and improved motor function in approximately one-third (Rades et al., 2007). The most important determinant of patients’ post-treatment motor function is their level of function prior to RT (Bach et al., 1992; Helweg-Larsen et al., 2000; Zaidat and Ruff, 2002). At least 80% of patients with lung cancer who are fully ambulatory prior to treatment maintain ambulation, while 20–30% of paraparetic patients and fewer than 10% of paraplegic patients can walk after RT. Given the same pretreatment status, patients with SCLC tend to have better response

342 E.J. DROPCHO to RT than patients with NSCLC. Patients with rapid proKim et al., 2012a). Once tumor is resected from bone gression of neurologic deficits or severe subarachnoid and the epidural space, the vertebral body defect is block also have relatively unfavorable outcomes replaced with methylmethacrylate cement and the spine (Rades et al., 2012). Exceptional patients regain ambulais stabilized by metal instrumentation and/or bone tion despite poor prognostic factors. RT alone cannot grafts. Several nonrandomized studies since the late relieve pain or neurologic deficits due to bone impinge1980s showed that patients unable to walk before treatment on the spinal cord, angulation deformity, or spinal ment were more likely to regain ambulation after aggresinstability. sive surgery and standard RT than after RT alone (Kim Following RT for spinal metastases, the median suret al., 2012b). In a prospective randomized trial of surgivival of patients with lung cancer is 3–6 months (Rades cal resection/spinal stabilization followed by standard et al., 2011). This is shorter than for patients with most fractionated RT versus RT alone (including 26% of other solid tumors. Patients who are nonambulatory genpatients with lung carcinoma), patients treated with surerally have shorter survival than those who can walk gery þ RT had a significantly higher overall postafter treatment (Helweg-Larsen et al., 2000; Zaidat treatment rate of ambulation (84% versus 57% for RT and Ruff, 2002). Approximately 5% of patients with alone), a higher likelihood of regaining ambulation if lung cancer who survive more than 12 months develop it had been lost (62% versus 19% for RT alone), and also local tumor recurrence at the site of spinal RT (Rades retained independent ambulation for a longer duration et al., 2007; Rades et al., 2011). than the RT group (Patchell et al., 2005). There was no Intensity-modulated RT or stereotactic radiosurgery excess morbidity or mortality in the RT þ surgery group. are increasingly being used in the treatment of spinal Aggressive surgical resection of spinal epidural metasmetastases (Yamada et al., 2007; Sahgal et al., 2008). tases is a considerable undertaking and requires urgent Treatment may be given as a single dose, or fractionated mobilization of a skilled surgical team. The ideal candidate over a few days. These focused RT techniques offer the for such surgery is a patient with epidural spinal cord comtheoretical advantage of improved local control in the pression limited to a single area, minimal or controlled sysvertebrae and epidural space compared to standard fractemic tumor burden, and an anticipated “reasonably” long tionated RT, especially for radioresistant tumors includduration of survival. Even in experienced hands the moring NSCLC, with relative sparing of the adjacent spinal bidity of resection is as high as 20%, and the perioperative cord. Focused RT has less theoretical advantage for mortality rate is as high as 5% (Wang et al., 2004; Patil et al., radiosensitive tumors including SCLC. 2007; Ibrahim et al., 2008). Complications include wound Most of the earlier published experience of intensitybreakdown or infection, cerebrospinal fluid (CSF) leak, modulated RT or stereotactic radiosurgery was for pneumonia, thromboembolic events, and failure of spinal patients who had recurrence of spinal metastases after stabilization. Patients who received prior RT to the site of prior standard RT, or within a previously irradiated field surgery are at higher risk of complications. Some patients such as chest RT for lung cancer (Gerszten et al., 2006; eventually suffer recurrence of tumor at the same or adjaYamada et al., 2008; Gagnon et al., 2009). More recently, cent vertebral levels, producing dislodgement of fixation focused RT is increasingly used as the primary sole treatmaterials and resultant pain and neurologic dysfunction. ment of spinal metastases. The great majority of treated Overall survival after surgery is shorter for patients with patients have prompt pain relief and long-term tumor lung cancer than for those with other solid tumors control within the RT target. Initial studies excluded (Tokuhashi et al., 2005; Choi et al., 2010). patients with epidural tumor extension, but more recent There is increasing use of percutaneous vertebrostudies have treated such patients as long as they do not plasty or kyphoplasty for patients with spine metastases. have high grade spinal cord compression or severe neuVertebroplasty is the percutaneous injection of methylrologic deficit (Yamada et al., 2008; Ryu et al., 2010). methacrylate cement into a diseased vertebral body. Patients with bony compression of the spinal cord or spiKyphoplasty is the percutaneous placement of a balloon nal instability do not benefit from RT alone, but may be into the vertebral body, followed by injection of methyltreated with focused RT after surgical decompression or methacrylate. These procedures are often effective in vertebroplasty/kyphoplasty (see below). relieving pain and can partly correct kyphotic deformity Surgical intervention for spinal epidural metastases from a pathologic compression fracture (Mendel et al., provides immediate decompression of spinal cord and 2009). Vertebroplasty or kyphoplasty by themselves cannerve roots, and the ability to concurrently stabilize not deal with epidural tumor extension or spinal cord the spinal column. The great majority of epidural metascompression, but may be followed by standard RT or tases arise from the vertebral body, so resection requires stereotactic radiosurgery (Gerszten et al., 2005). Verteban anterior, anterolateral, or posterolateral approach roplasty or kyphoplasty can palliate pain in patients with (Wang et al., 2004; Chen et al., 2007b; Xu et al., 2009; spinal epidural metastases who are terminally ill or are

NEUROLOGIC COMPLICATIONS OF LUNG CANCER 343 not candidates for surgery or other aggressive measures carcinoma, and melanoma are the most likely to spread (Saliou et al., 2010). There are recent studies of minito the leptomeninges (Balm and Hammack, 1996; mally invasive surgery (e.g., percutaneous transpedicuHerrlinger et al., 2004; Clarke et al., 2010b). In one large lar fixation and stabilization), combined with series of SCLC patients, the overall prevalence of leptokyphoplasty, for patients who are not good candidates meningeal metastasis was 2% and the 2 year cumulative for more aggressive surgery (Tancioni et al., 2012). incidence was 10% (Seute et al., 2004, 2005) (Table 22.1). Leptomeningeal metastasis is less common in NSCLC Spinal intramedullary metastases than SCLC, and occurs with adenocarcinoma more often than with other NSCLC histologic types (Chamberlain Intramedullary spinal cord metastases are believed to and Kormanik, 1998). The incidence of leptomeningeal arise from hematogenous tumor spread, and are genermetastases from NSCLC may be increasing as systemic ally far less common than spinal epidural metastases treatment has improved. The majority of patients with (Table 22.1). Lung cancer is the most common source leptomeningeal metastases from lung cancer have disof intramedullary spinal cord metastases, accounting seminated progressive systemic tumor, and at least for slightly more than 50% of reported cases (Schiff one-half have concurrent parenchymal brain metastases and O’Neill, 1996; Kalayci et al., 2004; Dam-Hieu (Herrlinger et al., 2004; Seute et al., 2005). et al., 2009). SCLC outnumbers NSCLC as the primary Tumor cells may reach the subarachnoid space by tumor type. Among lung cancer patients with intramehematogenous spread to vessels of the arachnoid or chodullary spinal cord metastases, at least 50% have new roid plexus, or by direct extension from metastases in the or previous parenchymal brain metastases, and up to brain parenchyma, dura, or bone. There is also some evi25% have concurrent leptomeningeal tumor disseminadence for spread of tumor cells along the perineural tion. The great majority have systemic metastases. sheaths or lymphatics of cranial nerves or nerve roots, Among patients with intramedullary spinal cord with subsequent entry into the subarachnoid space. Prior metastases, pain is less prominent than with epidural surgical resection of an intraparenchymal brain metastatumors, and patients are more likely to develop early sensis may increase the risk of subsequent leptomeningeal sory, motor, and bladder dysfunction (Schiff and spread, particularly after resection of posterior fossa O’Neill, 1996). Up to one-half of patients have elements metastases (Suki et al., 2008, 2009). The heaviest aggreof a Brown-Se´quard syndrome; this is distinctly unusual gations of tumor cells in leptomeningeal metastases tend in patients with epidural metastases. Most patients have to occur at the base of the brain and along the cauda lost independent ambulation by the time of diagnosis. equina, presumably due to relative stasis of CSF flow MRI shows a nodular or less commonly a ring-enhancing in those areas. Tumor cells can form a thin coating along lesion, usually with surrounding abnormal T2 signal the pial surface, and/or multifocal nodules. extending rostrally and caudally in the cord (Crasto Patients with leptomeningeal metastases display varyet al., 1997; Dam-Hieu et al., 2009). Most lesions are sining combinations of symptoms and signs reflecting difgle. An intratumoral or peritumoral cyst may be present. fuse encephalopathy, hydrocephalus, multiple cranial Differential diagnosis includes paraneoplastic necrotizneuropathies, and lumbosacral polyradiculopathy ing myelopathy or radiation-induced myelopathy. (Balm and Hammack, 1996; van Oostenbrugge and Most patients with intramedullary spinal cord metasTwijnstra, 1999). Headache, vomiting, lethargy, and/or tases have partial improvement or at least stabilization altered mental status are present in about one-half of of neurologic function after standard fractionated RT patients at diagnosis. Up to 25% of patients have hydro(Schiff and O’Neill, 1996). Improvement of neurologic cephalus and increased intracranial pressure. Focal or function, including regaining ambulation, is more likely generalized seizures and focal cerebral dysfunction among patients with SCLC than with NSCLC. There are may also occur. Cranial nerve findings include ocular recent reports of using stereotactic radiosurgery. Highly muscle paresis, facial weakness, hearing loss, tinnitus, selected patients with NSCLC, a single intramedullary visual loss, facial numbness or pain, and hoarseness or metastasis without leptomeningeal spread, and minimal dysphagia. Cauda equina involvement is manifested as or controlled systemic tumor may benefit from resection multifocal radicular pain and sensory loss, weakness, of the spinal cord metastasis (Dam-Hieu et al., 2009). reflex asymmetry, and bowel/bladder symptoms. The diagnosis of leptomeningeal metastasis is generLeptomeningeal metastases ally based on MRI and CSF findings in the appropriate Leptomeningeal metastasis (carcinomatous meningitis) clinical setting. Brain MRI scans may show communicatis a relatively uncommon but important cause of morbiding hydrocephalus, obliteration of the sulci and cisterns, ity and mortality for patients with lung cancer. Among and abnormal linear or multinodular contrast enhanceprimary systemic solid tumors, breast carcinoma, lung ment of the tentorium, subependymal surfaces, cerebral

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Fig. 22.3. Axial T1-weighted MRI scan from a patient with small cell lung carcinoma and leptomeningeal metastases, showing an irregularly thickened tentorium, and multiple small enhancing nodules in the fourth ventricle and in the subarachnoid spaces around the cerebellum and brainstem.

gyri, cisterns, or cranial nerves (Freilich et al., 1995; Bokstein et al., 1998) (Fig. 22.3). Spine MRI scans show thickened nerve roots, single or multiple subarachnoid tumor nodules, and/or linear or nodular enhancement along the pial surface of the spinal cord (Chamberlain, 1995; Bokstein et al., 1998; Gomori et al., 1998). At least 75% of patients with leptomeningeal metastasis from solid tumors have characteristic abnormalities on brain MRI, spine MRI, or both (Clarke et al., 2010b). Frequent but nonspecific CSF abnormalities in patients with leptomeningeal metastasis include pleocytosis in 50–80% of patients, elevated protein in 60–85%, and decreased glucose in 30–75% (Balm and Hammack, 1996; van Oostenbrugge and Twijnstra, 1999; Clarke et al., 2010b). Fewer than 5% of patients have completely normal cell count, protein, and glucose on the initial lumbar puncture. The most specific diagnostic test for leptomeningeal metastases is cytopathologic examination of the CSF. The yield of positive CSF cytology in patients with solid tumors is 50–60% after the first lumbar puncture, and about 80% after the second lumbar puncture (Balm and Hammack, 1996). The sensitivity of CSF cytology is partly dependent on the volume of CSF sent for study. For patients with a known diagnosis of lung cancer, especially SCLC, the diagnosis of leptomeningeal metastases can be made if there is an appropriate clinical presentation and supportive MRI findings, even without positive CSF cytologic confirmation (Freilich et al., 1995; Clarke et al., 2010b).

Patients with leptomeningeal metastases in whom aggressive therapy is considered should undergo an extent of disease evaluation, including MRI of the brain and entire spinal canal, and ideally an indium-111 or technetium-99 radionuclide CSF flow study. CSF flow studies in 30–60% of patients show abnormalities including delayed outflow from the ventricles, or focal obstruction(s) to flow in the basal cisterns, cerebral convexities, and/or along the spinal column (Chamberlain, 1998). Treatment options for patients with leptomeningeal metastases from solid tumors are generally palliative, with the goals of relieving pain and improving or maintaining neurologic function for as long as possible. Radiation therapy (RT) is the most commonly used treatment for leptomeningeal metastases (Gleissner and Chamberlain, 2006). A dose of 30 Gy is delivered to the area(s) of symptomatic disease, “bulky” disease on MRI, and areas of CSF compartmental flow block identified by radionuclide CSF flow studies. Patients with encephalopathy or cranial neuropathies receive whole brain RT. Total craniospinal axis RT is not generally recommended, as it carries more morbidity (especially mucositis and myelosuppression) and does not produce better neurologic outcome or survival. Some patients with leptomeningeal metastases receive intrathecal or intraventricular chemotherapy, usually begun after completion of RT (Gleissner and Chamberlain, 2006). The generally recommended method for delivering intrathecal chemotherapy is through an intraventricular (Ommaya) reservoir. The reservoir requires a surgical procedure for its placement but subsequently saves patients the discomfort of repeated lumbar punctures. The reservoir also allows more reliable delivery of drug into the subarachnoid space than lumbar puncture. Most importantly, drug injection into an Ommaya reservoir generally provides more uniform distribution of drug throughout the CSF than does lumbar instillation. The chemotherapy drugs most commonly used for intrathecal injection are methotrexate, cytarabine (AraC), and thioTEPA. A liposomal preparation of cytarabine extends the CSF half-life of the drug, providing cytotoxic concentrations for a longer time. Studies including small numbers of SCLC and NSCLC patients suggest that intrathecal liposomal cytarabine is at least as effective as methotrexate, as measured by time to neurologic progression and overall survival (Glantz et al., 1999, 2010; Jaeckle et al., 2002). Liposomal cytarabine has the practical advantage of allowing treatment to be given once every 2 weeks. Multiagent intrathecal chemotherapy is more toxic than single-agent therapy and does not improve patient outcomes. Patients with obstruction to CSF flow demonstrated by radionuclide studies respond less well to intrathecal

NEUROLOGIC COMPLICATIONS OF LUNG CANCER chemotherapy and have a poorer survival unless the CSF obstruction is first reopened by focal RT. Patients for whom intrathecal chemotherapy is planned should therefore ideally receive RT and a follow-up CSF flow study prior to beginning intrathecal chemotherapy. Most systemically administered chemotherapy drugs penetrate very poorly into the CSF. There is still a rationale for systemic chemotherapy in patients with nodular or bulky leptomeningeal metastases, since intrathecal chemotherapy penetrates only 2–3 mm into bulky tumor nodules or the neural parenchyma. Systemic chemotherapy is effective in some patients with leptomeningeal metastases from breast carcinoma, but there is very little published information for patients with lung cancer. There are anecdotal reports of response to the epidermal growth factor tyrosine kinase inhibitors erlotinib or gefitinib in patients with leptomeningeal metastases from NSCLC (Clarke et al., 2010a). Patients with symptomatic hydrocephalus often get significant palliation from placement of a ventriculoperitoneal shunt (Omuro et al., 2005). This generally precludes intraventricular chemotherapy, unless a reservoir is connected in series to an on–off valve and ventriculoperitoneal shunt (Lin et al., 2011). With treatment of leptomeningeal metastases patients generally have at least some improvement in pain. Neurologic deficits usually do not improve much, but may remain at least stable for a time. Post-treatment MRI scans are more likely to show improvement in SCLC than NSCLC. In published clinical trials the time to clinical neurologic progression is often the end point measured. The average published survival of patients with leptomeningeal metastases from lung cancer is 6–10 weeks (Chamberlain and Kormanik, 1998; Herrlinger et al., 2004; Seute et al., 2005; Waki et al., 2009; Clarke et al., 2010b). These figures include patients who did not receive RT or intrathecal chemotherapy and were treated with supportive care only. For most patients the leptomeningeal metastases were judged to be the sole or contributing cause of death. Of patients who receive aggressive treatment, 5–10% survive for 12 months or more. Patients with leptomeningeal metastases generally have a poor neurologic and survival outcome if any of the following are present at diagnosis: severe neurologic deficits, encephalopathy, poor overall performance status, bulky CNS disease on MRI, or extensive progressive systemic tumor. These factors need to be considered when deciding whether to attempt aggressive CNS treatment (Gleissner and Chamberlain, 2006).

Skull base and dural metastases Metastasis of lung cancer to the base of the skull presents as cranial neuropathies depending on location in

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the orbit, parasellar/cavernous sinus area, middle cranial fossa, jugular foramen, or occipital condyle (Greenberg et al., 1981; Laigle-Donadey et al., 2005). CT scanning and MRI are often complementary in diagnosing skull base metastases. CT scanning with thin cuts and bone windows is sensitive in detecting lytic skull base lesions. MRI scanning with fat suppression techniques provides multiplanar images, delineates soft tissue tumor, and can identify dural tumor involvement. Technetium single photon emission tomography (SPECT) scanning or fluorodeoxyglucose positron emission tomography (FDG-PET) scanning can occasionally identify skull base metastases when anatomic imaging is negative or equivocal. Fractionated RT is the standard treatment for most patients with skull base metastases. Patients generally have improved pain and a variable degree of improvement of neurologic deficits after RT. Relatively recent onset of symptoms is associated with a higher likelihood of recovery. Recent anecdotal reports of stereotactic radiosurgery describe good tumor control and clinical outcomes. Symptomatic metastases to the intracranial dura are more common among patients with carcinoma of the breast or prostate, but also occur with lung cancer (Nayak et al., 2009). Dural metastases most often arise from direct extension of skull metastases, and then either compress or invade the underlying brain. Patients present with headache, seizures, and/or focal symptoms depending on the tumor location. Treatment options include surgical resection, RT, and systemic chemotherapy.

Pituitary metastases Breast and lung carcinoma are the most common sources of pituitary metastases (Fassett and Couldwell, 2004). The lesion may be in the anterior pituitary, posterior pituitary, or both. Only a minority of affected patients are symptomatic. Symptoms and signs include headache, diabetes insipidus, visual deficit, opthalmoplegia, and anterior hypopituitarism. Radiation therapy is the most common treatment.

Brachial plexus metastases Lung cancer arises in the lung apex in about 5% of NSCLC cases and 1% of SCLC. Apical lung (Pancoast) tumors can directly spread to the nearby C8 and T1 nerve roots or to the brachial plexus, especially the inferior trunk and medial cord (Arcasoy and Jett, 1997). Patients typically develop early shoulder pain, and pain or dysesthesias in the C8–T1/ulnar nerve distribution. Weakness and atrophy of intrinsic hand muscles eventually occur. Horner syndrome is a common finding at presentation. The tumor also directly invades adjacent

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vertebrae and extends into the epidural space in up to one-third of patients, best visualized by MRI scanning. Lung cancer metastases to the axillary or supraclavicular lymph nodes can also involve the brachial plexus (Kori et al., 1981; Jaeckle, 2010). Patients present with pain, weakness and numbness or paresthesias in a distribution reflecting the part of the plexus affected by tumor. For patients with lung cancer who had previous chest RT, brachial plexus metastases need to be distinguished from radiation injury to the plexus. The anatomic distribution of signs and symptoms do not reliably distinguish metastatic brachial plexopathy from radiation plexopathy. The two most valuable clinical features in differential diagnosis are: Horner syndrome, which if present nearly always indicates tumor metastasis, and the fact that pain is a characteristic early and prominent feature of brachial plexus metastasis but is less common and less severe in patients with early radiation plexopathy. MRI of the brachial plexus is highly sensitive in diagnosing brachial plexus metastases, though some patients do not have a clearly visible tumor mass, and MRI changes in radiation plexopathy may be difficult to distinguish from tumor infiltrating along elements of the plexus. FDG-PET scanning may be useful if MRI is equivocal. RT for brachial plexus metastasis brings about significant pain relief in the majority of patients, but fewer than one-third have major improvement in motor or sensory deficits.

PARANEOPLASTIC DISORDERS Overview Neurologic paraneoplastic disorders are far less common than nervous system metastases in patients with lung cancer, but they have clinical importance for several reasons: (1) in most patients with a paraneoplastic disorder and lung cancer the neurologic symptoms are the presenting feature of the tumor; (2) among patients with a known cancer diagnosis, paraneoplastic syndromes are an important part of the differential diagnosis of neurologic dysfunction; (3) paraneoplastic disorders often cause severe and permanent neurologic morbidity; (4) prompt recognition of a paraneoplastic disorder maximizes the likelihood of successful tumor treatment and a favorable neurologic outcome. With the exception of myasthenia gravis associated with thymoma, SCLC is the tumor most often associated with neurologic paraneoplastic disorders in adults (Giometto et al., 2010), though even among SCLC patients neurologic paraneoplastic disorders are uncommon. Approximately 1–4% of patients with SCLC develop Lambert–Eaton myasthenic syndrome (Seute

Table 22.2 Neurologic paraneoplastic disorders associated with lung carcinoma Central nervous system

Peripheral nervous system

Multifocal encephalomyelitis* Subacute cerebellar degeneration* Limbic encephalitis* Opsoclonus-myoclonus* Extrapyramidal syndrome Brainstem encephalitis Myelopathy Motor neuron disease Stiff person syndrome Optic neuritis Retinal degeneration

Subacute sensory neuronopathy* Lambert–Eaton myasthenic syndrome* Dermatomyositis* Nerve vasculitis Sensorimotor polyneuropathy Motor neuropathy Neuromyotonia Autonomic insufficiency Necrotizing myopathy

*Indicate classic syndromes strongly associated with an underlying neoplasm (Graus et al., 2004).

et al., 2004; Maddison and Lang, 2008). The combined incidence of all other neurologic paraneoplastic disorders in SCLC is less than 1%. Any of the paraneoplastic disorders associated with SCLC may also occur, at a much lower frequency, among patients with NSCLC. Paraneoplastic disorders can affect any part(s) of the central or peripheral nervous systems (Graus et al., 2004). Some patients have a recognizable clinical syndrome predominantly affecting one anatomic location or system (Table 22.2). Many patients, particularly those with SCLC, have more than one discrete syndrome (e.g., cerebellar degeneration plus Lambert–Eaton syndrome), or have signs and symptoms of a multifocal encephalomyelitis or encephalomyeloneuritis (see below). Several syndromes are considered classic neurologic paraneoplastic disorders and should always raise the possibility of a paraneoplastic etiology; these include limbic encephalitis, subacute cerebellar degeneration, opsoclonus-myoclonus, subacute sensory neuronopathy, Lambert–Eaton myasthenic syndrome, and dermatomyositis (Graus et al., 2004). It is important to keep in mind, however, that there is no neurologic syndrome which is absolutely pathognomonic for a paraneoplastic etiology; each of the syndromes listed in Table 22.2 can occur with varying frequency in patients without a tumor.

Autoimmunity Most if not all neurologic paraneoplastic disorders associated with lung cancer are believed to be caused by an autoimmune response against shared tumorneuronal (onconeural) antigens. The special association between SCLC and paraneoplastic disorders probably

NEUROLOGIC COMPLICATIONS OF LUNG CANCER derives from SCLC’s neuroendocrine origin. It is not known why only a small fraction of SCLC patients develop clinically overt paraneoplastic disorders, despite the common expression of multiple onconeural antigens by tumor cells, and the demonstrable autoimmune response against one or more antigens in a fairly high percentage of SCLC patients who do not have neurologic symptoms. Patients with SCLC and paraneoplastic sensory neuronopathy, encephalomyelitis, or Lambert–Eaton syndrome are more likely to have limited-stage SCLC as compared with neurologically unaffected SCLC patients, and tend to have a relatively favorable tumor outcome (Keime-Guibert et al., 1999; Maddison and Lang, 2008; Titulaer et al., 2011a). This circumstantial evidence supports the presence of an effective antitumor immune response, but an alternative explanation is that the occurrence of neurologic symptoms leads to early tumor diagnosis and treatment. Since the mid-1980s there has been a steadily growing list of onconeural antibodies identified in the sera of patients with paraneoplastic disorders (Table 22.3). Some paraneoplastic antibodies have selective neuronal reactivity and are found only in patients with a particular clinical syndrome. Other autoantibodies show a more widespread or pan-neuronal reactivity and are

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associated with a variety of clinical neurologic syndromes, or with multifocal encephalomyelitis. The most prevalent onconeural antibodies associated with SCLC and NSCLC are anti-Hu and anti-CV2 (Pittock et al., 2004; Hoffmann et al., 2009; Giometto et al., 2010). Patients with SCLC not infrequently have more than one type of autoantibody. The exact immunopathogenesis of most neurologic paraneoplastic disorders remains unclear. The best understood disorder is the Lambert–Eaton myasthenic syndrome, caused by autoantibodies against presynaptic voltage-gated calcium channels at the neuromuscular junction (see below). For several other paraneoplastic syndromes there is varying evidence to support a direct pathogenic role of onconeural autoantibodies. These include paraneoplastic neuromyotonia (antibodies against axonal proteins associated with the voltage-gated potassium channel complex), stiff person syndrome (antiamphiphysin antibodies), retinal degeneration (antirecoverin antibodies), some cases of cerebellar degeneration (antivoltage-gated calcium channel antibodies), and some cases of limbic encephalitis (antibodies against proteins associated with the voltage-gated potassium channel complex, against NMDA receptors, against AMPA receptors, or against GABA receptors) (see below).

Table 22.3 Paraneoplastic disorders and autoantibodies associated with lung carcinoma Clinical syndrome

Autoantibodies

Multifocal encephalomyelitis Limbic encephalitis

Anti-Hu, anti-CV2, anti-amphiphysin, anti-Ri, ANNA-3, anti-Ma1 Anti-Hu, anti-CV2, PCA-2, ANNA-3, anti-NMDAR, anti-amphiphysin, anti-VGKC complex, anti-VGCC, anti-Zic4, anti-Ma1, anti-Ma2, anti-GAD, anti-AMPAR, anti-GABAR Anti-Hu, anti-CV2, PCA-2, ANNA-3, anti-amphiphysin, anti-VGCC, anti-GAD, anti-Ri, anti-Zic4, anti-Ma1 Anti-Hu, anti-Ri, anti-CV2, anti-amphiphysin, anti-Ma2, anti-VGCC Anti-CV2, anti-Hu Anti-Hu, anti-Ri, anti-Ma2 Anti-CV2 Anti-recoverin Anti-CV2, anti-amphiphysin Anti-amphiphysin, anti-Ri, anti-GAD Anti-Hu Anti-Hu, anti-CV2, ANNA-3, anti-amphiphysin, anti-Ma1 Anti-VGKC complex Anti-Hu, anti-CV2, ANNA-3 Anti-Hu Anti-Hu, anti-ganglionic AChR Anti-VGCC

Cerebellar degeneration Opsoclonus-myoclonus Extrapyramidal syndrome Brainstem encephalitis Optic neuritis Retinal degeneration Myelopathy Stiff person syndrome Motor neuron disease Sensory neuronopathy Neuromyotonia Sensorimotor polyneuropathy Vasculitic neuropathy Autonomic insufficiency Lambert–Eaton syndrome

AMPAR, amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ANNA, anti-neuronal nuclear antibody; AChR, acetylcholine receptor; GABAR, g-aminobutyric acid receptor; GAD, glutamic acid decarboxylase; MAG, myelin-associated glycoprotein; NMDAR, N-methyl-Daspartate receptor; SCLC, small-cell lung carcinoma; VGCC, voltage-gated calcium channels; VGKC, voltage-gated potassium channel.

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Current evidence indicates that a cellular immune reaction against onconeural antigens is the main cause of neuronal injury and death in patients with anti-Hu antibody-associated paraneoplastic encephalomyelitis/ sensory neuronopathy (Bien et al., 2012). Anti-Hu antibodies in these patients are a “footprint” for autoimmunity but are probably not directly involved or are minor factors in causing neuronal injury. It is postulated that Hu proteins and/or other onconeural antigens released by apoptotic tumor cells are presented to T lymphocytes in draining peripheral lymph nodes, initiating a Th1 helper response which eventually gains access to the CNS, dorsal root ganglia and autonomic ganglia, and attacks neurons expressing the antigens (Roberts and Darnell, 2004). The evidence for T lymphocyte-mediated neuronal injury includes: increased numbers of CD4 þ and CD8 þ T lymphocytes in the CSF of patients (de Graaf et al., 2008); the presence of CD8þ T cells expressing the cytotoxic protein TIA-1 and clustered around neurons in brain and dorsal root ganglia (Bien et al., 2012); stimulation of lymphocyte proliferation by recombinant HuD protein in vitro; clonal expansion of certain T cell receptors in patients with paraneoplastic sensory neuronopathy or encephalomyelitis; and circulating HuD-specific cytotoxic CD8þ T lymphocytes in some affected patients (Roberts et al., 2009). To date, there is no successful experimental model for anti-Hu antibody-associated paraneoplastic encephalomyelitis. Among patients with a suspected paraneoplastic neurologic disorder but no known tumor diagnosis, the discovery of a circulating onconeural antibody increases the clinical suspicion for a paraneoplastic etiology. The specific type of antibody can also guide the search for the most likely associated tumor. This is especially true for anti-Hu antibodies which are strongly associated with SCLC. Onconeural antibodies do have practical limitations as a clinical diagnostic tool, due to the heterogeneity of clinical-tumor-antibody associations, the presence of onconeural antibodies in some patients without a tumor (e.g., Lambert–Eaton syndrome or limbic encephalitis), the absence of detectable antibodies in some paraneoplastic patients, and the time lag between discovery of new onconeural antibodies and their ability to be detected in commercial assays.

Clinical syndromes MULTIFOCAL ENCEPHALOMYELITIS SCLC is by far the tumor most commonly associated with paraneoplastic encephalomyelitis (Dalmau et al., 1992; Graus et al., 2001; Sillevis Smitt et al., 2002; Giometto et al., 2010). A small percentage of patients have NSCLC. Paraneoplastic encephalomyelitis is characterized pathologically by patchy, multifocal

involvement of any or all areas of the cerebral hemispheres, limbic system, cerebellum, brainstem, spinal cord, dorsal root ganglia, and autonomic ganglia. Neuronal loss is accompanied by a variable degree of perivascular and leptomeningeal infiltration of mononuclear cells, including T and B lymphocytes and plasma cells. The most common clinical manifestations of paraneoplastic encephalomyelitis are subacute sensory neuronopathy and subacute cerebellar degeneration (see below). Other patients have a predominant clinical syndrome of focal cortical encephalitis, limbic encephalitis, extrapyramidal movement disorder (Vernino et al., 2002), brainstem encephalitis (Saiz et al., 2009), motor neuron disease, or dysautonomia. Regardless of individual patients’ predominant clinical manifestations, most display signs and symptoms of multifocal involvement of the CNS. Patients may additionally show involvement of the peripheral nervous system, including sensorimotor polyneuropathy, mononeuritis multiplex, dysautonomia, or Lambert–Eaton syndrome (see below). Most patients with paraneoplastic encephalomyelitis have circulating antineuronal autoantibodies, the most common of which are anti-Hu antibodies reacting with a group of RNA-binding proteins (Dalmau et al., 1992; Graus et al., 2001; Sillevis Smitt et al., 2002), or antiCV2 (CRMP-5) antibodies directed against a group of proteins expressed by neurons and oligodendrocytes (Yu et al., 2001). A minority of patients have one of several antibodies other than anti-Hu or anti-CV2, or no detectable antineuronal autoantibodies. The most common clinical course of paraneoplastic encephalomyelitis is deterioration over a period of weeks to months, and then stabilization at a level of severe neurologic disability, regardless of treatment. Subsequent stepwise or gradual neurologic deterioration can also occur, usually in patients with less than complete response of the associated SCLC to treatment (KeimeGuibert et al., 1999). Prominent brainstem or autonomic involvement may prove fatal to some patients.

LIMBIC ENCEPHALITIS The association between limbic encephalitis and cancer, especially SCLC, was first described in the 1960s. Approximately one-half of reported patients with paraneoplastic limbic encephalitis have SCLC (Alamowitch et al., 1997; Gultekin et al., 2000; Lawn et al., 2003), with a few cases of NSCLC. Paraneoplastic limbic encephalitis is currently considered a subset of autoimmune limbic encephalitis, whose incidence is greater than previously believed. Paraneoplastic limbic encephalitis can largely be divided into subtypes based on linkages among particular tumors, antineuronal antibodies, clinical features, and response to treatment. For at least some forms of limbic encephalitis,

NEUROLOGIC COMPLICATIONS OF LUNG CANCER a similar if not identical autoimmune etiology applies to paraneoplastic and nonparaneoplastic patients, analogous to Lambert–Eaton myasthenic syndrome. The diagnostic criteria for paraneoplastic limbic encephalitis include: (1) subacute onset of memory loss, seizures, and psychiatric symptoms; (2) neuropathologic, neuroimaging, or EEG evidence for involvement of the limbic system; (3) cancer diagnosis within a few years of onset of the neurologic syndrome (Gultekin et al., 2000; Graus et al., 2004). Paraneoplastic limbic encephalitis generally has a subacute onset evolving over days to weeks. Patients typically present either with an amnestic syndrome or psychiatric disorder; most patients eventually develop features of both. The memory loss includes short-term anterograde amnesia and a variable period of retrograde amnesia. Denial of the deficit and confabulation are common. The psychiatric disorder usually includes some combination of depression, anxiety, emotional lability, and personality change. Hallucinations and paranoid delusions may occur. The memory deficit may be overlooked or overshadowed by predominant behavior and psychiatric problems. Other features include obsessivecompulsive behavior, disinhibited behavior, hyperphagia, and hypersexuality. Generalized or partial complex seizures occur in most patients, may be the initial neurologic feature, and can be medically intractable. Some extralimbic clinical features have particular associations with certain tumors and antineuronal antibodies (Table 22.4). MR imaging in about two-thirds of patients with paraneoplastic limbic encephalitis shows areas of abnormal T2-weighted or FLAIR signal in the mesial temporal lobe and amygdala bilaterally and less commonly in the hypothalamus and basal frontal cortex (Gultekin et al., 2000; Lawn et al., 2003). The lesions enhance with gadolinium in a minority of cases. Some patients additionally have lesions in the extratemporal cerebral cortex, basal ganglia, diencephalon, or brainstem. In many patients the MRI lesions subsequently resolve with or without concomitant clinical improvement, sometimes eventuating in temporal lobe atrophy. Temporal lobe biopsy or autopsy in cases of paraneoplastic limbic encephalitis shows extensive neuronal loss, gliosis, and microglial nodules in the hippocampus and amygdala (Gultekin et al., 2000). Similar but less severe changes are often present in the parahippocampal gyrus, cingulate gyrus, insular cortex, orbital frontal cortex, basal ganglia, and diencephalon. Perivascular lymphocytic cuffing and leptomeningeal mononuclear cell infiltrates are patchy and variable. Most patients with paraneoplastic limbic encephalitis and SCLC have multifocal encephalomyelitis. Most patients with paraneoplastic limbic encephalitis have circulating onconeural autoantibodies (Alamowitch et al., 1997; Gultekin et al., 2000; Bataller

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et al., 2007) (Tables 22.3 and 22.4). Among patients with lung cancer and limbic encephalitis, anti-Hu and anti-CV2 are the most prevalent associated antibodies. Limbic encephalitis is an early and prominent feature in 10–20% of patients with paraneoplastic encephalomyelitis and anti-Hu antibodies. Several autoantibodies associated with paraneoplastic (and nonparaneoplastic) limbic encephalitis react with synaptic or neuronal cell surface proteins (Vincent et al., 2011). It is difficult to precisely know the relative proportions of patients with various onconeural antibodies, given the ongoing identification of “new” antibodies in patients who were previously considered to be antibody-negative. For some of these recently discovered antibodies only a very small number of patients have been described to date (Lai et al., 2009; Boronat et al., 2011). The proportion of patients with paraneoplastic versus nonparaneoplastic limbic encephalitis varies widely depending on the associated autoantibody. The great majority of patients with limbic encephalitis and antiHu, anti-CV2, or antiamphiphysin antibodies have a neoplasm, especially SCLC. Nearly all patients with anti-Ma2 antibodies have a testicular germ cell tumor; a few cases have SCLC, NSCLC, or other tumor, or no associated tumor. Most patients with antibodies against NMDA receptors, or against leucine-rich glioma-inactivated protein 1 (LGI1) or other proteins associated with voltagegated potassium channels, do not have an associated tumor; of the paraneoplastic cases, SCLC or thymoma are associated with antibodies against the voltage-gated potassium channel complex, while ovarian teratoma is highly associated with anti-NMDAR receptor antibodies.

CEREBELLAR DEGENERATION Ninety percent of patients with paraneoplastic cerebellar degeneration have SCLC, Hodgkin lymphoma, or carcinoma of the breast or ovary. A very small percentage have NSCLC. The most striking and consistent neuropathologic finding is severe, diffuse loss of Purkinje cells throughout the cerebellar cortex. There may also be some neuronal loss in the granular cell layer and deep cerebellar nuclei. Some patients have perivascular cuffing and mononuclear cell infiltrates in the cerebellum and overlying leptomeninges. The clinical onset of paraneoplastic cerebellar degeneration is typically fairly abrupt (Shams’ili et al., 2003). Patients display signs and symptoms reflecting diffuse dysfunction of the cerebellum, including dysarthria and severe appendicular and gait ataxia. Abnormalities of oculomotor function are common and include nystagmus, particularly downbeat nystagmus, disruption of smooth pursuit movements, ocular dysmetria, and opsoclonus. Superimposed on the cerebellar deficits, many

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Table 22.4 Antibody clinical associations in paraneoplastic limbic encephalitis

Onconeural antibody

Main tumor association(s)

Anti-Hu (Alamowitch et al., 1997; Gultekin et al., 2000)

Strongly associated with SCLC

Anti-CV2 (CRMP-5) (Yu et al., 2001)

SCLC, thymoma, a few NSCLC

Anti-VGKC complex{ (Jarius et al., 2008; Tan et al., 2008; Irani et al., 2010b, 2011, 2012; Lai et al., 2010)

Usually no tumor; some cases with SCLC or thymoma

Anti-NMDAR (Irani et al., 2010a; Dalmau et al., 2011)

Usually no tumor; ovarian teratoma, rarely SCLC

Anti-Ma2 (Dalmau et al., 2004; Graus et al., 2008; Hoffmann et al., 2008)

Testicular germ cell tumor > > various others including SCLC and NSCLC

Anti-Ma1 (Dalmau et al., 2004; Hoffmann et al., 2008) Anti-amphiphysin (Pittock et al., 2005; Graus et al., 2008) Anti-glutamate (AMPA) receptor (Lai et al., 2009) Anti-GABAR (Lancaster et al., 2010; Boronat et al., 2011) Anti-GAD (Boronat et al., 2011)

Various including SCLC and NSCLC SCLC, breast Various including SCLC and NSCLC SCLC (small number of patients) SCLC

Special clinical features* Ataxia, sensory neuronopathy, and/ or other features of multifocal encephalomyelitis Multifocal involvement of extralimbic cerebral cortex and/ or basal ganglia; polyneuropathy Hyponatremia; sleep disorders; faciobrachial dystonic seizures; neuromyotonia; Morvan syndrome Acute psychosis; central hypoventilation; autonomic instability; catatonia/ movement disorder Diencephalic (sleep disorder and/or autonomic dysfunction); brainstem (mainly ocular motor) Ataxia, brainstem involvement Stiff person syndrome

Neurological outcome{ Generally poor

Variable

Very good

Very good after protracted illness

Improvement in onethird of patients

Generally poor Variable Frequent neurologic relapses Good Good

SCLC, small cell lung carcinoma; NSCLC, non-small cell lung cancers. *Additional features variably present in addition to the features of classic limbic encephalitis; in some patients these features may overshadow the limbic component. { After tumor treatment and/or immunotherapy. { In most patients with anti-VGKC antibodies the antibody reactivity is actually against one or more proteins complexed with VGKC.

patients develop symptoms or signs of multifocal encephalomyelitis. Paraneoplastic cerebellar degeneration in patients with SCLC may occur in conjunction with paraneoplastic peripheral neuropathy or Lambert–Eaton myasthenic syndrome (Mason et al., 1997; Graus et al., 2002; Fukuda et al., 2003). The neurologic deficits in

paraneoplastic cerebellar degeneration generally worsen over a period of several weeks to months and then stabilize at a level of severe disability (Shams’ili et al., 2003). Anti-Hu antibodies are the most common onconeural antibodies among patients with paraneoplastic cerebellar degeneration and lung cancer (Mason et al., 1997; Shams’ili et al., 2003) (Table 22.3). The great majority

NEUROLOGIC COMPLICATIONS OF LUNG CANCER of patients have SCLC. Other patients with cerebellar degeneration have anti-CV2 antibodies (Hoffmann et al., 2009), anti-Zic4 antibodies (Bataller et al., 2004), or one of a number of less common autoantibodies. Anti-Yo and anti-Tr antibodies which are strongly associated with breast or ovarian cancer, or with Hodgkin lymphoma (respectively), are rarely associated with lung carcinoma.

OPSOCLONUS-MYOCLONUS Opsoclonus is defined as chaotic, continuous multidirectional rapid eye movements (saccadic oscillations) without an intersaccadic interval. Opsoclonus as a paraneoplastic disorder is less common in adults than in children and most often occurs in association with SCLC or breast carcinoma, occasionally with NSCLC (Bataller et al., 2001; Pittock et al., 2003). The neurologic symptoms and signs which accompany paraneoplastic opsoclonus in adults are heterogeneous and include multifocal limb myoclonus, pancerebellar dysfunction, and signs and symptoms of brainstem dysfunction, including vertigo, vomiting, dysphagia, and gaze palsy. A small number of autopsied cases variably implicate injury to cerebellar neurons and/ or to brainstem ocular motor nuclei in opsoclonus, but the exact pathophysiology remains unclear. Anti-Hu, anti-Ri (ANNA-2), anti-CV2, or antiamphiphysin antibodies are present in some patients with opsoclonusmyoclonus and SCLC or NSCLC (Pittock et al., 2003). Other patients with lung cancer and opsoclonusmyoclonus have no identifiable onconeural antibodies, or have one of several unnamed “atypical” antibodies with heterogeneous patterns of reactivity (Bataller et al., 2003).

EXTRAPYRAMIDAL SYNDROME Chorea, athetosis, dystonia, or parkinsonism are rare manifestations of paraneoplastic encephalitis, occurring most often in association with SCLC and rarely with NSCLC, lymphoma, thymoma, or other tumors (Vigliani et al., 2011). The extrapyramidal features may occur with or without other signs of multifocal encephalomyelitis. In most patients MRI shows focal lesions in the basal ganglia. Anti-Hu and anti-CV2 are the most commonly associated antibodies.

BRAINSTEM ENCEPHALITIS Paraneoplastic brainstem encephalitis manifests as a variety of gaze palsies or other ocular motor disturbance, possibly together with dysarthria, dysphagia, facial weakness, vertigo, central respiratory failure, or other signs and symptoms referable to the brainstem (Saiz et al., 2009). This most commonly occurs in the setting of multifocal encephalomyelitis associated with

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SCLC, or in patients with testicular germ cell tumor who generally have additional limbic and/or hypothalamic involvement. Most patients with SCLC have anti-Hu antibodies. The neurologic outcome is generally poor; in some patients the brainstem dysfunction proves fatal.

OPTIC NEURITIS Optic neuritis is a rare complication of SCLC, breast carcinoma, or other tumors. Patients present with unilateral or bilateral decreased visual acuity, afferent pupillary defects, cecocentral scotomas, and disc edema. Some patients have serum anti-CV2 or other antineuronal antibodies (Cross et al., 2003; Hoffmann et al., 2009).

CARCINOMA-ASSOCIATED RETINOPATHY More than 75% of reported patients with carcinomaassociated paraneoplastic retinopathy have SCLC (Adamus et al., 2004; Ohguro et al., 2004). There are a few reported patients with NSCLC. In nearly all patients the visual symptoms precede discovery of the tumor by intervals ranging from several months up to 2 years or more. The initial symptoms are most often a painless bilateral but asymmetric dimming or blurring of vision. Night blindness is common and may be the sole initial complaint. Many patients report episodic obscurations or positive symptoms described as distortions, “sparkles,” “shimmering,” or bizarre images. Some patients report visual glare or photosensitivity. Examination usually shows severely impaired visual acuity, with relative sparing of color vision. Some patients have a relative afferent pupillary defect. The most common visual field deficits are asymmetric central or ring scotomas and concentric constriction. The electroretinogram in almost all patients is flat or nearly so, reflecting diffuse dysfunction of both rod and cone photoreceptor cells. In most patients the visual symptoms worsen to severe impairment over several weeks to months, either in a steady or stepwise course. The great majority of patients with lung cancer and paraneoplastic retinopathy have circulating autoantibodies against the 23 kd calcium-binding protein recoverin. A minority of patients have antibodies against one of a number of other retinal proteins. Antirecoverin antibodies are occasionally present in patients with retinopathy but no identifiable neoplasm.

MYELOPATHY Patients with paraneoplastic encephalomyelitis associated with SCLC or NSCLC may present with a predominant myelopathy syndrome. Spine MRI in some patients

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shows focal or longitudinally extensive T2-weighted signal abnormality, with or without gadolinium enhancement. Some patients have myelopathy with rigidity, myeloradiculopathy, or myelopathy plus optic neuritis (Devic syndrome) (Cross et al., 2003; Pittock et al., 2005; Flanagan et al., 2011). Associated antibodies include anti-Hu, anti-CV2, and antiamphiphysin. Paraneoplastic necrotizing myelopathy is a rare syndrome which may occur in association with a variety of carcinomas and lymphoid tumors. Patients develop a rapidly ascending level of flaccid paralysis and numbness, often leading to death from respiratory failure or medical complications.

STIFF PERSON SYNDROME A syndrome of muscle rigidity and spasms which clinically resembles the “stiff person syndrome” is associated with a variety of neoplasms, including SCLC. Rigidity is probably caused by multifocal encephalomyelitis affecting the spinal cord and/or brainstem. Patients develop progressive aching and rigidity of the axial and proximal limb musculature, usually asymmetric at onset. There are superimposed painful and sometimes violent spasms, either occurring spontaneously or triggered by voluntary movement, passive movement, or sensory stimuli. Patients may eventually develop fixed flexion of the limbs or even opisthotonos and respiratory difficulty. Some patients with SCLC have antibodies against the synaptic vesicle-associated protein amphiphysin (Dropcho, 1996; Pittock et al., 2005).

MOTOR NEURON DISEASE Paraneoplastic motor neuron dysfunction occurs in a variety of different settings. Lower motor neuron signs and symptoms are among the presenting or predominant manifestations in up to 25% of patients with SCLC and multifocal encephalomyelitis associated with anti-Hu or other antibodies (Graus et al., 2001). Motor neuron involvement in these patients does not usually improve with treatment. There are several well-described patients with a lower motor neuron syndrome or combined upper and lower motor neuron syndrome who had significant neurologic improvement after resection of lung carcinoma.

SUBACUTE SENSORY NEURONOPATHY The most common clinical manifestation of paraneoplastic encephalomyelitis is subacute sensory neuronopathy reflecting involvement of the dorsal root ganglia (Dalmau et al., 1992; Graus et al., 2001; Sillevis Smitt et al., 2002). More than 90% of reported patients have SCLC; a very small percentage have NSCLC. Early

symptoms are patchy or asymmetric numbness and paresthesias, often involving face, trunk, or proximal limbs. The symptoms eventually spread to involve all limbs. Burning dysesthesias and severe aching or lancinating pain are common. Examination reveals severe sensory ataxia, predominant impairment of vibration sense and proprioception, frequent pseudoathetosis, and hypoactive or absent muscle stretch reflexes. Most patients cannot walk unassisted due to pain and profound loss of proprioception. A minority of patients have prominent pain and mechanical hyperalgesia with at least partial preservation of large fiber sensibility and muscle stretch reflexes (Oki et al., 2007). Most patients have additional signs and symptoms that reflect a multifocal encephalomyeloneuritis. The characteristic electrophysiologic profile of paraneoplastic sensory neuronopathy includes severely reduced amplitude or complete absence of sensory nerve potentials, with normal or only slightly reduced sensory nerve conduction velocities if a response is able to be elicited. Most patients do show at least minor abnormalities in motor nerve conduction studies, with or without symptoms of a mixed sensorimotor polyneuropathy (Camdessanche et al., 2002; Oh et al., 2005a). The clinical course of sensory neuronopathy in patients with SCLC is fairly stereotyped. By far the most common pattern is deterioration over a period of weeks to months, and then stabilization at a level of severe neurologic disability, regardless of treatment. Other patients have subsequent stepwise or gradual neurologic deterioration. A few patients have minimal CNS manifestations and a sensory neuronopathy that takes a relatively indolent course independent of any treatment (Graus et al., 1994).

NEUROMYOTONIA Patients with SCLC may develop peripheral nerve hyperexcitability which manifests as the “cramp-fasciculation syndrome” or as a syndrome of diffuse muscle stiffness, cramps, and myokymia similar to neuromyotonia or continuous muscle fiber activity (Isaacs’ syndrome) (Hart et al., 2002). Needle EMG shows repetitive bursts of rapidly firing motor unit discharges (myokymic potentials) and/or very high-frequency trains of discharges. Some patients have serum antibodies against proteins in the voltage-gated potassium channel complex, including contactin-associated protein-2 (Caspr2) (Irani et al., 2010b, 2012). Morvan syndrome (neuromyotonia, neuropsychiatric symptoms, dysautonomia, sleep disturbance, and neuropathic pain) is most often associated with thymoma, but may rarely occur in association with lung carcinoma.

NEUROLOGIC COMPLICATIONS OF LUNG CANCER 353 the relatively minor abnormalities seen on neurologic OTHER NEUROPATHIES examination. Symmetric weakness predominantly Rather than the more common sensory neuronopathy, a affects proximal leg muscles, and to a lesser extent minority of patients with SCLC and anti-Hu antibodies shoulder girdle muscles. Over time the weakness tends have a mixed sensorimotor polyneuropathy with a mixed to progress from proximal to distal muscles. Myalgia axonal-demyelinating electrophysiologic pattern (Oh and/or distal paresthesias are not uncommon. Muscle et al., 2005a). A few patients with anti-Hu antibodies stretch reflexes are characteristically diminished have what appears to be a primary demyelinating polyor absent. Over the course of illness, 90% of patients neuropathy superimposed on sensory neuronopathy. eventually develop symptoms of sympathetic or paraMononeuritis multiplex with biopsy-proven nerve vascusympathetic autonomic dysfunction, including dry litis can occur in association with SCLC or NSCLC, with or mouth, erectile dysfunction, blurred vision, constipawithout anti-Hu antibodies (Oh, 1997). Patients with antition, difficulty with micturition, orthostasis, and hypohiCV2 antibodies (most of whom have SCLC) may develop drosis. About one-third of patients have dysphagia, a sensorimotor polyneuropathy with mixed axonalptosis, or diplopia, which are generally mild and occur demyelinating electrophysiologic features (Antoine in the setting of significant limb weakness. et al., 2001; Hoffmann et al., 2009). Some of these The characteristic electrophysiologic profile of patients have both anti-Hu and anti-CV2 antibodies. LEMS includes reduced amplitude of muscle action potentials, a significant increase in amplitude of comAUTONOMIC INSUFFICIENCY pound muscle action potentials after several seconds of maximal voluntary contraction, a decremental Paraneoplastic autonomic dysfunction most commonly response at low rates of repetitive nerve stimulation, occurs as a part of encephalomyelitis in patients with and an incremental response at high rates of stimulation SCLC, or rarely in patients with NSCLC or other tumors. (Oh et al., 2005b). The electrophysiologic abnormalities In some patients the autonomic symptoms overshadow are often detected in clinically unaffected muscles, other manifestations of encephalomyelitis. These though not all muscles are equally affected. patients may develop severe and progressive gastrointesThe primary pathophysiologic abnormality in LEMS tinal dysmotility, with gastroparesis, chronic intestinal is a reduction of the calcium-dependent quantal release pseudo-obstruction, and severe constipation/obstipaof acetylcholine triggered by a nerve impulse. Ultrastruction, presenting up to several months prior to discovery tural studies of muscle from LEMS patients show a of the tumor (Condom et al., 1993; Lee et al., 2001; marked depletion of presynaptic active zones (the sites McKeon et al., 2009). Patients may also have other feaof synaptic vesicle exocytosis), paucity and disorganizatures of sympathetic dysfunction (e.g., orthostatic hypotion of active zone intramembrane particles, and aggretension or anhidrosis) and/or parasympathetic gation of the active zone particles into clusters. Active dysfunction (e.g., dry mouth, urinary retention, or impozone particles contain P/Q-type voltage-gated calcium tence). Patients generally have a poor neurologic outchannels that mediate the quantal release of acetylchocome and are at risk for sudden unexplained death. line in response to nerve impulses. Several lines of clinical and experimental evidence LAMBERT–EATON MYASTHENIC SYNDROME support an autoimmune etiology for LEMS. Passive Approximately one-half of patients with Lambert–Eaton transfer and in vitro experiments using sera from LEMS myasthenic syndrome (LEMS) have an associated neopatients have shown that autoantibodies against presynplasm, which is SCLC in over 90% of well-documented aptic P/Q-type voltage-gated calcium channels cross-link cases (O’Neill et al., 1988; Chalk et al., 1990; Sanders, and downregulate the channels, thereby blocking the 2003; Titulaer et al., 2011a). Conversely, LEMS is the sinnerve impulse-evoked release of acetylcholine. gle most frequent neurologic paraneoplastic syndrome The autoantibodies also impair neurotransmitter associated with SCLC. LEMS may also occur rarely in release from parasympathetic and sympathetic neurons. patients with NSCLC (Grommes et al., 2008). In at least Serum antibodies against P/Q-type voltage-gated cal75% of patients with paraneoplastic LEMS, the neurocium channels are found in over 90% of paraneoplastic logic symptoms precede discovery of the associated neoor nonparaneoplastic LEMS patients (Motomura et al., plasm; this interval is usually less than 6 months but may 1997). Patients with nonparaneoplastic LEMS cannot be be as long as 5 years. absolutely distinguished from paraneoplastic cases by Most patients with LEMS have an insidious and gradtheir neuromuscular symptoms, electrophysiologic abnorual onset of weakness and fatigue (Titulaer et al., 2011a). malities, or by the presence or titer of anticalcium channel Early in the course there is often a discrepancy between antibodies. A more rapid progression of neurologic symppatients’ subjective weakness and easy fatigability and toms is somewhat more likely among paraneoplastic

354 E.J. DROPCHO LEMS patients (Titulaer et al., 2011a). In patients Most patients with paraneoplastic LEMS improve presenting with LEMS, factors predictive of SCLC neurologically with successful treatment of the associinclude current or prior cigarette smoking, age over ated SCLC (Titulaer et al., 2011a). Pyridostigmine is of 50 years, poor performance status, erectile dysfunction benefit but is generally less effective for LEMS than in men, and early bulbar weakness (Titulaer et al., for myasthenia gravis. The potassium channel antago2011b). Some patients with paraneoplastic LEMS have nist 3,4-diaminopyridine prolongs the action potential concomitant cerebellar degeneration, multifocal encephaat motor nerve terminals and improves strength in nearly litis, or neuropathy. all patients with LEMS (Sanders, 2003). For patients with Antibodies against the SOX1 transcription factor are paraneoplastic LEMS who are receiving or will receive present in nearly two-thirds of patients with LEMS assotumor treatment, it is usually reasonable to use pyridosciated with SCLC but only in 5% of patients with nonpartigmine and/or diaminopyridine, and to defer immunoaneoplastic LEMS (Sabater et al., 2008; Titulaer et al., therapy, since many of these patients will improve 2009). Anti-SOX antibodies are also present in 40% of with successful tumor treatment. If this is not an option patients with SCLC but without neurologic symptoms. or patients still have severe weakness, prednisone and/or Anti-SOX antibodies are not directly involved in the azathioprine are generally effective after a lag period of pathogenesis of LEMS, but this seems to be a valuable several weeks or longer. Ciclosporin may be used for serologic marker for SCLC. patients who do not respond to or tolerate corticosteroids or azathioprine. Plasma exchange or intravenous MYOPATHIES immunoglobulin produce improvement in most patients, usually lasting from 2 to 3 months. There are anecdotal Lung cancer is one of several neoplasms that may occur reports of response to rituximab (Maddison et al., 2011). in association with dermatomyositis (Buchbinder et al., Successful tumor treatment and/or immunosuppres2001; Hill et al., 2001; Fardet et al., 2009). In most sive therapy often results in significant neurologic patients the myositis and the associated neoplasm are improvement for patients with several other syndromes, diagnosed within a short time of each other. There is including neuromyotonia and stiff person syndrome. For nothing distinctive about the neurologic symptoms, these syndromes it is postulated that onconeural antiEMG findings, muscle pathology, clinical course, or bodies cause neuronal or peripheral nerve dysfunction response to immunotherapy in patients with paraneobut not neuronal cell death, allowing for recovery if plastic myositis, though some reports suggest a more the autoimmune response can be suppressed. severe course of dermatomyositis in paraneoplastic Most patients with paraneoplastic retinal degenerapatients. A few published patients with polymyositis or tion and antirecoverin antibodies treated with prednidermatomyositis had significant neurologic improvesone show mild to moderate vision improvement, ment after treatment of the associated tumor, without often prior to discovery of the underlying neoplasm. immunosuppressive therapy. Some patients have a fluctuating steroid-dependent Severe necrotizing myopathy is a rare complication of course or deteriorate after an initial partial response. lung carcinoma or other neoplasms (Levin et al., 1998). There are no definite reports of visual improvement Patients develop severe, rapidly progressive weakness following surgery or chemotherapy of SCLC without with marked elevation of serum creatine kinase. Muscle concomitant corticosteroid therapy. Intravenous immubiopsy or autopsy show diffuse, extensive muscle fiber noglobulin may also be beneficial. degeneration and necrosis with minimal or no inflammaAs a group, adults with paraneoplastic opsoclonustory reaction. A few patients improved after tumor myoclonus have a better neurologic outcome than resection and corticosteroids, while others were severely patients with paraneoplastic cerebellar degeneration or disabled or died of bulbar and respiratory weakness. encephalomyelitis. In some patients the opsoclonus and other neurologic features spontaneously improve Treatment and outcomes prior to any therapy (Pittock et al., 2003). Some patients There is a wide spectrum of neurologic outcomes in show significant neurologic improvement with successpatients with paraneoplastic neurologic disorders folful treatment of the associated tumor (Bataller et al., lowing tumor treatment, with or without immunosup2001), or with corticosteroids, plasma exchange, or intrapressive therapy. For many syndromes there is venous immunoglobulin (Pittock et al., 2003). Other increasing evidence that successful tumor treatment is patients with SCLC show little neurologic response to a major factor in determining neurologic outcome, therapy and are left with severe neurologic disability. and that immunotherapy is more likely to be effective The neurologic course of paraneoplastic limbic when the tumor is also treated successfully (Graus encephalitis is variable and partly related to the type et al., 2001; Sillevis Smitt et al., 2002). of associated onconeural antibody. A few patients with

NEUROLOGIC COMPLICATIONS OF LUNG CANCER clinically “pure” limbic encephalitis show spontaneous neurologic improvement prior to any treatment (Sillevis Smitt et al., 2002). Overall, 30–50% of patients with limbic encephalitis and SCLC improve after tumor treatment, with or without immunotherapy (Dalmau et al., 1992; Alamowitch et al., 1997; Gultekin et al., 2000). Among patients with anti-Hu antibodies in whom limbic encephalitis is a component of multifocal encephalomyelitis, the “limbic” features may improve after tumor treatment, even if the other neurologic features do not improve. The most favorable neurologic outcomes among patients with lung cancer and limbic encephalitis are associated with antibodies against voltage-gated potassium channel-associated proteins (Irani et al., 2010b) or with anti-NMDAR antibodies (Dalmau et al., 2011). Some of these patients recover nearly completely. Some but not all patients with limbic encephalitis and other antibodies (e.g., anti-Ma2, antiAMPA, anti-GABAR) show at least partial neurologic improvement after therapy (Dalmau et al., 2004; Lai et al., 2009; Lancaster et al., 2010). The poorest neurologic outcomes among patients with lung cancer and paraneoplastic disorders are those with cerebellar degeneration (Keime-Guibert et al., 2000; Shams’ili et al., 2003), or with encephalomyelitis or other syndrome associated with anti-Hu antibodies (KeimeGuibert et al., 1999; Graus et al., 2001; Sillevis Smitt et al., 2002; Oh et al., 2005a). Fewer than 10% of these patients show significant neurologic improvement after successful tumor treatment and attempts at aggressive immunosuppressive therapy with corticosteroids, cyclophosphamide, intravenous immunoglobulin, or plasma exchange. Exceptional patients do improve with immunotherapy. For these few responders, the only factors which 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. The decision whether to try immunosuppressive therapies must therefore be based on the particular syndrome and on the individual patient’s circumstances. There are several potential explanations for the disappointingly poor response to immunotherapy in many patients. As noted above, 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 which is sequestered in the central nervous system. Unfortunately, for many central syndromes it is likely that

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patients have already suffered neuronal death or irreversible injury by the time the diagnosis of a paraneoplastic disorder is made. There is theoretical concern 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, there is no definite evidence that patients given immunosuppressive treatment have a worse tumor outcome (Keime-Guibert et al., 1999).

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