Neurologic Complications of Cancer and its Treatment

Clinical Presentation and Diagnosis

Seizures, headaches, and focal neurologic deficits, depending on location, usually lead to the diagnosis of brain metastases. Examination may reveal focal neurologic deficits such as focal weakness, numbness, or language problems. Head CT scans will reveal single or multiple discreet areas of contrast enhancement and associated vasogenic edema. Brain MRI may uncover metastases too small for CT resolution and prove more effective in defining size and location of lesions.

Treatment

Treatment of brain metastases includes symptomatic therapy for seizures and vasogenic edema. Although there are several anticonvulsants available, nonenzyme-inducing newer generation anticonvulsants are tolerated better and pose less risk of drug–drug interactions than older enzyme-inducing agents. Examples of nonenzyme-inducing anticonvulsants include levetiracetam, lacosamide, and pregabalin. Although seizure prophylaxis is still used, no evidence supports this practice. However, hemorrhagic metastases are more likely to cause seizures and prophylaxis may be prudent in these situations.

Vasogenic edema is treated with corticosteroids, usually dexamethasone. Depending on the degree of vasogenic edema and the presence or absence of mass effect, midline shift, and herniation of brain structures, high doses of corticosteroids (dexamethasone 12–24 mg daily) may be necessary. Short-term complications include hyperglycemia, psychoses, and weight gain.

Once patients are controlled on symptomatic therapy, more directed therapy for the metastastic lesions is planned. The most important modalities of treatment are surgery and radiation therapy. Chemotherapy has a modest role in the management of this cancer complication. Radiation therapy includes whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS). The best treatment for patients with BMs depends on several factors. Age, performance status, and the presence of systemic metastatic disease emerged as the most important factors in a recursive portioning analysis (RPA) of the Radiation Therapy Oncology Group (RTOG) trials that demonstrated benefit from WBRT [7, 8].

The prognostic classes from this analysis were defined as follows. RPA class I is characterized by younger than 65 years old and Karnofsky Performance Status greater than 70; no extracranial disease and primary tumor not progressive; and median survival of 7.1 months. RPA class II is characterized by patients other than those in RPA class I or III and median survival of 4.2 months. RPA class III is characterized by Karnofsky Performance Status less than 70 and median survival of 2.3 months. Tumor histology and number of brain metastases are also important factors in determining treatment.

The following guidelines apply given current available data. WBRT is indicated in RPA class I and II patients with single metastasis after surgical resection and as palliative therapy in patients with a poor performance status (RPA class III). WBRT may also be used in RPA class I and II patients with multiple metastases but emerging data indicate that SRS alone as a first-line intervention may be preferable in these patients given the early development of cognitive dysfunction with WBRT [9•].

Clinical Presentation, Pathophysiology, and Diagnosis

Patients present with evidence of spinal cord or nerve root involvement, cranial neuropathies, or symptoms and signs referable to the cerebral hemispheres [16•]. Patients may present with limb weakness, pain referable to the involved nerve roots or bladder, and bowel disturbances in spine and sacral root involvement. Examination confirms weakness, sensory loss, and changes in deep tendon reflexes. Cranial nerve VI, III, and IV dysfunction result in diplopia and optic nerve involvement causes visual blurring. The fifth cranial nerve is also involved in some cases. Extraocular nerve abnormalities or facial sensory deficits are present. Multiple cranial neuropathies in a patient with cancer are highly indicative of leptomeningeal metastases (LM).

Cerebral Symptoms

Cancer cells gain access to the cerebrospinal fluid (CSF) in three ways. The most common route is hematogenous, but direct extension from cancer sites contiguous to the central nervous system (CNS) and entry via perineural and perivascular spaces is also possible [16•]. The diagnosis of LM should be confirmed with CSF examination. This study also helps exclude other causes of cerebral, cranial nerve, and spinal/nerve root dysfunction in patients with cancer such as chronic (opportunistic) infections. The presence of malignant cells in the CSF is diagnostic; additionally high protein, low glucose, elevated opening pressures, and increased white cell count support the diagnosis when cytology is negative. A repeat CSF analysis increases the yield in such cases and should be performed [11]. Flow cytometry and polymerase chain reaction techniques are useful in cases of NHL with suspected lymphomatous meningitis [17]. Before CSF analysis, neuroimaging should be performed. MRI of the brain and entire spine is indicated in such cases to help stage the extent of LM and guide management. LM is often associated with increased intracranial pressure and concomitant parenchymal metastatic disease with mass effect. In such cases, a lumbar puncture (LP) for CSF analysis may be contraindicated. MRI imaging may demonstrate LM enhancement, which may be linear or more nodular (Fig. 1). Cranial nerve enhancement, especially in the presence of cranial neuropathies, is highly indicative of LM disease. MRI sensitivity is low (<50%) although it is considered more sensitive than CT [18]. CSF flow analysis in patients with LM is another important diagnostic and prognostic tool. Abnormal CSF flow is common in LM and ¹¹¹indium-diethylenetriamine pentaacetic acid or ⁹⁹Tc macroaggregated albumin tracers may be used to define the extent and location of such disturbances [19, 20].

Treatment

Treatment is palliative, and the patient and family should be made aware of this fact, as well as of prognostic implications. Surgery, radiation, and chemotherapy play a role, as the multidisciplinary care of these patients is very important. Patients with LM may require ventriculoperitoneal shunting for hydrocephalus. Surgery is also required for placement of Ommaya reservoirs for administration of intrathecal chemotherapy.

Radiation therapy may have significant palliative value in patients with LM. Radionuclide studies may demonstrate CSF flow abnormalities. Radiation therapy to areas of CSF block has been shown to be of benefit [21, 22]. Patients who have cerebral LM and concomitant brain metastases are treated with WBRT. Finally, focused radiation to bulky tumor involving the spine can help stabilize or improve neurologic function. Chemotherapy has shown activity in LM, especially lymphomatous and leukemic meningitis. The responses and palliation seen with chemotherapy in solid tumors are less robust but some benefit can also be derived in these cases. Most commonly, chemotherapy is administered via an Ommaya reservoir. DepoCyt (Enzon; New Brunswick, NJ) is considered the drug of choice for such administration. DepoCyt is sustained-release cytarabine (a liposomal formulation) and has shown benefit in patients with lymphomatous meningitis [23] and solid tumor LM [24]. In lymphomatous meningitis, Glantz et al. [23] demonstrated high response rates and better quality of life when liposomal cytarabine was compared with standard cytarabine. In solid tumors, the response rates noted to DepoCyt were similar to what had been reported for methotrexate administration [24]. However, the less-frequent administration of DepoCyt compared with methotrexate was felt to benefit the patient. This drug is also less toxic to the CNS than methotrexate. Direct spinal fluid injection of methotrexate, cytarabine, thiotepa, etoposide, topotecan, and rituximab have all been used in patients with LM. Chamberlain [16•] provided a very recent and comprehensive review on this subject.

Clinical Presentation and Diagnosis

The presenting features of ESCC depend on the level of involvement but pain is essentially universal in such patients. Pain may be reflective of nerve root involvement and have radicular or axial features. Thoracic spine involvement is most common so that mid-back pain, bilateral lower extremity weakness, and sensory disturbances tend to be the most common presenting symptoms. Patients may also develop bowel and bladder symptoms. Such dysfunction may be very prominent in compression occurring at the level of the conus medullaris or cauda equina.

The diagnosis of ESCC is clinical. However, neuroimaging is required to confirm the level of compression, assess for the presence of other levels of bone and epidural involvement, and determine the presence of LM. Chamberlain and Kormanik [27] found involvement at more than one level in 29% of cases within their series. In the occasional patient who cannot undergo MRI, CT or CT myelography can also be diagnostic.

Treatment

Supportive care includes high-dose steroid therapy, usually with dexamethasone to reduce edema. This often helps with pain control and stabilization and improvement of neurologic function. We usually use immediate intravenous administration of 10 mg of dexamethasone followed by 6 mg every 4 hours. Pain control is very important and specific pain therapy besides corticosteroids is almost always necessary. For definitive therapy, early liaison with a radiation oncologist and a neurosurgeon are key to success. The neurosurgeon may use vertebroplasty or kyphoplasty for pain relief in collapsed vertebrae, corpectomy to resect tumor in the vertebral body and decompress the spine (anterior decompression), or a laminectomy (posterior decompression). Radiation therapy is the most common therapeutic modality available to patients with ESCC and may be the only source of palliation for patients who are not surgical candidates. The various radiation therapy modalities include stereotactic radiotherapy, intensity modulated radiotherapy (IMRT), and conventional external beam radiation therapy. Conventional fractionated external beam radiation therapy is most commonly administered. Radiation therapy is administered one level above and below the site of compression to reduce the risk of recurrence from epidural tumor extension. Success with radiation is highly dependent on tumor histology (eg, melanoma and renal cell carcinoma are radioresistant).

Clinical Presentation and Diagnosis

Cancer may infiltrate a nerve plexus causing pain and sensorimotor deficits in one limb. Examination in such cases may reveal evidence of partial or complete injury to the plexus. In the case of the lumbosacral plexus, injury to the entire plexus from infiltrating neoplasm is seen in 18% of cases, upper plexus involvement (L1-L4) is seen in 31% and the lower plexus (L4-S1) in 51% [28, 29]. Patients with extensive lumbosacral plexus involvement would have weakness of thigh flexion, eversion and adduction, as well as leg extension [30]. Sensory loss over the genitoinguinal region, thigh, and medical aspect of the lower leg as well as loss of the patellar reflex would also be expected signs in such cases [30]. Similarly, involvement of the cervical or brachial plexus by cancer may cause typical findings on examination; the reader is referred to comprehensive texts on this subject [30].

Weakness or numbness may also result from individual nerve involvement. Metastases to a nerve are rare but involvement of nerves from bone, soft tissue, or CSF metastases is not. The numb chin syndrome (NCS) caused by malignant infiltration of the mental or inferior alveolar nerve is one example. Patients present with orofacial numbness involving the chin or lower lip. The most common cause is bone involvement by cancer and nerve compression, although some cases are associated with leptomeningeal metastases [31]. Appropriate diagnostic studies such as a Panorex radiograph of the jaw and cerebrospinal analysis often determines the etiology.

Neuroimaging with MRI is the diagnostic modality of choice for most cases of tumor-related compression neuropathy or plexopathy. It may show direct infiltration of a nerve plexus or a mass compressing an individual nerve. Neuroimaging of plexus lesions may be difficult to interpret, especially when previous radiation therapy to the area (eg, brachial plexus) raises the possibility of radiation plexopathy. In such cases, electrodiagnostic studies with electromyography and nerve conduction studies may be very helpful. This differential is discussed later under nervous system complications from radiation therapy (see below).

Treatment of PNS involvement by cancer includes steroids and analgesics to reduce pain. Pain relief may be accomplished using tricyclic or other antidepressants such as duloxetine as well as anticonvulsants. Pregabalin and gabapentin are often the first choices. More definitive therapy includes both radiation and chemotherapy, depending on the underlying histology and site of involvement.

Lambert-Eaton Myasthenic Syndrome

Patients with small cell lung cancer (SCLC) sometimes present with a neuromuscular syndrome consisting of fluctuating weakness, fatigue, and autonomic dysfunction caused by a defect in acetylcholine release from the presynaptic terminal at the neuromuscular junction. In turn, this is caused by antibodies to presynaptic voltage-gated calcium channels (VGCC). Examination confirms limb (especially lower extremity) weakness and hyporeflexia. Electromyography (EMG)/NCS show a decremental response to low-frequency repetitive nerve stimulation and an incremental response to higher frequency stimulation. Detection of VGCC antibodies in the presence of such findings should prompt an aggressive search for an underlying malignancy, usually SCLC. Treatment includes 3,4-diaminopyridine to improve acetylcholine release, pyridostigmine, and guanidine. Immunomodulatory therapy with intravenous Ig and plasmapheresis, as well as long-term steroid therapy, may also be necessary [32].

Ischemic Stroke

Cancer patients are at risk for cerebrovascular complications for three reasons: 1) cancer and its treatment result in disorders of coagulation; 2) cancer may directly affect blood vessels; and 3) infections in individuals who are immunocompromised may result in secondary stroke [36•].

Cancer induces a hypercoagulable state. Tumors produce procoagulant factors, such as tissue factor and cancer procoagulant, and interaction of these with the host blood vessels result in abnormal clotting [36•]. Additionally, there is some downregulation of anticoagulant pathways, activated protein C resistance, or an imbalance between tissue factor expression and tissue factor plasminogen inhibitor [36•]. The normal coagulation balance tips in favor of a hypercoagulable state resulting in localized thrombosis or even a chronic disseminated intravascular coagulation (DIC) in cancer patients. As recently reviewed by Rogers [36•], there are two thrombotic syndromes in cancer that may result in cerebrovascular disease: nonbacterial thrombotic endocarditis (NBTE) and cerebral intravascular thrombosis without NBTE. Graus et al. [37] described nonbacterial thrombotic endocarditis as the most common cause of stroke in cancer patients. This complication—often seen in patients with lung or gastrointestinal mucin-producing adenocarcinoma—results from cardiac vegetations that embolize to main cerebral arteries, often the middle cerebral [36•]. As a result, patients present with typical stroke symptoms such as aphasia, focal weakness, and numbness. Heparin has been recommended in such cases, as well as consideration for valve replacement if the patient is felt to have a reasonable prognosis [36•]. In non-NBTE cerebral thrombosis, the process of thrombosis is more widespread and affects smaller blood vessels than in NBTE cases; heparin is also recommended in such cases [36•]. Because the process is multifocal, more generalized presentations (eg, encephalopathy) than in NBTE are common.

There are also documented cases of embolic stroke from tumor cell embolization and tumors can cause direct compression of blood vessels, especially venous sinuses [38]. In such cases, direct management of the tumor is the only therapy possible [36•].

Venous sinus thrombosis occurring in cancer patients is yet another manifestation of hypercoagulability. Diagnosis is confirmed with magnetic resonance venography and this complication is treated with anticoagulation [39].

Hemorrhagic Stroke

Intracranial blood may be seen in patients with hemorrhagic metastases. Melanoma, lung cancer, and renal cell cancer are the most likely metastatic histologies to be hemorrhagic. Such cases may present with seizures, headache, and are diagnosed and managed in a similar manner to nonhemorrhagic metastases. The occurrence of a consumptive coagulopathy (DIC) may result in intracranial hemorrhage in hematologic malignancy.

Spinal Cord Injury

In the spinal cord, radiation-induced damage may be early-delayed, which is almost always reversible and late-delayed, which is more likely to be permanent [42]. Because the former improves spontaneously, specific treatment is not really necessary. Leung et al. [44] noted Lhermitte’s sign in 121 (10.3%) of 1171 nasopharyngeal carcinoma patients treated with radiation. They also noted that median development time for such signs was 3 months and that it was more likely to happen when the dose to the cervical cord exceeded 48.9 Gy [44]. In rare instances, late-delayed radiation myelopathy has been noted to improve clinically and on imaging [45]. However, in most cases, deficits persist or progress. Patients may present with weakness and sensory loss in the legs and a paraparesis and sensory level are confirmed on examination; another presentation is with Brown-Sequard syndrome [45]. Problems with bladder and bowel control are also possible. MRI of the spinal cord may show increase signal at the level affected and even contrast enhancement [45]. Although anticoagulation and hyperbaric oxygen are used occasionally, corticosteroids are the most commonly used therapy that may result in improvement.

Peripheral Nerve Involvement: Plexus and Individual Nerve Damage from Radiation Therapy

The brachial and lumbosacral plexi may also be involved in the radiation fields for treatment of breast and lung cancers and pelvic tumors respectively. As with CNS involvement, the tempo of the injury helps predict the prognosis. Thus, early-delayed brachial plexopathy occurring in the first few months after treatment usually improves whereas late-delayed injury is a progressive, disabling disorder [42]. In both cases, sensorimotor deficits in the limb supplied by the plexus are typical. EMG and nerve conduction studies are helpful, especially in helping distinguish brachial plexopathy of the late-delayed type from tumor recurrence with infiltration of the plexus. Myokymic discharges on EMG and the absence of severe pain favors radiation damage as the likely diagnosis. Neuroimaging with dedicated MRI of the plexus may show a mass involving the plexus; nonuniform, asymmetric diffuse, or focal enlargement especially eccentric masses with contrast enhancement favor neoplastic infiltration [46, 47, 48•]. In postradiation plexopathy, a more uniform symmetric swelling of the plexus is noted [49, 50]. In difficult cases, plexus biopsy may be necessary. Treatment of radiation-induced plexopathy includes steroids and pain management combined with physical therapy.

Peripheral Neuropathy

Conventional chemotherapy agents such as vinca alkaloids, platinum compounds, and taxanes are well known to cause neuropathy syndromes [53]. However, some newer agents such as bortezomib, a proteosome inhibitor, are also associated with this complication.

The presentation of chemotherapy-induced neuropathy depends on the offending agent and type of neuropathy induced, duration of treatment, and patient-related factors. In sensory neuropathies, numbness, tingling, and pain in the extremity is typical.

Investigation with EMG/NCS is not strictly necessary in most cases but is done occasionally when the presentation is atypical (eg, worsening of symptoms with withdrawal of chemotherapy). In axonopathies, a decrease in the amplitude of action potentials and prolonged latencies are noted. Demyelination results in delayed conduction velocities.

Among prevention strategies for chemotherapy-induced neuropathy, perhaps the most obvious is the limitation in cumulative drug dosing with drugs such as thalidomide or the vinca alkaloids. However, there are chemotherapy-specific strategies, such as the use of magnesium and calcium salt infusions to limit oxaliplatin neuropathy (Table 2). Other examples of specific treatments, as well as a list of nervous system complications of chemotherapy, are provided in Table 2.

Neurologic Complication of Stem Cell Transplantation

The regimen used in stem cell transplantation (SCT) for treatment of cancers such as leukemias and lymphomas has been associated with neurologic complications such as seizures, encephalopathy, and stroke. In addition, severe immunosuppression associated with this treatment may result in severe infections of the nervous system. Allogeneic stem cell transplantation was associated with neurologic complications in 18% of patients at day100 after transplant in a series of patients treated for malignant and nonmalignant disease [54].

Seizures may occur with high-dose busulfan conditioning SCT regimens and benzodiazepine prophylaxis has been advocated in such cases [55]. The occurrence of seizures in this setting has been reported as high as 37% [54].

Encephalopathy may have multiple causes in SCT patients. The chemotherapy agents used are the commonest offenders and ifosfamide, melphalan, and etoposide may all be associated with this complication.

Stroke occurring as a complication of therapy for cancer has been discussed. The severe bone marrow suppression with thrombocytopenia in SCT makes this population high-risk for intracerebral hemorrhage. Hemorrhage can also be a result of septic emboli to the brain caused by opportunistic infections in this population.

Infections

Infections include opportunistic infections with bacteria, viruses, fungi, and parasites. Aspergillus fumigatus is the most common fungal infection in such cases and Toxoplasma gondii is the most common parasite to result in CNS infection. Viruses of the herpes group are very neurotropic and may result in skin eruptions from sensory nerve involvement, as well as encephalitis. JC virus reactivation, a consequence of treatment- or disease-related immunosuppression, results in progressive multifocal leukoencephalopathy with a very poor prognosis.