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(27-51) Autopsy specimen shows bilateral IAC/CPA metastases to CNs VII and VIII . This is colon carcinoma. (Courtesy R. Hewlett, MD.)

(27-52A) Axial T1 C+ scan shows that the cisternal, Meckel cave segments of both trigeminal nerves are thickened, enhance .

(27-52B) Axial T1 C+ in the same patient shows that both oculomotor nerves are also thickened. This is acute lymphoblastic leukemia.

DIFFERENTIAL DIAGNOSIS OF ENLARGED/ENHANCING CRANIAL NERVES

Solitary Cranial Nerve

•Most common

○Schwannoma

○Metastasis (hematogenous, perineural)

•Less common

○Neurofibromatosis type 1 (NF1) (plexiform neurofibroma)

○Multiple sclerosis

○Lymphoma

○Viral/postviral neuritis (including acute disseminated encephalomyelitis)

○Lyme disease

○Neurosarcoid

•Rare but important

○Ischemia, diabetes

○Leukemia

Multiple Cranial Nerves

•Most common

○NF2

○Metastasis (hematogenous > perineural)

•Less common/rare

○Lymphoma

○Chronic interstitial demyelinating polyneuropathy

○Langerhans cell histiocytosis (disseminated)

Paraneoplastic Syndromes

We close this chapter with a brief discussion of cancer-induced remote neurological effects, collectively called paraneoplastic syndromes or paraneoplastic neurologic disorders (PNDs). By definition, PNDs are not related to direct (local or metastatic) tumor invasion, adverse effects of chemotherapy, malnutrition, or infection. In a paraneoplastic syndrome, extra-CNS tumors exert their adverse influence on the brain not via metastasis but indirectly.

Most PNDs are mediated by antibodies against known neural antigens ("onconeuronal antibodies") although some cases appear to be mediated by nonhumoral mechanisms. The most commonly accepted theory of paraneoplastic immune-mediated neurologic injury is that primary tumors contain immune cells such as CD4+T cells, NK cells, macrophages, and dendritic cells. When tumor cells undergo apoptosis, the dendritic cells may phagocytose them and then travel to various lymphoid structures, where they present antigens to various T and even B cells. Activated T cells and autoimmune antibodies then cross the blood-brain barrier, where neurons can be targeted.

Paraneoplastic neurologic syndromes are rare, affecting less than 1% of all patients with systemic cancer. In most cases, a paraneoplastic syndrome is diagnosed only after other etiologies—primarily metastatic disease—have been excluded. However, in 70% of patients with PND, neurologic symptoms are the first manifestation of a tumor.

PNDs may involve any part of the CNS (brain, spinal cord) or peripheral nervous system although the temporal lobes seem to be the most favored site.

Several types of PND have been recognized. These include paraneoplastic limbic encephalitis, paraneoplastic encephalomyelitis, paraneoplastic

cerebellar degeneration, paraneoplastic opsoclonusmyoclonus, paraneoplastic sensorimotor neuropathy, retinopathy, stiff-person syndrome, and Lambert-Eaton myasthenic syndrome.

At least 60% of PND patients have various antineuronal antibodies that can be detected in the serum or CSF, but imaging may offer the first clues to the presence of a possible PND.

We first consider the most common paraneoplastic syndrome—paraneoplastic limbic encephalitis—and then discuss a few miscellaneous PNDs. We conclude with a brief mention of extralimbic paraneoplastic disorders and seronegative autoimmune syndromes that can mimic paraneoplastic limbic encephalitis.

Paraneoplastic

Encephalitis/Encephalomyelitis

Paraneoplastic encephalitis/encephalomyelitis can involve the limbic system, brainstem (midbrain, pons, medulla), cerebellum, or spinal cord.

The most common form of paraneoplastic encephalomyelitis is paraneoplastic limbic encephalitis (PLE). Note that limbic encephalitis is a heterogeneous group of immune-mediated disorders that also includes nonparaneoplastic autoimmune encephalitides such as anti-GAD and LGI1 encephalitis. The nonparaneoplastic autoimmune encephalitides were discussed in Chapter 15.

Four components are generally required for the diagnosis of PLE. These are (1) presence of neurologic symptoms, (2) diagnosis of cancer within 4 years from onset of the neurologic manifestations, (3) exclusion of other neurologic disorders, and (4) at least one of the following: CSF analysis showing inflammation with negative cytology, a temporal lobe lesion on brain MR, or epileptic activity in the temporal lobes on EEG.

Terminology

By definition, paraneoplastic limbic encephalitis is a limbic system disorder. The medial temporal lobes are preferentially involved, but the inferior frontal region, insular cortex, and cingulate gyrus can also be affected.

Etiology

The most frequent neoplasm associated with PLE is small cell lung cancer, identified in about half of all cases. Other associated tumors include testicular neoplasms (20%), breast carcinoma (8%), thymoma, and lymphoma.

Antineuronal antibodies are frequently but not invariably found in the CSF or serum of patients with PLE. The most common is the anti-Hu antibody, which is present in about half the patients with small cell lung cancer-associated PLE. AntiMa2 PLE is associated with testicular germ cell tumors.

Other neuronal autoantibodies include anti-Ri (breast, small cell lung cancer), anti-Yo (ovarian, breast), and anti-Ma2

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(testicular germ cell cancer). These often affect the brainstem (midbrain, pons, medulla) either in isolation or as part of a more widespread autoantibody-mediated encephalitis.

Clinical Issues

Presentation. Neurological symptoms often precede identification of the inciting tumor by weeks or months. The nonspecific nature and diversity of symptoms add to the difficulty of diagnosing PLE. Symptoms gradually develop and evolve over a period of days to weeks. Confusion and shortterm memory loss with relative preservation of other cognitive functions—with or without mood and behavioral changes—are typical. Complex partial seizures are common.

Pathology

The histologic features of PLE are similar to those of viral encephalitis and myelitis. A lymphoplasmacytic inflammatory infiltrate with variable degrees of neuronal loss is typical.

Imaging

MR is the procedure of choice in diagnosing PLE. T2/FLAIR shows hyperintensity in one or both medial temporal lobes

(27-53) (27-54).

PARANEOPLASTIC NEUROLOGICAL DISORDERS AND ANTINEURONAL ANTIBODIES

Paraneoplastic Limbic Encephalitis

•Primary autoantibody = anti-Hu (small cell lung)

•Other = anti-Ma2 (testicular germ cell)

Paraneoplastic Brainstem Encephalitis

•Anti-Hu, Anti-Ri (breast)

•Anti-NMDA (ovarian teratoma)

Paraneoplastic Cerebellar Degeneration

•Primary autoantibody = anti-Yo (ovarian, breast)

•Anti-Hu, anti-Ri, anti-Tr, or pmGLuR1 (Hodgkin lymphoma)

•Anti-VGCC (small cell lung)

Stiff-Person Syndrome

•Primary antineuronal antibody = anti-GAD65

•Other = anti-amphiphysin

Opsoclonus-Myoclonus Syndrome

•Primary antineuronal antibody = anti-Ri

•Other = anti-Yo, anti-Hu, anti-amphiphysin, anti-Nova 1/2

Differential Diagnosis

The major differential diagnosis of PLE is herpes encephalitis. Other causes of LE that can mimic PLE include glutamic acid decarboxylase 65 (GAD65) autoantibody-associated LE, posttransplant acute limbic encephalitis (PALE) syndrome, and human herpesvirus 6 (HHV-6) encephalitis.

Autoimmune nonparaneoplastic LE with positive GAD65 antibodies typically presents with seizures and/or status

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epilepticus. T2/FLAIR hyperintensity in both hippocampi and amygdalae is typical. Enhancement is generally absent.

HHV-6 encephalitis is associated with hematological malignancies such as Hodgkin and angioimmunoblastic T-cell lymphoma and leukemia.

Patients with neurologic manifestations that are unexplained by any other neurologic disorder should be tested for antineural antibodies. Paraneoplastic syndromes that affect the CNS and some of their major antineuronal antibodies are summarized in the box below. Although the sensitivity and specificity of these assays are not 100%, they can be helpful in establishing the diagnosis of a PND.

Miscellaneous Paraneoplastic

Syndromes

Paraneoplastic Cerebellar Degeneration

Paraneoplastic cerebellar degeneration (PCD) is seen in less than 1% of cancers, typically with small cell lung carcinoma, Hodgkin lymphoma, breast cancer, and gynecologic malignancies.

PCD selectively affects the cerebellum and typically presents with ataxia and gait instability, vertigo, dizziness, and oscillopsia. Onset can be acute or subacute and occurs in the absence of brain metastases. Anti-Yo (the most common) or anti-Ri (antineuronal nuclear) antibodies may be detected in the serum and/or CSF of affected patients. Noncerebellar and psychiatric symptoms are more common with anti-Hu PCD.

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Macroscopic abnormalities are generally minimal, most commonly enlargement of the cerebellar folia (27-55). The microscopic hallmark of PCD is widespread severe loss of Purkinje cells with variable loss of granule cells. Inflammatory infiltrates are usually sparse or absent.

MR is normal ("remarkably unremarkable") in most patients. Some cases demonstrate transient cerebellar enlargement with focal or diffuse hyperintensity on FLAIR. Subacute or chronic PCD shows mild to moderate generalized cerebellar atrophy on MR (27-56) and hypometabolism on PET.

Stiff-Person Syndrome

Stiff-person syndrome (SPS), previously known as stiff-man syndrome, is a disorder characterized by fluctuating muscle rigidity and painful spasms. SPS is a reported paraneoplastic neurologic manifestation of breast cancer, especially invasive ductal carcinoma. About 90% of cases are associated with glutamic acid decarboxylase (anti-GAD) antibodies, an

(27-57A) Axial FLAIR scan in a 32y man with a 6- month history of progressive dementia shows enlarged sylvian fissures, prominent temporal horns, and striking volume loss in both hippocampi. Bilaterally symmetric uncal-hippocampal hyperintensity is present. (27-57B) Coronal FLAIR scan shows generalized supratentorial volume loss with symmetric hippocampal hyperintensity .

(27-57C) T1 C+ FS scan shows no evidence of enhancement. (27-57D) Coronal FDG PET scan shows strikingly reduced uptake in both medial temporal lobes . Imaging diagnosis was paraneoplastic limbic encephalitis. Extensive evaluation for systemic neoplasm and infectious pathogens was negative. Final diagnosis was seronegative autoimmune limbic encephalitis (SNALE).

autoantibody that is also often seen in type 1 diabetes mellitus. Less commonly, paraneoplastic SPS is associated with anti-amphiphysin antibodies. The target antigen for antiamphiphysin is a 128-kDa brain protein found at synapses.

Few imaging findings in SPS have been published. MR is usually normal although T2/FLAIR hyperintensity in the medial temporal lobe and F-FDG-PET uptake in the medial temporal lobes have been reported in patients with SPS and those with symptoms of paraneoplastic limbic encephalitis.

Paraneoplastic Opsoclonus-Myoclonus

Syndrome

Paraneoplastic opsoclonus-myoclonus syndrome (OMS) is usually seen in children with neuroblastoma, less commonly in adults with breast or small-cell lung cancer. It is usually associated with anti-Ri antibodies that cross react with two antigens, Nova-1 and Nova-2, that are widely expressed in the CNS.

(27-58A) Coronal bone CT in a 36y woman with tumor-induced osteomalacia caused by a malignant phosphaturic mesenchymal tumor of the skull base shows the partially calcified destructive lesion of the sphenoethmoidal complex .

OMS is characterized by rapid involuntary conjugate eye movements (opsoclonus) and brief, involuntary muscle twitching (myoclonus) with or without ataxia, aphasia, strabismus, or mutism.

VGKC-Associated Encephalitis

Only 25-30% of patients with antibodies against VGKCassociated proteins such as LGI1 and Caspr2 have remote solid organ or hematologic malignancy, primarily small cell lung cancer and thymoma. Imaging findings are nonspecific and include T2/FLAIR hyperintensity in the limbic system and/or basal ganglia (27-54). Reported cases of PET/CT show intense symmetrical uptake in the basal ganglia.

Lobar Extralimbic and Seronegative

Autoimmune Paraneoplastic

Encephalopathies

Lobar extralimbic paraneoplastic encephalopathies and seronegative autoimmune limbic encephalitis have received less attention than the more classic PLE and PCD syndromes. In these syndromes, exhaustive searches for infectious pathogens and autoantibodies are negative.

Imaging findings are similar to those of herpes encephalitis and paraneoplastic limbic encephalitis with uncal-hippocampal T2/FLAIR hyperintensity and hypometabolism on PET (27-57). Some reported cases can resemble glioma with a focal masslike enhancing lesion.

Oncogenic Osteomalacia

(27-58B) Coronal T1 C+ FS shows that the lesion erodes the planum sphenoidale and extends intracranially . Final histopathologic diagnosis was malignant solitary fibrous tumor causing TIO.

syndrome. It usually affects the limbs or axial skeleton but occasionally involves the skull base. Tumors that cause TIO are phosphaturic mesenchymal tumors with mixed connective tissue that secrete fibroblast growth factor 23 (FGF-23). Hemangiopericytoma (malignant solitary fibrous tumor) causes approximately 70-80% of TIO cases (27-58).

IMAGING OF MAJOR PARANEOPLASTIC

NEUROLOGICAL DISORDERS

Paraneoplastic Encephalomyelitis

•Limbic encephalitis most common form

•T2/FLAIR hyperintensity in one or both medial temporal lobes

•No enhancement on T1 C+

Paraneoplastic Cerebellar Degeneration

•Usually normal

•Subacute/chronic may show cerebellar atrophy

Stiff-Person Syndrome

•Usually normal

•SPS with limbic encephalitis may exhibit T2/FLAIR hyperintensity in medial temporal lobes

•F-FDG-PET may show hypermetabolism in medial temporal lobes

Voltage-Gated Potassium Channel-Complex Disorders

•Only 25% associated with systemic malignancy

•T2/FLAIR hyperintensity in medial temporal lobes, basal ganglia

•PET/CT intense uptake in basal ganglia