Introduction
Paraneoplastic neurological disorder (PND) syndromes are immune-mediated disorders that affect the central, peripheral, or autonomic nervous system in the setting of a cancer. These disorders are not caused by a direct tissue invasion of cancer; instead, they are associated with cancer-induced immune responses directed toward neuronal proteins. They are extremely rare, estimated to affect less than 0.1% of patients with cancer. This, however, is likely an underestimate. The recognition of PND syndromes is crucial given that they often occur before the diagnosis of a cancer or a cancer recurrence, offering an opportunity to diagnose and treat cancer earlier and with associated improved outcomes.
PND syndromes may be related to benign tumors, such as thymoma, or malignant tumors, such as small-cell carcinoma of the lung (SCLC) and breast cancer. SCLC is the most frequent malignancy associated with PND syndromes. The most commonly accepted theory is that the immune system reacts against proteins expressed by tumors, which are similar to neuronal proteins, allowing for a response to cancer as well as a mistaken response against the brain, spinal cord, nerves, neuromuscular junction, or muscle individually as well as in combination. Several antibodies have been described since the first report in 1949 (e.g., anti-Hu, anti-CV2/collapsing response mediator protein 5 [CRMP5/CV2], anti– N -methyl- d -aspartate receptor [NMDAR] and anti-Yo). , These antibodies can recognize intracellular as well as cell-surface antigens, and their associated syndromes differ in terms of clinical profile, pathogenesis, and outcome.
In this chapter, we will present case-based discussions of the classic PND syndromes as well as paraneoplastic mononeuritis multiplex (MM), with special attention paid to their respective clinical presentations, treatments, and prognoses. We begin with a brief discussion of the classification, pathophysiology, clinical presentation, general diagnostic approach, and treatments. This is followed by a case-based presentation of the common and clinically relevant PND syndromes.
Classification
Broadly, PND syndromes can be classified by the location of the antibody target and, specifically, whether the target is an intracellular antigen or an antigen found on the neuronal cell surface.
Intracellular antigen syndromes . Antibodies to intracellular antigens are associated with subacute onset, progressive illness, and poor outcomes, given that they result from rapid and irreversible neuronal damage. These antibodies can recognize any area of the neuroaxis in isolation or combination, leading to characteristic syndromes such as paraneoplastic cerebellar degeneration (PCD), limbic encephalitis, and sensory neuronopathy. PND syndromes have been associated with anti-Hu, anti-Yo, anti-CRMP5/CV2, anti-Ri, anti-Ma1, anti-Ma2, anti-amphiphysin, anti-Purkinje cell antibody type 2 (PCA-2), and anti-neuronal nuclear antibody type 3 (ANNA-3), among others. Detection of these antibodies should be followed by screening for an occult neoplasm. Their pathophysiology is thought to be primarily mediated by CD8+ T lymphocytes that induce cell death through cytotoxic activity. As a consequence, motor and sensory functions are markedly affected in these patients. , For instance, in anti-Yo PCD, 90% of patients become non-ambulatory. , Tumor treatment is related to the stabilization of neurological syndrome, rather than improvement.
Cell surface antigen syndromes . There are also syndromes associated with antibodies against cell-surface antigens targeting membrane receptors, ion channels, and synaptic proteins that occur less commonly in the setting of cancer ( Table 20.1 ). The past decade has seen a rise in the number of newly described syndromes. They are typically associated with better response to immunotherapy and thus better outcomes. Some of these antibodies include anti-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), anti-gamma-aminobutyric acid type B receptor (GABA B ), anti-GABA A receptor, anti-NMDAR, anti-dipeptidyl-peptidase-like protein 6 (DPPX), anti-voltage gated calcium channel (VGCC; associated with malignant tumors), anti-leucine-rich glioma inactivated 1 (LGI1), and anti-contactin-associated protein 2 (CASPR2). In some instances, the antibodies against cell-surface proteins appear to be related directly with the disease pathophysiology. For instance, antibodies to the NMDA receptor crosslink the receptor, leading to receptor internalization, whereas antibodies against LGI1 interfere with protein-protein interactions. , Clinical presentation varies from limbic encephalitis to, more rarely, cerebellar ataxia and dysautonomia.
| Antigens | Antibody | Associated Cancers |
|---|---|---|
| Intracellular | anti-Tr | Hodgkin lymphoma Non-Hodgkin lymphoma |
| anti-PCA-2 | SCLC | |
| anti-ANNA-3 | SCLC, lung, and esophageal adenocarcinoma | |
| anti-Ma1 | Breast, parotid, colon, lung, testis, and ovarian cancer | |
| anti-Recoverin | SCLC | |
| anti-Zic4 | SCLC, Hodgkin lymphoma, ovarian cancer | |
| anti-Hu (ANNA-1) | SCLC and other neuroendocrine tumors | |
| anti-Yo (anti-PCA-1) | Breast, ovary, endometrium, and fallopian tube cancers | |
| anti-CRMP5 (CV2) | SCLC and thymoma | |
| anti-Ri (ANNA-2) | Breast cancer, gynecologic cancers, and SCLC | |
| anti-Ma2 | Testicular cancer | |
| anti-amphiphysin | Breast cancer, ovarian carcinoma, SCLC | |
| Cell-surface | anti-NMDAR | Ovarian teratomas, SCLC, uterine adenocarcinoma, prostate adenocarcinoma, Hodgkin lymphoma, pineal dysgerminoma, neuroblastoma, and NETs |
| anti-LGI1 | Thymoma, lung cancer, NETs, abdominal mesothelioma | |
| anti-CASPR2 | Thymomas, lung cancer, endometrial adenocarcinoma | |
| anti-AMPAR | Hematologic malignancy, cutaneous T-cell lymphoma | |
| anti-GABA A receptor | Prostate cancer | |
| anti-GABA B receptor | SCLC | |
| anti-GlyR | Hodgkin lymphoma | |
| anti-DPPX | B-cell lymphoma | |
| anti-mGluR1 | Hodgkin lymphoma, prostate adenocarcinoma | |
| anti-mGluR5 | Hodgkin lymphoma | |
| anti-VGCC | Brain, breast, kidney, and lung cancers | |
| anti-Ganglionic α 3-AchR | SCLC, adenocarcinomas | |
| anti-Muscular α 1-AchR | Thymoma, SCLC |
Pathophysiology
Although the pathophysiology of PND syndromes is incompletely understood, autoimmune responses are believed to be involved, with patients developing T-cells and antibodies that are directed against antigens of the central nervous system (CNS), peripheral nervous system (PNS), or autonomic nervous system. When the body surveys for and attempts to eliminate tumor cells, an immune reaction is triggered against tumor antigens. This immune reaction mistakenly cross-reacts with similar proteins on neural tissues. In other cases, the cause is not identified; however, a previous viral infection or a family history of autoimmune diseases may play a role. In addition, cancer treatments such as immunologic checkpoint inhibitors may also provoke autoimmune reactions leading to neurological immune-related adverse events similar in many respects to PND syndromes (also see Chapter 30 for discussion of neurological syndromes associated with immune checkpoint inhibitors).
These anti-cancer immune responses often yield antineuronal antibodies that can be measured in the cerebrospinal fluid (CSF), as well as the serum. Antibodies facilitate the localization of an occult neoplasm associated with the PND syndrome and, in some cases, can narrow the search to a few associated organs. Seronegative cases appear to be mediated by cellular immune effectors or may reflect yet to be described syndromes. Further studies are necessary to clarify this mechanism.
Tumor prognosis is believed to be better among patients with PND syndromes as often the neoplasm is asymptomatic or undetectable at the time of presentation. However, a review of large series of patients has demonstrated that the oncologic outcome of patients with PND syndromes is not different from those patients who do not have antibodies against neural tissues.
Clinical presentation
PND syndromes may manifest in different ways such as encephalitis (inflammation of the brain), myelitis (inflammation of the spinal cord), cerebellar degeneration (ataxia, dysarthria), neuropathy (progressive numbness and weakness in lower and upper extremities), myoclonus/opsoclonus (involuntary, rapid, irregular body jerks and multidirectional eye movements), Lambert-Eaton myasthenic syndrome (LEMS; weakness of several muscle groups), and dermatomyositis (DM; proximal weakness and skin lesions). Clinical presentations may develop acutely over the course of a few days or subacutely over the course of weeks or months.
General diagnostic approach
The diagnostic evaluation for a PND syndrome should begin with a complete medical examination, including palpation of lymph nodes, breasts and testes, rectal and pelvis, and neurological examination. Diagnostic testing of the CNS includes: (1) lumbar puncture with CSF analysis (e.g., white blood cell [WBC], glucose, protein, oligoclonal bands, immunoglobulin G [IgG] index, molecular and immunologic testing, cultures, and flow cytometry), (2) MRI of the brain and/or spinal cord, and (3) electroencephalography (EEG). Paraneoplastic antibody panel testing in both serum and CSF helps to identify autoimmune markers and paraneoplastic etiologies. Electromyographic and nerve conduction studies (EMG and NCS) should be performed if neuropathy, myasthenia, or myopathy raise suspicion for PNS involvement. Serum paraneoplastic autoantibody testing alone is appropriate for evaluation of these peripheral syndromes. Serum tumor markers are also useful as part of the malignancy screen, for instance, carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), cancer antigen 125 (CA-125), and prostate-specific antigen (PSA). CT of the chest, abdomen, and pelvis are helpful in evaluating for an occult malignancy, as are testicular and vaginal ultrasounds and mammography. Other tests that should be included are complete blood cell count with platelets (to assess for infection and immunosuppression), prothrombin time and activated partial thromboplastin time, electrolytes and osmolarity, toxicology screen, vitamin levels, liver function tests, and infectious tests. In the event that initial tumor screening is not revealing, repeat screening 3–6 months after the initial evaluation, and every 6 months up until 4 years is advised for patients with a diagnosis of a PND syndrome.
Typical findings in a PND syndrome involving the CNS include CSF pleocytosis, hyperproteinorachie (i.e., elevated spinal fluid protein), intensification of intrathecal immunoglobulin synthesis and presence of oligoclonal bands. MRI of the brain may reveal T2-weighted hyperintense signals or atrophy in different parts of the brain or spinal cord, depending of the neurological syndrome. EEG may demonstrate focal slowing, focal or diffuse paroxysmal sharp waves, or electrographic seizures.
General treatment considerations and prognosis
The first approach to a PND syndrome should be tumor treatment as appropriate for the given malignancy with hopes of removing the immune response target. Studies have shown that rapid antitumor treatment is associated with a higher likelihood of neurologic improvement or stabilization as well as lower mortality rates. Initial treatment includes corticosteroids (e.g., intravenous methylprednisolone or prednisone), intravenous immunoglobulin (IVIg), and plasmapheresis. Alternative immunosuppressant medications that may be considered include mycophenolate mofetil, rituximab, azathioprine, and cyclophosphamide. The latter agents are typically used for chronic immunosuppression.
Some PND syndromes respond better to treatment than others. For instance, immunosuppressive therapy (e.g., corticosteroids, plasmapheresis, and IVIg) is usually effective for myasthenia gravis (MG), encephalitis, and LEMS. In contrast, syndromes such as PCD, encephalomyelitis (EM), and limbic encephalitis tend to be resistant to first-line immunotherapy and may require early use of cyclophosphamide or rituximab.
The failure of a PND syndrome to respond to therapy may be related to irreversible neuronal damage. In rare cases, patients may develop a recurrent PND syndrome after recovery, revealing a cancer relapse or the development of a new primary cancer.
Clinical cases: classic and common paraneoplastic neurological disorder syndromes
Case . A 24-year-old woman without a significant past medical or family history presented to the emergency room with subacute onset of anxiety, agitation, insomnia, auditory hallucinations, and paranoid ideations with subsequent progression to mutism and catatonia, choreiform movements, seizures, and confusion. Her initial general medical examination was notable for evidence of anxiety without other neurological findings. MRI of the brain was unremarkable ( Fig. 20.1 ). CSF assessment demonstrated a lymphocytic predominant pleocytosis (WBC: 26 cells/mm , 97% lymphocytes), normal glucose (72 mg/dL), low protein (14 mg/dL), normal IgG index (0.4), and no oligoclonal bands in CSF or serum. CSF venereal disease research laboratory (VDRL), Lyme, human herpesvirus 6 (HHV-6), West Nile virus (WNV), herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), enterovirus polymerase chain reactions (PCRs), and serological tests were negative, as were gram stain cultures and cytology. Toxic, metabolic, and nutritional testing as well as serum tumor markers were normal. EEG demonstrated right frontotemporal seizures and episodes of lateralized body shaking without associated epileptiform changes. Anti– N -methyl- d -aspartate receptor (anti-NMDAR) antibodies were reported as positive at a titer of 1:160 in serum. She was treated with intravenous corticosteroids and IVIg over 5 days. CT imaging demonstrated a mass compatible with right ovarian teratoma. She underwent a laparoscopic ovarian cystectomy with the removal of the dermoid cyst on the right ovary and pathology confirmed the diagnosis of a teratoma. Three months later, she developed dysautonomia symptoms (urinary retention, hypertension, tachycardia, and hyperthermia), disorientation, inattention, confusion, agitation and aggressiveness, seizures, dysphagia, and self-injurious behaviors. A follow-up CT study demonstrated a 12-mm lesion on the left ovary contralateral to the area of prior resection, concerning for an ovarian teratoma ( Fig. 20.2 ). She underwent resection of the left ovary, and pathology was consistent with teratoma. Following surgery, she became less violent and agitated, although she did not return to her baseline status. She received five treatments of plasmapheresis, as well as three doses of rituximab, with slow modest improvement. After hospital discharge, she experienced gradual improvement; however, she continued to experience episodes of movement and psychiatric disorders (bipolar mania), and cognitive impairment (inattention). This resolved in time. After nearly 5 years, she has not experienced new episodes of hallucinations, psychiatric disorders, seizures or other focal neurological symptoms. She was weaned off antipsychotic medications without issue.
Teaching Points . This case provides a typical presentation of anti-NMDAR encephalitis in the setting of ovarian teratoma and highlights several important teaching points including (1) the common neuropsychiatric features that occur at presentation in patients with encephalitis and limbic encephalitis, (2) that neuroimaging may be normal and CSF analysis may reveal subtle findings that require a high index of suspicion, and (3) source control with identification and removal of the associated neoplasm is paramount. In this case, the patient presented with prominent neuropsychiatric signs and symptoms that included hallucinations, paranoid ideations, choreiform movements, new-onset seizures, and mutism. Although primary mental illnesses can develop in the third decade, the subacute onset of symptoms required evaluation of explanatory pathology. Workup revealed only a mild lymphocytic pleocytosis and the clinician must have an appropriate index of suspicion for sending antibody testing in both the serum and CSF. In this case, control of the associated malignancy—the ovarian teratomas—was critical for managing the patient.
Paraneoplastic encephalitis
Definition and epidemiology . Encephalitis is an infectious or autoimmune condition of the brain, potentially involving the limbic system as well as other cortical and subcortical areas. Two types of autoimmune encephalitis have been described: (1) paraneoplastic encephalitis syndromes associated with cancer which typically involve antibodies to intracellular proteins, and (2) autoimmune encephalitis syndromes occurring in the absence of cancer which are more frequently observed in the setting of antibodies to cell surface proteins. Encephalitis can also occur with restricted involvement of limbic structures (e.g., hypothalamus, cingulate gyrus, insula, hippocampus, and amygdala).
History . In 1968, postinflammatory changes in the mesial temporal lobes were described among patients with progressive memory loss in the setting of lung cancer. Over a decade later, anti-Hu antibodies were discovered and associated with the pathogenesis of this disease. Subsequently, several antibodies have been associated with encephalitis and limbic encephalitis, including anti-Hu, anti-Ma2 (anti-TA), anti-NMDAR, anti–metabotropic glutamate receptor 5 (anti-mGluR5), anti-GABA B receptor, anti-AMPAR, anti-LGI1 and anti-CASPR2. Not all autoimmune encephalitis and limbic encephalitis syndromes are paraneoplastic. For instance, in anti-LGI1 encephalitis, less than 10% of cases are paraneoplastic.
Epidemiology . As paraneoplastic syndromes, encephalitis and limbic encephalitis are estimated to affect 1 per 10,000 patients with cancer, with 50% of cases occurring in the setting of SCLC, 20% with testicular tumors, and 8% with breast cancer. ,
Classification . It is important to mention that not all paraneoplastic encephalitis can be categorized as limbic encephalitis. For instance, anti-NMDAR encephalitis is the most studied autoimmune encephalitis to date, and the majority do not follow the classic clinical and radiological profile for limbic encephalitis. , , This syndrome has been identified in association with neoplasms in less than 50% of cases, mainly ovarian teratoma, and in a few cases with other types of tumors such as testicular germ cell tumor, Hodgkin lymphoma, mediastinal teratoma, and SCLC.
Pathophysiology . Histopathology of patients with paraneoplastic encephalitis demonstrates T-cell infiltration, neural loss, and microglial activation in the hippocampus, amygdala, insula, orbitofrontal cortex, hippocampal gyrus, cingulate gyrus, thalamus, and hypothalamus. , Patients may have lesions in other non-limbic areas such as cerebral hemispheres, subcortical grey matter, brainstem, cerebellum, spinal cord, dorsal root, and autonomic ganglia. For instance, patients with anti-CRMP5 (anti-CV2) antibodies and limbic encephalitis may have extra-limbic lesions of the cerebral cortex or basal ganglia. The inflammatory changes do not necessarily correlate with the clinical presentation or neuronal loss.
Whereas some paraneoplastic syndromes appear to be driven by cell-mediated inflammatory responses, others appear to be largely antibody driven. For example, anti-NMDAR encephalitis, in the presence or absence of cancer, is mediated by antibodies against the GluN1 subunit. Three immunopathogenic mechanisms have been proposed :
- 1.
Receptor internalization: antibody-mediated endocytosis of cell surface receptors that results in movement of receptors from the plasma membrane to the inside of the cell.
- 2.
Antibody blockade of ion entry: when bound to their receptor, these antibodies obstruct enzyme function and prevent ion entry into the cell.
- 3.
Complement-mediated cell lysis: antibody-induced activation of the complement cascade.
Molecular mimicry of the NMDA receptors appears to be the trigger of the autoimmune dysregulation. The tumor cell’s antigens are taken by antigen-presenting cells, activating an immune cascade, and plasma cells which produce antibodies cross-react with NMDA receptors in the brain.
Clinical presentation . Encephalitis and limbic encephalitis can precede tumor diagnosis by many months or years. Also, there are recent cases of patients with cancer who develop these syndromes after the initiation of immune checkpoint inhibitors (also see Chapter 30 for discussion of neurological syndromes from immune checkpoint inhibitors). The clinical presentation is characterized by a subacute onset developing over days to weeks. Patients usually present with cognitive dysfunction (e.g., disorientation, altered mental status, short-term memory loss); psychiatric symptoms (e.g., change in personality, irritability, hallucinations, depression, anxiety, emotional lability, aggression, disinhibited behavior, bipolar disorder); paresis; catatonia; generalized, partial, or complex seizures; dysautonomia; and movement disorders (e.g., orofacial dyskinesia or choreoathetosis). Frequently, patients initially present to medical attention when psychiatric symptoms develop, which are often first seen by a psychiatrist and misdiagnosed as an initial presentation of a psychiatric disorder in 40% of the cases.
In anti-NMDAR encephalitis, adult patients typically develop memory loss and psychiatric disorders. Children, however, frequently experience seizures or movement disorders (e.g., orofacial dyskinesias, dystonic posturing, choreoathetoid movements, or general rigidity) without severe behavioral changes. Seizures commonly occur after a few weeks of on set. Patients may develop agitation or catatonia, central hypoventilation, and autonomic dysfunction.
Diagnostic approach. In patients with autoimmune/paraneoplastic encephalitis or limbic encephalitis, MRI of the brain is unremarkable in more than 50% of cases, but abnormalities may become evident later. Regarding autoantibody testing, both blood and CSF antibody testing should be performed given reports of increased sensitivity of CSF antibody testing over serum in anti-NMDAR encephalitis. EEG is abnormal in up to 90% of cases, commonly showing sharp and slow waves in the temporal lobes in addition to electrographic seizures. , Fluorodeoxyglucose positron emission tomography scanning (FDG-PET) scan was observed to be more sensitive than brain MRI in one retrospective study, warranting prospective evaluation. In addition, occipital lobe hypometabolism appears to be a biomarker for anti-NMDAR encephalitis, suggesting the potential role of FDG-PET not only in the diagnosis of autoimmune encephalitis and limbic encephalitis but also specific antibody syndromes. , First-line screening for underlying malignancies is done with MRI, CT, and ultrasound, as appropriate for the suspected malignancy. Serological tumor markers are usually negative in most patients. Brain biopsy typically shows normal tissue or nonspecific inflammatory changes (e.g., neuronal loss, astrocytosis, inflammatory infiltration of perivascular and leptomeningeal tissue), and is therefore a high-risk diagnostic approach with low benefit. ,
Diagnostic criteria . The diagnosis of encephalitis and limbic encephalitis is difficult and commonly involves the exclusion of other clinical syndromes, which may present similarly. Recent consensus clinical diagnostic criteria are useful in making the diagnosis of encephalitis.
Possible autoimmune or paraneoplastic encephalitis . The clinical diagnosis of possible autoimmune encephalitis can be made when three of the following criteria is present: (1) rapid progression (within 3 months) of working memory deficits, seizures, or psychiatric symptoms; (2) at least one of the following: new focal CNS findings, new onset of seizures, CSF pleocytosis, MRI suggestive of encephalitis (T2/fluid attenuated inversion recovery [FLAIR] hyperintensities in medial temporal lobes, T2/FLAIR hyperintensities in multifocal areas of grey, white matter, or both compatible with demyelination or inflammation), and (3) exclusion of other possible causes. ,
Definite limbic encephalitis . The clinical diagnosis of definite limbic encephalitis requires that all four of the following criteria are met: (1) rapid progression (within 3 months) of working memory deficits, seizures or psychiatric symptoms, (2) T2-FLAIR MRI or FDG-PET scan demonstrating unilateral or bilateral abnormalities primarily in medial temporal lobes, (3) at least one of the following: CSF pleocytosis, or EEG showing epileptic or slow-wave activity involving one or both temporal lobes, (4) exclusion of other possible causes.
Treatment . Encephalitis associated with cell-surface antibodies or synaptic proteins (e.g., GABA B receptor, anti-NMDAR, anti-AMPAR, anti-LGI1) is typically responsive to first-line immunosuppressive therapies. In the setting of refractory encephalitis or minimal response, rituximab or cyclophosphamide are used as second-line options. Tocilizumab and bortezomib have shown additional benefits in cases of refractory anti-NMDAR encephalitis. Studies report that tocilizumab has better long-term outcomes than rituximab, whereas bortezomib therapy led to a fall in CSF antibodies levels and correlation with clinical improvement. Treatment of associated seizures may require multiple anticonvulsant medications. Catatonia has been managed with benzodiazepines (e.g., lorazepam) and, in some cases, with amantadine. ,
Prognosis . In general, cancer diagnosis and early treatment improve outcomes and prognosis. Patients with anti-Hu and anti-Ma/Ta antibodies have a poor prognosis given their strong associations with aggressive cancers, although seronegative cases may have a better prognosis. Patients with anti-GABA B receptor encephalitis typically respond well to immunosuppressant medications. , Anti-NMDAR, anti-AMPAR, anti-GABA B receptor, anti-CASPR2, and anti-LGI1 encephalitis are also associated with excellent outcomes; however, these conditions may relapse. , For instance, among those with anti-NMDAR encephalitis, 80% achieve their clinical baseline and 12–25% experience relapse within 24 months. , The prognosis is more favorable if immunotherapy is initiated in the first 4 months of symptom onset. After discharge, a multidisciplinary group of specialists should be involved in the treatment of impairments in attention, memory, executive function, and vision. However, these sequelae could persist for many years and impair patients’ ability to return to their pre-morbid independence in daily life.
Case . A 42-year-old woman with a past medical history of left breast cancer treated by unilateral mastectomy, chemoradiation, and tamoxifen; migraines; and possible complex partial seizures presented to the emergency room for a subacute onset of leg weakness, fatigue, and memory loss. On examination, she had long-term memory impairment, difficulty with ambulation, and wide-based gait, with normal motor and sensory examinations. CSF findings were notable for a lymphocytic pleocytosis (WBC 120 cell/μL, 99% lymphocytes) and elevated protein (91 mg/dL), low glucose (48 mg/dL), a mildly elevated IgG index (0.9), and presence of oligoclonal bands in CSF only. CSF VDRL, Lyme, HHV-6, WNV, HSV, VZV, EBV, CMV, enterovirus PCRs, serology testing, gram stain, cultures and cytology were negative. Spinal cord and brain MRI demonstrated T2/FLAIR hyperintensities of the hypothalamus and gray matter of the spinal cord from C1 to the conus, without associated enhancement ( Figs. 20.3 and 20.4 ). Paraneoplastic antibody testing demonstrated anti-Ri antibody in serum. In addition, erythrocyte sedimentation rate was elevated (35 mm/h) and metabolic testing including vitamin D, aldolase, copper, zinc, vitamin B 12 , vitamin B 1 , TSH, and methylmalonic acid, were all within normal limits. Serological assays for antineutrophil cytoplasmic antibodies (ANCA), double-stranded DNA, Ro/La, and syphilis were normal. Mammography and FDG-PET scan did not demonstrate evidence of breast cancer recurrence. She was treated with corticosteroids for 5 days, followed by a corticosteroid taper with improvement of her symptoms. After discharge, she slowly deteriorated despite aggressive immunotherapy, and 4 months later, she died of a cardiac arrest.
Teaching Points . This case demonstrates the spectrum of potential CNS involvement that can occur in patients with encephalomyelitis. Paraneoplastic encephalomyelitis (EM) is characterized by multifocal inflammation involving the brain, brainstem, and/or spinal cord. This case highlights the difficulty in treating patients with intracellular antigen syndromes. In contrast to the favorable outcome of the patient in Case 20.1 with a cell-surface antibody syndrome, this patient failed to respond to aggressive immunotherapy which could not rescue her progressive deterioration in neurological function, and she ultimately died.
Paraneoplastic encephalomyelitis
Definition and Epidemiology . EM is a multifocal inflammatory disorder that affects several areas of the central nervous system in association with a neoplasm, postinfectious process, or other autoimmune-related syndromes. Post-infectious and post-vaccinal encephalomyelitis account for 75% of cases. Postvaccine-encephalomyelitis cases have been described with rabies, tetanus, polio, measles, mumps, rubella, Japanese B encephalitis, pertussis, and influenza vaccines. In contrast, the incidence of paraneoplastic EM is unknown. Approximately 0.4% of patients with bronchial carcinoma develop this syndrome without predilection for either sex. With that said, anti-Hu associated with EM is slightly more prevalent in females. The most common associated malignancy is SCLC (75% of cases), although other associated cancers have been reported such as lung adenocarcinoma, multiple myeloma, lymphoma, chondrosarcoma, and neuroblastomas. Middle-aged and older adults are typically affected.
EM most frequently involves the temporal lobe limbic structures, brainstem, spinal cord, dorsal root ganglia, and autonomic nervous system. , , Several antibodies have been associated with EM including anti-Hu, anti-CRMP5/CV2, anti-Ma2, anti-amphiphysin, anti-Yo, anti-Ta, anti-Ma1, anti-LG1, and anti-PCA-2. ,
Pathophysiology . Anti-Hu antibodies are the most common antibodies detected in EM. These antibodies react with RNA-binding proteins (e.g., PLE21/HuC, HuD, HuR, Hel-N1) affecting the function of the CNS. Pathologic examination demonstrates perivascular and interstitial lymphocytic infiltrates, neuronophagic nodules, neuronal loss, gliosis, and plasma cell infiltration. , In addition, studies have reported the presence of HSV by PCR and 14-3-3 protein in patients with paraneoplastic EM, but the significance of these findings is still unknown. ,
Clinical presentation . Generally, EM follows a subacute onset with a subsequent progression over weeks to months before achieving a clinical plateau. The typical presentation is characterized by psychiatric symptoms, cognitive impairment, seizures, cranial nerve palsies, cerebellar signs, sensory-motor neuropathy or motor neuron dysfunction, and dysautonomia. , , , Isolated symptoms are extremely rare, although isolated cerebellar presentations have been described.
Diagnostic approach . Brain and spinal cord MRI with and without gadolinium are the image studies of choice to evaluate symptoms and signs of myelopathy. The diagnosis is supported by infratentorial and supratentorial grey and white matter lesions, and the absence of destructive hypointense white matter lesions on T1-weighted MRI in the chronic stages of the disease. However, most patients have unremarkable imaging of the brain. , In contrast, MRI abnormalities in the spinal cord are more frequent, with 60–70% of patients developing longitudinally extensive lesions often associated with contrast enhancement. FDG-PET scan may show hypermetabolism of limbic structures initially, and hypometabolism during recovery. The most frequently detected antibodies include anti-Hu, anti-CRMP5/CV2, and, less frequently, anti-amphiphysin antibodies.
Treatment . Paraneoplastic EM tends to be resistant to immunosuppression, and clinical trials have not been done. In this setting, the use of second-line immunotherapies such as rituximab and cyclophosphamide should be considered early. A case report described the use of rituximab and cyclophosphamide with partial improvement. Prompt control of the tumor while also treating with immunosuppressive therapy may help to stabilize the course of the syndrome.
Prognosis . The clinical course of paraneoplastic EM is uncertain. High titers of anti-Hu antibodies are related to worse outcomes, including death, most likely because of the strong association of this antibody with SCLC. Patients with brainstem and autonomic dysfunction, in general, develop worse outcomes and have a high mortality rate. Although resection and treatment of the associated tumor improve outcomes, neurological function rarely improves without treatment. , Paresis and paraparesis are common, and patients benefit from physical therapy and deep venous thrombosis prophylaxis. In children, the syndrome has worse outcomes and is associated with cognitive impairment and long-lasting seizures. Anticonvulsants such as fosphenytoin have been used for seizure management.
Case . A 70-year-old woman with a past medical history of hypertension, type 2 diabetes mellitus, gallstone pancreatitis, and gastroesophageal reflux presented to the emergency room with a subacute onset of memory loss followed by progressive irritability, difficulty reading and writing, diplopia, dysarthria, and gait disturbance associated with unintentional weight loss. Her neurological examination demonstrated dysarthria, rotational nystagmus noted in all directions, dysmetria, dysdiadochokinesia, and ataxia. CSF testing revealed normal WBC (2 cell/mm 3 ), hyperproteinorachie (59 mg/dL), normal glucose (90 mg/dL), and presence of oligoclonal bands in CSF only. VZV, EBV, CMV, HSV PCRs and serological tests were negative, as were gram stain, cultures, and cytology. Paraneoplastic antibody testing, metabolic, and rheumatologic tests were unremarkable. Brain MRI demonstrated bilateral cerebellar atrophy and anterior temporal lobe encephalomalacia ( Fig. 20.5 ). CT scan of the chest and abdomen demonstrated a right middle lobe nodule, multiple pulmonary nodules in the left lower lobe, and a heterogeneously enlarged left thyroid lobe with the presence of numerous hypodense nodules. Ultrasound of the thyroid demonstrated a multinodular goiter with more nodules in the left lobe as compared with the right. Thyroid biopsy did not demonstrate evidence of malignancy. FDG-PET scan revealed an active hypermetabolic right middle lobe pulmonary nodule with a prominently enlarged and hypermetabolic subcarinal lymph node ( Fig. 20.6 ). Bronchoscopy with endobronchial ultrasound-guided biopsies confirmed a diagnosis of metastatic grade 1 neuroendocrine lung carcinoma. She underwent surgery and chemotherapy for lung cancer and received treatment with IVIg for 5 days with partial improvement. After discharge, she continued treatment with IVIg and mycophenolate as well as physical and speech therapy. Over the 2 years following diagnosis, she has experienced progressive improvement of her symptoms; however, dysphagia remains an issue.
Teaching Points . This case highlights the common and uncommon tumors associated with PND syndromes. PCD is classically associated with breast and ovarian malignancies. However, neuroendocrine tumors including small-cell carcinoma (e.g., SCLC) and hematologic malignancies such as lymphoma are not infrequently associated with PND syndromes and should be considered in patients who present with a typical clinical syndrome. Also, this patient was seronegative for a paraneoplastic autoantibody, as is observed in 50% of cases of PCD, emphasizing the importance of syndrome recognition.
Paraneoplastic cerebellar degeneration
Definition and epidemiology . PCD is one of the most devasting PND syndromes. This condition was first described in 1919, but its association with neoplastic tumors was established in 1951. This syndrome is commonly associated with Hodgkin lymphoma, ovarian, breast, and SCLC, and rarely with prostate and gastrointestinal tumors (gastric and esophageal tumors). , , Women are more frequently affected than men in a proportion of 7:3. In the United States, PCD occurs in approximately 2 of 1,000 patients with cancer. The most common and specific subtype of PCD is the syndrome related to anti-Yo (PCA-1), accounting for 50% of cases. PCD manifests in different age ranges. Anti-Yo and anti-Hu associated PCD typically occurs among middle-aged patients with breast or ovarian (anti-Yo) and lung cancer (anti-Hu) whereas patients with anti-Tr associated PCD are typically young men with Hodgkin lymphoma. In accordance with the rarity of this syndrome, the literature is largely limited to case series and reports.
Pathophysiology . Antibodies seem to be involved at the initial stage of the disorder; however, the T-cell immune response appears to be principally responsible for PCD ( Table 20.2 ). The Yo antigen is a protein found in the cytoplasm that interacts with c-Myc in the Purkinje cells of the cerebellum. T cells recognize the antigen and cause severe or complete loss of Purkinje cells which is eventually seen by brain MRI. , This condition initially affects the vermis and midline cerebellum and later the cerebellar hemispheres. Approximately half of patients with PCD are seronegative for an associated antibody on commercially available testing. Thus, clinical recognition of PCD rather than reliance on antibody testing results should guide concern for malignancy. ,
| Antibody | Related tumor | Features |
|---|---|---|
| Anti-Yo | Gynecological malignancies (ovarian, pelvic related malignancies including of the fallopian tube, uterus, and cervix) Breast carcinoma | Precedes the cancer diagnosis By the time of neurological presentation, cancer is metastatic to regional lymph nodes |
| Anti-Tr or PCA-Tr | Hodgkin lymphoma | 80% of cases after diagnosis or remission Less severe Stabilize with treatment |
| anti-Hu (ANNA-1) | SCLC (most common) Others: pancreas, prostate, cervix, and skin | Sensory or sensorimotor neuropathy (most common), cerebellar ataxia (10–20%), limbic encephalitis, or gastrointestinal dysmotility |
| anti-Ri (ANNA-2) | Lung (SCLC and non-small cell) and breast carcinoma | 50% of patients have cerebellar degeneration. A better outcome than anti-Hu or ANNA-1 Median survival >60 months PCD with opsoclonus has a better prognosis |
| anti-CRMP5 (CV2) | SCLC Less common, thymoma | Neuropathy, dementia, chorea, cranial neuropathy, optic neuropathy Cerebellar ataxia (25%), usually in combination with the above disorders |
Clinical presentation . PCD is a condition that evolves over the course of a few weeks to months. It usually starts as mild unsteadiness when walking associated with episodic vertigo, motion sickness, ataxic dysarthria, and diplopia. Subsequently, it progresses to ataxia of gait and trunk, and bilateral eye abnormal movements. Limb ataxia regularly occurs after the development of gait ataxia, characterized by marked postural and intention tremor affecting activities of daily living. Up to 80% of people lose the ability to ambulate or sit independently.
Dysarthria can impair effective communication and contributes to social isolation, frustration, and depression. Patients lose prosody and have irregular articulation, speech rate, and volume. Less commonly, patients develop dysphagia, which may require gastrostomy placement. Visual disturbances may include oscillopsia, diplopia, oculomotor palsy, and opsoclonus. Other unusual associated manifestations include drowsiness, coma, dementia, and severe cognitive impairment. Mood changes are frequent, especially depression, which may be related to the damage of the cerebellar control of affect in the cerebellum. However, this could also be an expected reaction to a new diagnosis of cancer and the PCD-associated disability.
Diagnostic approach . The diagnostic approach begins with clinical suspicion for PCD in the setting of subacute onset and progression of gait instability, dysarthria, vertigo, intention, and postural tremor. CSF analyses may be normal; however, inflammatory/autoimmune findings may help to differentiate PCD from other neurological disorders. Pleocytosis is present in 75% of cases (e.g., often ∼20 cells, but sometimes more than 100 cells/mm 3 ), and hyperproteinorachie in nearly all cases. High IgG index and synthesis rate suggest intrathecal antibody production. CSF oligoclonal bands are usually seen in cases of SCLC. MRI of the brain is usually normal in early stages of the disease, but diffuse atrophy of the cerebellum may be seen months after symptom onset. Signal abnormalities in the brainstem and mesial temporal lobes have also been reported. ,
Treatment . Therapy with corticosteroids, plasma exchange, and IVIg has not been proven to be beneficial. As such, cyclophosphamide or rituximab should be implemented early. Also, aggressive tumor therapy in association with immunosuppressive therapy appears to stabilize or improve the symptoms. The impact of this therapeutic combination is still unknown.
Prognosis . Patients with PCD have a better outcome compared with neurologically healthy patients with the same associated cancers. Survival depends on the cancer type and tumor stage at the time of diagnosis. Nearly half of deaths are attributable to complications of the neurological condition and the other half due to cancer complications. Survival after diagnosis of PCD varies, ranging from 10 months for SCLC and 12 months for ovarian carcinoma to 100 or more months for breast cancer and Hodgkin lymphoma.
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