Continuing Education Activity

Paraneoplastic Encephalomyelitis is a subtype of paraneoplastic neurological syndromes. This group of neurological disorders is associated with antibodies against intracellular and extracellular neuronal proteins related to cancer, involving focal or multifocal inflammation of the brain, spinal cord, or both. This article describes the pathophysiology, clinical features, diagnostic approach, and management of paraneoplastic encephalomyelitis and highlights the role of the interprofessional team in evaluating and treating patients to avoid high morbidity and mortality associated with this condition.

Objectives:

• Summarise the etiology of paraneoplastic encephalomyelitis.
• Describe different clinical manifestations of paraneoplastic encephalomyelitis.
• Summarize the treatment options available for paraneoplastic encephalomyelitis.

Introduction

Paraneoplastic encephalomyelitis (PEM) is a subtype of paraneoplastic neurological syndromes (PNS), a group of neurological manifestations associated with antibodies against intracellular and extracellular neuronal proteins that are invariably cancer-related, involving focal or multifocal inflammation of the brain or spinal cord or both.[1][2]

The definite diagnosis of paraneoplastic neurological syndromes, per the 2004 definition, encompasses:

1. A classical syndrome (includes encephalomyelitis, limbic encephalitis, subacute cerebellar degeneration, and opsoclonus-myoclonus) and cancer develops within 5 years of diagnosis of the neurological disorder.
2. A non-classical neurological syndrome is one that resolves or significantly improves after cancer treatment, without immunotherapy.
3. A non-classical neurological syndrome with paraneoplastic antibodies and cancer develops within 5 years of the diagnosis of the neurological disorder.[3][4]

Paraneoplastic encephalomyelitis typically involves B-cell activation, with the production of autoantibodies that identify immune marker disease subtypes.  Originally thought to be totally separable from primary autoimmune disease, paraneoplastic antibody markers are now thought to be of three types:

- Autoantibodies targeting intracellular epitopes thought to cross-react between cancer and central nervous system proteins, glycoproteins, and complex carbohydrates. Associated diseases can include limbic encephalitis, encephalomyelitis, subacute cerebellar degeneration, opsoclonus myoclonus, optic neuritis, and rapidly progressive sensory polyneuropathy.  These antibodies are not pathogenic in the classical sense. Patients do not usually respond to standard immunomodulatory therapies when these are the sole immune targets identified in the paraneoplastic process. Their function is just now being elucidated as providing targets for cytotoxic T cell infiltration into tumor and non-neoplastic cells with cross-reactive intracellular epitopes, the latter producing bystander destruction and paraneoplastic syndromes (for review, see).[5]   Understanding the mechanism of such intracellular antibody targeting against intracellular tumor antigens may eventually provide an effective cancer therapeutics method.[6]

- Autoantibodies targeting intracellular epitopes at synaptic sites, producing potentially treatable conditions.  Diseases like progressive encephalomyelitis with rigidity and myoclonus (PERM), stiff person syndrome, and cerebellar ataxia have been linked to such antibodies, and passive transfer of such intracellular epitope targeted antibodies from patients to naïve animal models can reproduce symptoms of the disease.[7]

- Autoantibodies targeting extracellular epitopes that directly cause neurologic dysfunction.  These autoantibodies were originally identified in non-paraneoplastic autoimmune disease, can be suppressed by antibody depleting or blocking therapies, and are often recognized as the first cancer evidence. Diseases produced by such antibodies include paraneoplastic myasthenia gravis, Lambert Eaton myasthenic syndrome, limbic encephalitis, encephalomyelitis, anti-myelin oligodendrocyte glycoprotein antibody-associated disease, and neuromyelitis optica spectrum disorder, among others.   Recognizing the evolving concepts surrounding paraneoplastic and non-paraneoplastic autoimmune CNS disease has helped identify and treat these disorders.[8]

There is overlap between traditional paraneoplastic disorders and extracellular epitope associated autoimmune encephalitides, a group of syndromes associated with autoantibodies against extracellular neuronal cell surface proteins, synaptic proteins, ion channels, or receptors, usually most common in the non-paraneoplastic disease.[9][10]  This is especially important in the era of cancer chemotherapy with checkpoint inhibitors. The incidence of immunological toxicity is much higher with these therapies than in traditional cancer chemotherapy, producing immune-related adverse events that may present as paraneoplastic neurologic syndromes.[11][12]  Recognizing which antibody targets are important in secondary immune disease production and which paraneoplastic antibodies are not amenable to immunomodulatory therapy is important for treatment decisions.[5]

Etiology

As the name entails, paraneoplastic encephalomyelitis is associated with the presence of cancer, especially prevalent in small cell lung cancer (SCLC), in addition to breast cancer, testicular cancer, gynecologic cancers, and Hodgkin’s lymphoma.[13]

Immune checkpoint inhibitors are believed to unleash paraneoplastic neurological syndromes as well, more frequently with anti-PD1 agents eg. pembrolizumab, nivolumab, and cemiplimab.[11]

Epidemiology

The true incidence of paraneoplastic syndromes is unknown, though older reports or those limiting assessment to classic immune antibody markers describe an incidence of paraneoplastic disease as 1 in 10,000 cases of malignancy (0.01%), with paraneoplastic neurological syndromes having an incidence of 0.86 per 100,000 and prevalence of 4.37 per 100,000 cases.[11][14][15] However, in carefully reviewed patients in a specialized center, reported incidence of PNS was much higher, approaching an incidence of 0.25% of reviewed cases.  Therefore, as newer technologies are developed to identify immune responses to cancer, we may expect the reported incidence and prevalence of paraneoplastic processes to increase.

Paraneoplastic Encephalomyelitis (PEM) constitutes 10% of all encephalomyelitis cases.[16] Small cell lung cancer is the malignancy associated with PEM in 75% of cases.[17]

Pathophysiology

Ectopically presented antigens on the tumor cells that are otherwise exclusively expressed in neurons are presumably the triggers for paraneoplastic encephalitis. Postulated mechanisms of these abnormally expressed antigens include tumor genetic alterations, gene amplification, and protein overexpression. Also, some of these so-called onconeural antigens are normally expressed in immunologically privileged sites like the testes, but for unknown reasons, they get identified by the immune system as foreign, which in turn mounts an immune attack.

Antigen-presenting cells then activate antigen-specific cytotoxic T cells against neuronal structures, which in turn activate B cells to turn into plasma cells that produce the detectable antibodies. It is the parenchymal invasion of the cytotoxic T cells that leads to neuronal cell damage. As mentioned earlier, the antibodies are directed to intracellular antigens, therefore, cannot cause the disease directly but simply serve as a valuable marker for the underlying tumor, e.g. Anti-Yo antibodies in patients with paraneoplastic cerebellar degeneration are characteristically associated with ovarian cancer.[11][14]

Interestingly, it was shown that this same immune attack sometimes limits the growth of cancer itself and may rarely stop it.[18] The histological features of tumors in paraneoplastic neurological disorders do not differ from those of other tumors, except that the tumors may be heavily infiltrated with inflammatory cells.[16]

In addition, immune checkpoint blockers may trigger a similar cytotoxic T cell-mediated immune attack, which can cause adverse effects, including limbic encephalitis.[19]

Most commonly, PEM is associated with the Anti-Hu antibody, which is also called ANNA-1 (Anti-Neuronal Nuclear Antibody type 1). Sometimes, it is associated with Anti-CRMP5 (Collapsin Response Mediator Protein 5). Other times, the associated antibodies are the Anti-Amphiphysin.[16]

Table 1. Common paraneoplastic antibodies with their respective associated tumors and clinical presentations.[13][20][21][22][23][5][24] SCLC- small cell lung carcinoma; PERM- Progressive encephalomyelitis with rigidity and myoclonus;  NMOSD-Neuromyelitis optica spectrum disorders.

Histopathology

In classic PEM, the pathology involves extensive CNS neuronal destruction, inflammation with T cell infiltrates perivascular B cells, intra-neuronal deposits of antibodies, gliosis, and neuronophagic nodules.[14] Paraneoplastic encephalomyelitis produced by extracellular targeted antibodies does not produce this type of cellular injury. In the case of NMDAR antibody-associated disease, brain pathology results from an antibody-targeted immune response.[25][26] Such subtle pathology may be difficult to identify as caused by paraneoplastic disease without the appropriate clinical history.

History and Physical

In general, neurological symptoms often manifest weeks to months before recognition of the tumor in at least 80% of PEM cases.[11] Onset and progression are usually acute or subacute rather than insidious.

Any part of the nervous system can be affected by paraneoplastic disorders:

• Single cell-type involvement eg. Cerebellar Purkinje cells
• Single area involvement eg. Limbic encephalitis
• Multi-level involvement eg. Encephalomyelitis, is the main focus of this article.[14]

All assessments should begin with a careful history, focusing on the patient’s neurological complaints, the time-course of symptom complex onset and rate of progression, and more general questions that might suggest the presence of an oncologic process.  A family member or multiple patient contacts might need to be questioned to obtain this history in cognitively impaired patients.

In paraneoplastic encephalomyelitis, there is widespread neural dysfunction, involving symptoms from at least two or more regions, such as the temporal lobes, limbic areas, brainstem, cerebellum, spinal cord, dorsal root ganglia, and the autonomic nervous system. The clinical presentation therefore widely varies depending on the neural axis components affected, which can manifest as a relatively isolated syndrome, a multifocal process, or a more generalized syndrome involving widespread CNS regions.[14][17][27][28]

1. Paraneoplastic Limbic Encephalitis (PLE) which predominates in 20% of cases of PEM, affects the hippocampus, hypothalamus, and amygdala. Patients often present with cognitive impairment, personality change, short-term memory loss, mood changes, behavioral changes, and temporal seizures.[19]
2. Paraneoplastic Brainstem Encephalitis / Rhombencephalitis develops in around 30% of cases of PEM and can occur as an isolated clinical syndrome affecting the brainstem or more often is a part of widespread encephalomyelitis. It can present with the involvement of 1 or more cranial nerves in the pons and medulla with trismus, horizontal conjugate gaze palsy, extraocular movement deficits, opsoclonus, nystagmus, dysphagia, dysarthria, sensorineural deafness, central hypoventilation, and vertigo. Anti-Hu antibodies are more linked with the lower brainstem, while Anti-Ma2 antibodies are commonly associated with upper brainstem involvement.[17][29][30][31][32][33]
3. Paraneoplastic Cerebellar Degeneration is predominant in 15% of cases of PEM. It can be relatively isolated to the cerebellum when associated with Anti-Yo and Anti-Tr antibodies but can be associated with any of the other mentioned paraneoplastic antibodies when present as a part of PEM. Cases usually present with dizziness, closely followed by motor gait ataxia, oscillopsia, diplopia, dysphagia, and dysarthria.[20]
4. Myelitis can take place with PEM as well, in the form of either neuronal degeneration, inflammatory infiltrates, necrotizing myelitis, or demyelination. It is known to most commonly involve the dorsal root ganglia. Subsequently, patients show a predominant Subacute Sensory Neuronopathy (SSN) which is distinct from the common peripheral neuropathy in early involving the proximal sensory areas, usually asymmetrically and starting with the loss of vibration and proprioception, which can progress to sensory ataxia. In addition, it can also involve the anterior horn cells causing paraneoplastic motor neuron syndromes, which usually present as spastic paresis that differs from typical ALS by the involvement of other CNS areas and functions, while other times Subacute Motor Neuronopathy is seen leading to asymmetric flaccid weakness.[17]
5. Paraneoplastic Stiff Person Syndrome represents about 5% of all SPS cases, with tumors typically arising from breast, lung, colon, thymus, and Hodgkin's lymphoma. It is believed to occur through loss of GABA inhibition of the interneurons at the brainstem and spinal cord levels. It presents as progressive muscle stiffness or rigidity, mainly affecting the proximal and axial muscle groups especially of the neck and upper limbs, and is associated with muscle spasms which are exacerbated by noise, touch, or emotions.[34] It is often linked with anti-amphiphysin antibodies.[35][36]
6. Autonomic Dysfunction occurs in 10% to 30% of cases of PEM when the pathology affects the autonomic centers and can predominate in the form of orthostatic hypotension, pupillary defects, gastroparesis, intestinal disturbances, neurogenic bladder, and impotence.
7. Paraneoplastic Neuromyelitis Optical Spectrum Disorders (NMOSD) occurs in 4-5% of AQP4 antibody-positive cases of NMOSD and 15% of cases among the older population. Reported neoplasms associated with this syndrome include breast, lung, nasopharyngeal, genitourinary, thyroid cancers, and thymoma. 

Involved CNS regions are usually detected by completing a detailed neurologic examination, focusing on regions of the CNS identified as involved by clinical history. This exam can verify the level of neurologic involvement (e.g. – cortical region(s), diencephalon, basal ganglia, cerebellum, brainstem, spinal cord), Historical data on cognitive dysfunction can be tested with focused cognitive testing at the time of initial neurological exam, to address regional or more generalized cortical or subcortical encephalopathy. 

Evaluation

CSF & Serum Antibodies

PNS antibodies are detected before, during, or years after diagnosis of a neurological syndrome.[37]

Simultaneous testing of both serum and CSF for antibodies should be done to maximize detection rates.[11][19] CSF antibody testing has a higher specificity for identifying the antibody associated with the paraneoplastic syndrome because the serum might have multiple antibodies that are not directly associated with the paraneoplastic syndrome.

Basic panel diagnostics study for the following antibodies is recommended: Hu, Ri, Yo, Tr, Ma, CRMP5, and amphiphysin. However, it must be noted that various antibodies might be associated with the same paraneoplastic syndrome, and one antibody may be associated with different syndromes. Several antibodies may be found simultaneously in the same patient with SCLC or thymoma.[38][39][40][41][42][43][44][45][46]

Higher titers of paraneoplastic antibodies correlate well with the diagnosis as well as the level of differentiation of the tumor.[37]

In general, CSF analysis shows mild pleocytosis, i.e., 30 to 40 white blood cells per cubic millimeter, slightly elevated protein level 50 to 100 mg/dL, elevated IgG level, and presence of oligoclonal bands. Cytologic testing should be performed on CSF samples to exclude meningeal metastasis of cancer.[14]

Electroencephalogram (EEG)

EEG in PNS often shows nonspecific findings like generalized slowing and periodic lateralized epileptiform discharges (PLEDs). However, PNS patients with anti-neuronal antibodies are significantly more likely to have observed frontal intermittent rhythmic delta activity (FIRDA) relative to control patients without the paraneoplastic disease.   A characteristic finding also is the presence of epileptiform activity over temporal regions in limbic encephalitis. In addition, EEG helps to exclude subclinical seizures or nonconvulsive status epilepticus, the latter present at increased frequency in patients with PNS.  While typically not specific for paraneoplastic neurological syndromes, the presence of simultaneous rhythmic delta waves with beta frequency activity producing a “delta brush” pattern is specific for NMDAR Ab positive encephalitis among paraneoplastic conditions, even though it can also be seen rarely in non-paraneoplastic disease.[47][48] A link between mesial temporal lobe epilepsy and the presence of VGKC antibodies has also been reported.[49]

Imaging 

Increased MRI signal in T2 weighted/FLAIR imaging in bilateral medial temporal lobes supports the diagnosis of definite limbic encephalitis in the appropriate clinical context. MRI is also used to exclude stroke or metastatic disease. FDG-PET CT shows hypermetabolism in the medial temporal lobes and is more sensitive than MRI in the diagnosis and evaluation of paraneoplastic limbic encephalitis.[50]

Both extensive optic neuritis identified on gadolinium-enhanced brain MRI and enhancing T1 and/or T2 hyperintense longitudinally extensive transverse myelitis (LETM) on spinal cord MRI, the latter by definition extending more than 3 vertebral segments, have been identified in paraneoplastic and non-paraneoplastic forms of NMOSD and MOG antibody-positive myelitis.[51][52][53]

Cancer Screening

Since detecting the tumor is essential for treatment, a Whole-body PET scan is the best screening method for localizing occult cancer.[14]

The likelihood of a tumor being revealed by a whole-body CT scan or FDG-PET is more than 95% when the patient presents with a classical PNS like PEM and a well-characterized onconeural antibody.[11]

The 2010 task force recommended repeat cancer screening 3 to 6 months after the initial evaluation, followed by screening every 6 months for up to 4 years if testing remains unrevealing.  Also, if an identified cancer is not consistent with the PNS or the identified antibody, a continued search for another cancer should be considered.[54]

Sometimes the tumor may never be identified as a result of immune-mediated eradication of tumor cells.[18]

Treatment / Management

Neuronal damage often progresses rapidly in PNS. Treatment should be started immediately without waiting for antibody analysis results.

Tumor removal: Once the tumor is identified, a prompt, complete removal is recommended so as to eliminate the ectopically produced antigen present on it.

Immunosuppression/Immunomodulation: Classic paraneoplastic encephalitis is hard to treat because the neuronal damage is cell-mediated. Hence, antibody directed therapies like IVIG and plasmapheresis are ineffective. On the other hand, T cell-directed therapies such as cyclophosphamide, rituximab, steroids, mycophenolate mofetil, and tacrolimus have been shown to have a modest effect in some cases.

Therapy in PNS is often delayed, and substantial irreversible neuronal cell damage has already occurred at the time of presentation.  After 3 to 6 months of therapy, repeat brain imaging is recommended.  If the disease has progressed, immunotherapy should be stopped.[14][55][56]

Symptomatic: Anti-epileptic drugs are to be used for seizures. Muscle rigidity and spasms can be managed with muscle relaxants such as baclofen, tizanidine, and benzodiazepines.

Stop immune checkpoint inhibitors promptly if suspected to be causing PNS.[19]

Differential Diagnosis

Infectious etiologies; viral [herpes viruses, hepatitis C, HIV, Varicella zoster virus, Ebstein Barr virus], bacterial [Listeria, Rickettsia, Tropheryma whipplei, Bartonella, Mycoplasma], spirochetal [syphilis, Lyme, leptospirosis], fungal [cryptococcus, coccidioidomycosis, histoplasmosis, aspergillosis], TB, and CJD should be considered in the differential diagnosis of paraneoplastic disease.

Toxic/metabolic; Alcohol, ketamine or phencyclidine ingestion, intrathecal chemotherapy or radiotherapy effect, carbon monoxide, Wernicke's encephalopathy, NMS-neuroleptic malignant syndrome.

Vascular disorders; posterior reversible encephalopathy syndrome, angiitis of the CNS, Behcet's disease, Susac’s syndrome.

Neoplastic disorders; leptomeningeal or epidural metastasis, diffuse glioma, CNS lymphoma.

Demyelinating/Inflammatory disorders; multiple sclerosis, neurosarcoidosis, NMO-neuromyelitis optica, ADEM [acute disseminated encephalomyelitis], neurosarcoidosis, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, Bickerstaff encephalitis.

Neurodegenerative dementias; Alzheimer's disease, frontotemporal dementia, and vascular dementia, dementia with Lewy bodies.

Psychiatric diseases; schizophrenia, bipolar disorder

Inherited/metabolic disorders; mitochondrial encephalopathies, Hashimoto's encephalitis[30]

Prognosis

For classic paraneoplastic syndromes, the prognosis is overall poor, with the exception of young males with testicular cancer and anti-Ma-2 antibodies who are known to have a better prognosis. Children with anti-Hu encephalomyelitis are exceptionally treatment-resistant.[5][57] However, for patients with an extracellular epitope targeted antibodies, and for many patients with intracellular neuromuscular junction targeted antibodies, both direct suppression of the paraneoplastic antibodies and prompt removal of the tumor can produce significantly better outcomes.

Factors associated with poor neurological outcomes include delay in administering immunotherapy, need for mechanical ventilation, intrathecal inflammation, and need for tracheostomy.[58]

The main causes of death are brainstem or autonomic dysfunction, severe pneumonia, multiple organ dysfunction syndromes, and refractory status epilepticus.[17]

Some patients may develop a second paraneoplastic syndrome after recovering stabilizing from the first, indicating cancer relapse or the presence of second cancer.[59]

Limbic encephalitis from immune checkpoint inhibitors is secondary to cancer treatment and usually responds well to drug cessation and rapid initiation of steroids.[19]

Complications

The most common reasons for ICU care include altered mental status requiring intubation, status epilepticus/refractory status epilepticus, severe hyperkinetic movements, respiratory failure, autonomic dysfunction, and increased intracranial pressure.

Deterrence and Patient Education

Patients with known cancer or being treated with immune checkpoint inhibitors should seek immediate medical attention if they develop any neurological symptoms.

Pearls and Other Issues

• Classic paraneoplastic encephalomyelitis belongs to a group of neurological syndromes associated with antibodies against intracellular neuronal proteins that are invariably cancer-related.
• Non-classical paraneoplastic encephalomyelitis is directly produced by surface epitope or intracellular neuromuscular junction epitope-targeted antibodies, similar to those producing primary autoimmune encephalomyelitis.
• PEM can be seen with multiple cancers (i.e. - small cell lung cancer, thymoma, testicular cancer) as well as with the use of immune checkpoint inhibitors (i.e. - pembrolizumab).
• For all PEM types, the underlying trigger is thought to be ectopically presented neural antigens on tumor cells causing either a cell-mediated or antibody-mediated immune attack of the central nervous system.
• Common presentations of PEM include limbic encephalitis, brainstem encephalitis, cerebellar degeneration, myelitis, stiff-person syndrome, NMOSD, and autonomic dysfunction.
• Recommended workup includes antibody panel testing of serum and CSF, MRI/FDG-PET CT scan, EEG, and cancer screening.
• PEM is a diagnosis of exclusion and extensive evaluations are often needed to exclude other causes of encephalomyelitis.
• Treatment involves prompt tumor removal, and use of T cell-directed therapies like cyclophosphamide, steroids, and tacrolimus for classic PEM, and IVIg, plasmapheresis, or steroids for non-classic PEM.  
• The overall prognosis varies, depending on the cancer type, paraneoplastic marker antibody, and type of immune response produced in the paraneoplastic disease.

Enhancing Healthcare Team Outcomes

Early clinical suspicion for the disease entity can lead to rapid diagnosis and better outcomes. Oncologists, neurologists, psychiatrists, intensivists, hospitalists, physical medicine/rehabilitation physicians, nurses, physical therapists, and occupational therapists should be involved early in the patient's care, to speed diagnosis and therapy initiation. Patient education about the condition is important to ensure compliance with therapies provided. Palliative care should be involved in cases where the prognosis is poor.