Neurologic Complications of Cancer Immunotherapy.

Immunotherapy has revolutionized cancer treatment over the past decade. As it is increasingly introduced into routine clinical practice, immune-related complications have become more frequent. Accurate diagnosis and treatment are essential, with the goal of reduced patient morbidity. This review aims to discuss the various clinical manifestations, diagnosis, treatments, and prognosis of neurologic complications associated with the use of immune checkpoint inhibitors, adoptive T-cell therapies, and T-cell redirecting therapies. We also outline a suggested clinical approach related to the clinical use of these agents.

The man who could not see what he could not eat.

A 55-year-old Hispanic man born in New Mexico presented with progressively worsening bilateral upper eyelid ptosis and dysphagia. External levator advancement 5 years before did not improve his ptosis. A thorough systemic workup for myasthenia gravis was negative, but electromyography suggested a myopathic process. Molecular genetic testing was positive for oculopharyngeal muscular dystrophy.

Mitochondrial pseudomyasthenia.

The classic ocular motor presentation of mitochondrial disorders is chronic, symmetric, and diffuse weakness. We describe a man with 25 years of asymmetric ptosis, ophthalmoparesis, and facial weakness that partially responded to steroid therapy. Serologic and electrophysiological investigations for myasthenia gravis were negative, but muscle biopsy confirmed a mitochondrial myopathy. This case illustrates the potential of mitochondrial ophthalmoparesis to mimic the features of ocular myasthenia.

Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy.

PURPOSE To assess efficacy and safety of single-agent bortezomib in previously untreated patients with multiple myeloma, investigate prevalence of baseline and treatment-emergent polyneuropathy, and identify molecular markers associated with response and neuropathy. PATIENTS AND METHODS Patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, for up to eight 21-day cycles. A subset of patients underwent neurophysiologic evaluation pre- and post-treatment. Bone marrow aspirates were performed at baseline for exploratory whole-genome analyses. Results Among 64 patients, 41% had partial response or better, including 9% complete/near-complete responses; median duration of response was 8.4 months. Response rates did not differ in the presence or absence of adverse cytogenetics. After median follow-up of 29 months, median time to progression was 17.3 months. Median overall survival had not been reached; estimated 1-year survival was 92%. Thirty-two patients successfully underwent optional stem-cell transplantation. Bortezomib treatment was generally well tolerated. At baseline, 20% of patients had sensory polyneuropathy. Sensory polyneuropathy developed during treatment in 64% of patients (grade 3 in 3%), but proved manageable and resolved in 85% within a median of 98 days. Neurologic examination, neurophysiologic testing, and measurements of epidermal nerve fiber densities in 35 patients confirmed pretreatment sensory neuropathy in 20% and new or worsening neuropathy in 63%. Pharmacogenomic analyses identified molecular markers of response and treatment-emergent neuropathy, which will require future study. CONCLUSION Single-agent bortezomib is effective in previously untreated myeloma. Baseline myeloma-associated neuropathy seems more common than previously reported, and bortezomib-associated neuropathy, although a common toxicity, is reversible in most patients.

Peripheral nerve complications of medical disease.

Neuropathies are associated with several systemic diseases. This article provides a general overview of the clinical presentation and management of the various neuropathies associated with common medical illnesses. The term "neuropathy" is used relatively broadly to encompass pathology from the level of the cell body to the terminal axon. Peripheral nerve disorders associated with diabetes, thyroid disease, connective tissue disease, cancer, and infection are discussed. The relationship between the various neuropathies and systemic illness is important to recognize because neuropathy may be the initial presentation of one of these underlying medical conditions. Alternatively, the presence of a known associated medical condition in a patient presenting with neuropathy may affect management decisions and limit unnecessary investigations.

My, what asthenia you have.

A 59-year-old woman noted intermittent ptosis, diplopia, dysphagia, and proximal muscle weakness for several years. She had a strong family history of myasthenia gravis. Chest computed tomography and sternotomy revealed a micronodular spindle cell thymoma. Electromyography and antibody testing was negative for myasthenia gravis. Genetic testing confirmed a diagnosis of oculopharyngeal muscular dystrophy.

Neuromuscular diseases in pregnancy.

Neuromuscular disease in pregnancy is a broad topic and includes focal neuropathies that occur with increased incidence during pregnancy and the puerperium, as well as preexisting inherited neuropathies or myopathies and chronic autoimmune diseases such as myasthenia gravis and chronic inflammatory demyelinating polyneuropathy. Although the precise etiology of the focal neuropathies is not completely understood, they do seem to be a direct effect of pregnancy or delivery. In most cases, prognosis for complete recovery is good. The incidence of inherited and autoimmune neuromuscular diseases in women of childbearing age is relatively rare, and our knowledge of their impact in pregnancy is limited. Most are able to deliver healthy infants; however, these patients present specific challenges to the neurologist and obstetrician. The most recent literature on this topic is reviewed.

Interferon-alpha/beta-mediated innate immune mechanisms in dermatomyositis.

Dermatomyositis has been modeled as an autoimmune disease largely mediated by the adaptive immune system, including a local humorally mediated response with B and T helper cell muscle infiltration, antibody and complement-mediated injury of capillaries, and perifascicular atrophy of muscle fibers caused by ischemia. To further understand the pathophysiology of dermatomyositis, we used microarrays, computational methods, immunohistochemistry and electron microscopy to study muscle specimens from 67 patients, 54 with inflammatory myopathies, 14 with dermatomyositis. In dermatomyositis, genes induced by interferon-alpha/beta were highly overexpressed, and immunohistochemistry for the interferon-alpha/beta inducible protein MxA showed dense staining of perifascicular, and, sometimes all myofibers in 8/14 patients and on capillaries in 13/14 patients. Of 36 patients with other inflammatory myopathies, 1 patient had faint MxA staining of myofibers and 3 of capillaries. Plasmacytoid dendritic cells, potent CD4+ cellular sources of interferon-alpha, are present in substantial numbers in dermatomyositis and may account for most of the cells previously identified as T helper cells. In addition to an adaptive immune response, an innate immune response characterized by plasmacytoid dendritic cell infiltration and interferon-alpha/beta inducible gene and protein expression may be an important part of the pathogenesis of dermatomyositis, as it appears to be in systemic lupus erythematosus.

Inflammatory neuropathies.

We discuss two of the most common of the acquired inflammatory neuropathies: Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy, as well as their variants. We review their clinical presentation, electrophysiologic findings, and management, highlighting knowledge gained from the recent literature. Unfortunately, although treatments exist for both Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy, none are completely curative and all have significant potential side effects and/or expense. Better understanding of the underlying pathophysiology of these diseases is needed in order to develop more targeted therapies.

Transthyretin amyloidosis presenting with multifocal demyelinating mononeuropathies.

We describe a patient with transthyretin amyloidosis who presented with multifocal mononeuropathies with features of demyelination on nerve conduction studies, a constellation of findings not previously described in amyloid polyneuropathy. Genetic testing revealed a valine122isoleucine mutation in the coding region of the transthyretin gene, a mutation that generally presents with late-onset cardiac amyloidosis. Our patient was also unusual in that she was 34 years old at the time of presentation and had no cardiac involvement.

Dermatomyositis and Polymyositis.

Dermatomyositis (DM) and polymyositis (PM) are idiopathic inflammatory myopathies characterized by proximal greater than distal muscle weakness, elevated serum creatine kinase levels, electrophysiologic abnormalities, and inflammation on muscle biopsy. Clinically and electrophysiologically, DM and PM appear very similar, and muscle biopsy is the gold standard for diagnosis. Much of the PM literature based the diagnosis on Bohan and Peter's criteria, which is now obsolete given the advances of immunopathology. As diagnostic criteria for the inflammatory myopathies have been refined, it has become apparent that PM is much less common than previously thought, and, in fact, is probably quite rare. More recent literature, using strict histopathologic criteria for diagnosis of PM, has brought into question previously reported associations. Because of this, the clinical entity of PM is poorly defined. The exact incidence of each is unknown because previous epidemiologic studies often grouped them together, but overall the annual incidence of the inflammatory myopathies is approximately one in 100,000. DM and PM respond to immunomodulating therapies. High-dose oral prednisone is generally accepted first-line therapy. In patients who do not respond adequately to prednisone alone, or in whom prednisone cannot be weaned, methotrexate or azathioprine can be added. In the authors' experience, methotrexate works faster and is more effective than azathioprine. However, because of the increased risk of interstitial lung disease with methotrexate, the authors avoid this in patients with anti-Jo-1 antibodies and, obviously, in patients who already have pulmonary disease. If patients do not respond adequately to the combination of prednisone and methotrexate or azathioprine, a trial of intravenous immunoglobulin is administered.

Neuromuscular complications of cancer.

Neuromuscular complications of cancer are common and can affect any component of the peripheral nervous system from peripheral nerve cell body to muscle. Perhaps the most common complication is a length-dependent symmetric axonal polyneuropathy that is often multifactorial in etiology, resulting from metabolic and treatment effects of the primary malignancy. However, neuromuscular disorders may also be the presenting complaint in many conditions, including disorders caused by malignant infiltration of nerve and disorders cause by paraneoplastic syndromes. Although many of the paraneoplastic conditions are poorly responsive to treatment, not all are, and one hopes that prompt diagnosis of the underlying malignancy will lead to improved patient outcome. Recognition of iatrogenic neuromuscular complications is also important to modify treatment protocols when possible and thus decrease the risk of long-term neurologic disability.

Multifocal conduction block in peripheral nerve vasculitis.

Peripheral nervous system (PNS) vasculitis and Guillain-Barré syndrome (GBS) are two distinct entities. Although there may be similarities in clinical presentation, the two are rarely confused. PNS vasculitis typically presents as a mononeuritis multiplex, as an overlapping mononeuritis multiplex, or as a distal symmetric sensorimotor polyneuropathy. Electrophysiologic studies are consistent with a primary axonal pathophysiologic process. In contrast, GBS typically presents with variable, mild sensory symptoms followed by symmetric progressive weakness. Early electrophysiologic studies, when abnormal, usually demonstrate findings consistent with demyelination. We describe two cases of PNS vasculitis in which the initial clinical presentation and the presence of multifocal conduction block on electrophysiologic studies led to the incorrect diagnosis of GBS early in the hospital course. Although GBS must always be considered in patients with rapidly progressive weakness, physicians must remain vigilant for alternative diagnoses, as illustrated by our cases.