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Peripheral Nerve and Motor Neuron Disorders p. 10.1212/01.CON.0000718940.59848.68 October 2020, Vol.26, No.5 doi: 10.1212/01.CON.0000718940.59848.68
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Peripheral Nerve and Motor Neuron Disorders

Article 1: A Structured Approach to the Diagnosis of Peripheral Nervous System Disorders

Zachary N. London, MD, FAAN. Continuum (Minneap Minn). October 2020; 26 (5 Peripheral Nerve and Motor Neuron Disorders):1130–1160.

ABSTRACT

PURPOSE OF REVIEW

Neuroanatomic localization and pattern recognition can be used to diagnose both focal lesions and generalized disorders of the peripheral nervous system. This article describes the nature and pattern of sensory and motor deficits associated with lesions of specific spinal nerve roots, plexus, or peripheral nerves. It also describes the patterns of sensory and motor deficits that suggest multifocal or generalized disorders of the motor neurons, sensory neurons, and peripheral nerves.

RECENT FINDINGS

The pattern of sensory and motor deficits may be used to distinguish lesions of the peripheral nervous system from those of the central nervous system. The spinal roots, nerve plexus, and peripheral nerves supply specific muscles and receive sensory input from distinctive cutaneous regions. Focal lesions of these structures therefore produce characteristic patterns of sensory and motor deficits. Multifocal or generalized disorders of the peripheral nervous system may be distinguished by categorizing their sensory and motor involvement, proximal and distal predominance, and degree of symmetry. Serum tests, CSF analysis, electrodiagnostic studies, MRI, ultrasound, nerve biopsy, and skin biopsy have unique roles in the diagnosis of suspected neuromuscular disorders.

SUMMARY

A structured approach to the diagnosis of nerve and motor neuron disorders can lead to hypothesis-driven diagnostic testing. Ancillary tests should be reserved for cases in which confirming or refuting a diagnosis will change patient management.

KEY POINTS

  • The presence of neuropathic pain in an affected limb is more suggestive of a peripheral nervous system lesion than a central nervous system lesion.
  • Features that suggest a central nervous system lesion rather than a peripheral nervous system lesion include a sensory level on the trunk, hyperreflexia, hemibody symptoms, weakness of extensors in an arm, and weakness of flexors in a leg.
  • Neuralgic amyotrophy may appear to localize to multiple nerves in the same limb rather than a specific part of the brachial plexus.
  • Injuries to nerve roots and mixed nerves, both of which contain both sensory and motor components, may present with pain or sensory symptoms without weakness.
  • Chronic inflammatory demyelinating polyradiculoneuropathy progresses for more than 8 weeks after symptom onset. Unlike acute inflammatory demyelinating polyradiculoneuropathy, it is generally not associated with dysautonomia, weakness of cranial muscles, or dyspnea.
  • Mononeuritis multiplex affects named nerves but not necessarily at the common entrapment sites.
  • Mononeuritis multiplex is usually an axonal process, but multifocal acquired demyelinating sensory and motor neuropathy and hereditary neuropathy with liability to pressure palsies are multifocal demyelinating neuropathies.
  • Distal symmetric polyneuropathy usually begins to involve the distal upper extremities around the time that the lower extremity sensory symptoms progress to the level of the knees.
  • Clinical features that should raise suspicion for a hereditary cause of neuropathy include young age of onset, family history, and high arches and hammer toes.
  • Spinal bulbar muscular atrophy may cause fasciculations in the face or tongue, signs of androgen deficiency (including gynecomastia), and slowly progressive bulbar and proximal weakness.
  • The pseudobulbar affect seen in patients with amyotrophic lateral sclerosis represents dysregulation of emotional output rather than a mood disorder.
  • Overt dementia is not common in amyotrophic lateral sclerosis, but up to half of patients will have some impaired cognition or behavioral problems.
  • Brachial amyotrophic diplegia and leg amyotrophic diplegia present with painless flaccid weakness starting in one body segment, which may or may not eventually progress to involve other body segments or cause upper motor neuron pathology.
  • Systemic infections with West Nile Virus and specific enteroviruses may cause a poliolike illness characterized by flaccid paralysis with or without encephalitis.
  • The extensor digitorum brevis muscle may atrophy in sensorimotor distal symmetric polyneuropathy but is often relatively spared in distal myopathies.
  • The weakness in amyotrophic lateral sclerosis tends to follow a myotomal pattern, whereas the weakness in multifocal motor neuropathy may be in the distribution of specific peripheral nerves.
  • Early in the course of multifocal motor neuropathy, patients may have significant weakness with little or no atrophy, suggesting that the motor axons are still intact.
  • Hirayama disease (monomelic amyotrophy) presents in young men with unilateral or bilateral hand weakness that progresses for years and then plateaus.
  • Proprioception is often involved early in disorders affecting the dorsal columns and late in disorders affecting the peripheral nerves.
  • Patients with sensory neuronopathy may initially appear weak on confrontational testing but are able to generate full power when they look at the limb being tested.
  • Sensory neuronopathy may be idiopathic or associated with Sjögren syndrome, a paraneoplastic syndrome, human immunodeficiency virus, or pyridoxine overdose.
  • The most useful screening laboratory tests for the workup of distal symmetric polyneuropathy are tests for diabetes or prediabetes, serum lipids and cholesterol, a vitamin B12 level, and serum protein electrophoresis and immunofixation.
  • Paraproteinemia may be associated with chronic inflammatory demyelinating polyradiculoneuropathy, is common in patients with distal acquired demyelinating symmetric neuropathy, and is present in most patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) syndrome.
  • The overreliance on modest CSF protein elevations is a common reason for the overdiagnosis of chronic inflammatory demyelinating polyradiculoneuropathy.
  • Electrodiagnostic testing is an important part of the workup for mononeuropathies, mononeuritis multiplex, demyelinating neuropathy, sensory neuropathy, and motor neuron disease, but it is not sensitive for small fiber polyneuropathy or pure sensory radiculopathy.
  • MRI of the spine can identify common causes of radiculopathy and aid in the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy and Hirayama disease but may show degenerative changes of questionable significance in both symptomatic and asymptomatic individuals.
  • Ultrasound imaging is useful in the workup of entrapment neuropathies and has emerging indications in the workup of other neuromuscular disorders.
  • A nerve biopsy is the diagnostic test of choice for suspected nonsystemic vasculitic neuropathy. In the setting of known systemic vasculitis, nerve biopsy should only be performed if demonstrating peripheral nerve involvement will lead to a change in immunomodulatory treatment.

Article 2: Diabetes and Metabolic Disorders and the Peripheral Nervous System

Christopher H. Gibbons, MD, MMSc, FAAN. Continuum (Minneap Minn). October 2020; 26 (5 Peripheral Nerve and Motor Neuron Disorders):1161–1183.

ABSTRACT

PURPOSE OF REVIEW

This article provides an up-to-date review of the manifestations of neuropathy seen in the setting of diabetes and other metabolic disorders.

RECENT FINDINGS

Although a number of metabolic disorders cause or are associated with peripheral neuropathy, the neuropathies associated with glucose dysregulation make up the vast majority of cases. Recent investigations have determined major differences in the neuropathies associated with type 1 and type 2 diabetes. Neuropathy in type 1 diabetes is closely linked to glycemic control, whereas neuropathy in type 2 diabetes is linked to dyslipidemia, central obesity, hypertension, insulin resistance, and glucose control. Although length-dependent axonal distal symmetric polyneuropathy is the most common clinical presentation, diabetes is also associated with acute, asymmetric, painless, and autonomic neuropathies.

SUMMARY

The prevalence of diabetes and metabolic syndrome is increasing across the globe. The need to recognize and treat the wide array of clinical manifestations of neuropathy detected in individuals with metabolic disorders will continue to grow. As a consequence, an increasing number of well-trained physicians who can manage these patients is needed. At present, treatment is largely focused on prevention and symptomatic management. Investments into funding for both basic and clinical science are necessary to bring novel therapeutic interventions into clinical practice.

KEY POINTS

  • A number of manifestations of neuropathy are seen in diabetes, including length-dependent neuropathy, acute generalized or focal neuropathies, mononeuropathies, and autonomic neuropathies.
  • The risk of neuropathy in type 1 diabetes is primarily linked to glucose control, whereas the risks of neuropathy in type 2 diabetes include glucose control, hyperlipidemia, hypertension, abdominal obesity, low levels of high-density lipoproteins, and tobacco use.
  • Approximately half of patients with diabetic neuropathy have neuropathic pain; however, it is important to recognize that the absence of pain does not rule out a neuropathy.
  • Small unmyelinated axons are affected earlier than large fibers in most cases of axonal neuropathy in type 2 diabetes, so an examination should always include testing for signs of small fiber dysfunction (thermal or pain sensation) as well as large fiber function (reflexes, vibration detection).
  • The presence of atypical features in a patient with suspected distal symmetric polyneuropathy, such as a significant asymmetry, an acute onset, or early motor involvement, suggests a different neuropathy type or diagnosis and should prompt further diagnostic evaluation, including nerve conduction studies and EMG.
  • Nerve conduction studies and EMG are not required as part of the routine diagnosis of distal symmetric polyneuropathy in diabetes unless atypical features are present.
  • The diagnosis of distal symmetric polyneuropathy provides a valuable opportunity to educate patients on the health benefits of addressing risk factors associated with neuropathy (glucose control, hyperlipidemia, hypertension, tobacco use), advocate for exercise, and counsel on the importance of proper foot care.
  • The risks associated with neuropathy development exist in the prediabetes state. The individual components of the metabolic syndrome, including glucose dysregulation/insulin resistance, dyslipidemia (hypertriglyceridemia and low high-density lipoprotein level), central obesity, and hypertension, all contribute to the risk of developing distal symmetric polyneuropathy.
  • The acute to subacute onset of pain and weakness in the hip and leg of an individual with diabetes should raise suspicion for diabetic lumbosacral radiculoplexus neuropathy. Early recognition and intervention with IV corticosteroids may improve neuropathic pain and reduce the associated morbidity.
  • Treatment-induced neuropathy of diabetes should be suspected in an individual with diabetes who presents with the acute to subacute onset of neuropathic pain in a symmetric pattern that is accompanied by predominantly small fiber findings. A significant improvement in glycemic control that precedes the development of pain is the clue to the diagnosis.
  • The earliest clinical manifestation of a diabetic autonomic neuropathy is a resting tachycardia.
  • Cardiovascular autonomic neuropathy (particularly with orthostatic hypotension) is associated with significantly increased mortality risk in patients with diabetes, with 5- to 10-year mortality rates greater than 50%.
  • Gastroparesis is a common and disabling manifestation of diabetic autonomic neuropathy, but the potential for symptomatic improvement exists with better glycemic control.
  • Constipation may be a manifestation of diabetic autonomic neuropathy but is also frequently due to medication. A careful review of both prescribed and over-the-counter medications may identify potential opportunities to improve symptoms.
  • Diabetic diarrhea is often profuse and watery; it frequently occurs at night with fecal incontinence. Medications should be reviewed carefully because identification and removal of offending medications may improve symptoms.
  • Bladder dysfunction is common in diabetes and often related to medication side effects. As with other diabetic autonomic neuropathies, offending medications should be removed as the initial step in management.
  • Sexual dysfunction is common in both men and women with diabetes and frequently is due to a combination of psychological and physical factors, both of which should be addressed.
  • Neuropathy involving the sympathetic cholinergic nerves results in a length-dependent region of anhidrosis, but patients typically present with complaints of proximal hyperhidrosis.
  • Recurrent hypoglycemia blunts future autonomic responses to low levels of glucose, creating a vicious cycle of recurrent hypoglycemia because of the body’s inability to sense low glucose levels.
  • Recurrent hypoglycemia is associated with an increase in cardiovascular mortality, although the exact mechanism for the increase in mortality is still under investigation.
  • It is controversial whether chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) occurs more frequently in individuals with diabetes; however, CIDP is widely overdiagnosed. A diagnosis of CIDP in a patient with diabetes should be based on typical clinical features, not on nerve conduction study findings alone.
  • Uremia is linked to an increased risk of length-dependent neuropathy but may improve with dialysis or kidney transplantation.
  • An acute optic neuropathy may also be seen in uremia and should be treated with hemodialysis and corticosteroids.

Article 3: Guillain-Barré Syndrome

Kazim A. Sheikh, MBBS. Continuum (Minneap Minn). October 2020; 26 (5 Peripheral Nerve and Motor Neuron Disorders):1184–1204.

ABSTRACT

PURPOSE OF REVIEW

This article reviews the clinical features, diagnosis and differential diagnosis, prognosis, pathogenesis, and current and upcoming treatments of Guillain-Barré syndrome (GBS).

RECENT FINDINGS

GBS is an acute inflammatory neuropathic illness with striking clinical manifestations and significant morbidity. A substantial proportion of patients with GBS do not respond to current immunomodulatory therapies (ie, plasma exchange and IV immunoglobulin [IVIg]), highlighting the need for new therapies. Prognostic models that can accurately predict functional recovery and the need for artificial ventilation have emerged. These models are practical, and online calculators are available for clinical use, facilitating early recognition of patients with poor outcome and the opportunity to personalize management decisions. Clinical and experimental studies have identified innate immune effectors (complement, macrophage lineage cells, and activating Fcγ receptors) as important mediators of inflammatory nerve injury. Two complement inhibitors are undergoing clinical testing for efficacy in GBS.

SUMMARY

GBS is the most common cause of acute flaccid paralysis in the United States and worldwide. New treatments for GBS have not emerged since the 1990s. Our understanding of the pathogenesis of this disorder has progressed, particularly over the past decade; as a result, new therapeutic agents targeting different components of the complement cascade are at advanced stages of clinical development.

KEY POINTS

  • Guillain-Barré syndrome (GBS) encompasses a spectrum of acute neuropathic disorders, with muscle weakness being the cardinal manifestation in the majority of patients. It is the most common cause of acute flaccid paralysis in the United States and worldwide.
  • The National Institute of Neurological Disorders and Stroke diagnostic criteria for paralytic GBS are simple and practical for routine clinical use; the key features of the criteria include symmetric flaccid weakness, decreased deep tendon reflexes, and exclusion of alternative causes.
  • Although the first symptoms of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) are often sensory, it is primarily a motor polyradiculoneuropathy causing symmetric weakness of proximal and distal muscles. The classic pattern is of ascending weakness, but symptoms may also begin proximally.
  • Of patients with GBS, 25% to 30% will require intubation because of respiratory muscle weakness or pharyngeal muscle weakness (airway protection); patients should be closely monitored for the need of mechanical ventilation.
  • Miller Fisher syndrome, the most common minor subtype of GBS, is characterized by a triad of ophthalmoplegia, ataxia, and areflexia.
  • An altered level of consciousness or hyperreflexia with external ophthalmoplegia and ataxia reflects central nervous system involvement indicative of Bickerstaff brainstem encephalitis. Miller Fisher syndrome–related disorders are considered a clinical continuum with Bickerstaff brainstem encephalitis on one end and Miller Fisher syndrome on the other.
  • Residual symptoms after GBS are common and include fatigue, pain, paresthesia, and reduced muscle strength.
  • Nerve conduction studies and EMG provide confirmation of an acute neuropathic process and may differentiate between demyelinating and axonal variants of GBS. They are often relatively normal early in the course; serial studies are often necessary and may be useful for prognostication.
  • Partial motor nerve conduction block without temporal dispersion may be seen in acute motor axonal neuropathy because of reversible conduction failure at the nodes of Ranvier. Other demyelinating features, such as reduced conduction velocity and prolonged minimal F-wave or distal motor latencies, are absent.
  • CSF analysis typically shows albuminocytologic dissociation. A mild pleocytosis (<50 cells/mm3) can be seen in up to 10% to 15% of patients with GBS. A pleocytosis of greater than 50 cells/mm3 suggests an alternative diagnosis.
  • Prognostic models for GBS based on clinical parameters, including Medical Research Council (MRC) sum score, which are collected as part of standard care, can reliably predict the need for mechanical ventilation in the first week and functional outcomes at 4 weeks to 6 months after admission.
  • AIDP, acute motor axonal neuropathy, and acute motor-sensory axonal neuropathy share common pathologic features, including activation of components of the innate immune system such as complement activation and upregulation of Fc receptors for IgG (FcγRs). These are promising therapeutic targets.
  • It is believed that GBS is triggered by environmental exposures in genetically susceptible hosts.
  • Campylobacter jejuni is the most common trigger for GBS, particularly the axonal forms, with an estimated prevalence of 30%. However, the risk of GBS with C. jejuni infection is low (less than 2 in 10,000).
  • Noninfectious events, including trauma, vaccinations, immunosuppression, and pregnancy, may rarely trigger GBS.
  • The risk of developing GBS following influenza infection is much higher than the risk of GBS following vaccination. Patients who develop GBS following influenza or any other vaccine should not receive the same vaccine again.
  • Postinfectious molecular mimicry is the predominant pathophysiologic mechanism in Miller Fisher syndrome and axonal variants and in patients who develop AIDP following Mycoplasma pneumoniae infection.
  • Supportive and intensive care remains the cornerstone of management of patients with GBS during the acute phase of this monophasic illness, and immune therapy with plasma exchange or IV immunoglobulin (IVIg) hastens recovery.
  • Randomized clinical trials indicate that IVIg and plasma exchange hasten recovery in patients with GBS, and both treatments were found to be equally efficacious.
  • Of patients with GBS treated with IVIg or plasma exchange in clinical trials, 40% to 50% did not have a clinical response (ie, did not meet primary end point), emphasizing the need for new therapies.
  • Randomized controlled data indicate that combination treatment with plasma exchange followed by IVIg is not superior to treatment with IVIg or plasma exchange alone, and anecdotal observations indicate that combination treatment with IVIg followed by plasma exchange is no better than IVIg alone. Combination therapy is generally discouraged.
  • No evidence- or consensus-based recommendations are available for additional immunomodulatory treatments for patients with GBS for whom initial IVIg or plasma exchange treatment has failed, and further supportive medical management should be tailored according to individual needs in such cases.
  • Biologics targeting the complement cascade are at various stages of clinical trials in GBS, and neonatal Fc receptor (FcRn) inhibitors (which can reduce IgG autoantibody burden) and modulators of FcγR are at advanced stages of clinical development with potential applicability to GBS.

Article 4: Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Its Variants

Kelly Gwathmey, MD. Continuum (Minneap Minn). October 2020; 26 (5 Peripheral Nerve and Motor Neuron Disorders):1205–1223.

ABSTRACT

PURPOSE OF REVIEW

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and its variants comprise a group of immune-mediated neuropathies with distinctive clinical presentations and electrodiagnostic features. Prompt recognition of these treatable disorders is mandatory as delays result in significant disability and morbidity. This article highlights the clinical presentation, pathophysiology, diagnostic evaluation, and treatment approach of these polyneuropathies.

RECENT FINDINGS

The spectrum of CIDP is expanding with the recent characterization of neuropathies associated with nodal and paranodal antibodies. These neuropathies are distinguished by their unique presentations and are often refractory to IV immunoglobulin (IVIg) therapy. Subcutaneous immunoglobulins have recently been approved as a treatment option for CIDP and join corticosteroids, IVIg, and plasma exchange as first-line treatment.

SUMMARY

CIDP is characterized by progressive symmetric proximal and distal weakness, large fiber sensory loss, and areflexia, with clinical nadir reached more than 8 weeks after symptom onset. Autoimmune demyelinating neuropathies fall on a continuum, with differences in the type of nerve fibers affected and pattern of deficits. Distinguishing between typical CIDP and its variants allows for selection of the most appropriate treatment.

KEY POINTS

  • One-half of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have a typical presentation of symmetric proximal and distal weakness, length-dependent loss of large fiber sensation, and areflexia.
  • Up to 18% of patients with CIDP will have an acute onset that mimics Guillain-Barré syndrome.
  • CIDP is differentiated from Guillain-Barré syndrome by a protracted time course, absence of autonomic dysfunction, and absence of respiratory impairment in most patients.
  • All patients with suspected CIDP should be screened for a monoclonal gammopathy.
  • Albuminocytologic dissociation is expected on CSF analysis in CIDP. The presence of leukocytosis raises suspicion for other conditions, such as neurosarcoidosis, human immunodeficiency virus (HIV), or carcinomatous meningitis.
  • The sural sparing pattern is an electrophysiologic hallmark of CIDP and is often found in addition to other acquired demyelinating features.
  • Patients with suspected CIDP do not require a nerve biopsy if the electrodiagnostic findings and clinical features are consistent with an acquired demyelinating polyradiculoneuropathy.
  • More than 15 sets of diagnostic criteria for CIDP have been published; the most widely accepted is the European Federation of Neurological Sciences/Peripheral Nerve Society criteria.
  • The first-line treatments for CIDP include immunoglobulins (IV and subcutaneous), corticosteroids, and plasma exchange. Given the need for long-term venous access and limited facilities capable of outpatient plasma exchange, in practice, plasma exchange is considered second- or third-line treatment by many experts.
  • Clinical trials suggest IV immunoglobulin (IVIg) can be discontinued successfully without relapse in approximately 50% of patients. The treating physician should work toward reducing or discontinuing the IVIg if possible.
  • Use of clinically appropriate outcome measures, such as disability scales and quality-of-life instruments, helps to inform medical decision making in CIDP.
  • Multifocal motor neuropathy may mimic amyotrophic lateral sclerosis given its painless progressive weakness, but it is differentiated by its lack of upper motor neuron signs and electrophysiologic evidence of conduction block on motor nerve conduction studies.
  • Distal acquired demyelinating symmetric (DADS) neuropathy is often associated with IgM monoclonal gammopathy and myelin-associated glycoprotein antibodies. Patients with DADS are often refractory to treatment.
  • Autoantibodies directed toward paranodal and nodal antigens are present in approximately 10% of cases of CIDP; these cases have unique clinical presentations and are often IVIg refractory.
  • Patients with nodal and paranodal autoantibodies may respond to rituximab as the autoantibodies are of the IgG4 isotype.

Article 5: Charcot-Marie-Tooth Disease and Other Hereditary Neuropathies

Christopher J. Klein, MD, FAAN. Continuum (Minneap Minn). October 2020; 26 (5 Peripheral Nerve and Motor Neuron Disorders):1224–1256.

ABSTRACT

PURPOSE OF REVIEW

This article provides an overview of Charcot-Marie-Tooth disease (CMT) and other inherited neuropathies. These disorders encompass a broad spectrum with variable motor, sensory, autonomic, and other organ system involvement. Considerable overlap exists, both phenotypically and genetically, among these separate categories, all eventually exhibiting axonal injury and neurologic impairment. Depending on the specific neural and non-neural localizations, patients experience varying morbidity and mortality. Neurologic evaluations, including neurophysiologic testing, can help diagnose and predict patient disabilities. Diagnosis is often complex, especially when genetic and acquired components overlap.

RECENT FINDINGS

Next-generation sequencing has greatly improved genetic diagnosis, with many third-party reimbursement parties now embracing phenotype-based panel evaluations. Through the advent of comprehensive gene panels, symptoms previously labeled as idiopathic or atypical now have a better chance to receive a specific diagnosis. A definitive molecular diagnosis affords patients improved care and counsel. The new classification scheme for inherited neuropathies emphasizes the causal gene names. A specific genetic diagnosis is important as considerable advances are being made in gene-specific therapeutics. Emerging therapeutic approaches include small molecule chaperones, antisense oligonucleotides, RNA interference, and viral gene delivery therapies. New therapies for hereditary transthyretin amyloidosis and Fabry disease are discussed.

SUMMARY

Comprehensive genetic testing through a next-generation sequencing approach is simplifying diagnostic algorithms and affords significantly improved decision-making processes in neuropathy care. Genetic diagnosis is essential for pathogenic understanding and for gene therapy development. Gene-targeted therapies have begun entering the clinic. Currently, for most inherited neuropathy categories, specific symptomatic management and family counseling remain the mainstays of therapy.

KEY POINTS

  • Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy but accounts for only a minority of the gene abnormalities among inherited neuropathies.
  • Patients with inherited neuropathy often describe their symptoms as subacute in onset, but foot and ankle abnormalities (hammer toes, pes cavus, pes planus, cavovarus) and shin and hand atrophy along with needle EMG changes support the chronicity of disease course.
  • The presence of ankle reflexes and normal sensation in patients with symmetric ankle weakness raises the possibility of inherited distal myopathy or inherited distal hereditary motor neuron disease mimicking CMT. The genes responsible for distal myopathy and progressive muscular atrophy should be considered in next-generation sequencing panel testing for inherited neuropathies.
  • Gene names are increasingly being included in the nomenclature of inherited disorders including inherited neuropathies.
  • Historical clues of inherited neuropathies should be sought, including frequent ankle sprains and foot fractures, recurrent ingrown toenails (paronychia), and painless foot ulcers.
  • Prolonged blink R1 response latency greater than 13 milliseconds, regardless of severity or age, suggests primary demyelinating inherited neuropathy.
  • Patients with inherited neuropathy are more susceptible to clinical declines from superimposed acquired neuropathies such as diabetes and neurotoxic chemotherapy.
  • PMP22 duplications account for approximately 70% of cases of primary demyelinating neuropathy.
  • Mutations of MFN2 are the most common known cause of primary axonal CMT.
  • Not all patients with inherited demyelinating neuropathies have CMT; some may have disorders such as mitochondrial neurogastrointestinal encephalomyopathy or metachromatic leukodystrophy.
  • Absence of male-to-male transmission and females being more mildly affected than males within a family suggests CMTX1-GJB1, the second most common form of CMT.
  • Patients with hereditary sensory autonomic neuropathy commonly have pain, and some forms also have gastrointestinal dysmotility, insensate injuries with amputations, and mortality from respiratory and feeding difficulties.
  • Patients with hereditary neuropathy with liability to pressure palsies need to be recognized to avoid unnecessary decompressive surgeries at points of compression.
  • Family history, recurrent episodes, and, possibly, younger age of onset distinguish hereditary brachial plexus neuropathy from idiopathic neuralgic amyotrophy (Parsonage-Turner syndrome).
  • Two drugs that knock down RNA expression of mutant and wild-type TTR (patisiran and inotersen) have been recently approved for hereditary transthyretin amyloidosis neuropathy.
  • Standard next-generation sequencing cannot identify nucleotide repeat expansion mutations such as those occurring in Friedreich ataxia and cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS).
  • Enzyme replacement therapy with recombinant α-galactosidase was the first available specific treatment for Fabry disease. Recently, migalastat, a new drug using chaperone therapy, was approved by the US Food and Drug Administration. Migalastat is a small molecule drug that stabilizes and facilitates trafficking of rescuable mutant forms of α-galactosidase A protein, partially restoring the enzyme activity in lysosomes.
  • Next-generation sequencing is simplifying the genetic diagnosis of inherited neuropathies.
  • The accuracy of next-generation sequencing testing correlates to the depth of coverage of all targeted genes represented in panel testing.
  • Foot and ankle surgeries should be reserved for patients for whom bracing for ankle stability has failed, with tendon transfers favored over joint fusions.

Article 6: Peripheral Neuropathies Associated With Vasculitis and Autoimmune Connective Tissue Disease

Chafic Karam, MD. Continuum (Minneap Minn). October 2020; 26 (5 Peripheral Nerve and Motor Neuron Disorders):1257–1279.

ABSTRACT

PURPOSE OF REVIEW

This article discusses peripheral neuropathies associated with vasculitis (isolated or in the setting of systemic vasculitis) and autoimmune connective tissue disease and provides a brief overview of their diagnostic evaluation and management.

RECENT FINDINGS

The classification of systemic vasculitic neuropathy and nonsystemic vasculitic neuropathy continues to evolve. Classification according to the presence of antineutrophil cytoplasmic antibodies and their subtypes facilitates prognostication and management. Recent research on antineutrophil cytoplasmic antibody–associated vasculitis has added to our understanding of its neurologic complications. The treatment of vasculitis is also evolving, and new nonsystemic vasculitic neuropathy classification has impacted the treatment and management of this disorder. New classification criteria for Sjögren syndrome (which commonly causes neurologic complications) facilitate accurate and timely diagnosis.

SUMMARY

Vasculitis and autoimmune connective tissue disease are underrecognized and treatable causes of peripheral neuropathy. Furthermore, peripheral neuropathy may reveal an underlying rheumatologic or vasculitic disorder. Rapid recognition and treatment are essential. Familiarity with the diagnosis and treatment of neuropathies in the setting of connective tissue disease and vasculitis reduces morbidity and, in some cases, mortality.

KEY POINTS

  • Asymmetric signs or symptoms or stepwise progression, especially when associated with systemic symptoms, are highly suggestive of vasculitic neuropathy.
  • Nerve conduction studies done on opposite limbs, even if asymptomatic, are essential to demonstrate asymmetry or multifocality, which can be missed clinically.
  • Nerve biopsy is necessary for a diagnosis of definite vasculitis, but, because of the patchy nature of the disease process, a negative biopsy does not rule out vasculitis.
  • Biopsy of a nearby muscle increases the diagnostic yield of biopsy for suspected vasculitic neuropathy by about 15%.
  • Laboratory testing is essential to determine whether vasculitis is secondary to a systemic disorder or exposure that may require different management.
  • Adult-onset asthma in a patient with a subacute asymmetric neuropathy or multifocal neuropathy strongly suggests eosinophilic granulomatosis with polyangiitis.
  • Testing for antineutrophil cytoplasmic antibodies (ANCA) in the setting of vasculitis is essential to determine prognosis and appropriate treatment.
  • In the rare instance in which both myeloperoxidase and proteinase 3 are positive in the same patient, drug-induced vasculitis should be suspected.
  • In polyarteritis nodosa, testing for hepatitis B virus is essential. Testing for ANCA is negative, and glomerulopathy is not present.
  • Appropriate blood handling, including temperature control, is essential for testing for cryoglobulinemia.
  • In mild cases of cryoglobulinemic neuropathy associated with infection, immunosuppression may not be required when the infection is treated adequately.
  • In nonsystemic vasculitic neuropathy, systemic symptoms and signs are usually absent and serologic markers are negative.
  • Different syndromes of nonsystemic vasculitic neuropathy carry different prognoses. The diagnosis is usually made clinically, and patients should be treated if the disease is active.
  • Tumor necrosis factor-α inhibitors, which are commonly used to treat rheumatoid arthritis, can cause inflammatory autoimmune neuropathies.
  • Patients with Sjögren syndrome frequently present to the neurologist first because of peripheral neuropathy.
  • The presence of a significant sensory neuropathy or dorsal root ganglionopathy should prompt a thorough evaluation for Sjögren syndrome.

Article 7: Peripheral Neuropathies Due to Vitamin and Mineral Deficiencies, Toxins, and Medications

Nathan P. Staff, MD, PhD, FAAN. Continuum (Minneap Minn). October 2020; 26 (5 Peripheral Nerve and Motor Neuron Disorders):1280–1298.

ABSTRACT

PURPOSE OF REVIEW

Vitamin and mineral deficiencies, neurotoxins, and, particularly, prescription medications, are some of the most common causes of peripheral neuropathy. Recognition and prompt treatment of these neuropathies require a high index of suspicion and an accompanied detailed history. This article provides a comprehensive approach and list of items that must be considered in the setting of new-onset neuropathy.

RECENT FINDINGS

Although many of the neuropathies described in this article have decreased in prevalence in developed countries because of public health interventions and occupational/environmental regulations, new causes for this class of neuropathy continue to be uncovered.

SUMMARY

The peripheral nervous system is susceptible to a broad array of metabolic and toxic abnormalities, which most often lead to a length-dependent sensory-predominant axonal peripheral neuropathy. A careful history accompanied by recognition of multisystem clues can increase recognition of these neuropathies, which is important as many have specific treatments that may either improve the neuropathy or halt its progression.

KEY POINTS

  • A broad review of systems that includes skin, nails, and hematologic and gastrointestinal systems may provide clues to a neuropathy caused by vitamin deficiencies or toxins.
  • Vitamin B12 deficiency secondary to inadequate oral intake is uncommon, except in cases of a strict vegan diet.
  • Simultaneous onset of sensory symptoms in the hands and feet suggests cervical cord pathology, which may be seen in vitamin B12 or copper deficiencies.
  • When investigating vitamin B12 deficiency, it is important to also consider copper deficiency because the clinical picture can be very similar.
  • Vitamin B6 supplementation is only routinely recommended in the setting of isoniazid or hydralazine treatment, in which vitamin B6 deficiency may occur. Otherwise, vitamin B6 supplementation itself can cause a sensory neuropathy or sensory ganglionopathy.
  • Neuropathy due to thiamine deficiency has many presentations, including length-dependent sensorimotor, cranial nerve, and motor-predominant polyneuropathy, all of which may precede cognitive and systemic symptoms.
  • Establishing a causal link between alcohol use and neuropathy can be difficult for a variety of reasons, but it is recommended that all patients with neuropathy ingest minimal alcohol. Early referral to a chemical dependence specialist is recommended when alcohol use disorder is suspected.
  • Uremic neuropathy in the setting of chronic dialysis is typically a mild axonal sensorimotor peripheral neuropathy; other etiologies should be considered if a severe neuropathy is encountered.
  • Intoxication from arsenic or thallium is preceded by severe gastrointestinal illness, and the neuropathy may mimic Guillain-Barré syndrome.
  • Obtaining a detailed occupational and hobby exposure history is critical for discovering many toxic neuropathies.
  • Medications may cause peripheral neuropathy in a dose-dependent fashion or may be a rare idiosyncratic reaction.
  • Coasting is a phenomenon in which a neuropathy worsens for weeks to months after the discontinuation of a toxic agent. This is most often observed in chemotherapy-induced peripheral neuropathy due to platinum-based chemotherapy but can also be seen in neuropathies due to hexanes and vitamin B6 excess.
  • Oxaliplatin causes cold-induced dysesthesia.
  • Paclitaxel is associated with acute toxicity causing a pain syndrome that is not clearly due to nerve damage.
  • Patients with cancer are more commonly being treated with immune-checkpoint inhibitors, which result in a neurologic adverse event in 3% of patients. These neurologic adverse events include central or peripheral nervous system syndromes, which may be life-threatening.

Article 8: Management of Neuropathic Pain in Polyneuropathy

Amanda C. Peltier, MD, MS; Derek Wood, MD. Continuum (Minneap Minn). October 2020; 26 (5 Peripheral Nerve and Motor Neuron Disorders):1299–1322.

ABSTRACT

PURPOSE OF REVIEW

Many polyneuropathies cause significant neuropathic pain, resulting in substantial morbidity and reduced quality of life. Appropriate management is crucial for maintaining quality of life for patients with painful polyneuropathies. The US Food and Drug Administration (FDA) has only approved one new drug for painful diabetic neuropathy in the past decade, a topical capsaicin patch that was initially approved for the treatment of postherpetic neuralgia in 2009. Gabapentinoids and serotonin norepinephrine reuptake inhibitors (SNRIs) continue to have an advantage in safety profiles and efficacy. Other antiepileptic medications remain second-line agents because of fewer studies documenting efficacy.

RECENT FINDINGS

This article reviews recent literature on complementary and pharmacologic therapies for the management of painful polyneuropathies. Exercise has emerged as an important therapeutic tool and may also improve the underlying polyneuropathy in the setting of obesity, metabolic syndrome, and diabetes.

SUMMARY

The approach to management of painful polyneuropathies is multifactorial, using both pharmacologic and nonpharmacologic measures to improve pain severity and patient quality of life.

KEY POINTS

  • Painful polyneuropathy is one of the most common causes of neuropathic pain and may affect up to 1 in 20 Americans.
  • Painful polyneuropathy is associated with significantly reduced quality of life and increased health care costs, as well as costs to society in lost worker productivity.
  • Neuropathic pain leads to sleep disruption and vice versa. Up to 80% of patients with neuropathic pain have sleep disturbance.
  • Half of patients with painful diabetic neuropathy have depression or anxiety, and one-fourth have both.
  • Although the specific role of SCN9A sequence variants in the pathogenesis of small fiber neuropathy is uncertain, voltage-gated sodium channels play an important role in neuropathic pain, and pharmacologic inhibition is a promising therapeutic strategy.
  • No new medications for neuropathic pain have been approved in the past 10 years (although the high-dose capsaicin patch that was approved for postherpetic neuralgia in 2009 was recently approved for use in painful diabetic polyneuropathy in July 2020). The most commonly used medications are the gabapentinoids, which act on α2δ calcium channels, and medications that increase norepinephrine at the synapse.
  • Each neuropathic pain medication should generally be tried at the maximal tolerated dose for 6 to 8 weeks before concluding it is ineffective.
  • Differentiating painful polyneuropathy from restless legs syndrome (RLS), which may coexist with painful neuropathy, is important as most pain medications (with the exception of the gabapentinoids) are ineffective for RLS, and some agents (such as tricyclic antidepressants) may worsen RLS.
  • Setting realistic treatment expectations for pain management is essential. Complete pain relief is typically not a realistic goal.
  • Gabapentin is absorbed in the intestine via an active-transport mechanism and displays nonlinear pharmacokinetics with saturable absorption and decreased bioavailability at higher doses.
  • Gabapentin and pregabalin have similar efficacy, although patients may respond to, or tolerate, one and not the other. Gabapentin displays nonlinear pharmacokinetics with saturable absorption and decreased bioavailability at higher doses, which may favor the use of pregabalin.
  • The two most commonly used tricyclic antidepressants for painful polyneuropathy are amitriptyline and nortriptyline.
  • Caution should be exercised when initiating tricyclic antidepressants in elderly individuals or those with preexisting cognitive or autonomic dysfunction as they may be more susceptible to anticholinergic side effects, and their use should be avoided in patients with severe depression or history of suicide attempt because of the risk of intentional overdose.
  • Duloxetine may be a particularly good agent for patients with painful diabetic neuropathy with comorbid depression, anxiety, or fibromyalgia.
  • Despite a lower efficacy compared to gabapentinoids and serotonin norepinephrine reuptake inhibitors, antiepileptic drugs and mexiletine may still be worth a trial in some patients with refractory pain.
  • Topical agents (such as lidocaine patches or cream) are of modest efficacy but may add symptomatic relief in selected patients with neuropathic pain and have the advantage of minimal side effects.
  • Opioid analgesics, including tramadol, should not be used as first- or second-line medications for neuropathic pain and should only be considered in severe and refractory cases when all other options have failed. In general, referral to a pain clinic is recommended if opioid therapy is being considered.
  • Opioid-induced hyperalgesia causes patients to have increased pain and diffuse allodynia that is often different than their initial pain manifestation.
  • High-quality clinical trial data supporting the use of cannabinoids for neuropathic pain are lacking, and side effects are common. Their use outside of clinical trials is discouraged.
  • Recognition and individualized treatment of depression is important, and cognitive therapy can be a useful tool in multidisciplinary pain clinics.
  • Given the multiple health benefits of exercise and improvement in other parameters of health, exercise should be highly encouraged in all patients with painful polyneuropathy.
  • An algorithmic approach that integrates pharmacologic and nonpharmacologic therapy with specific attention to comorbid sleep and mood disorders is the most effective approach to neuropathic pain management.

Article 9: Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases

Colin Quinn, MD; Lauren Elman, MD. Continuum (Minneap Minn). October 2020; 26 (5 Peripheral Nerve and Motor Neuron Disorders):1323–1347.

ABSTRACT

PURPOSE OF REVIEW

This article reviews the clinical features, diagnostic approach, and treatments available for amyotrophic lateral sclerosis (ALS) and other motor neuron diseases. The article also provides an update on the genetics and pathophysiology of ALS.

RECENT FINDINGS

ALS remains a clinical diagnosis without a unique biomarker. The areas of greatest progress include a large expansion in the number of genes associated with familial and sporadic ALS. The discovery of these genes, along with other work, has provided a deeper understanding of the mechanisms of motor neuron failure in ALS. Areas of particular interest include the role of transactive response DNA-binding protein 43 and other RNA-processing proteins in the development of disease.

SUMMARY

ALS remains a relentlessly progressive disorder with an elusive core pathophysiology. The current mainstay of treatment remains symptom management and palliation, particularly in the setting of a multidisciplinary clinic. The future holds potential for targeted therapies based on an ever-evolving understanding of the pathophysiology of both familial and sporadic ALS.

KEY POINTS

  • The incidence of amyotrophic lateral sclerosis (ALS) has remained constant at around 2 per 100,000 per year to 3 per 100,000 per year and is slightly higher in men than in women.
  • Of patients with ALS, 90% have sporadic disease and 10% have familial ALS, which follows an autosomal dominant pattern of inheritance.
  • Patients with ALS typically have a combination of upper motor neuron and lower motor neuron signs that affect multiple segments of the body.
  • Frontotemporal dementia occurs in 5% to 15% of patients with ALS, and a larger proportion of patients will have subtle findings of personality change or executive dysfunction.
  • The diagnostic evaluation of ALS does not need to be extensive in the setting of the appropriate clinical history and physical examination, although it is imperative to exclude all treatable conditions.
  • MRI should be performed at the lowest level of upper motor neuron findings and above in patients with suspected ALS.
  • Isolated upper motor neuron examination findings should prompt careful examination of the neuraxis, with MRI performed to exclude lesional causes of upper motor neuron injury.
  • Gene discovery for ALS has accelerated remarkably over the past decade, leading to improved understanding of ALS pathophysiology that will ideally result in targeted therapies in the near future.
  • SOD1 mutations were the first genetic mutations discovered in familial ALS. However, SOD1 pathology is distinct from the pathology seen in the majority of ALS cases.
  • Hexanucleotide repeat expansions in C9orf72 are the most common cause of familial ALS.
  • No single cause of ALS has been determined, although multiple critical pathways in motor neuron degeneration have been identified. Of particular current interest are abnormalities in RNA processing.
  • Cytoplasmic transactive response DNA-binding protein 43 (TDP-43) inclusions are a hallmark of ALS pathology in the vast majority of patients.
  • No curative therapy has been identified for ALS. The mainstay of treatment is multidisciplinary care and palliative symptom management.
  • The oral drug riluzole is the most widely used disease-modifying agent in ALS and has a well-established, albeit modest, effect on survival.
  • Edaravone is an IV disease-modifying agent that slowed the rate of functional decline in a small number of select ALS patients with early, diffuse, and rapidly progressing disease. However, a prior trial in a broader population was negative and questions remain regarding its long-term effectiveness in the general ALS population.
  • The presence of isolated lower motor neuron or upper motor neuron abnormalities should broaden the differential diagnosis but does not preclude an ALS diagnosis.
  • Monomelic amyotrophy presents in young men with atrophy of one or both arms, typically in the lower cervical myotomes. The diagnosis is typically confirmed by findings on cervical MRI, including dynamic flexion demonstrating forward displacement of the dura. Although the cause of injury is not certain, the most common theory is microvascular disturbance due to compression with resultant ischemia of the anterior horn cells at C8 and T1.
  • Spinal bulbar muscular atrophy is a rare cause of motor neuropathy but should be considered in men with lower motor neuron disease, sensory neuropathy on nerve conduction studies, predominant bulbar symptoms, and facial twitching. It is caused by an X-linked trinucleotide repeat disorder in the androgen receptor gene. Neurodegeneration is due to a toxic gain of function that occurs in the setting of ligand (testosterone and dihydrotestosterone) binding to the mutant receptor.

Article 10: Spinal Muscular Atrophy

Jessica Rose Nance, MD. Continuum (Minneap Minn). October 2020; 26 (5 Peripheral Nerve and Motor Neuron Disorders):1348–1368.

ABSTRACT

PURPOSE OF REVIEW

This article provides an overview of the pathophysiology and clinical presentations of spinal muscular atrophy (SMA) and reviews therapeutic developments, including US Food and Drug Administration (FDA)–approved gene-targeted therapies and mainstays of supportive SMA care.

RECENT FINDINGS

Over the past decades, an understanding of the role of SMN protein in the development and maintenance of the motor unit and the intricate genetics underlying SMA has led to striking developments in therapeutics with three FDA-approved treatments for SMA, one targeting SMN1 gene replacement (onasemnogene abeparvovec-xioi) and two others enhancing SMN protein production from the SMN2 gene (nusinersen and risdiplam). These therapies are most effective in infants treated at younger ages, and improvement is most striking in babies treated as neonates. Despite improvements in motor function, patients (especially those treated at older ages) continue to experience significant weakness and require continued close monitoring of respiratory and orthopedic symptoms.

SUMMARY

Striking therapeutic advancements have changed the clinical course of SMA dramatically, although supportive care continues to play an important role in patient care.

KEY POINTS

  • Spinal muscular atrophy (SMA) is a progressive motor neuron disease caused by mutations/deletions in the survival motor neuron 1 (SMN1) gene. It has a broad phenotypic spectrum and is classified into categories based on age of onset, motor milestone achievement, and copy number of the paralogous SMN2 gene.
  • SMA type 1 (SMA1) is the most common form of SMA and is characterized by onset of weakness in the first few months of life. Without disease-modifying therapy, babies with SMA1 never achieve the ability to sit independently, and the average time to death or requirement for permanent ventilation for an infant with untreated SMA1 is 13.5 months.
  • In SMA, both copies of the SMN1 gene are absent. Thus, motor neuron survival is dependent on the number of SMN2 copies. Patients with SMA with more SMN2 copies have a milder phenotype.
  • The majority of patients with SMA type 1 possess two SMN2 gene copies. Those with SMA type 2 usually have three copies, those with SMA type 3 have three or four copies, and patients with SMA type 4 typically have more than four copies. Those with SMA type 0, which presents with arthrogryposis multiplex congenita and severe respiratory failure, typically have one copy.
  • In December 2016, the US Food and Drug Administration approved nusinersen as the first therapy for SMA. An antisense oligonucleotide, nusinersen targets increased efficiency of inclusion of exon 7 during splicing of SMN2 RNA.
  • Neonates with SMA with two or three SMN2 copies treated with nusinersen before the onset of symptoms demonstrate striking improvement in motor function, with the large majority able to walk independently.
  • Onasemnogene abeparvovec-xioi is an adeno-associated virus 9–mediated SMN1 gene replacement therapy given as a single IV dose. It is indicated for patients of all SMA types who are 2 years of age or younger at the time of dosing. Similar to nusinersen, the impact of therapy is greatest in patients treated at a younger age and greater in those with three SMN2 copies than in those with two copies.
  • Risdiplam was approved in August 2020 and is a daily oral small molecule therapy that increases production of full-length SMN protein from the SMN2 mRNA. After 12 months, nearly half of infants with SMA type 1 treated first between 1 and 7 months of age were able to sit supported for at least 5 seconds. Older individuals with SMA type 2 or SMA type 3 treated with risdiplam also showed improvement in motor function compared to a placebo-controlled group.
  • Response to nusinersen, onasemnogene abeparvovec-xioi, and risdiplam therapies is more striking when they are delivered during the first months of life. Early treatment of SMA type 1 enables patients to achieve motor milestones never before possible. Some patients with SMA type 1 treated within the first weeks of life are able to walk.
  • Although striking improvement in motor milestone achievement is seen in patients with SMA after treatment with nusinersen, onasemnogene abeparvovec-xioi, or risdiplam, they still experience significant weakness.
  • Clinical trials are currently evaluating agents that promote muscle growth (antimyostatin antibody) and enhance muscle function (an activator of fast skeletal muscle troponin).
  • Increased need exists for early diagnosis of SMA, which drives the inclusion of SMA testing in newborn screening programs and the promotion of female carrier testing in pregnant women.
  • All newborns with two, three, or four copies of SMN2 (especially those in whom an SMA type 1 or type 2 phenotype is expected) should receive immediate therapy with either onasemnogene abeparvovec-xioi or nusinersen. In patients with five or more copies (who are expected to develop an SMA type 4 phenotype), treatment can be deferred with close monitoring for symptom development.
  • The efficacy of nusinersen, onasemnogene abeparvovec-xioi, and risdiplam appears to be equivalent. Decisions between the medications should be based on the patient’s age and discussion of mode of delivery and side effects with the patient or the patient’s parents or guardians.
  • Clinical trials evaluating the potential benefits of combination treatments with SMN1- and SMN2- enhancing therapies are anticipated or currently under way.
  • The extraordinary cost of SMN-targeted therapies may complicate the process of obtaining prior insurance authorization.
  • Supportive therapy, including pulmonary, nutritional, and rehabilitative management, plays a vital role in the treatment of SMA since many patients continue to experience significant weakness.
  • Rehabilitative management should focus on accommodating weakness and promoting mobility to improve patients’ engagement and minimize the orthopedic complications of progressive weakness. Positioning and bracing are especially important for both sitting and nonsitting patients to avoid worsening contractures and scoliosis.

Article 11: Peripheral Neuropathies Associated With Monoclonal Gammopathies

Elie Naddaf, MD; Michelle L. Mauermann, MD, FAAN. Continuum (Minneap Minn). October 2020; 26 (5 Peripheral Nerve and Motor Neuron Disorders):1369–1383.

ABSTRACT

PURPOSE OF REVIEW

Neurologists commonly evaluate patients with a monoclonal gammopathy and peripheral neuropathy. As both monoclonal gammopathy and peripheral neuropathy are common in the general population, their coexistence may, in some instances, be purely coincidental. However, monoclonal gammopathies or underlying lymphoplasmacytic disorders can affect the peripheral nervous system by various mechanisms. This article discusses how to approach patients with monoclonal gammopathy and peripheral neuropathy, highlighting clinical and laboratory clues that may aid in establishing a diagnosis in a timely manner.

RECENT FINDINGS

From a hematologic standpoint, a monoclonal gammopathy may be of undetermined significance or can be associated with an underlying myeloma, lymphoplasmacytic lymphoma, or amyloidosis. Each of these conditions can cause peripheral neuropathy, with varying clinical and electrodiagnostic profiles. Treatment usually consists of treating the underlying hematologic disorder. IgM-associated peripheral neuropathy may not require treatment from a hematologic standpoint, and only anecdotal evidence exists for the use of immunotherapy in such patients. Therefore, treatment should be determined on a case-by-case basis.

SUMMARY

Evaluating for an association between a monoclonal gammopathy and a peripheral neuropathy in a patient depends on the monoclonal gammopathy subtype and the clinical and electrodiagnostic characteristics of the peripheral neuropathy.

KEY POINTS

  • The coexistence of a monoclonal gammopathy and peripheral neuropathy in an individual patient is often coincidental.
  • A monoclonal gammopathy has undetermined significance from a hematologic standpoint when the patient has a low serum monoclonal protein level (<3 g/dL), less than 10% plasma cells in the bone marrow, and less than 500 mg/24 hour of M protein in the urine) and no evidence of end organ damage.
  • Whereas a monoclonal gammopathy may be of undetermined significance from a hematologic standpoint, it may still be of clinical significance from a neurologic standpoint.
  • IgM peripheral neuropathy usually presents with progressive sensory loss resulting in gait ataxia, with no to minimal weakness (distal acquired demyelinating symmetric [DADS] phenotype).
  • IgM peripheral neuropathy, distal acquired demyelinating symmetric (DADS) phenotype, is a demyelinating neuropathy with characteristic prolongation of motor distal latencies on electrodiagnostic testing.
  • Waldenström macroglobulinemia–associated peripheral neuropathy can look similar to IgM peripheral neuropathy but with more prominent systemic symptoms and cytopenias.
  • Chemotherapy-induced peripheral neuropathy is the most common neuropathy type encountered in multiple myeloma.
  • POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) neuropathy can mimic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) as associated features may be easily overlooked.
  • The presence of thrombocytosis in a patient with CIDP should prompt evaluation for underlying POEMS.
  • Any type of monoclonal gammopathy can be associated with amyloidosis.
  • Among all patients with paraproteinemic disorders, patients with immunoglobulin light chain (AL) amyloidosis appear the sickest and may display cardiorespiratory, gastrointestinal, genitourinary, and systemic symptoms at presentation.
  • Most commonly, patients with AL amyloidosis with peripheral nerve involvement present with generalized autonomic failure and a painful length-dependent sensory and motor peripheral neuropathy.
  • The majority of patients with AL amyloidosis are not autologous stem cell transplantation eligible at diagnosis; hence, early diagnosis is important.
© 2020 American Academy of Neurology.