Acute steroid responsive small-fiber sensory neuropathy: a new entity?Some 30 years ago, Dyck coined the term chronic inflammatory demyelinating polyneuropathy CIDP to describe a steroid-responsive polyneuropathy. Immune-mediated neuropathies are treatable conditions but are still likely to be underdiagnosed. Establishing animal models of acute and chronic polyneuritis such as steroif autoimmune neuritis EAN has fostered the understanding of human disease pathophysiology and has helped to dissect different forms of polyneugopathy neuropathies [ 1 ]. The nomenclature and classification esteroides anabolicos no aromatizantes immune-mediated neuropathiesthough still under debate, is converging Table 1. By contrast, in disimmune polyneuropathy, endoneural deposition of steroid sensitive polyneuropathy leads steroid sensitive polyneuropathy malfunctioning, and a local inflammatory reaction may be secondary or even absent.
Immune-mediated Neuropathies - an overview | ScienceDirect Topics
Some 30 years ago, Dyck coined the term chronic inflammatory demyelinating polyneuropathy CIDP to describe a steroid-responsive polyneuropathy. Immune-mediated neuropathies are treatable conditions but are still likely to be underdiagnosed. Establishing animal models of acute and chronic polyneuritis such as experimental autoimmune neuritis EAN has fostered the understanding of human disease pathophysiology and has helped to dissect different forms of immune-mediated neuropathies [ 1 ].
The nomenclature and classification of immune-mediated neuropathies , though still under debate, is converging Table 1. By contrast, in disimmune polyneuropathy, endoneural deposition of immunoglobulins leads to malfunctioning, and a local inflammatory reaction may be secondary or even absent.
The latter holds true in multifocal motor neuropathy MMN and polyneuropathy associated with immunoglobulin M IgM paraprotein. Peripheral nerve injury may be secondary to systemic inflammation, namely vasculitis.
Last, but not least, the immune-mediated disease process may be superimposed on a preexisting nerve disorder, as exemplified by hereditary and diabetic neuropathies.
The immune system is characterized by a well-balanced network of immunological factors. Dysbalance may be two sided: By contrast, when self-tolerance breaks down, heightened adaptive immune responses governed by T and B cells damage specific organs, as in the case of immune-mediated neuropathies [ 2 ].
Principles of the pathophysiology of immune-mediated neuritis may be translated to and verified in other human autoimmune diseases.
For instance, in GBS and the animal model of EAN, the hypothesis of molecular mimicry has been studied extensively and has substantially contributed to our understanding of the initial phase of autoimmune disease [ 3 ]. Acute immune-mediated neuropathies can arise as a complication of allogeneic hematopoietic stem cell transplantation in both children and adults.
Chronic inflammatory neuropathy following bone marrow transplantation complicated by severe graft-versus-host disease has also been reported in a 7-month-old girl. Although children are at risk of peripheral neuropathy as part of a graft-versus-host response, other causative or contributory factors such as toxins, infections, and paraneoplastic processes must also be considered and excluded. GBS is an immune-mediated neuropathy characterized by rapidly ascending muscle weakness or paralysis accompanied by absent or depressed deep tendon reflexes and elevated cerebrospinal fluid protein levels Hughes and Cornblath, Most cases of GBS are preceded by vaccination or by respiratory or gastrointestinal infections, but this phenomenon may also occur in the setting of malignancies.
Whether GBS arises as a result of the underlying cancer or whether this is simply a chance association is still under debate Giometto et al.
Regardless, GBS has been more commonly associated with lymphomas Lisak et al. In one report, nine of patients with GBS had been diagnosed with cancer in the 6 months preceding or following onset of the neurological disorder Vigliani et al. Five patients had electrophysiological findings consistent with acute inflammatory demyelinating polyneuropathy, two with acute motor axonal neuropathy, one with acute motor sensory axonal neuropathy, and one was not characterized. Three patients had non-small cell lung cancer, and the remainder of the patients had chronic lymphocytic leukemia, Hodgkin lymphoma, metastatic disease of unknown primary, kidney cancer, esophageal cancer, or vocal cord cancer.
Among GBS and other immune-mediated neuropathies , nodal and myelin-based glycoprotein autoantibodies are commonly found, but for many of these autoantibodies clear causality has not been established. Nevertheless, autoantibody glycoconjugate testing has proved useful and reproducible in clinical testing as reviewed Table Several clinical presentations benefit most from autoantibody testing against glycolipid or glycoprotein antigens: These four disorders have different clinical features and courses, wide differential diagnoses with clear mimics, and autoantibody testing is helpful.
In other cases, where there is no clearly associated autoantibody, and no tumor or onocneural antibody, these tests are not as useful. As an example, autoantibodies for GALOP and sulfatide are commonly ordered in evaluation of sensory and motor polyneuropathies, but their utility in identification of specific treatable disorders or associated malignancy has not been established.
For Miller—Fisher and acute motor axonal neuropathy, typical therapies for GBS are as outlined above, whereas in MMN, where GM1 antibodies help to distinguish it from amyotrophic lateral sclerosis, IVIg can be titrated to achieve optimal clinical response. Among DADS patients, the response to any immune-modulating therapy is minimal, with most patients refractory to all treatments.
For most DADS patients with typically an insidious progressive course, supportive devices like a cane or a walker should be the mainstay of care. Attempts at empiric treatment are likely low-yield, as demonstrated by a recent large double-blinded clinical trial in which even rituximab was ineffective Leger et al.
Stommel 1 , in Nerves and Nerve Injuries , MMN is a chronic immune-mediated neuropathy formally named in when it was linked to IgM GM1 anti-ganglioside serum antibodies. It has been demonstrated to be a positive response to immunosuppressive treatment Pestronk et al.
MMN typically presents with slowly progressive asymmetric distal upper extremity weakness without sensory complaints. The disease involves individual motor nerves. Initial involvement of median, ulnar, and radial nerves has been reported.
This leads to isolated third and fourth finger weakness Figure MMN may also less commonly involve the distal leg early in the disease with a foot drop typically secondary to a peroneal neuropathy. Cranial neuropathy and respiratory involvement are very rare. Although steady progression with multiple sequential nerve involvement over months to years is most common, many patients present with clear stepwise nerve involvement.
Spontaneous improvement of focal neuropathy occasionally occurs. It is important to note that fasciculations of affected nerves are commonly discovered by examination.
The associated weakness, cramps, and lack of sensory exam findings often cause concern for early motor neuron disease. However, some exam features that include minimal atrophy with significant muscle weakness, select nerve involvement e.
Some patients with MMN have normal or brisk reflexes that could lead to diagnostic confusion. Another interesting finding in MMN is that patients commonly report worsening weakness with cold weather, likely because of ionic channel dysfunction Straver et al. The pathogenesis of MMN is not clear but has been determined to be immune mediated because of the typically excellent response to immunomodulatory treatment i.
A significant problem with pathology studies is that sural nerve biopsies tend to be unremarkable because a sensory nerve is not significantly involved in MMN. MMN is rare, affecting about 1 person per , The mean age of clinical onset is about ; most patients present at ages A key characteristic of MMN is the presence of conduction block in motor nerve studies outside the typical sites of nerve compression most common are ulnar, median, and radial.
Conduction block may also not be seen if the patient presents later in the disease course when significant axonal loss has occurred. Other features of demyelination, such as prolonged distal motor latencies and prolonged F wave, may be demonstrated. Sensory nerve studies are normal or demonstrate only mildly reduced amplitudes and conduction velocities. A positive GM1 antibody test can help confirm the diagnosis if the clinical and electrophysiologic data fit with MMN; however, a negative antibody test result does not exclude the diagnosis of MMN.
Also note that GM1 antibodies may occasionally be highly positive in motor neuron disease a common differential diagnosis of MMN and in other immune neuropathies such as CIDP. However, for atypical presentations, CSF can be quite helpful. About one-third of patients have mildly elevated protein.
A high protein level i. As is the case for CIDP, nerve biopsy is not performed in evaluating MMN except in atypical cases when there is concern for another diagnosis such as vasculitis or neoplastic infiltration. This includes determining maintenance therapy based on patient clinical response. In contrast to CIDP, immunomodulatory treatment options are limited. Also a randomized placebo-controlled trial showed no benefit for mycophenolate mofetil as additional therapy to IVIG Piepers et al.
Small uncontrolled trials suggested a benefit in some patients from cyclophosphamide, cyclosporine, methotrexate, azathioprine, and rituximab Joint Task Force of the EFNS and the PNS, These options may be considered on a case-by case-basis in severe disease refractory to IVIG.
Risk of cyclophosphamide toxicity is a concern. MMN in a few patients significantly compromises quality of life, and the continued study of MMN complex pathophysiology is required to develop better treatments. For mild disease, immunomodulatory treatment can be deferred with close clinical follow-up, but any evidence of significant disability should lead to treatment.
Multifocal motor neuropathy is an acquired immune-mediated neuropathy characterized by slowly progressive asymmetrical arm and leg weakness sparing cranial nerves, and beginning in a single peripheral nerve distribution.
Typically, there is painless weakness, focal wasting, and sporadic fasciculations with preserved or absent tendon reflexes, although minor sensory complaints may also be present. However, unlike motor neuropathy, clinical weakness is generally out of proportion to atrophy, manifestations are characteristically asymmetrical and progression is slow. Men are more frequently affected with an average age of onset around 40 years.
Electrophysiological evidence of denervation is accompanied by the defining abnormality—multifocal motor conduction block, that is, the failure of a nerve impulse to conduct through an intact axon away from typical sites of nerve compression. However, lesser signs of demyelination, such as temporal dispersion, and minor sensory abnormalities are also described.
Ultrasonographic nerve enlargement has been noted. Motor nerve biopsies have shown variable features, including demyelination, rare focal inflammatory changes, frequent axonal loss, and signs of axonal regeneration. Sophisticated electrophysiological techniques suggest that focal depolarization or hyperpolarization may explain how conduction may be impaired without easily identifiable conduction block and how some patients may respond promptly to treatment.
The prime importance of a correct diagnosis is that the weakness of multifocal motor neuropathy is potentially reversible with intravenous immunoglobulin treatment; there is partial to complete improvement of symptoms and decrease of anti-GM1 antibody titers.
Improvement begins within 14 days and lasts an average of 2 months, although intravenous immunoglobulin effectiveness may decrease after years of treatment. Conduction block is not a permanent state and eventual axonal loss may ensue, especially if the condition is not treated. Unlike in chronic inflammatory demyelinating neuropathy, steroids are ineffective. Other immunosuppressive agents have been empirically used on the basis of open label trials, but no controlled trials have been conducted for cyclophosphamide, plasmapheresis, mycophenolate mofetil, azathioprine, rituximab, and some other agents.
Francesc Graus 3 , in Handbook of Clinical Neurology , Antibodies against several neural antigens have been associated with different chronic immune-mediated neuropathies. A significant association between polyneuropathy and monoclonal gammopathy was noted by Kelly and colleagues in Kelly et al.
In the s, our understanding of the neurological manifestation of monoclonal gammopathies was considerably advanced by two major observations: The pathogenicity of these antibodies was convincingly demonstrated in passive transfer experiments, where neuropathy was induced in experimental animals by systemic administration of monoclonal IgM antibodies with anti-MAG activity from a patient with neuropathy Hays et al. Monoclonal IgM anti-GM1 antibodies were first reported in patients with IgM monoclonal gammopathy and lower motor neuron disease Freddo et al.
For a review see Renaud et al. Min Htut, in Clinical Biochemistry: Metabolic and Clinical Aspects Third Edition , Chronic inflammatory demyelinating polyneuropathy CIDP is a heterogeneous group of acquired immune-mediated neuropathies.
It may present in isolation or as part of a systemic disease. The classic form of CIDP is symmetrical with motor involvement greater than sensory.
Weakness is present in both proximal and distal muscles. It can be associated with various systemic diseases such as HIV infection, connective tissue disorders and paraproteinaemia see Chapter