Chronic inflammatory demyelinating neuropathies and their variants

The Chronic Inflammatory Demyelinating Polyradiculoneuropathies (CIDP) constitute a syndrome whose incidence is difficult to evaluate, and is probably underestimated. In the course of this presentation, we deliberately restricted discussion to issues raised in recent years concerning the extent of this syndrome. We discuss diagnostic criteria, especially electrophysiological ones. As the criteria proposed by the ad hoc committee of the American Academy of Neurology in 1991 have been questioned due to lack of sensitivity, new ones have been proposed recently. We briefly discuss the different types of chronic dysimmune demyelinating neuropathy: not only the CIDP, but also the Lewis and Sumner syndrome or multifocal inflammatory demyelinating neuropathy and the multiple conduction block neuropathies. At last, we point out the consistent finding of axonal involvement in the course of a chronic demyelinating neuropathy; over time, it can become predominant, which may make diagnosis difficult by suggesting a chronic axonal neuropathy that may be assumed to be primary. Consideration of these points may help clinicians recognize more chronic dysimmune neuropathies, for which immunosuppressive therapy has been found to be effective.     

Diagnosis of atypical forms of chronic inflammatory demyelinating polyradiculoneuropathy: a practical overview based on some case studies

Background: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare disease and the diagnosis is complicated by heterogeneity of the variant forms. Underdiagnosis is undesirable as effective treatments exist. Conversely, overdiagnosis can lead to inappropriate and expensive treatment and delay the initiation of appropriate treatment. Summary: The European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) diagnostic criteria are used widely in clinical trials and clinical practice. A limitation of the criteria is the requirement for at least one demyelinating parameter as there are certain situations (e.g. proximally located demyelinating process, secondary axonal loss, predominant involvement of sensory fibers) where this criterion may be not apparent; this can lead to misclassification of the neuropathy as axonal. To prevent this situation, the French CIDP Study Group has proposed a set of clinical and electrophysiological signs that are atypical for chronic idiopathic axonal polyneuropathy and suggestive for CIDP. Greater use of supportive diagnostic tools such as magnetic resonance imaging in clinical practice is not only extending the boundaries of CIDP but also contributing to over-representation of some variants, such as those involving the plexus, and sensory or minimal forms of CIDP. Many misdiagnoses can be avoided by adapting the diagnostic strategy to the clinical phenotype of CIDP. Key Messages: Early and accurate diagnosis of CIDP facilitates the selection of appropriate therapy to improve prognosis. Understanding the limitations of diagnostic criteria and adapting the diagnostic strategy to clinical phenotype can enhance precision and avoid diagnostic pitfalls.     

The diagnosis of chronic axonal polyneuropathy: the poorly understood chronic polyradiculoneuritides

Chronic inflammatory demyelinating polyradiculoneuropathy is an autoimmune disease that target myelin sheats of peripheral nerves. Its diagnosis is often difficult to make, and a number of cases are probably not identified because of the clinical and electrophysiological heterogeneity. Typical cases associate progressive or relapsing-remitting motor and sensory deficit with increased CSF protein content and electrophysiological features of demyelination. In some cases electrophysiological studies fail to show evidence of demyelination, conventional electrophysiological diagnostic criteria are not filled yet the patient may respond to immunomodulatory treatments. In such cases, presence of clinical characteristics suggestive of CIDP (that means not compatible with a length-dependent axonal process) are critical justifying fully investigations including sural nerve biopsy. The main clinical characteristic are: a symmetric proximal and distal motor weakness predominantly affecting the lower limbs, a diffuse areflexia, a sensory deficit characterized by a preferential involvement of large fibers, an evolution which may be either chronic progressive or recurrent. Usual therapeutic agents (corticosteroids, intravenous immunoglobulins, plasma exchanges) seem to have the same efficacy whatever the electrophysiologic profile.     

Amyloid neuropathy mimicking chronic inflammatory demyelinating polyneuropathy

Introduction: Amyloid neuropathy is a rare peripheral neuropathy that classically presents as a progressive sensory neuropathy with prominent autonomic involvement. Methods: We describe 5 patients with amyloid neuropathy (familial amyloid polyneuropathy or acquired amyloidosis) who were initially mistaken to have chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) based on history, clinical examination, electrodiagnostic studies, and cerebrospinal fluid (CSF) analysis. Results: The diagnosis of CIDP had been retained on clinical and electrophysiological grounds for all patients, but we observed no improvement after immunomodulatory treatment. Nerve biopsy confirmed amyloid deposits in nerves, and molecular genetic analysis showed a mutation of the transthyretin (V30M) gene for 3 patients; the 2 other patients had acquired amyloidosis. Conclusions: This report emphasizes the need to look for an alternative diagnosis in CIDP patients who do not respond to treatment and to look carefully for symptoms or signs of autonomic involvement in such patients. Muscle Nerve 45: 26–31, 2012     

Review of the evolution of electrodiagnostic criteria for chronic inflammatory demyelinating polyradicoloneuropathy

Chronic inflammatory demyelinating polyradicoloneuropathy (CIDP) is a treatable form of neuropathy. Efforts to devise sets of electrodiagnostic (nerve conduction) criteria to distinguish primary demyelination from primary axonal neuropathies have been elusive, and at least 16 criteria have been proposed. Modifications to criteria frequently represent minor changes based on applying a set to a small number of patients with the clinical diagnosis of CIDP, whereas others are based on physiological changes related to demyelination and other pathophysiological features. The various modifications continue to result in limited sensitivity, likely related to the wide range of nerve conduction abnormalities among CIDP patients. Although some sets are appropriate for formal clinical drug trials, their complexity makes them difficult to apply in the clinic or electromyography laboratory. This study considers the evolution of the criteria, discusses their limitations, and ends with a simplified set of guidelines that can be applied in the clinic or laboratory.     

Atypical electrophysiologic findings in chronic inflammatory demyelinating polyneuropathy (CIDP)--diagnosis confirmed by nerve biopsy.

OBJECTIVES: Numerous sets of electrophysiological criteria of chronic inflammatory demyelinating polyneuropathy (CIDP) have been proposed, among which the criteria established by an ad hoc subcommittee of the American Academy of Neurology (AAN) in 1991 (Neurology 41 (1991) 617) are the most widely used. As they seemed rather restrictive, the Inflammatory Neuropathy Cause and Treatment (INCAT) group (Ann. Neurol. 50 (2001) 195) proposed modifications of these electrophysiological criteria. However, even using these criteria, some cases of CIDP may not be recognized. In such cases, nerve biopsy has proven useful for confirmation of the diagnosis by demonstrating specific abnormalities. The objective of the study was to determine the profile of electrophysiological abnormalities in patients with atypical electrophysiologic criteria of CIDP and the diagnostic value of multiple A waves and a low median to sural amplitude ratio. PATIENTS AND METHODS: Over a period of 3 years, we classified 44 patients into two categories: those presenting the strict AAN and/or INCAT criteria and those who we regarded as cases of CIDP not meeting these criteria. All patients benefited from one or more clinical and electrophysiological examination. Extensive biological workup and genetic study when appropriate excluded other causes of neuropathy. Nerve biopsies were taken from all patients and samples were included in paraffin and epon for systematic light, teasing and electron microscopic examination. RESULTS AND CONCLUSION: Out of 44 patients, 36 fulfilled the INCAT or AAN criteria. In eight other patients, the diagnosis of CIDP was suspected on clinical and EMG examinations and confirmed by nerve biopsy. In these cases, the electrophysiological exploration showed some abnormalities such as multiple A waves in four out of eight patients or an abnormal pattern of the sensory responses of the median and sural nerves in four out of eight patients that were more indicative of an initial demyelinating process. Six of our patients received immunomodulatory treatment, and five responded favorably.     

Chronic inflammatory demyelinating polyneuropathy

Chronic inflammatory demyelinative polyneuropathy (CIDP) is an acquired neuropathy, presumably of immunological origin. Its clinical presentation and course are extremely variable. CIDP is one of the few peripheral neuropathies amenable to treatment. Typical cases associate progressive or relapsing-remitting motor and sensory deficit with increased CSF protein content and electrophysiological features of demyelination. In other instances the neuropathy is predominantly or exclusively motor or sensory, CSF normal and electrophysiological studies fail to show evidence of demyelination. In such cases conventional diagnostic criteria are not filled yet the patient may respond to immunomodulatory treatments. In this paper we review the diagnostic pitfalls and clinical variants of CIDP to illustrate the problems that may arise. The different therapeutic options are reviewed. Axon loss associated with demyelination is the most important factor of disability and resistance to treatment.     

Biomarkers of CIDP in patients with diabetes or CMT1

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease that targets the myelin sheaths in peripheral nerves. Primary demyelination can be detected by electrodiagnostic studies or nerve biopsy, but these do not distinguish between demyelination resulting from CIDP or from non-inflammatory causes such as diabetes or Charcot-Marie-Tooth type I. Consequently, the diagnosis of CIDP in such patients is often missed. Studies are needed to establish electrodiagnostic criteria for CIDP in patients with diabetes, and to identify biomarkers that distinguish between inflammatory and non-inflammatory causes of demyelinating neuropathy.     

The spectrum of chronic inflammatory demyelinating polyneuropathy

Research criteria for the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) were proposed by an Ad Hoc Subcommittee of the American Academy of Neurology (AAN) in 1991, and since then these criteria have been widely used in clinical studies. We have been impressed by the frequent finding of electrophysiological changes of a demyelinating neuropathy in patients whose clinical presentation does not conform to the usually accepted clinical phenotype of CIDP. To determine the clinical spectrum of CIDP, we conducted a retrospective review of patients of the peripheral electrophysiology laboratory of the University of Miami-Jackson Memorial Medical Center. Diagnostic criteria for acquired demyelination of an individual nerve were adapted from the AAN research criteria for the diagnosis of CIDP (1991). Patients were accepted for inclusion when such evidence was demonstrated in at least one motor nerve or at least two sensory nerves. We then reviewed the clinical phenotype and the underlying etiology of the neuropathy in these cases. Eighty-seven patients, 63 male and 24 female, age of onset 4-84 (mean 49.3) years, met these inclusion criteria. Forty-seven patients (54%) had distinct features outside the usual clinical presentation of CIDP. Of these, 15 (17%) had predominantly distal features, 13 (15%) had exclusively sensory polyneuropathy; seven (8%) had markedly asymmetric disease, seven (8%) had associated CNS demyelination, four (5%) had predominant cranial nerve involvement, and one (1%) had only the restless legs syndrome. An associated medical condition that may have been responsible for the acquired demyelinating neuropathy was present in 60% of the patients. We conclude that spectrum of CIDP is broader than would be indicated by the strict application of the AAN research criteria, and that many of the cases meeting more liberal criteria frequently respond to immunosuppressive therapy.     

Focal neuropathy preceding chronic inflammatory demyelinating polyradiculoneuropathy by several years

We report three patients who exhibited an unusual clinical course of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in which mononeuropathic limb weakness developed 2, 11 and 23 years, respectively, before the development of generalized polyradiculoneuropathy. The eventual diagnosis remained uncertain until other causes of neuropathy were excluded, and the clinical disorder progressed to involve the other limbs. Focal or regional variants of CIDP suggest that the pathologic, and perhaps the immunologic, abnormalities can be localized and selective for prolonged periods of time. Although this clinical variant seems to account for a small number of CIDP cases, its recognition may aid in making an early diagnosis.     

Fatigue as the main presenting symptom of chronic inflammatory demyelinating polyradiculoneuropathy: a study of 11 cases

Fatigue has been shown to be more frequent than previously thought in immune-mediated polyneuropathies. However, fatigue has not been reported as the main cause of referral in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients. Between January 2001 and December 2003, we investigated 11 patients referred for fatigue, for which we established a final diagnosis of CIDP. All patients had at least two clinical examinations including assessment of the fatigue severity scale (FSS) and one electrophysiological and laboratory work up. Additionally, 10 of the 11 patients had a nerve biopsy. There were 11 male patients. Mean age at onset was 53 +/- 11 years. Main cause of referral was fatigue in all patients. Additional symptoms included cramps (one case), distal paresthesias (six cases), limb pain (seven cases) and vasomotor disturbances (one case). Cerebrospinal fluid (CSF) analysis displayed a moderate increase in protein content in four patients. Electrophysiological analysis showed abnormalities in all patients. Among 11 patients, one fulfilled the American Academy of Neurology electrodiagnostic criteria for CIDP and three fulfilled the inflammatory neuropathy cause and treatment group or the Nicolas et al. criteria. In the eight remaining patients, a nerve biopsy confirmed the diagnosis of CIDP. Ten patients were treated, among which seven showed a significant improvement based on the FSS scale. This study shows that fatigue is a possible cause of referral for patients with CIDP and, like previous reports, emphasizes the lack of sensitivity of widely accepted electrophysiological criteria of CIDP. Long-term follow up of these patients is warranted to determine the prognosis of these minimal forms of CIDP and establish the best therapeutic strategy in such cases.     

New trends in neuropathy practice: clinical approach to CIDP]

Our recent study showed that the overall prevalence of CIDP was estimated as 2.2 per 100,000 population in Aomori Prefecture, in Northan Honshu of Japan. In our series of more than 80 cases with CIDP, a chronic acquired inflammatory demyelinating polyneuropathy, nearly 30% showed clear laterality of weakness, and electrophysiologic laterality or multifocality was apparent in almost all cases. Nearly 90% of patients were able to walk without walking aids or other assistance. Sixty% showed distal dominant muscular weakness. In 12 patients with age of onset under 15, pes cavus deformity was seen in 5. Two thirds complained numbness in the extremities during progressive phase. Four cases initially showed severe sensory ataxia associated with motor conduction block. It should be, thus, reminded that clinical spectrum of CIDP is enormously wide: chronic acquired demyelinating multiple mononeuropathy showing asymmetric involvement (Lewis-Summer syndrome) should be put on one side of the clinical presentation of CIDP. Multifocal motor neuropathy (MMN) is, on the other hand, an unique syndrome mimicking amyotrophic lateral sclerosis (ALS). There may be, however, true association syndrome of CIDP and ALS presenting both peripheral nerve demyelination and pyramidal sign with progressive bulbar involvement. Recently, several atypical varieties of CIDP showing only one-limb involvement, upper limb weakness rather than lower limb power loss, or proximal weakness, etc ... have been reported in the literature. To realize such clinical variations of chronic acquired demyelinating neuropathy is important for early diagnosis and commencement of treatment of CIDP. Clinical guideline for suspicion of CIDP could be useful for general physicians and neurologists unfamiliar to peripheral neuropathies.     

Comparison of electrodiagnostic abnormalities and criteria in a cohort of patients with chronic inflammatory demyelinating polyneuropathy

BACKGROUND: Current electrodiagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) are research oriented favoring specificity over sensitivity. Application of such criteria in clinical practice may miss the diagnosis in potentially treatable patients. OBJECTIVES: To analyze the electrophysiologic abnormalities in a cohort of patients with clinically defined CIDP, to compare these data with published electrodiagnostic criteria, and to identify a set of abnormalities that is shared by all patients with CIDP. DESIGN: Retrospective medical record review. SETTING: Academically based neuromuscular clinic.Patients Fifteen patients with clinically diagnosed relapsing sensorimotor CIDP. INTERVENTIONS: Administration of intravenous immunoglobulin or prednisone. MAIN OUTCOME MEASURES: Electrodiagnostic studies. RESULTS: All patients had electrodiagnostic abnormalities in at least 3 nerves with possible partial conduction block or demyelinating range abnormalities in at least 1 nerve. The diagnostic sensitivities of 5 published CIDP criteria were as follows: the Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force (40%), Saperstein et al (47%), Nicolas et al (53%), Hughes et al for the Inflammatory Neuropathy Cause and Treatment Group (60%), and Thaisetthawatkul et al (70%). CONCLUSIONS: Current electrodiagnostic criteria for CIDP are insensitive and may fail to diagnose the condition in a substantial number of patients. More inclusive criteria that allow identification of patients in routine clinical practice are needed.     

Treatment of immune-mediated, dysimmune neuropathies

This review focuses on the actual status and recent advances in the treatment of immune-mediated neuropathies, including: Guillain-Barre syndrome (GBS) with its subtypes acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, Miller Fisher syndrome, and acute pandysautonomia; chronic inflammatory demyelinating polyneuropathy (CIDP) with its subtypes classical CIDP, CIDP with diabetes, CIDP/monoclonal gammopathy of undetermined significance (MGUS), sensory CIDP, multifocal motor neuropathy (MMN), multifocal acquired demyelinating sensory and motor neuropathy or Lewis-Sumner syndrome, multifocal acquired sensory and motor neuropathy, and distal acquired demyelinating sensory neuropathy; IgM monoclonal gammopathies with its subtypes Waldenstrom's macroglobulinemia, myelin-associated glycoprotein-associated gammopathy, polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes syndrome, mixed cryoglobulinemia, gait ataxia, late-onset polyneuropathy syndrome, and MGUS. Concerning the treatment of GBS, there is no significant difference between intravenous immunoglobulins (IVIG), plasma exchange or plasma exchange followed by IVIG. Because of convenience and absent invasiveness, IVIG are usually preferred. In treating CIDP corticosteroids, IVIG, or plasma exchange are equally effective. Despite the high costs and relative lack of availability, IVIG are preferentially used. For the one-third of patients, who does not respond, other immunosuppressive options are available. In MMN IVIG are the treatment of choice. Inadequate response in 20% of the patients requires adjunctive immunosuppressive therapies. Neuropathies with IgM monoclonal gammopathy may respond to various chemotherapeutic agents, although the long-term effects are unknown. In addition, such treatment may be associated with serious side effects. Recent data support the use of rituximab, a monoclonal antibody against the B-cell surface-membrane-marker CD20.     

Acute-onset multifocal motor neuropathy (AMMN): how we meet the diagnosis

Multifocal motor neuropathy (MMN) usually progresses insidiously with lower motor neuron-type weakness, minimal or no sensory symptoms. Diagnostic criteria include motor conduction block (CB) at sites not exposed to compression or entrapment. CBs may persist or reverse irrespective of clinical outcome. Acute onset with generalized weakness is uncommon. We report four patients who presented acutely areflexia, pure motor deficits without sensory disturbances, multifocal CBs persisting at the same motor nerves on serial electrophysiological studies. Three patients had preceding infections; two showed IgM reactivity against the ganglioside GM1. Intravenous immuneglobulin (IVIg) improved or stabilized symptoms. Patients 2,3,4 receive maintenance therapy with IVIg for years. Acute-onset MMN (AMMN) should be differentiated from other immune-mediated neuropathies such as acute inflammatory polyneuropathy either demyelinating (AIDP) or axonal (AMAN), acute motor conduction block neuropathy (AMCBN), acute-onset chronic inflammatory demyelinating polyneuropathy (CIDP). The correct diagnosis deserves implications for patient long-term treatment and prognosis. Moreover, the authors address the problem of defining the spectrum of MMN particularly in the acute setting.     

Chronic inflammatory demyelinating polyradiculoneuropathy with autonomic involvement

We report a case of chronic acquired neuropathy predominantly affecting sensory and autonomic nerves. Investigations showed a demyelinating polyradiculoneuropathy with axonal degeneration and depletion of postganglionic noradrenergic fibers in the rectal mucosa. Intravenous immunoglobulin and corticosteroid administration were effective in alleviating symptoms and improving electrophysiological abnormalities. This neuropathy may be a novel variant of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), in which autoimmunoreactivity is directed not only against myelin but also against axon- or ganglion-composing protein. Autonomic nerve involvement does not exclude a diagnosis of CIDP.     

Electrophysiological manifestations of chronic inflammatory demyelinating polyradiculoneuropathy

There are four basic electrophysiological parameters of demyelination: reduced motor conduction velocity, prolonged distal motor latency and F waves, and motor conduction blocks. These parameters are combined to determine an electrophysiological set of criteria for chronic inflammatory demyelinating polyneuropathy (CIDP). Whereas their specificity is good, their sensitivity level does not exceed 75 percent. However, these sets of criteria are not commonly used especially in benign forms, at the beginning of the disease, in associated forms or in case of secondary axonal degeneration. We can push the limits using others criteria such as the terminal latency index, sensory criteria, or by the contribution of others electrophysiological procedures such as the radicular stimulation or sensory evoked potentials. Due to the therapeutic implications, any axonal neuropathy without aetiologia, with at least one demyelinating electrophysiological criteria, could be considered as a putative CIDP.     

Current diagnosis of CIDP: the need for biomarkers

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic neuropathy characterized by symmetrical proximal and distal weakness, with large-fiber sensory loss, impaired balance, and areflexia. This condition is often underdiagnosed due to the frequent absence of these classical clinical features as well as abnormalities that arise during confirmatory tests. Current diagnostic tests involve the measurement of cerebrospinal fluid protein levels, nerve biopsy, electrodiagnostic testing, and treatment response. Due to the clinical heterogeneity of the condition and a lack of a consistent confirmatory test, a variety of diagnostic criteria were developed. At least 14 different sets of diagnostic criteria have been proposed that each have varying diagnostic sensitivities. Although the diagnostic tests used within these criteria are useful, they individually offer evidence to support, rather than definitively confirm, the diagnosis of CIDP. Currently, there is no biomarker that can reliably identify all patients with CIDP, but it is evident that such a biomarker is urgently needed to ensure effective disease management.     

Patterns of sensory nerve conduction abnormalities in demyelinating and axonal peripheral nerve disorders

The pattern of an abnormal median-normal sural (AMNS) sensory response is associated with acute and chronic inflammatory demyelinating polyradiculoneuropathy (AIDP and CIDP) and considered unusual in other types of neuropathy, although specificity and sensitivity of this pattern have not been evaluated. We compared sensory responses (patterns and absolute values) in patients with AIDP, CIDP, diabetic polyneuropathy (DP), and motor neuron disease (MND). Using strict criteria, the AMNS pattern occurred more frequently in recent onset AIDP (39%) compared with CIDP (28%), DP (14%–23%), or MND (22%) patients. This pattern was found in 3% of control subjects. The extreme pattern of an absent median-present sural response occurred only in AIDP and CIDP patients and in no other groups. Abnormalities of both nerves were more common in long-standing polyneuropathies such as CIDP and DP compared with AIDP or MND. Median nerve amplitudes were reduced significantly in AIDP, CIDP, and DP patients compared with MND patients, whereas sural nerve amplitudes were significantly reduced only in DP and CIDP patients. These findings may reflect early distal nerve involvement particularly in AIDP patients which is highlighted by differences in median and sural nerve recording electrode placement. We conclude that, in the appropriate clinical setting, the AMNS pattern, an absent median-present sural response pattern, or a reduced median amplitude compared with the sural amplitude supports a diagnosis of a primary demyelinating polyneuropathy. © 1993 John Wiley & Sons, Inc.     

Chronic inflammatory demyelinating polyneuropathy-like disorder associated with amyotrophic lateral sclerosis

The association between demyelinating neuropathy and amyotrophic lateral sclerosis (ALS) has been reported rarely. We report four patients who presented with clinical features and investigations suggestive of a neuropathy but who later progressed and received a final diagnosis of ALS according to the original El Escorial criteria. Three patients met the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) 2006 definition for "definite" chronic inflammatory demyelinating polyneuropathy (CIDP), as well as the American Academy of Neurology (AAN) 1991 and Nicolas et al. [2002] electrodiagnostic criteria for CIDP. Two of them showed segmental demyelination on teased-fiber preparations and one had a raised cerebrospinal fluid protein level. Another patient met the Nicolas et al. CIDP criteria and presented with brachial plexus hyperintensity on T2-weighted magnetic resonance imaging, indicative of an inflammatory process. No significant objective response to immunomodulatory treatment was observed in any of these patients who all subsequently progressed unfavorably.