Chronic inflammatory demyelinating polyradiculoneuropathy: diagnostic strategy. Guidelines of the French CIDP study group

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) comprises a group of dysimmune neuropathies easily diagnosed in more than half of the patients. Diagnosis is based on clinical, electrophysiological and biological clues. In some patients, diagnosis is unclear because of the debated value of the available clues. In such circumstances, dysimmune neuropathies may not be diagnosed, leading to insufficient treatment. This is an important category of patients because immunomodulatory drugs have proven efficacy. The CIDP spectrum includes a relatively wide range of diseases. Besides the easily recognized classic forms, there are many clinical variants, sometimes with a paucisymptomatic presentation leading to uncertain diagnosis. The French CIDP study group has established guidelines for diagnostic strategy in CIDP patients. The first part of this paper is devoted to the clinical aspects of the disease, classical forms and variants. In the second part, the results of electrophysiological studies are reported. In a third chapter, complementary examinations useful for diagnosis are discussed. The fourth chapter deals with the diagnostic strategy, discussed in relation to the different situations which may be encountered in clinical practice. details the technical modalities of appropriate electrophysiological studies and presents normal results together with those indicating demyelinating neuropathy. Nerve biopsy technique and results are given in appendix II.     

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.     

Demyelinating neuropathy during anti-TNF alpha treatment with a review of the literature

INTRODUCTION: Tumor necrosis factor- (TNF) blockers are efficient in the treatment of autoimmune disorders such as inflammatory bowel disease and rheumatoid arthritis, but can induce CNS adverse effects including retrobulbar optic neuritis or aggravation of multiple sclerosis. OBSERVATION: We report a case of progressive demyelinating polyneuropathy after initiation of Adalimumab (Humira). Corticosteroid and intravenous immunoglobulins were ineffective but the neuropathy improved within six months after adalimunab discontinuation. DISCUSSION: This case, and other reports recently published suggest that anti-TNF alpha drugs can induce demyelinating neuropathy. CONCLUSION: Clinicians should be on the lookout for signs evocating neuropathy in patients given anti TNF alpha.     

Biochemical features of chronic inflammatory demyelinating polyradiculoneuropathy

Although there are no specific biological markers of chronic inflammatory demyelinating polyneuropathies (CIDP), biological investigations have played an important role in determining the limits of the concept of CIDP. This is best exemplified by the individualisation of demyelinating neuropathies associated with IgM monoclonal proteins reacting with glycolipids. The signification of CIDP associated with diabetes mellitus, monoclonal IgG or IgA, or mutations of myelin proteins has recently been discussed as they may have implications in our understanding of the pathophysiology of CIDP and raise the question of knowing whether they confer to CIDP a particular clinical presentation or evolution.     

The extent of the clinical manifestations of chronic polyradiculoneuropathy

BACKGROUND: 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 heterogeneity. Numerous sets of diagnostic criteria have sought to define CIDP but clinical criteria are generally not detailed. OBJECTIVES: To review the main clinical characteristics suggestive of CIDP (that means not compatible with a length-dependent axonal process) and the critical clinical points of the neuropathy which make the differential diagnosis with the main other forms of chronic auto immune neuropathy sometimes difficult. RESULTS: 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. These aspects raise many questions concerning overlap with other inflammatory neuropathies such as Guillain Barre syndrome, Lewis-Sumner neuropathy, chronic ataxic neuropathy. The distinction of a subgroup of CIDP associated with other diseases such as diabetes or HIV are also controversial. CONCLUSION: The growing body of knowledge on the pathogenesis of CIDP and clinical or electrophysiological differentiation of subforms may help to develop more effective therapies for CIDP in the next few years.     

Lesion mechanism dependent, differential changes in neurofilaments and microtubules: a pathological and experimental study

INTRODUCTION: The consequences of axonal or demyelinating injuries on the axonal cytoskeleton have rarely been described. METHODS: We have compared the density of fibers labeled by anti-neurofilaments (NF) and -beta tubulin (TUB) to the density of total fibers in nine patients with axonal neuropathies of undetermined etiology (AUE), six with necrotizing angeitis with neuropathy (NAN), seven with chronic inflammatory demyelinating neuropathy (CIDP) and in five controls, as well as in six patients with chronic multiple sclerosis (MS). We also studied demyelinated rat corpus callosum after lysophosphatidyl (LPC) microinjection. RESULTS: In AUE and NAN NF positive fibers decreased together with total fiber density, whereas TUB increased. In demyelinating lesions TUB was not altered (CIDP) or strongly decreased (MS, LPC); NF were strongly reduced in MS (where axon loss was prominent) and in LPC lesions (despite the lack of fiber degeneration) and for fiber densities<3900/mm2 in CIDP. CONCLUSION: The initial mechanism of a disease, either axonal degeneration or demyelination, could result into a specific pattern of axonal cytoskeleton alterations.     

Hereditary neuropathy with liability to pressure palsy presenting with an acute inflammatory demyelinating polyneuropathy

INTRODUCTION: Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant peripheral neuropathy characterized by compressive focal neuropathies and an underlying sensorimotor demyelinative polyneuropathy. It is usually caused by a 1.5 Mb deletion of the PMP22 gene (17p11.2). CASE REPORT: We describe the case of a 31 year-old woman who presented with acute demyelinative peripheral polyneuropathy affecting the four limbs and elevated cerebrospinal fluid protein content a few days after a viral illness. Acute inflammatory demyelinating polyneuropathy (AIDP, Guillain-Barré syndrome) was suspected. However, electrophysiologic examination suggested HNPP and subsequent genetic testing was confirmatory. CONCLUSION: This case demonstrates that HNPP can present in an acute manner, mimicking AIDP.     

T-cell lymphoma revealed by a mononeuritis multiplex: case report and review of literature

INTRODUCTION: Lymphoma occasionally affects the peripheral nervous system. Neuropathy usually appears in patients with known lymphoma but rarely represents the initial manifestation of underlying malignancy. We report a case in which mononeuritis multiplex (MM) was the dominant feature in the clinical presentation of a peripheral T-cell non-Hodgkin lymphoma (NHL). OBSERVATION: A 32-year-old man suffered from an asymmetric progressive sensory-motor peripheral neuropathy. The left peroneal nerve was affected first, then the left median nerve after one month, followed by the left trigeminal nerve ten months later. The electrophysiological study confirmed the diagnosis of axonal sensory-motor MM. Mediastinal adenopathies, splenomegaly, pancytopenia and inflammatory syndrome were also found. An osteo-medullary biopsy showed a T-cell NHL. Nerve biopsy study found an inflammatory lymphoid infiltration without malignant cell supporting the hypothesis of an inflammatory pathogenic process. Chemotherapy including cyclophosphamide, hydralazine, vincristine and prednisone were administered monthly during 8 months. No improvement was obtained. DISCUSSION: It must be emphasised that this case is an uncommon one. On the one hand, NHL is rarely associated with MM and on the other hand, it can exceptionally be revealed by a MM. We were able to find 30 reported cases of distal neuropathy revealing a NHL including, 8 mononeuritis simplex, 9 MM and 13 polyneuropathies. Polyradiculoneuritis cases were excluded from this study because the neuropathy is usually caused by a meningeal infiltration. The neuropathy was in the majority of the cases chronic and axonal. The lymphoma was more often B-cell than T-cell. The B-cell lymphoma was frequently associated with a poor prognosis. All mechanisms were present with a predominance of neurolymphomatosis.     

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.     

Pathogenesis of chronic inflammatory demyelinating polyradiculoneuropathy

The acute lesions of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) consist of endoneurial foci of chemokine and chemokine receptor expression and T cell and macrophage activation. The myelin protein antigens, P2, P0, and PMP22, each induce experimental autoimmune neuritis in rodent models and might be autoantigens in CIDP. The strongest evidence incriminates P0, to which antibodies have been found in 20% of cases. Failure of regulatory T-cell mechanism is thought to underlie persistent or recurrent disease, differentiating CIDP from the acute inflammatory demyelinating polyradiculoneuropathy form of Guillain-Barré syndrome. Corticosteroids, intravenous immunoglobulin and plasma exchange each provide short term benefit but the possible long-term benefits of immunosuppressive drugs have yet to be confirmed in randomised, controlled trials.     

Treatment of chronic inflammatory demyelinating polyradiculoneuropathy with methotrexate

We discovered many reports of other immunosuppressive drugs being used in adults with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) but none of methotrexate. As weekly low dose oral methotrexate is safe, effective, and well tolerated in other diseases, we treated 10 patients with otherwise treatment resistant CIDP. Seven showed improvement in strength by at least two points on the MRC sum score and three worsened. Only two showed an improvement in disability and both were also receiving corticosteroids. We discuss the difficulty of detecting an improvement in treatment resistant CIDP and propose methotrexate as a suitable agent for testing in a randomised trial.     

Employment status of patients with chronic inflammatory demyelinating polyradiculoneuropathy

It has been previously shown that patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who are unemployed or retired have worse quality of life. The aim of this study was to assess predictors of early retirement in CIDP. One hundred five patients with CIDP were included. Following measures were used: questionnaire on employment status, Medical Research Council Sum Score, INCAT disability score, Beck Depression Inventory, and Krupp's Fatigue Severity Scale. At the moment of testing, 2% of patients were students, 15% were employed, 9% were unemployed due to CIDP, 9% were unemployed but not due to CIDP, 28% were retired early due to disability caused by CIDP, and finally 37% were in old‐age pension. Mean age when patients retired due to CIDP was 50 ± 8 years. Mean time from CIDP onset to retirement was 2.7 ± 2.3 years. Older age at onset, lower education, and more severe weakness at the time of diagnosis were significant predictors of early retirement due to CIDP. Retired patients were 12 times more likely to suffer from depression, compared to employed patients (OR = 12.2, 95% CI = 1.41‐100, P < 0.01), and eight times more likely to have fatigue (OR = 8.2, 95% CI = 1.89‐35.82, P < 0.01). Older patients with lower education and more severe weakness at the time of diagnosis were most likely retired due to CIDP. Early retirement was associated with depression and fatigue. Therefore, maintaining employment should be an important aim in the management of CIDP patients.     

Challenges in the treatment of chronic inflammatory demyelinating polyradiculoneuropathy

Chronic idiopathic demyelinating polyradiculoneuropathy (CIDP) is a rare disease, the most frequent one within the spectrum of the so-called “chronic immune-mediated neuropathies”. Challenges in the treatment of CIDP firstly concern its diagnosis, which may be difficult, mainly for the atypical forms. Secondly, challenges encompass the choice of the first-line treatment, such as corticosteroids, intravenous immunoglobulins (IVIg), and plasma exchanges (PE) that have been proven as efficacious by several randomized controlled trials (RCT). Recent reports have focused on both different regimens of corticosteroids, and the occurrence of relapses following treatment with either corticosteroids or IVIg. These data may be helpful for the choice of the first-line treatment and may result in changing the guidelines for treatment of CIDP in clinical practice. The third and more difficult challenge is to manage long-term treatment for CIDP, since no immunomodulatory treatment has to date been proven as efficacious in this situation. Lastly, challenges in the treatment concern the choice of the best outcome measure for CIDP in RCT and clinical practice. The aim of this article is to overview the results of the more recently reported published trials for CIDP, and to give some insights for the current and future management of CIDP.     

Prospective analysis of gait characteristics in chronic inflammatory demyelinating polyradiculoneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a disorder that may lead to functional impairment, including gait abnormalities. Our aim was to analyze gait characteristics in patients with CIDP compared to healthy controls (HC). Moreover, we sought to determine changes of gait parameters after six-month follow-up period. Twenty-four patients with CIDP and 24 HCs performed basic walking task, dual-motor task, dual-mental task, and combined task using the same GAITRite system. Lower limb MRC-SS and lower limb INCAT disability score were assessed. Fourteen patients were retested after six months. Majority of gait parameters showed significant differences in all experimental conditions when compared between CIDP and HCs. The most consistent findings in CIDP were shorter stride length (SL), prolonged cycle time (CT) and double support time (DS), as well as increased variation of SL and of swing time (ST) (p < 0.05). During follow-up, INCAT improved in nine (64.3%) of 14 patients and MRC-SS improved in eight (57.1%) patients. Six-month changes of CT and its variation during combined task significantly differentiated patients with improved vs. non-improved INCAT (p < 0.05). In conclusion, patients with CIDP had slower gait with prolonged DS and with shorter SL compared to HCs. Increased variation of SL and of ST in CIDP may suggest a potential risk for instability and falls. Shorter CT duration and less CT variation during time correlated well with improvement in disability.     

Ataxic form of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).

We reported a 64-year-old male with an eight-month history of gait disturbance and sensory impairment. The patient initially noticed unsteadiness of gait and numbness in his feet, and these symptoms progressed until he was unable to walk without assistance five months later. Vibratory sensation and position sense were markedly diminished, and deep tendon reflexes were absent in all extremities. Motor conduction velocities were slow with prolonged distal latencies, and sensory nerve action potentials (SNAP) were not elicited. Sural nerve biopsy revealed a mild loss of myelinated fibres and segmental demyelination. Cerebrospinal fluid showed normal cell count with protein 526 mg/dL. Anti-GM1, anti-GM2 and anti-GA1 antibodies in serum were positive. We diagnosed chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) presenting ataxia. Steroid therapy provided immediate improvement of symptoms and signs. This case suggests that CIDP should be considered as one of the potential causes of ataxic neuropathy.     

Isolated unilateral adduction deficit and ptosis as the presenting features of chronic inflammatory demyelinating polyradiculoneuropathy.

A patient with chronic inflammatory demyelinating polyneuropathy (CIDP) presented with an isolated unilateral adduction deficit and ptosis. Investigations were negative until the onset of limb weakness and fatigue 2 years later. At that time, electroneuromyography, cerebrospinal fluid examination, and magnetic resonance imaging confirmed the diagnosis of CIDP. Thus, ophthalmic signs can precede extremity and bulbar signs with a long latency in CIDP.     

Acute motor conduction block neuropathy pattern occurring in the course of an acute inflammatory demyelinating polyradiculoneuropathy

OBJECTIVE: To describe the case of a young woman with the diagnosis of acute inflammatory demyelinating polyradiculoneuropathy (AIDP), who during the course of the disease developed an electrophysiologic pattern of acute motor conduction block neuropathy (AMCBN). METHODS: Electrophysiologic techniques including needle EMG, standard motor and sensory nerve conductions studies, and somatosensory evoked potentials were carried out over the four months after symptom onset. RESULTS: The results of four neurophysiological studies, performed on Days 14, 26, 35 and 125 after symptomatic onset are reported. All immunological determinations including antiganglioside antibodies (GM1, GM2, GM3, asialoGM1, GD1a, GD1b, GD3, GQ1b and GT1b) were negative. The patient had a favorable evolution following treatment with intravenous immunoglobulins (IVIg). CONCLUSIONS: We conclude that the electrophysiologic hallmark of AMCBN may occur in the course of AIDP. Serial investigation including proximal, intermediate and distal segments of all nerves from upper and lower limbs is essential for its detection.     

An autopsy case of chronic inflammatory demyelinating polyradiculoneuropathy with respiratory failure

An 85-year-old Japanese woman presented with progressive symmetrical proximal and distal muscle weakness, numbness in the distal extremities, and sudden onset of hemifacial weakness. The results of laboratory studies fulfilled the American Academy of Neurology criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). She died of respiratory failure after two courses of intravenous immunoglobulin treatment, each resulting in transient improvement in strength and sensory symptoms. Autopsy revealed multifocal demyelinative or axonal lesions of varying severity affecting the cranial and peripheral nerves and including the phrenic nerve. These findings suggest that the clinical phenotype of CIDP depend on distribution and severity of the anatomical lesions.     

Phrenic nerve palsy as a feature of chronic inflammatory demyelinating polyradiculoneuropathy

We report four patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who presented with phrenic nerve palsy, which was unilateral in two instances. The two patients with bilateral phrenic nerve involvement required mechanical ventilation. After treatment with intravenous immunoglobulins (i.v.Ig) or steroids, the sensorimotor deficit and respiratory parameters improved in three patients, but the fourth patient remained ventilator dependent and died from pulmonary infection. Although rare, phrenic nerve palsy may be a feature of CIDP and may be responsive to treatment with i.v.Ig or steroids.