science revisited

An autoimmune–inflammatory etiology for CIDP has been proposed based on: (1) clinical observations describing infections and immunizations triggering onset and exacerbations of various forms of the disorders; (2) association with systemic immune disorders; (3) similarities with rodent models of autoimmune experimental neuritis; (4) detection of both T- and B-cell-mediated responses to certain myelin antigens, perivascular endoneurial infiltration by lymphocytes, and macrophages; (5) spinal fluid cytoalbuminological dissociation in some of the forms; and (6) response to immunomodulation. No specific common autoantigens have so far been identified. Certain human leukocyte antigens (HLAs) occur more frequently in patients with CIDP (HLA-Dw3, -DRw3, -A1, and -B8).

Clinical Features of CIDP

The clinical presentation of CIDP is heterogeneous and varies from purely motor to purely sensory forms to a multifocal (Lewis–Sumner syndrome) presentation, although most typically patients present with a combination of proximal and distal muscle weakness and paraesthesia. The patients complain of difficulty with gait such as tripping and unexplained falling, may have trouble taking stairs, and/or hand dexterity may be impaired. Loss of sensory function is more frequent than pain but paraesthesiae are fairly common. Rarely, extremely high CSF protein levels have been associated with pseudotumor cerebri syndrome, with headache, papilledema, visual loss, and field cuts. Clinical examination needs to include a thorough general physical examination to look for evidence of disorders that have been associated with CIDP (skin changes, lymph nodes, malignancy, etc.) Neurological examination needs to extend to all levels of the neuraxis to detect not only peripheral but also CNS pathology. Cranial nerve III–VII palsies may be suggested by diplopia (occurs in at least 10%) and lower face weakness, but bulbar muscle dysfunction as an initial presentation has also been described.

Gait abnormalities depend on the extent and combination of motor and sensory deficits, and may vary from steppage to slapping gait due to foot drop and proprioceptive deficits or inability to ambulate due to marked proximal weakness. Confrontational strength exam usually shows symmetric weakness of both proximal and distal muscles in both arms and legs. Atrophy points to secondary axonal degeneration which accounts for the persistent deficits that lead to longstanding disability. Fasciculations may be observed, including some in the tongue, which would lead one to consider the diagnosis of amyotrophic lateral sclerosis. Coordination is consistent with the extent of weakness, and patients may have superimposed sensory ataxia due to large-fiber involvement. Muscle stretch reflexes are absent or diminished. Sensory exam reveals mainly reduced large-fiber modalities such as diminished proprioception and vibration often in a glove-and-stocking distribution. Usually no pathological reflexes are obtained. Autonomic dysfunction and respiratory failure are rare (<10%).

Atypical Forms of CIDP

Despite the heterogeneity in the clinical presentation of the different CIDP variants in terms of the pattern of distribution of their symptoms and signs, they share a similar dysimmune demyelinating mechanism. Their identification is important because they are as amenable to treatment modalities as the classic form.

Pure Sensory CIDP/CISP

A significant proportion of patients (about 15%) have a pure sensory form of CIDP due to isolated/primary involvement of the sensory roots or sensory nerve fibers (CISP). Some patients show marked sensory ataxia, with normal nerve conduction studies but somatosensory evoked potentials may show sensory root involvement. Some patients have marked slowing of motor nerve conduction despite normal strength. It can be very difficult to distinguish this form of CIDP from sensory neuronopathies. The benefit of treatment of this form of CIDP is unclear.

Pure Motor CIDP

This is much more uncommon than pure sensory CIDP and is considered by some to be part of the spectrum of multifocal motor neuropathy, However, the disorder is symmetric, proximal, and distal, and is otherwise similar to classic CIDP. It typically responds to treatment with intravenous immunoglobulin (IVIG).

Distal Acquired Demyelinating Symmetric Polyneuropathy

These patients present similar to the idiopathic length-dependent polyneuropathies with overwhelmingly sensory complaints, but show marked demyelinating features on nerve conduction studies. Many patients with DADS have an IgM paraprotein, and about half of these patients have antibodies directed against myelin-associated glycoprotein (MAG). This latter group is considered distinct from CIDP in the EFNS/PNS guidelines but the other IgM DADS patients are considered atypical CIDP. The authors’ experience differs with this approach as they find IgM DADS with and without anti-MAG to behave identically.

CIDP Associated with Concurrent Illnesses

Concurrent illness-associated CIDP is clinically similar to classic CIDP. The exact pathophysiology is not known. The multifocal variants of illness-associated CIDP feature segmental demyelination and remyelination on teased fiber preparation and biopsy, in contrast to the wallerian degeneration of vasculitic mononeuropathy multiplex. Nerve conduction studies may show conduction block, an electrodiagnostic marker of segmental demyelination, and disorders of the node of Ranvier.

CIDP may occur with human immunodeficiency virus (HIV) infection, frequently at the time of conversion with typical CSF pleocytosis, chronic active hepatitis B and C without cryoglobulinemia, CNS demyelination/multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease (IBD), and the use of tumor necrosis factor α (TNF-α) blockers in patients with rheumatoid arthritis (etanercept and infliximab).

There have been reports of CIDP in patients with diabetes mellitus and Charcot–Marie–Tooth disease (CMT), but whether there is a clear increase in incidence is unclear. Pregnancy has also been associated with CIDP in the third trimester or postpartum.

Monoclonal Gammopathy of Undetermined Significance-Associated CIDP

A small but significant proportion of CIDP patients (up to 20% according to some estimates) have MGUS. The M protein is mostly IgA or IgG based on serum immunofixation. Response to therapy is similar to classic CIDP and better than IgM MGUS CIDP patients. IgM MGUS patients usually have a distally predominant clinical presentation (DADS) and may respond to immunomodulatory treatment less, although they may respond to rituximab. MGUS may also be associated with axonal polyneuropathies requiring a different therapeutic approach.