cidp handbook

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CIDP: Clinical Manifestations

Demyelination which causes weakness, numbness pain stiffness.

�Weakness

�Sensory symptoms of tingling, numbness, pain are common but motor symptoms of weakness, fatigue, tiredness, stiffness usually predominate

�Autonomic system dysfunction do occur consisting of dysautonomia. May consisit of cardiac rhythm problems, diarrhea, constipation, dizziness on standing up, burning type feeling, feeling of swelling. Increased sweating which could be just on one side of the body. Loss of consciousness while standing. This can be reproduced with tilt table testing.

�Slow progressive course is seen in approximately 2/3 of cases

�Children usually have a more quick precipitous onset of symptoms

�Relapsing course with partial or complete recovery between recurrences is seen in approximately 1/3 of cases

�Periods of worsening and improvement usually last weeks or months

�Patients with a younger age of onset are said to have a higher frequency of relapsing course

CIDP: Incidence

�In one study, prevalence was estimated to range from 1-7.7 per 100,000

�These are likely underestimates, since the criteria to select cases were strict

�CIDP accounted for 13% of patients seen in one neuromuscular center

�Incidence increases with increasing age

�Children are rarely affected

CIDP: Pathophysiology

�In one study, CIDP occurred within a few weeks after an infectious event in 16% of the patients

�Because of the insidious onset, documenting precipitating illnesses or events is very difficult

�Both respiratory and gastrointestinal infections have been cited, but no causative organism has been identified

�With Guillain-Barre syndome, the most common preceding infection is Campylobacter

�The classical picture that suggests CIDP is the presence of proximal (Shoulder and hip) and distal ( Hand and foot) weakness, with large fiber sensory loss and reduced or absent reflexes.

�Few patients present with classic symtpoms.

�Some authors have suggested subclassifications based on the clinical varied clinical presentation in order to aid in diagnosis and treatment

�Currently these subclasses are not thought to be distinct diseases

CIDP: Regional Variants

�Lewis-Sumner syndrome : (LSS) is a dysimmune peripheral nerve disorder, characterized by a predominantly distal, asymmetric weakness mostly affecting the upper limbs with sensory impairment, and by the presence of multifocal persistent conduction blocks.

Multifocal Motor Neuropathy is an autoimmune disease in which
patients begin producing antibodies against GM1 ganglioside, a lipid present on nerve fibers. These antibodies are rarely present in any other disease or in normal patients. In Multifocal Motor Neuropathy there is marked weakness caused by disrupting the nerves� ability to conduct electricity producing, a syndrome known as conduction block. Conduction block can be demonstrated by EMG/NCS. The weakness typically begins in the hands and can make people unable to care for themselves. Over time, the weakness can spread to involve the legs and feet causing patients to be confined to wheelchairs.

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�Multifocal demyelinating neuropathy with persistent conduction block The chronic motor involvement associated with fasciculations and cramps, mainly in the arms, led, in most patients, to an initial diagnosis of motor neuron disease. In some patients (nine of 24), there was no appreciable muscle atrophy. Tendon reflexes were often absent or weak. The finding of persistent multifocal conduction block confined to motor nerve fibres raises questions about the nature and the importance of this syndrome. Segmental reduction of motor conduction velocity occurred at the site of the block, but significant slowing of motor nerve conduction was not found outside this site. The response to intravenous IVIg treatment seems to be correlated with the absence of amyotrophy. Patients with little or no amyotrophy had an initial and sustained response to IVIg, and did not develop amyotrophy during the follow up study.

�Distal CIDP M-proteins were present in 22% of patients with CIDP. There were no features that distinguished clearly between CIDPpatients with or without an M-protein, and nearly all of these patients responded to immunomodulating therapy. In contrast,nearly two-thirds of the patients with DADS neuropathy had immunoglobulinM (IgM) kappa monoclonal gammopathies, and this specific combinationpredicted a poor response to immunomodulating therapy. Antimyelin-associatedglycoprotein (anti-MAG) antibodies were present in 67% of these patients

�Distal acquired demyelinating sensory neuropathy and sensory CIDP. Sensory CIDP patients had gait ataxia, large fiber sensory loss, and paresthesias, and nine had frequent falls. The disease course was chronic and progressive (median duration 5 years, range 3 months to 18 years. Can present with a sensory ataxia .Sensory CIDP may present as cryptogenic sensory polyneuropathy with normal or axonal electrophysiologic features.

�ANTI-MAG (Myelin Associated Glycoprotein) Neuropathy Patients with polyneuropathy and antibodies to myelin-associated glycoprotein (MAG) and sulphated glucuronyl paragloboside (SGPG) differ from chronic inflammatory demyelinating polyneuropathy (CIDP) because of a slower, progressive course, symmetrical and predominantly sensory involvement of legs, predominantly distal slowing of motor conductions, and poorer response to therapy

�CIDP with Hypertrophic nerves

�Subacute demyelinating polyneuropathy

�Chronic Inflammatory demyelinating neuropathies

CIDP: Associated Conditions

�Most frequently CIDP is an idiopathic illness

�Has been known to occur with several conditions

�In these cases, the associated condition is included in the main diagnosis to separate those cases from the idiopathic variety

�Example: �CIDP with HIV infection�

�HIV infection

Mild lymphocytic pleocytosis and increased gamma globulin level in the CSF are seen frequently

�Hodgkin lymphoma

�Associated neuropathy is not caused by direct infiltration of the peripheral nerves but is a consequence of the autoimmune cascade that occurs with this disease, but the mechanism is not completely clear

�Paraproteinemias and/or plasma cell dyscrasias

�CIDP is seen with monoclonal gammopathies (eg MGUS), most frequently gammopathy of immunoglobulin M (IgM)

�Evidence suggests that CIDP with IgM MGUS has specific clinical and electrophysiologic characteristics

�Usually predominance of distal weakness with sensory symptoms greater than motor

�Multiple sclerosis

�Reports describe CNS white matter changes in patients with CIDP

�Whether a true association exists between CIDP and multiple sclerosis remains unclear

�Systemic lupus erythematosus

�Chronic active hepatitis (B or C)

�CIDP associated with hepatitis should be differentiated from cryoglobulinemic vasculitis

�The latter causes either symmetric distal sensorimotor polyneuropathy or mononeuropathy multiplex but on pathologic examination shows wallerian degeneration and not the segmental demyelination seen in CIDP

�Inflammatory bowel disease

�CIDP has been described in association with Crohn disease and other inflammatory bowel conditions, although no direct correlation between the two afflictions is known

�The mechanism of development of CIDP is presumed to be an autoimmune abnormality that is also causing the primary problem in inflammatory bowel disease, although the details are not known

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�Diabetes mellitus

�Increasing evidence supports the suggestion that some patients with diabetes who have severe neuropathy or unusually progressive neuropathy may have CIDP superimposed on their diabetic disorder

�Diabetes may predispose patients to CIDP

�Pregnancy

�Known to worsen CIDP

�Worsening usually occurs in the third trimester or in the postpartum period

CIDP: Monitoring and Prognosis

�Sometimes difficult to assess the activity of a chronic neuropathy

�Nerve biopsy can be used to detect active nerve lesions and inflammatory infiltrates

�Axonal loss has more long-term prognostic impact than active demyelination or inflammatory infiltrates in demyelinating disorders of the peripheral and central nervous systems

CIDP: Diagnosis

�The diagnosis of CIDP is typically based on the clinical presentation, absence of other causes of the neuropathic syndrome, and results of electrodiagnostic studies

�Presence of increased cerebrospinal fluid (CSF) protein and demyelinating changes on nerve biopsy are supportive of the diagnosis, but these are not always present

�Because of the clinical heterogeneity and the lack of a diagnostic test, various diagnostic criteria have been proposed

�In one series of patients all of whom had proximal and distal weakness and in whom 95% of patients had improvement with treatment, only 30% had the classic triad of slow nerve conduction velocity, elevated CSF protein and demyelination on nerve biopsy

American Association of Neurology: Criteria

�Developed criteria for the identification of patients with CIDP for research studies

�Pathologic criteria

�Electrophysiologic criteria: Require 3 demyelinating range abnormalities (either slow conduction velocity, prolonged distal motor latencies or F wave latencies or conduction block) in 2 nerves

�Criteria are not sensitive and may miss more than 50 % of patients with CIDP

�Specificity approaches 100%

�Majority of patients seen in clinical practice fail to meet all of the criteria

Laboratory Studies: CSF

�Protein level is increased significantly in 80% of patients

�Usually between 50 and 200 mg/dL, but can be higher

�10% of patients also have mild lymphocytic pleocytosis (<50 cells) and increased gamma globulin (usually associated with HIV infection)

�CBC, sedimentation rate, antinuclear antibody, biochemistry profile, and serum and urine immunoelectrophoresis are necessary to exclude important associated systemic disorders

CIDP: EMG

�Critical test to determine whether the disorder is truly a peripheral neuropathy and whether the neuropathy is demyelinating

Findings of a demyelinating neuropathy

�Multifocal conduction block or temporal dispersion of compound muscle action potential

�Prolonged distal latencies

�Variable conduction slowing to less than 70% of normal

�Absent or prolonged F wave latencies

�As the disease progresses, patients tend to develop secondary axonal degeneration

Patients can have a normal emg in small fiber CIDP.

CIDP: Peripheral nerve biopsy (A skin biopsy should be considered) Dr King Engle and Dr. Jonathan Katz do not recommend a nerve biopsy)

�Indications

�Patients in whom the diagnosis is not completely clear

�Cases where other causes of neuropathy (eg, hereditary, vasculitic) cannot be excluded

�Caes where profound axonal involvement is observed on EMG

�Some experts recommend biopsy for most patients prior to initiating immunosuppressive therapy

CIDP: Histologic Findings

�Interstitial and perivascular infiltration of the endoneurium with inflammatory T cells and macrophages with local edema

�Evidence exists of segmental demyelination and remyelination with occasional onion bulb formation, particularly in relapsing cases

�Some evidence of axonal damage also is observed, with loss of myelinated nerve fibers

�The inflammatory infiltrate with neutrophil infiltration is observed in only a minority of patients

CIDP: Histology

�Demyelinated fibers (D)

�Fibers undergoing active macrophagemediated demyelination (M)

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�First line treatments

Plasmapheresis

Proposed mechanism

�Removal of antibodies and complement components that are responsible for immune-mediated damage of peripheral nerves

�Has been shown to have similar efficacy as IVIg in treatment of CIDP

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�3 plasma exchanges per week for first 2 weeks

�Additional treatment is determined by clinical response

IVIG

�Solution composed mostly of heterogenous human IgG but also small amounts of IgA and IgM

�Proposed mechanism of action

�IVIg contains random set of antibodies that would neutralize immune factors, causing damage to peripheral nerve in CIDP

�Activates complement cascade and provides multitude of antibodies capable of neutralization of many microorganisms, toxins, viruses, and presumably autoantibodies

Used in infectious diseases to provide immediate passive immunity in situations in which time constraints do not allow development of active immunity via vaccination.

�Also used to treat multiple immune-mediated conditions, such as idiopathic thrombocytopenic purpura, GBS, and myasthenia gravis

Several studies showed significant benefit in CIDP

�Useful alternative to plasmapheresis

�On average, improvement seen by day 10 and continues through day 42

�Serum half-life is approximately 21-29 days

�Patients usually require repeated treatments every few weeks or months to maintain remission or treat recurrences

�Agents used for refractory patients

�Cyclosporine (Sandimmune, Neoral)

�Cyclophosphamide (Cytoxan)

�Azathioprine (Imuran)

�Mycophenolate (CellCept)

�Several controlled studies confirmed benefit

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�The outcome of CIDP is difficult to predict owing to the variety of clinical patterns and evolution

�If left untreated, it can become disabling, with loss of ability to ambulate, work, or function independently

Prognosis The long term prognosis of CIDP patients was generally favorable, but 39% of patients still required immune treatments and 13% had severe disabilities. Mode of onset, distribution of symptoms, and electrophysiological characteristics may be prognostic factors for predicting a favorable outcome.

Refrences

�Acquired demyelinating neuropathy�. Brain. 119. 257�270.

�Ad Hoc Subcommittee of the American Academy of Neurology, AIDS Task Force (1991). �Research criteria for diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)�. Neurology. 41. 617�618.

�Bouchard, et al. �Clinicopathologic findings and prognosis of chronic inflammatory demyelinating polyneuropathy�. Neurology. February (1 of 1). 1999. 52. 498-503.

�Kuwabara, S, et al. �Distribution patterns of demyelination correlate with clinical profiles in chronic inflammatory demyelinating polyneuropathy�. Journal of Neurology Neurosurgery and Psychiatry. 2002. 72. 37-42.

�Latov N. �Diagnosis of CIDP�. Neurology. 59. S2�S6.

Chin Sensory CIDP presenting as cryptogenic sensory polyneuropathy 2004 Sep;9(3):132- Clinical and subclinical autonomic dysfunction in chronic inflammatory demyelinating polyradiculoneuropathy

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