Chronic Inflammatory Polyradiculoneuropathy (CIDP)

1
Chronic Inflammatory Polyradiculoneuropathy (CIDP)
2
Outline

• General
• Clinical Manifestations
• Diagnosis
• Treatment and prognosis

3
CIDP

• Acquired, immune-mediated polyradiculoneuropathy
• Heterogeneous disorder with a wide range of
  clinical expression ranging from subacute to a
  progressive or relapsing-remitting course
• Diagnosis is based on clinical symptoms and
  signs, electrodiagnostic studies, CSF
  examination, and other laboratory tests

4
CIDP Clinical Manifestations

• Demyelination
• May be detected on nerve conduction studies or
  nerve biopsy
• Multifocal demyelination is a diagnostic hallmark
  of CIDP, but distribution of demyelinative
  lesions varies among patients
• Weakness
• Characteristically, involves both proximal and
  distal muscles
• Typically symmetric, but can begin asymmetrically
  
• Sensory symptoms are common but motor symptoms
  usually predominate
• Autonomic system dysfunction can occur

5
CIDP Clinical Manifestations

• Slow progressive course is seen in approximately
  2/3 of cases
• Children usually have a more 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

6
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

7
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

Bouchard et al. NEUROLOGY 199952498503
8
CIDP Regional Variants

• The classical phenotype that suggests CIDP is the
  presence of proximal and distal weakness, with
  large fiber sensory loss and areflexia
• Few patients present with classic symtpoms
• Some authors have suggested subclassifications
  based on the clinical phenotype in order to aid
  in diagnosis and treatment
• Currently these subclasses are not thought to be
  distinct diseases

9
CIDP Regional Variants

• Lewis-Sumner syndrome
• Distal acquired demyelinating sensory neuropathy
  and sensory CIDP
• Multifocal demyelinating neuropathy with
  persistent conduction block
• Distal CIDP
• Sensory CIDP

• ANTI-MAG (Myelin Associated Glycoprotein)
  Neuropathy
• CIDP with Hypertrophic nerves
• Subacute demyelinating polyneuropathy
• Chronic Inflammatory demyelinating neuropathies

10
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

11
CIDP Associated Conditions

• 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

12
CIDP Associated Conditions

• 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

13
CIDP Associated Conditions

• 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

14
CIDP Associated Conditions

• 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

15
CIDP Associated Conditions

• 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

16
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

17
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

18
CIDP Diagnosis

• 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

19
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

20
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 (lt50 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

21
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

22
CIDP Peripheral 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

23
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

24
CIDP Histology

• Note the decreased density of nerve fibers
  (arrows)
• Demyelinated fibers (D)
• Fibers undergoing active macrophagemediated
  demyelination (M)

Bouchard, et al. NEUROLOGY 199952498503
25
CIDP Therapy

• Prednisone, IVIg and plasmapheresis have all been
  demonstrated to be effective in controlled
  clinical trials
• In one study, response was seen to at least 1 of
  these 3 main therapies in 66 of patients
• Only 1/3 of patients have a sustained remission
  after initial treatment and most require ongoing
  treatment
• Early treatment is advisable to prevent axonal
  loss and motor neuron loss which leads to
  functional decline
• May be irreversible

26
CIDP Therapy

• A positive therapeutic response is measured by
  improvement or stabilization of previously
  documented progressive weakness, sensory loss, or
  ataxia
• In responsive patients, treatment is continued
  until maximal improvement or stabilization is
  achieved, at which point it can be tapered or
  discontinued
• If there is further deterioration or a relapse,
  the therapy can be re-instituted
• Patients with chronic progressive disease require
  maintenance therapy, although tapering the
  treatment can be re-attempted periodically to
  determine continued need

27
CIDP Therapy

• Prednisone
• First line therapy
• Agents used for refractory patients
• Cyclosporine (Sandimmune, Neoral)
• Cyclophosphamide (Cytoxan)
• Azathioprine (Imuran)
• Mycophenolate (CellCept)

28
CIDP Therapy

• Neuropathic pain
• Antiepileptics
• Carbamazepine (Tegretol)
• Gabapentin (Neurontin)
• Tricyclic antidepressants
• Amitriptyline (Elavil)

29
CIDP Plasmapheresis

• Several controlled studies confirmed benefit
• 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

30
CIDP Plasmapheresis

• Treatment regimens
• Not standardized due to a lack of controlled
  studies
• Common regimen
• 3 plasma exchanges per week for first 2 weeks
• Additional treatment is determined by clinical
  response

31
IV Ig

• 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

32
IV Ig

• 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

33
CIDP IV Ig

• 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

34
CIDP Prognosis

• 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

35
References

• Acquired demyelinating neuropathy. Brain. 119.
  257270.
• 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. 617618.

36
References

• 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.
  S2S6.