AIDP/CIDP Part 2: Treatment

Disease/Disorder

See AIDP/CIDP Part 1: Evaluation and Diagnosis.

Essentials of Assessment

See AIDP/CIDP Part 1: Evaluation and Diagnosis.

Initial Medical Management

At different disease stages

Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP)

AIDP can be a life-threatening medical emergency that often requires ICU admission. As approximately 10–30% of patients with GBS require ventilation within the first week of admission, patients at risk of respiratory failure should be identified promptly.^1,2 The Erasmus GBS Respiratory Insufficiency Score (EGRIS) prognostic tool can be used to calculate the probability (1–90%) of a patient requiring ventilation within 1 week of assessment.^2,3 Ventilatory parameters including vital capacity (VC) should be monitored every 1–3 hours initially. If the patient develops hypercarbia, hypoxemia, or a significant drop in VC to < 15 mL/kg body weight, mechanical ventilation may be required.^2,3

Additionally, cardiac and hemodynamic monitoring is indicated, as autonomic instability may cause labile blood pressures and life-threatening cardiac arrhythmias. Pharmacologic treatment or cardiac pacing may be necessary.^2,3

Early treatment of acute demyelination is paramount to limiting functional decline, hastening recovery, and preventing axonal damage, as ‘time is nerve.’⁴ Long-term mobility prognosis, defined as the probability of being able to walk unaided at 4 and 26 weeks can be calculated by the modified Erasmus GBS Outcome Score (mEGOS).⁵ First-line disease-modifying treatments include the use of intravenous immunoglobulin and plasma exchange (also referred to as plasmapheresis), which have equivalent efficacy in Guillain–Barré syndrome (GBS).^6,7

Plasma Exchange (PLEX)/Plasmapheresis for AIDP

PLEX was first described for the treatment of GBS in 1978 and consists of separating plasma from cells using membrane filtration or centrifugation. Its mechanism of action is presumed to involve the removal of soluble factors and, in particular, complement components and circulating autoantibodies. Albumin diluted with gelatin or fresh frozen plasma is simultaneously reinfused to maintain plasma volume and osmotic equilibrium.⁸

Serious side effects are uncommon but may include hypotension or hypertension, bradycardia or tachycardia, immunosuppression, hypocalcemia, local catheter-related hematoma or infection, hemolysis, deep venous thrombosis, and the inherent risk of potential exposure to blood products.⁸

Overall, PLEX should be started within 2-4 weeks of symptom onset to improve recovery time as compared to supportive care alone, which can be shown by improved time to recover with walking aid and/or walking unaided, improvement in one or more disability grades and decreased time on ventilator. After one year post-injury, full muscle strength was more likely when patients underwent PLEX.^2,3,9

Intravenous Immunoglobulin (IVIg) for AIDP

Human immunoglobulin therapies are derived from purified plasma pooled from multiple donors and can be administered intravenously (IVIg) or subcutaneously (SCIg). Despite the lack of studies comparing IVIg with a placebo, it is easier to administer and generally more widely available than plasma exchange, making it the preferred treatment of choice.^2,6

Common side effects following the administration of IVIg include headache, myalgia, transient hypertension or hypotension, and flushing. These can be addressed by slowing the infusion rate. More significant adverse events, such as neutropenia, pancytopenia, infection, aseptic meningitis, renal tubular necrosis, worsening of renal failure, electrolyte imbalances, alopecia, as well as thromboembolic events and stroke-like episodes (attributable to hyperviscosity and coagulopathy), have rarely been reported.^6,9

Overall, starting IVIg within two weeks of symptom onset improves recovery as much as PLEX. In the pediatric population, IVIg is the preferred method of treatment.^4,6

Other Immunotherapies for AIDP

Besides IVIg and plasma exchange, no other procedures or drugs have been proven effective.²

Measuring Prognosis in AIDP

Poor prognosis is associated with older age, rapid progression, preceding Campylobacter jejuni infection with severe diarrhea, and positive CMV serology. Gender, bulbar and facial weakness, sensory deficit, and pain did not correlate with outcome. Many studies support the prognostic value of EMG.⁵

A high Erasmus GBS respiratory insufficiency score (EGRIS) can predict need for mechanical ventilation. The modified Erasmus GBS outcome scale (mEGOS) administered upon hospital admission and at day 7 can predict functional outcomes at 6 months and is based on age, preceding diarrhea, and GBS disability score. Both are easily accessed via a simple online calculator.¹⁰

Pediatric Considerations for Treatment of AIDP

Patients should be closely monitored for motor, respiratory and autonomic function. Treatment should be considered in severe cases involving progressive weakness, respiratory compromise or bulbar symptoms. There is no difference between IVIG and plasma exchange; however, IVIG is typically chosen for ease of administration. Children typically have better prognosis than adults, with over 80% of children with good long-term recovery.¹¹

Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)

The majority of patients with CIDP experience chronic onset of a progressive or relapsing phase of over 8 weeks. However, up to 16% of all patients with CIDP present with acute onset of prominent sensory symptoms and signs resembling GBS, but deterioration continues >2 months from onset or 3 or more treatment-related fluctuations occur.⁹ Hospitalization is less common and supportive care is less aggressive compared with AIDP.

There are many disease-modifying treatments for CIDP, but first-line therapies include IVIg, corticosteroids, and PLEX. The mechanism of action of these treatments is not completely understood, as the mechanism of CIDP is not completely understood. According to a Cochrane systematic review, comparative effective studies demonstrate no clear difference in short-term improvement in impairment with IVIg when compared with intravenous methylprednisolone and probably no improvement when compared with either oral prednisolone or PLEX.⁹ A more recent review from the Netherlands suggests that, compared with corticosteroids, IVIg has fewer adverse events and leads to faster improvement (within 6 weeks). Corticosteroids seemed to induce remission over a longer period of time, but adverse events of long-term corticosteroid use should be balanced against the high costs of IVIg.¹³

IVIg for CIDP

There is level A evidence to recommend IVIg as first-line treatment for CIDP with a NNTB (number needed to treat for benefit) of three.¹² The pooled immunoglobulins are thought to interfere with the complement system and compete with the autoantibodies. Additionally, IVIg should be considered as the initial treatment in pure motor CIDP.¹²

Corticosteroids for CIDP

There is level C evidence recommending corticosteroids in the treatment of CIDP.¹² It is thought that corticosteroids suppress genes that are commonly activated in inflammatory conditions.⁹ Corticosteroids are inexpensive and easy to administer, and multiple clinical trials have investigated types of corticosteroids, routes of administration, and dosing schedules.

Despite the lack of high-quality evidence, corticosteroids are still widely used due to global availability, ease of administration, low cost and familiarity. The duration of corticosteroid treatment for CIDP often last months to years; therefore, clinicians should take steps to mitigate the adverse sequelae of chronic corticosteroids.¹² Serious side effects of long-term use include Cushing syndrome, adrenal insufficiency, diabetes mellitus, gastritis/esophagitis and ulcer, increased blood pressure, osteoporosis, psychosis, weight gain, and cataracts. Long-term use of corticosteroids in the pure motor variant of CIDP and multifocal motor neuropathy may actually be harmful.¹²

PLEX for CIDP

There is level A evidence recommending PLEX if IVIg and corticosteroids are ineffective.¹² There is moderate to high-quality evidence that twice-weekly PLEX produces short-term improvements in disability, but effects are not long lasting, and rapid deterioration may occur after cessation of treatments within one to five weeks.¹² Therefore, PLEX is recommended as a short-term treatment option for CIDP.⁶

Other Immunotherapies for CIDP

Combination treatments or augmentation with an immunosuppressant or immunomodulatory agent should be considered if response to monotherapy is inadequate, or the maintenance doses are unacceptably high.¹²

There is low-quality evidence that adjunctive azathioprine (2 mg/kg) added to prednisone may improve impairment compared with prednisone alone, with adverse effects reported in 10%.⁹

Low-quality evidence failed to demonstrate a 20% reduction in corticosteroid or IVIg doses with the addition of methotrexate 15mg/kg, yet with the added known methotrexate risks of teratogenicity, abnormal liver function, and pulmonary fibrosis.⁹

Trials with interferonbeta-1a (in comparison to placebo), failed to show improvement at 12 weeks and 32 weeks. Serious adverse events were no more common than placebo. Observational studies of these and other drugs, including cyclophosphamide, cyclosporine, mycophenolate mofetil, etanercept, rituximab, alemtuzumab, natalizumab, peripheral blood stem cell transplantation, and alpha interferon are of insufficient quality to determine potential benefit.⁹

Rehabilitation Management

In the acute setting, multidisciplinary treatment involves a neurologist, intensivist, rehabilitation medicine physician, physical therapist, occupational therapist, speech therapist, and respiratory therapist.

In addition to the above disease-modifying therapies, the following general rehabilitation management principles are applicable to the acute care setting

• Prophylaxis for deep vein thrombosis
• Management of potential bladder and/or bowel dysfunction
• Proper positioning, weight shifts, and skin monitoring to prevent skin breakdown and decubitus ulcer formation in immobile patients
• Initiation of therapy services with a focus on early mobility
• Psychosocial support
• Pain management using neuropathic pain medications, nonsteroidal anti-inflammatories (NSAIDs), and/or opiates. High-quality studies of pharmacotherapy of pain in GBS are lacking, but low-quality evidence exists in support of gabapentin and carbamazepine, limited only by sedation.¹⁴

In the ambulatory/chronic care setting, patients with residual deficits from AIDP or CIDP may also benefit from

• Orthotic management (ankle foot orthoses) for foot drop
• Pain management using neuropathic pain medications, nonsteroidal anti-inflammatories (NSAIDs), and/or opiates.

Patient & family education

Patients with AIDP and their families should be counseled early in the disease course about prognosis, various treatment options, and long-term management. In severe cases, proper education on mechanical ventilation, tracheostomy care, bowel and bladder management, skin monitoring, pain management, orthotics, household modification, contracture prevention, exercise, diet and lifestyle management, fall prevention and recovery, driving safety, and foot care should be included.

Additionally, since CIDP may be associated with peripheral nerve and/or nerve root hypertrophy due to redundant layers of myelin, patients should be cautioned and educated regarding:

• Neuroprotective strategies, owing to the potential increased likelihood of peripheral compression mononeuropathies, and
• Monitoring for the development of neurogenic claudication from lumbar spinal stenosis caused by potential root enlargement.

Additionally, studies demonstrate that up to 6% of patients with AIDP may relapse, and up to 10% may exhibit new symptoms or fluctuations in their disease state while undergoing IVIg or PLEX treatment.⁴²⁶ Therefore, the patient and family should be counseled regarding signs/symptoms of medical complications or disease recurrence/relapse, which should prompt follow-up.

Patients with CIDP may find additional social support locally or online. One such online organization is the GBS-CIDP Foundation International (http://www.gbs-cidp.org/).

Pediatric Considerations for Treatment of CIDP

Childhood CIDP is rare, with an estimated 1in 200,000 cases¹⁵. First-line treatment options include IVIG or corticosteroids. IVIG is typically preferred given the side effects of steroids, including osteoporosis. For relapsing cases, some new studies have suggested that pulsed weekly corticosteroids can be effective. However, nonsteroidal immunosuppressive agents have not shown to be effective. Childhood CIDP tends to have a more favorable outcome than adult CIDP, with most children having minimal residual weakness.¹⁵

Emerging/unique interventions

Home IVIg Infusion

A pair of Canadian studies demonstrated that IVIg infused both in patient homes and in ambulatory/outpatient infusion centers is feasible and safe for CIDP maintenance therapy. Both studies reported high patient satisfaction and preference for non-inpatient treatments.¹⁶ For chronic neuromuscular conditions the UK, home infusion is a first-line preferred treatment option.¹⁶

Subcutaneous Immunoglobulin (SCIg) for CIDP

The half-life of SCIg does not differ appreciably from that of IVIg, and it can be administered at lower dosages and more frequent intervals than IVIg resulting in higher and more stable serum IgG levels, potentially improving efficacy and reducing adverse effects and ‘end-of-dose’ effect (treatment wearing-off before the next dose is due).¹⁷

Outcomes measures for both AIDP and CIDP have been proposed to quantify response to therapeutic interventions and may be increasingly used by payers to justify ongoing value of pharmacotherapy.

GBS

Clinical trials have used the GBS disability score, time to recover unaided walking, Sickness Impact Profile, Medical Outcomes Study 36-Item Short-Form Health Survey, and the EuroQol-5D to measure the patient’s activity and health-related quality of life.¹⁸

CIDP

Recent clinical trials have assessed disability in patients with CIDP using the Inflammatory Neuropathy Cause and Treatment overall disability severity score (INCAT-ODSS) and physical impairment using the Medical Research Council strength sum score and/or INCAT sensory sum score.¹⁸

The Rasch-built Overall Disability Scale (R-ODS) is a 24-item functional questionnaire that can easily be completed by patients in a clinical practice setting. R-ODS is more sensitive for detection of clinically meaningful changes over time than the Inflammatory Neuropathy Cause and Treatment-Overall Neuropathy Limitation Scale (INCAT-ONLS) in patients with CIDP or GBS.¹⁸

Promising therapies using monoclonal antibodies, such as rituximab and natalizumab and stem cell therapies for treatment of CIDP warrant further research.⁹

Translation into practice: Practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Immunotherapy

• IVIg and PLEX are first-line treatments for AIDP. Up to 6% of patients with AIDP may relapse and up to 10% exhibit new symptoms or fluctuations in their disease state while undergoing IVIg or PLEX.⁴
• IVIg, PLEX, and corticosteroids are mainstay treatments for CIDP. Approximately 30% to 60% of patients with CIDP treated with mainstay therapies will substantially improve.⁹ If corticosteroids are used in the management of CIDP, the treating physician should mitigate long-term adverse effects.
• Functional outcomes measures such as the INCAT-ODSS or R-ODS should be administered to objectively measure treatment responses and have potential to become a required part of payer authorization for costly immunotherapy¹⁸.

Misdiagnosis of CIDP

It is estimated that 15–55% of patients may receive unnecessary IVIg treatments for misdiagnosed CIDP.¹³ This may be perpetuated by (1) heterogeneity of disease, (2) fear of deterioration after stopping IVIg, (3) subjective patient reports of treatment benefit, (4) liberal electrodiagnostic interpretation of demyelination, and (5) overreliance on CSF findings.¹⁹ Furthermore, misinterpretation of electrodiagnostic data as ‘demyelinating’ may occur in the setting of: (1) amplitude-dependent conduction velocity slowing in length-dependent axonopathy, (2) amplitude-independent slowing in diabetics, (3) overreliance on fibular CMAP from the EDB, (4) absent conduction block, and (5) velocity slowing limited to compressible sites.²⁰⁰ Strict adherence to published EFNS/PNS diagnostic criteria of demyelination is crucial.¹²

Cutting Edge/Emerging and Unique Concepts and Practice

Preliminary studies of complement inhibitors nafamostat mesilate (in anti-GM1 rabbits) and eculizumab (in anti-GQ1b mice) appear promising. Furthermore, combination therapy with complement inhibitors and IVIg is being considered.⁹

Gaps in the Evidence-Based Knowledge

Further research is needed to identify which factors predict response and deterioration after various therapies. Comparative effectiveness studies are urgently needed to determine the cost-effectiveness of corticosteroids, IVIg, and SCIg, and whether adjunctive treatment with immunosuppressive agents is superior to monotherapy.

Future trials should have improved designs and longer treatment durations, and should measure function and other outcomes relevant to patients with CIDP9.³

Large, well-designed RCTs are required to investigate further the efficacy and safety of potential interventions for patients with pain in both GBS and CIDP.

References

1. Green C, Baker T, Subramaniam A. Predictors of respiratory failure in patients with Guillain-Barré syndrome: a systematic review and meta-analysis. Med J Aust. 2018;208(4):181-188. doi:10.5694/MJA17.00552
2. Leonhard SE, Mandarakas MR, A Gondim FA, et al. Diagnosis and management of Guillain–Barré syndrome in ten steps. doi:10.1038/s41582-019-0250-9
3. Willison HJ, Jacobs BC, van Doorn PA. Guillain-Barré syndrome. Lancet. 2016;388(10045):717-727. doi:10.1016/S0140-6736(16)00339-1
4. Verboon C, van Doorn PA, Jacobs BC. Treatment dilemmas in Guillain-Barré syndrome. J Neurol Neurosurg Psychiatry. 2017;88(4):346-352. doi:10.1136/JNNP-2016-314862
5. Doets AY, Lingsma HF, Walgaard C, et al. Predicting Outcome in Guillain-Barré Syndrome. Neurology. 2022;98(5):e518-e532. doi:10.1212/WNL.0000000000013139
6. Hughes RAC, Swan A v., van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2014;2014(9). doi:10.1002/14651858.CD002063.PUB6
7. Ortiz-Salas P, Velez-Van-Meerbeke A, Galvis-Gomez CA, Rodriguez JH. Human Immunoglobulin Versus Plasmapheresis in Guillain-Barre Syndrome and Myasthenia Gravis: A Meta-Analysis. J Clin Neuromuscul Dis. 2016;18(1):1-11. doi:10.1097/CND.0000000000000119
8. Oaklander AL, Lunn MPT, Hughes RA, van Schaik IN, Frost C, Chalk CH. Treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): an overview of systematic reviews. Cochrane Database Syst Rev. 2017;1(1). doi:10.1002/14651858.CD010369.PUB2
9. IGOS GBS Prognosis tool. Accessed October 1, 2022. https://gbstools.erasmusmc.nl/prognosis-tool
10. A C, M D. Guillain-Barré Syndrome. Pediatr Rev. 2018;39(1):54. doi:10.1542/PIR.2017-0189
11. van den Bergh PYK, Van Doorn, PA, Hadden RDM, et al. European Federation of Neurologys/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force – second revision. Eur J Neurol. 2021;28(11):3556-3583. doi.org/10.1111/ene.14959
12. Adrichem ME, Eftimov F, van Schaik IN. Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyradiculoneuropathy, a time to start and a time to stop. J Peripher Nerv Syst. 2016;21(3):121-127. doi:10.1111/JNS.12176
13. Liu J, Wang LN, Mcnicol ED. Pharmacological treatment for pain in Guillain‐Barré syndrome. Cochrane Database Syst Rev. 2015;2015(4). doi:10.1002/14651858.CD009950.PUB3
14. Harada Y, Herrmann DN, Logigian EL. Pediatric CIDP: Clinical Features and Response to Treatment. J Clin Neuromuscul Dis. 2017;19(2):57-65. doi:10.1097/CND.0000000000000179
15. Katzberg HD, Rasutis V, Bril V. Infusing IVIG through Community Care Access Services in Patients with CIDP. Can J Neurol Sci. 2016;43(2):326-328. doi:10.1017/CJN.2015.303
16. Rajabally YA. Subcutaneous immunoglobulin therapy for inflammatory neuropathy: current evidence base and future prospects. J Neurol Neurosurg Psychiatry. 2014;85(6):631-637. doi:10.1136/JNNP-2013-305644
17. Allen JA, Bril V. Improving the management of chronic inflammatory demyelinating polyradiculoneuropathy. Neurodegener Dis Manag. 2016;6(3):237-247. doi:10.2217/NMT-2015-0011
18. Allen JA, Lewis RA. CIDP diagnostic pitfalls and perception of treatment benefit. Neurology. 2015;85(6):498-504. doi:10.1212/WNL.0000000000001833
19. Allen JA, Ney J, Lewis RA. Electrodiagnostic errors contribute to chronic inflammatory demyelinating polyneuropathy misdiagnosis. Muscle Nerve. 2018;57(4):542-549. doi:10.1002/MUS.25997

Original Version of the Topic

Jeremy I. Simon, MD, Joshua Armstrong, DO. AIDP/CIDP Part 2: Treatment. 9/20/2014.

Previous Revision(s) of the Topic

Jeremy I. Simon, MD, Joshua Armstrong, DO. AIDP/CIDP Part 2: Treatment. 6/29/2018

Amanda Ly, MD, Nikhil Gopal, MBBS, Rajashree Srinivasan, MD, MBBS. AIDP/CIDP Part 2: Treatment. 12/14/2022

Author Disclosure

Elisabeth Frankini, DO
Nothing to Disclose

Rajashree Srinivasan, MD, MBBS
Nothing to Disclose

Priya Chitta Nangrani, MD
Nothing to Disclose