Neuro-ophthalmic Manifestations of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

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Article initiated by:

Andrew Go Lee, MD, Luke Newton, Peter W. Mortensen, MD, Subahari Raviskanthan, MBBS

All contributors:

Nagham Al-Zubidi, MD, Peter W. Mortensen, MD, Subahari Raviskanthan, MBBS, Sonali Singh MD

Assigned editor:

Sonali Singh MD

Review:

Assigned status Update Pending

 by Sonali Singh MD on May 5, 2023.

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Contributing Editors:	add

Disease Entity

Chronic inflammatory demyelinating polyneuropathy (CIDP) is the most common, immune-mediated, chronic inflammatory polyneuropathy. CIDP is an acquired autoimmune. The typical presentation of CIDP is a bilateral, symmetric, polyneuropathy with an equal affect on proximal and distal muscles that may be progressive or relapsing in course. The patient may develop a symmetric tetraparesis with areflexia and bilateral peripheral sensory loss. Although CIDP is predominantly a peripheral nervous system (PNS) disorder central nervous system (CNS) involvement can occur. The diagnosis of CIDP is made clinically but is supported by cerebrospinal fluid (CSF) abnormalities (e.g., albuminocytologic dissociation), imaging, electrophysiologic, and sometimes histopathologic findings. Although primarily a neurologic disorder, this Eyewiki describes the possible neuro-ophthalmic manifestations of CIDP (e.g., ophthalmoplegia, papilledema, optic neuropathy, proptosis, and pupillary abnormalities).

Epidemiology

The prevalence of CIDP ranges from 0.8 to 8.9 per 100,000. In southeast England the prevalence rate was reported at 2.84 per 100,000 inhabitants with a ratio of male patients outnumbering female patients 2:1 and a patient population with the highest predominance of disease onset between 70 to 79 years. The prevalence was 8.9 per 100,000 inhabitants in Olmsted County, USA (Mayo Clinic), 5.87 per 100,000 inhabitants in Ireland, and 0.8 per 100,000 inhabitants in Tottori, Japan. Overall, there is a male predominance of 1.5 to 4:1 with increasing incidence with advancing age.

Pathogenesis

The proposed pathogenesis of CIDP is autoimmune, humoral and cell-mediated damage to myelin and Schwann cells but the precise mechanisms for disease remain ill defined.

Diagnosis

Signs

Table 1 lists the possible neuro-ophthalmic findings of CIDP.

Finding	Possible Symptoms and Signs	Imaging/Tests
Ophthalmoplegia	Diplopia, variable patterns of ophthalmoplegia (including gaze palsies and internuclear ophthalmoplegia), blurred vision, oscillopsia, ptosis	Although CIDP is a peripheral nervous system disease some cases have been reported to have central involvement. Brain imaging is typically normal but in cases with brainstem involvement (central) there may be demyelinating lesions visible on magnetic resonance imaging (MRI).
Papilledema	Headache, nausea, vomiting, ataxia, altered consciousness, diplopia	Ophthalmoscopic findings may included elevation of the optic disc, obscuration of major blood vessels leaving the disc, and peripapillary halo.
Proptosis		MRI/CT may show enhancement and enlargement of the orbital segments of the ocular motor nerves or trigeminal nerve.
Optic neuropathy	Decreased vision, relative afferent pupillary defect (RAPD), or pain with ocular movement	MRI findings may reveal high signal lesion(s) on optic nerve, optic nerve inflammation, and/or optic nerve hypertrophy.
Pupillary abnormalities	RAPD in cases of optic neuropathy. Anisocoria with miosis or mydriasis may be present.	May be intracranial or orbital involvement of optic nerve or oculomotor cranial nerve.

The diagnosis of CIDP is made clinically by neurology and is based upon progressive or relapsing, symmetrical or asymmetrical polyradiculoneuropathy greater than 2 months. The clinical diagnosis of CIDP can be confirmed with further diagnostic testing including the following:

• Electrodiagnostic studies (e.g., sensory and motor nerve conduction studies)

• CSF examination (e.g., albuminocytologic dissociation of elevated protein and relative lower CSF white blood cell count)

• Nerve biopsy

• MRI of brachial plexus, lumbosacral plexus, and spinal roots (MRI brain for CNS cases)

• Diffusion Tensor Imaging (DTI)

EFNS/PNS Diagnostic Criteria for CIDP

At least one of the following is required:

• Meet definitive electrodiagnostic criterion + clinical criteria 1 (a or b) without meeting any of the exclusionary clinical criteria 2

• Meet probable electrodiagnostic criterion + ≥1 supportive criterion

• Meet possible electrodiagnostic criterion + ≥2 supportive criteria

EFNS/PNS Clinical Criteria for CIDP

Inclusion criteria

One of the following is required:

a) Typical CIDP

Findings include progressive or recurrent symmetric distal and proximal sensory dysfunction and weakness of all extremities over ≥2 months, reduced or absent reflexes in tendons in all extremities and cranial nerves that may be affected

b) Atypical CIDP

Findings include tendon reflexes that may be normal in unaffected limbs, findings seen in Typical CIDP, and one of the following:

- Distal acquired demyelinating symmetric (DADS)

- Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM)

- Focal (lumbosacral plexus, brachial plexus, or ≥1 peripheral nerve involvement in one upper or lower limb)

- Pure motor

- Pure sensory

Exclusion criteria

Any of the following is exclusionary:

a) Exposure to drug, toxin, diphtheria, or Borrelia burgdorferi infection as suspected cause of neuropathy

b) Presence of hereditary demyelinating neuropathy

c) Presence of prominent sphincter disturbance

d) Multifocal motor neuropathy diagnosis

e) IgM monoclonal gammopathy accompanied with high titer antibodies to myelin-associated glycoprotein

f) Presence of demyelinating neuropathy from other causes including osteosclerotic myeloma, diabetic and non-diabetic lumbosacral radiculoplexus neuropathy, Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes (POEMS) syndrome, amyloidosis or PNS lymphoma.

EFNS/PNS Electrodiagnostic Criteria for CIDP

Definitive Electrodiagnostic Criteria

At least one of the following is required:

• ≥50% prolongation in motor distal latency above upper limit of normal in 2 nerves (excluding carpal tunnel syndrome median neuropathy at the wrist)
• ≥30% motor conduction velocity reduction below lower limit of normal in 2 nerves

• ≥30% F-wave latency prolongation above upper limit of normal in two nerves or ≥50% if the amplitude of distal negative peak compound muscle action potential is <80% of lower limit of normal values

• ≥20% of distal negative peak compound muscle action potential amplitudes of lower limit of normal in two nerves with absent F-waves + ≥1 additional demyelinating parameter in ≥1 additional nerve

• Partial motor conduction block defined as ≥50% reduction of amplitude of the relative to distal proximal negative peak compound muscle action potential in two nerves, if there is a ≥20% of lower limit of normal of distal negative peak compound muscle action potential, OR in one nerve + ≥1 additional demyelinating parameter in ≥1 additional nerve

• Abnormal temporal dispersion defined as >30% proximal and distal negative peak compound muscle action potential duration increase in ≥ 2 nerves

• Increase in distal compound muscle action potential duration in ≥1 nerve + ≥1 additional demyelinating parameter in ≥1 additional nerve

Probable Electrodiagnostic Criteria

• Increase in distal compound muscle action potential duration in ≥1 nerve + ≥1 additional demyelinating parameter in ≥1 additional nerve

Possible Electrodiagnostic Criteria

• At least one of the criteria seen in the definitive electrodiagnostic criteria but seen in only one nerve

EFNS/PNS Supportive Criteria for CIDP

• CSF protein elevation with CSF white blood cell count <10/mm3

• Gadolinium enhancement and/or cauda equina, lumbosacral, cervical nerve roots, brachial plexus, or lumbosacral plexus hypertrophy on MRI
• Specified sensory electrophysiology abnormalities in ≥1 nerve

• Objective clinical improvement after immunomodulatory therapy

• Clear evidence of demyelination and/or remyelination on nerve biopsy visualized through teased fiber analysis or microscopy

Differential Diagnoses

The following conditions are included in the differential diagnoses for CIDP:

• Acute inflammatory demyelinating polyneuropathy
• Multifocal motor neuropathy (MMN)
• Chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies (CANOMAD)
• POEMS syndrome
• Demyelinating neuropathy associated with checkpoint and tumor necrosis factor-alpha blocker medications
• Diabetic and inherited polyneuropathy
• Hereditary motor sensory neuropathy (HSMN) type I and type III
• Charcot-Marie-Tooth (CMT), particularly CMT1A, CMT1B, CMT1X, and CMT4
• Transthyretin (TTR) familial amyloid polyneuropathy (FAP)
• Fibromyalgia
• Multiple Sclerosis

Management

The management of CIDP is best coordinated with a neurologist. The ophthalmologist role is to provide information on the potential ophthalmic manifestations and define the CNS and orbital findings in order to exclude alternative etiologies.

Medical Therapy

Generally, first line treatment includes corticosteroid or immunomodulatory therapy, intravenous immunoglobulin (IVIg), or plasma exchange. Other medical therapies with reported beneficial effects include rituximab treatment in CIDP patients positive for anti-NF155 and anti-CNTN1 antibodies as well as subcutaneous bortezomib treatment in severely affected treatment-refractory CIDP patients.

Treatment of ocular manifestations:

Systemic treatment of CIDP with the neurologist is the first line therapy for the neuro-ophthalmic manifestations (e.g., papilledema, diplopia and optic neuropathy). Some cases of refractory papilledema have required treatment for elevated intracranial pressure (e.g., acetazolamide, optic nerve sheath fenestration, or CSF diversion surgery).

Prognosis

The majority of patients with CIDP have a favorable treatment response and long-term prognosis. Although, 13-24% of patients with CIDP demonstrate severe disability despite treatment and 40% require continuous immunosuppressant treatment.

More specifically, the heterogeneity of the disease with presentation of approximately half of patients presenting with ‘typical’ CIDP and the other half as one of the atypical CIDP variants results in variable prognosis depending on CIDP type. In particular, ‘typical’ CIDP reports 3-22% of patients with severe disability on long-term prognosis. Alternatively, 40-50% of MADSAM patients had severe disability with long term prognosis and 23-33% showed no response to first-line therapy. Patients with DADS also report less favorable response to treatment in comparison to ‘typical’ CIDP however report a lower disability score. A single study reported favorable response rates at 90% and 88% respectively for pure sensory and pure motor CIDP in patients diagnosed with these conditions. Finally, patients with presence of NF155, CNTN1, or CASPR1 also report worse treatment response to first-line therapy compared to ‘typical’ CIDP patients.

Summary

CIDP is a common autoimmune cause of chronic inflammatory demyelinating polyneuropathy. The diagnosis is made clinically but supported by CSF (e.g., albuminocytologic dissociation), electrophysiologic, neuroimaging, and sometimes histopathologic findings. Ophthalmologists should be aware that CIDP can present with neuro-ophthalmic findings including visual loss from papilledema or optic neuropathy, ophthalmoplegia from CNS or orbital involvement of ocular motor cranial nerves, pupillary abnormalities (e.g., RAPD or anisocoria), or proptosis (orbital ocular motor cranial nerve or trigeminal nerve enlargement). CIDP is best evaluated and managed by a neurologist and the role of the ophthalmologist is to provide information on the eye examination that might suggest CNS rather than PNS involvement in CIDP or prompt consideration for further neuroimaging and consideration of alternative etiologies.