Enlargement of peripheral nerves has been reported in a variety of congenital and acquired neuropathies, for which the term “hypertrophic neuropathy” has generally been used (1). Hypertrophic neuropathy is characterized histologically by onion bulb formation, which consists of concentrically arranged layers of redundant Schwann cell processes with interspersed collagen surrounding a thinly myelinated axon (2). Onion bulbs are thought to originate from repeated episodes of demyelination and remyelination (2). The swollen appearance of the nerve may result from mucopolysaccharides in the endoneurium and interstitial edema (1). The presence of these components in peripheral nerves is the hallmark of hereditary motor and sensory neuropathies (HMSN) type I (Charcot-Marie-Tooth disease), type III (Dejerine-Sottas disease), and Refsum disease (2).
Onion bulbs are also a recognized pathologic finding in patients with chronic inflammatory demyelinating polyneuropathy (CIDP), occurring in 10%-40% of peripheral nerve biopsies (2,3). There have also been a few descriptions of hypertrophy of cranial nerves (1). The concurrence of ophthalmoplegia and proptosis in relation to cranial nerve hypertrophy in CIDP is highly unusual. There are two reported cases of cranial nerve hypertrophy in CIDP manifesting with ophthalmoplegia (2,4) and four with ophthalmoplegia and proptosis (5-7), none of which mention the presence of lid retraction.
We present a single patient with a long-standing diagnosis of CIDP who also manifested proptosis, lid retraction, and ophthalmoplegia. MRI showed enlarged, enhancing cranial nerves that initially gave rise to diagnostic confusion with Graves disease or orbitocavernous mass lesions.
A 53-year-old woman developed double vision, left upper lid ptosis, and numbness and weakness in all four extremities in 1980 after an upper respiratory tract infection. Her initial neurologic evaluation showed four-limb proximal and distal weakness, four-limb areflexia, and decreased pinprick sensation in a distal gradient distribution with decreased vibratory sensation extending up to the ankles. She had an ataxic gait.
She was clinically diagnosed as having the Fisher variant of Guillain-Barré syndrome and treated temporarily with oral prednisone. She was left with residual partial left upper lid ptosis, areflexia, and foot numbness. In 1984, in the context of a Mycoplasma pneumoniae infection, her neurologic manifestations worsened briefly, after which they returned to baseline. In the early 1990s, she twice underwent surgical correction of ptosis. In the mid-1990s, her lower extremity motor and sensory symptoms worsened slowly. Diplopia and bilateral proptosis with eyelid retraction developed.
In 1996, nerve conduction velocity studies revealed a predominantly sensory chronic demyelinating polyneuropathy. Tests for anti-myelin-associated glycoprotein (MAG), anti-GM1, anti-GQ1b, and antinuclear antibodies (ANA), vitamin B12, methylmalonic acid, and rapid plasma reagin (RPR) and immunofixation were either negative or normal. Anti-double-stranded DNA antibodies were slightly elevated. Cerebrospinal fluid studies revealed no cells with an elevated protein of 80 mg/dL.
A diagnosis of CIDP was established, and in 1998 she began monthly treatment of intravenous immunoglobulin (IVIg). One week after each infusion she would report improvement in limb strength, sensation, and diplopia and worsening in these symptoms several days before her next treatment. She noted that diplopia would be the first symptom to improve with treatment and the first symptom to worsen as she neared her next treatment. She had stable proptosis, eyelid retraction, and ophthalmoplegia.
In 2001, she was noted to have an enlarged thyroid gland, normal thyroid function tests, and positive results for anti-thyroglobulin antibodies. Orbit MRI in 2001 was reported to show contrast enhancement along the left orbital apex into the cavernous sinus. Repeat MRI in 2002 reportedly showed no change.
She had seasonal allergies, cervical disc disease with resultant radiculopathy, factor V Leiden positivity, and anti-phospholipid antibody syndrome. Medications included prednisone, loratadine, estradiol, medroxyprogesterone, warfarin, and monthly IVIg.
A neuro-ophthalmic consultation was sought in 2003 to settle the question of whether her clinical and imaging features were consistent with Graves disease or orbitocavernous tumors.
Our evaluation disclosed best-corrected visual acuities of 20/25 in both eyes. Color vision was 10/10 using Hardy-Rand-Rittler color plates, and the Amsler grid was normal. Humphrey automated perimetry 24-2 revealed subtle depression in both eyes in a nonspecific distribution. The pupils under dim illumination measured 6 mm in the right eye and 6.5 mm in the left eye. The pupils had 2+ reaction to direct light and near, and there was no relative afferent pupillary defect. There was abnormal resistance to retropulsion of both eyes without tenderness. There were no ocular or cranial bruits. There was fluctuating bilateral upper eyelid retraction but no eyelid lag. Exophthalmometry at a base of 103 was 25 mm bilaterally (Fig. 1).
The extraocular movements were full except for 10% supraduction in the left eye and 90% adduction in both eyes (Fig. 1). Ocular alignment, measured with the cover test while the patient was viewing a distant target, revealed a right hyperdeviation of 2 PD which increased to 4 PD on right gaze, 5 PD on left gaze, 10 PD on upgaze, and 5 PD on downgaze. Biomicroscopic and funduscopic examinations were normal.
Neurologic examination was significant for absent deep tendon reflexes and distal limb hypesthesia to pinprick and vibration testing in a gradient distribution.
She was lost to our follow-up from 2003 to 2005, during which her neurologic condition was stable. A neuro-ophthalmologic evaluation in 2005 did not, however, reveal any significant change relative to the examination in 2003.
On orbitocranial MRI performed in 2005, there were no orbital or cavernous sinus neoplasms, and no orbital changes suggestive of Graves disease. However, the study showed bilateral enhancement and enlargement of ocular motor cranial nerves extending from the subarachnoid space into the orbits with resultant proptosis (Figs. 2, 3). MRI of the lumbosacral plexus showed massive enlargement of the ventral rami of multiple lumbosacral spinal roots (Fig. 4).
Our patient had bilateral ophthalmoplegia, proptosis, and fluctuating eyelid retraction caused by enlarged (hypertrophied) cranial nerves associated with CIDP. Her neuro-ophthalmic findings had been erroneously attributed to Graves disease clinically and to orbitocavernous neoplasms radiologically. The MRI findings were reinterpreted as showing hypertrophy of multiple cranial nerves as occurs in CIDP. Consequently, MRI of the lumbosacral plexus was performed to confirm the multifocal nature of the disease, which indeed showed similar changes in the spinal roots.
Several cases of CIDP have been reported in which cranial nerve involvement was manifested through ocular motor signs of ophthalmoplegia with or without proptosis (2,4-7). In none of these cases was there any mention of eyelid retraction.
Ophthalmoplegia without mention of proptosis as a result of cranial nerve hypertrophy was noted by McCann et al (2), who described a 69-year-old man with CIDP whose presentation consisted of impaired visual acuity, decreased upward and lateral gaze, diplopia, slowed pupillary reflexes, and ptosis. Autopsy demonstrated widespread onion bulb formation in multiple cranial nerves, including III, IV, V, and VI. His treatment course included prednisone and eventually plasmapheresis, neither of which had a beneficial effect.
Bilateral ophthalmoplegia without proptosis was also described in the context of facial palsy and tongue atrophy by Inoue et al (4) in a 61-year-old man with CIDP and bilateral nerve root hypertrophy of cranial nerves III, V, VI, and VII. No treatment modalities or further eye findings were mentioned.
Cases of CIDP with cranial nerve hypertrophy causing ophthalmoplegia and proptosis have also been described. Aidi et al (5) reported two patients with hypertrophy of cranial nerves III and V causing proptosis and “gaze palsies.” The authors described the response to corticosteroid treatment as excellent but provided no further information. Guibord et al (6) reported a 15-year-old woman with CIDP and bilateral proptosis along with slightly limited adduction and left eye nystagmus on leftward gaze. MRI revealed enhancement of hypertrophied trigeminal nerves extending from the gasserian ganglia to the terminal branches of all three divisions with secondary cavernous sinus enlargement and resultant optic nerve and superior rectus displacement. The patient was treated with weekly IVIg infusions with no apparent change in proptosis. The authors provided no additional information about eye movements. Duarte et al (7) reported a case of a 30-year-old woman who presented with bilateral marked proptosis and horizontal diplopia on left gaze. As with our patient, diagnostic confusion arose after MRI disclosed a mass-like lesion and enlarged, enhancing cranial nerves in the cavernous sinuses and orbits. The patient was treated initially with intravenous dexamethasone and later with IVIg. However, no information was provided as to the course of her neuro-ophthalmic manifestations.
The presence of lid retraction in our patient is a unique finding not previously reported in similar cases and would seem to be independent of the existence of proptosis. Its presence may be falsely attributed to a Graves orbitopathy or to orbitocavernous mass lesions. We propose that the lid retraction is due to chronic “remodeling” within lid tissues.
Although glucocorticosteroids, plasma exchange, IVIg, and immunosuppressive agents are treatment options for CIDP, they do not cause regression of onion bulb hypertrophy of nerves. However, inasmuch as our patient did have symptomatic improvement in her extraocular movements after IVIg infusions, perhaps the ophthalmoplegia is not entirely mechanical. There may be a component of the palsy related to immune-mediated segmental demyelination. Clinicians should be aware of these possibilities when examining patients with ophthalmoplegia, lid retraction, and proptosis.