Check Your Diagnosis — Patient 15

Albert Yen, M.D.

Diagnosis

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) involving Ocular Cranial Nerves

Clinical Summary

This patient presented with the gradual onset of progressive weakness that eventually involved all four extremities. The pattern of weakness suggested localization to the muscle, neuromuscular junction, peripheral nerve, nerve root, or anterior horn cell. Diplopia can result from disorders of the extraocular muscles, neuromuscular junction, or the cranial nerves involved in eye movements (III, IV, VI). The later development of bilateral leg numbness is most consistent with peripheral nerve involvement, but can also be seen in polyradiculopathy or spinal cord disease.

The neurologic exam confirmed symmetric weakness of all extremities, perhaps proximally more than distally. This pattern of weakness is usually more consistent with either a myopathy or a disorder of neuromuscular transmission. However, other neuropathies may begin proximally (Guillain-Barré syndrome, chronic inflammatory demyelinating neuropathy, diabetes). The exam also confirmed the presence of ocular motility dysfunction involving bilateral lateral recti and bilateral third nerves. Glove-stocking sensory loss suggested a peripheral neuropathy. The presence of hyporeflexia/areflexia increased the possibility of a polyneuropathy/polyradiculopathy, but could also be seen in myopathies and neuromuscular junction disorders.

The EMG/NCV and CSF analysis provided valuable information. The EMG/NCV confirmed the presence of a mainly motor demyelinating polyneuropathy. The absence of CSF pleocytosis also lowered the likelihood of an infectious or neoplastic etiology. However, the elevated CSF protein suggested an inflammatory condition, which was supported by an elevated CSF IgG synthesis and IgG index. The elevated CSF Q-albumin implied an impairment in the blood-brain barrier. The normal MRI of the brain made intrinsic brainstem pathology (such as ischemia or demyelination) less likely.

The key issue was whether or not the patient's diplopia was related in etiology to her progressive weakness. Conditions which can cause both extremity weakness and ophthalmoparesis include:

Myasthenia Gravis (MG)
  • The EMG revealed a polyneuropathy, not myopathy or neuromuscular junction deficit. The absence of a decremental response during repetitive nerve stimulation and the negative Tensilon test also did not support this diagnosis. Moreover, this would be a late age for the initial presentation of MG.
Diabetes
  • Although diabetes can cause almost any type of neuropathy, the most common pattern is a distal, symmetrical sensorimotor polyneuropathy that is primarily axonal in nature. Cranial nerve infarcts may lead to eye motility problems in diabetics, but this usually involves an acute, painful onset of ophthalmoparesis, and would be unlikely to involve four separate cranial nerves. In this patient, both the glucose tolerance test and the glycosylated hemoglobin level were normal, effectively ruling out diabetes.
Guillain-Barré Syndrome (GBS)
  • The Miller Fisher variant accounts for about 5 percent of GBS cases and is characterized by total external ophthalmoplegia, ataxia, and areflexia. Elevated anti-GQ1b ganglioside antibodies are consistently found. In this patient, the progressive extremity weakness for several months prior to the onset of diplopia is not consistent with GBS.
Thyroid Disease
  • Ophthalmoparesis in thyroid disease involves chronic lymph infiltration of extraocular muscles. This often evolves into stable extraocular muscle fibrosis and a restrictive myopathy. The commonly affected eye muscles are inferior rectus > medial rectus > superior rectus. It can occur in any thyroid state: euthyroid (8-20%), hypo- (2.4%), hyper- (75-90%) {Wiersinga 1988}. Euthyroid eye disease was a consideration in this patient; however, a euthyroid state would not account for the presence of a polyneuropathy.
Oculopharyngeal Dystrophy
  • This condition causes eye muscle weakness and mild ptosis early, but eventually results in marked dysphagia (not seen in this patient). Facial, hip, and shoulder weakness occur in the late stages. This condition is usually inherited in an autosomal dominant fashion with almost complete penetrance (negative family history in this patient).
Mitochondrial Cytopathy
  • The Kearns-Sayre Syndrome (KSS) is a progressive multisystem disorder which has childhood onset, progressive external ophthalmoplegia, cardiac conduction block, retinal degeneration, and dementia. The weakness of mitochondrial cytopathies is secondary to myopathy (ragged red fibers), not neuropathy.
Intrinsic Brainstem Disease
  • Brainstem ischemia, neoplasm, and demyelination are all essentially ruled out by a normal brain MRI with contrast.
Toxins (Botulism, Organophosphates)
  • Unlikely to cause chronic weakness and would not cause neuropathy.
CIDP with Rare Involvement of Ocular Cranial Nerves
  • The diagnosis of CIDP in this patient is supported by the clinical symptoms (progressive/relapsing muscle weakness present for more than 2 months, symmetrical proximal and distal extremity weakness, hyporeflexia) and laboratory findings (demyelinating polyneuropathy supported by EMG/NCV and nerve biopsy, CSF protein >45 mg/dl, CSF cell count <10/ul). Given the absence of any other identifiable condition, it was felt that the patient's eye motility problems were related to CIDP.

Clinical Course and Follow-up

She was treated with three cycles of plasmapheresis, followed by IV Cytoxan for three days. Cytoxan had to be discontinued secondary to the development of neutropenia. As alternative immunosuppressive therapy, she was given six monthly doses of intravenous IgG.

On follow-up (two months following discharge), she no longer had diplopia and felt her strength and eye movements had improved. Objectively, she demonstrated improvement in extremity strength as well as eye motility and was not diplopic during the examination.

Discussion

CIDP is an important clinical diagnosis because: (1) it represents about one third of all initially undiagnosed acquired neuropathies; and (2) most patients with CIDP will respond to immunosuppressive therapy, although relapses are common.

Clinical Features

Patients with CIDP usually present with progressive, step-wise or relapsing muscle weakness that is present for at least two months. The degree of weakness is variable. Sensory complaints usually consists of numbness and tingling; painful paresthesias are uncommon. The peak incidence is 40-60 years of age.

Neurologic exam usually reveals proximal muscle weakness, sometimes even more affected than distal musculature. Both upper and lower extremities are involved, although the legs are usually affected more severely. Neck flexor weakness distinguishes CIDP from most other neuropathies. Cranial nerves are usually spared, although facial muscles may be affected. Ophthalmoplegia in CIDP is rare and the prevalence ranges from 3 to 8 percent in several case series. Of note, the ophthalmoplegia may precede the systemic weakness by days to months. Deep tendon reflexes are absent or depressed. Sensory findings are typically mild and often include impaired touch and vibratory sensation, with less involvement of small-fiber sensation (pain and temperature).

Laboratory Findings

The major laboratory tests for CIDP are electrophysiologic studies, CSF examination, and nerve biopsy.

  • EMG is useful to differentiate other causes of muscle weakness, particularly anterior horn cell diseases, other forms of peripheral neuropathies, disorders of neuromuscular transmission, and primary muscle diseases. In typical CIDP, the nerve conduction studies confirm demyelination as the predominant process. These findings include: (a) a non-uniform reduction in nerve conduction velocities in two or more motor nerves in a range considered to be indicative of a demyelinating disorder; (b) the presence of conduction block or abnormal temporal dispersion in at least one motor nerve; (c) prolonged distal latencies in at least two nerves; (d) absent F waves or prolonged minimum F wave latencies in at least two motor nerves.
  • CSF Examination: Cytoalbuminologic dissociation (elevated CSF protein >45 in the absence of a high cell count <10) is characteristic of CIDP. CSF pleocytosis is rare except in HIV-associated CIDP. An elevated IgG index and IgG synthesis rate is consistent with the immune-related nature of CIDP. An elevated Q-albumin shows an impairment of the blood-brain barrier, which in CIDP is at the level of the inflamed nerve root sheaths within the thecal sac.
  • Nerve biopsy: Because nerve biopsy is usually restricted to sensory nerves (sural or superficial peroneal nerves), the findings of a cutaneous nerve biopsy may not fully represent the pathologic process in a predominantly motor disease. In the series reported by Barohn et al, nerve biopsy revealed demyelination in 48%, axonopathy in 21%, mixed demyelination/axonopathy in 13%, and normal in 18%. The nerve biopsy is mainly important in excluding other causes of neuropathy (e.g., amyloidosis, vasculitis, inherited, toxic, etc).

Pathogenesis

The immunopathogenesis of CIDP is not understood. Support for a cell-mediated component comes from the finding of mononuclear cell infiltration, both diffuse and perivascular, in spinal roots, spinal ganglia, and proximal nerve trunks of postmortem cases. Evidence for a humoral component comes from the observation of clinical response of patients with CIDP to plasma exchange.

Treatment

James Austin first documented the steroid responsiveness of CIDP in 1958. More recent randomized controlled studies have documented that prednisone and plasma exchange are both beneficial. Some advocate initiation of single, daily-dose prednisone until patients show significant improvement. The mean time for initial response is two months. After attaining maximum benefit (usually 6-12 months), prednisone is slowly tapered. Unfortunately, the tapering of prednisone may result in a relapse of CIDP. The addition of azathioprine offers no advantage over prednisone alone. The possible adverse effects of long-term steroid use must also be considered. The use of high-dose intravenous steroids has only recently been investigated.

Plasma exchange performed twice weekly for three weeks generally result in transient improvement in both progressive and recurrent cases. The optimal schedule for plasma exchanges has not been established.

Intravenous immune globulin (IVIG) has also been found to be beneficial. IVIG is usually given in divided doses over 4 or 5 consecutive days. Maintenance doses are often needed at variable intervals to maintain clinical response. Serious side effects of IVIG treatment are rare (fatal anaphylaxis in IgA-deficient patients; potential nephrotoxicity, especially in patients with pre-existing renal disease). The main recognized role for IVIG treatment in CIDP is for patients refractory to corticosteroids or for patients with steroid side effects or contraindications (e.g., diabetes).

For patients refractory to steroids, plasma exchange, and IVIG, alternative forms of immunosuppressive treatment can be considered. These agents include azathioprine, cyclophosphamide, and cyclosporine. However, there are no clear guidelines for their use in the treatment of CIDP.

A recent report suggests the possible benefit of interferon-alpha 2A in CIDP patients. The authors of that report postulate that interferon-alpha may modulate proinflammatory cytokines that have a role in immune-mediated demyelination.

Prognosis

Unlike the overall good prognosis in Guillain-Barré syndrome, CIDP is less likely to have spontaneous remissions and is often associated with prolonged neurological disability. Although 95% of patients will show initial improvement following immunosuppressive therapy, the relapse rate is high. In the series of Dyck et al, only 64% of 53 patients were improved or in remission and able to return to work, 8% were ambulatory but unable to work, 11% were bedridden or wheelchair bound, and 11% died of the disease. Six percent died from other diseases.

References

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  2. Barohn RJ, Kissel JT, Warmolts JR, Mendell JR. Chronic inflammatory demyelinating polyradiculoneuropathy. Arch Neurol. 1989;46:878-84.
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  8. Dyck PJ, OBrien P, Oviatt KF, Dinapoli RP, Daube JR, et al. Prednisone improves chronic inflammatory demyelinating polyradiculoneuropathy more than no treatment. Ann Neurol. 1982;11:136-41.
  9. Dyck PJ, OBrien P, Swanson C, Low P, Daube J. Combined azathioprine and prednisone in chronic inflammatory demyelinating polyneuropathy. Neurology. 1985;35:1173-6.
  10. Gorson KC, Allam G, Simovic D, Ropper AH. Improvement following interferon-alpha 2A in chronic inflammatory demyelinating polyneuropathy. Neurology. 1997;48:777-80.
  11. Ryo M, Saito T, Kuni N, et al. A case of chronic inflammatory demyelinating polyneuropathy with recurrent ophthalmoplegia, persistent conduction block, antibody activity against ganglioside GM-1. Rinsho Shinkeigaka-Clin. Neurol. 1994;34:702-6.
  12. Wiersinga W, et al. Temporal relationship between onset of Graves' ophthalmopathy and onset of thyroidal Graves' disease. J Endocrinol Invest. 1988;11:615.

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