What’s Causing This Strange Constellation of Symptoms in an Older Woman?

What has caused this 75-year-old woman to develop ptosis in her left eye, a 3-day headache, jaw pain, and recent weight loss? That’s the diagnostic challenge facing Jeannette Stallworth, MD, of the University of California San Francisco, and colleagues, as they reported the case in JAMA Neurology.

The patient presented with horizontal binocular diplopia, right-sided ptosis, and a headache that she noted had been worsening since it started 3 days earlier. She also told clinicians that she found it difficult to open her mouth, chewing was painful, and she had recently lost about 2.3 kg (about 5.1 lb).

A week before, her left eyelid had become droopy; that lasted for 2 days, but then resolved. Her vision was otherwise normal, her eyes were not painful, and she had no scalp tenderness or muscle pain. The patient’s past medical history included schizophrenia, hypothyroidism, and supraventricular tachycardia.

Physical examination showed both eyes to have normal visual acuity. Her pupils were of equal size, round, and reacted normally to light. The ptosis affected her right upper eyelid, and tests of extraocular motility showed bilateral limitations in elevation and abduction.

Results of a dilated fundus examination were normal, as was the rest of her neurologic assessment. Fatiguability, rest, or an ice-pack test had no effect on the patient’s ability to move her eye or on the ptosis.

Lab tests showed elevated levels of both C-reactive protein and erythrocyte sedimentation rate — 292 mg/L (normal <10 mg/L) and 93 mm/h (normal <30 mm/h), respectively. Clinicians performed a lumbar puncture which indicated normal opening pressure, cell count, and glucose and protein levels.

Brain MRI with contrast showed diffuse edema and enhancement of the scalp, skull base, neck, and paraspinal soft tissues, and the extraocular muscles of both eyes demonstrated T2 hyperintensity and enhancement.

Diagnostic Considerations

Stallworth and co-authors considered several possible diagnoses, including anti–transfer RNA synthetase myositis, immunoglobulin G4–related disease, myasthenia gravis, and giant cell arteritis (GCA).

First, given that the inflammation and loss of muscle tissue usually associated with aminoacyl transfer RNA synthetase does not usually affect the facial and extraocular muscles, and that the patient had no evidence of interstitial lung disease, nonerosive arthritis, or Raynaud phenomenon, all typically associated with antisynthetase syndrome, the team considered that diagnosis unlikely.

Another possibility: while enlarged extraocular muscles may reduce ocular motility in immunoglobulin(Ig) G4–related disease, the patient had no signs of hypertrophic pachymeningitis and sclerosing lesions of the abdomen and lungs that are usually associated with IgG4 disease, and thus that possible diagnosis was ruled out.

Similarly, myasthenia gravis was dismissed based on the fact that the patient was not suffering from fatigue, and that results of the ice-pack test were normal, and the MRI had shown soft tissue changes.

A final investigation helped clinicians arrive at a diagnosis: They performed a biopsy of the patient’s temporal artery, which identified intimal hyperplasia and transmural inflammation with giant cells, signs that pointed to GCA. Although large and medium-sized arteries are classically involved in GCA, recent definitions suggest that vessels of any size may be affected, the authors noted.

Discussion

Patients with ocular manifestations of GCA generally present with acute vision loss, which in 80% of cases is caused by arteritic anterior ischemic optic neuropathy related to ischemia of the posterior ciliary arteries, Stallworth and co-authors wrote.

Data indicate that about 50% of patients with GCA have visual symptoms over the course of their disease, and 14-20% have permanent vision loss, although notably, that can be prevented with early diagnosis and treatment.

Of GCA symptoms, those commonly reported as initial and overall signs include headache (a presenting symptom in 33% of patients and in 72% overall), concomitant polymyalgia rheumatica including pain in the neck, torso, shoulder, and pelvic girdle (early symptoms in 25% of patients and present in 58% overall), fatigue and malaise (20% and 56%), jaw claudication (4% and 40%), and fever (11% and 35%).

Diplopia is reported by 5-15% of patients with GCA, but only a small proportion of those present with demonstrable oculomotor impairments — “suggesting that ophthalmoplegia may be transient and underreported,” Stallworth and co-authors said.

They explained that two pathophysiologic mechanisms for ophthalmoplegia in GCA have been proposed: arteritic involvement of the vasa nervorum of the ocular motor nerves, and arteritis of the vascular supply of the extraocular muscles.

GCA-related loss of ocular motility does not tend to reflect the pattern of a cranial nerve, the case authors added. Regarding arteritis affecting the blood supply to the extraocular muscles, “despite the rich anastomotic vasculature from both the ophthalmic artery and branches of the external carotid artery, ischemia of the extraocular muscles has been observed,” the authors wrote.

They pointed to a case of GCA with severe ophthalmoparesis, in which histopathologic assessment of the entire ocular motor apparatus identified inadequate blood supply to the extraocular muscles with preservation of cranial nerves 3, 4, and 6 along the entire course from the nerve nuclei to the orbits.

Ophthalmoplegia-related ptosis in GCA may be caused by similar mechanisms, the team suggested. “Ptosis has also been reported in relation to Horner syndrome secondary to vasculitis affecting the vasa nervorum supplying the sympathetic plexus or direct granulomatous involvement of the sympathetic nerve fibers as they run alongside the inflamed vessel wall of the cavernous internal carotid artery.”

The ocular motility deficits and ptosis observed in this patient did not follow the pattern of the ocular motor nerves and there were no other signs of Horner syndrome, Stallworth and co-authors noted. Examination did not identify any ataxia or hemiparesis, and a brainstem infarct was ruled out by MRI findings.

The patient’s presentation was most suggestive of vasculitis that resulted in loss of blood flow to the periorbital muscles, and prompt treatment with high-dose intravenous steroids led to symptomatic improvement within hours, the authors said.

“This case demonstrates the multifaceted presentation of GCA and the importance of maintaining a high suspicion in patients with elevated inflammatory markers, headache, and uncommon neuro-ophthalmic symptoms,” the team concluded.

They added that in patients with abnormal eye alignment or difficult-to-control eye movements that don’t suggest a typical ocular motor nerve palsy, ischemic myopathy should be considered, and corticosteroids should be started immediately to prevent loss of vision and complications from GCA.