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Diagnosis Deconstructed

Diagnosis Deconstructed: Walking along a Dual Diagnosis

Morchi, Ravi MD

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doi: 10.1097/01.EEM.0000451954.22260.aa
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    A middle-aged man presents with double vision that he has had for three months. Symptoms have been slowly progressing, but he never sought medical attention before.

    He has no past medical history, his vital signs are normal, and he is in good health with cognition intact and no mood disturbance. His pupils are anisocoric but reactive; visual acuity is normal. He cannot abduct either eye, and the contralateral eye will only adduct minimally. Upward and downward gaze are similarly limited. Mild bilateral ptosis, no exophthalmos.

    The rest of him is fully functional: facial expression and sensation muscles, hearing, balance, swallowing, posterior palate phonation, tongue movement, head rotation, and shoulder shrug. No pronator drift, toes are down-going. Gait, motor strength, and reflexes are all normal. A noncontrast head CT is negative.

    Is this a dense deficit to CN VI and III bilaterally? If so, it's quite disproportionate to any of the other CNs. Shall we jump to tempting diagnoses like myasthenia gravis, Miller-Fischer variant of GBS, orbital tumor or pseudotumor, cavernous sinus thrombosis? No. Most problems can be deciphered along an anatomic template. Today the walk begins at the brainstem.

    Cranial nuclei. If he had III and VI cranial nuclei out bilaterally, I would expect other tract signs. CN VII nerve fibers run close to VI, yet he has normal facial expression. Just a few centimeters separate the III and VI nuclei, and there lie longer tracts: spinothalamic fibers carrying sensation and corticospinal and corticobulbar axons controlling motor function of the lower face, arms, and legs. Cranial nuclei will not be our answer with none of the accompanying tracts involved.

    Medial longitudinal fasciculus. Patients with loss of communicating fibers between III and VI can abduct one eye but not the other on lateral gaze. Convergence should be preserved, demonstrating that bilateral III nuclei can be activated directly from cortical centers without input of the MLF. He cannot converge, and he cannot abduct. Neither a sole MLF lesion nor the condition one-and-a-half syndrome can be the answer.

    Meninges. Move anteriorly, and watch the III and VI nerves pierce through meninges. Meningeal infiltrates pooling inferiorly along the reflection of the skull base can inflame cranial nerves. But this is haphazard, less dense, and less symmetric than what we see today.

    Compression. VI nerves may be pinched against the sphenoid bone from elevated ICP above, but compression of CN III generally affects fibers bound for the pupil before devitalizing fibers heading for the extraocular muscles. We expect dilated pupils before paresis of motion in PCOM aneurysms or herniation of an ipsilateral temporal lobe. Keep walking.

    Thrombosis and phlebitis within the cavernous sinus can engulf cranial nerves millimeters away, but no proptosis or conjunctival injection from impaired venous drainage. Let's go on.

    CN III and VI slide through the superior orbital fissure before entering the bony confines of the orbit. Pathology around this fissure has occasionally ensnared passerby cranial nerves. Tolosa-Hunt syndrome is an acute granulomatous inflammation but is usually unilateral. Progressing over months, without trauma, the pathology we seek could be neoplastic. Skull base metastases entangling III and VI? This should remain on the differential.

    Nerves can be inflamed or compressed by orbital cellulitis, abscess, tumor, or pseudotumor. Gather all of these entities under the premise that the more clutter there is in the cramped space between orbital walls, the less likely cranial nerves will work. The problem for our man is that he has no deficits to V1. We expect a feeble nerve also running in the orbit to be devoured by the same process that took III and VI, but sensation is intact.

    Stop. Consider a defect in nerves themselves. Myelinopathy: disruption of myelin, acute or chronic. Axonopathy: immune-, inflammatory-, or toxin-mediated conditions where the axon has degenerated, but myelin is intact. Neurovasculopathy: the most familiar to us is vasonervorum insufficiency of diabetic microvasculopaths producing a single cranial nerve deficit. But can it produce multiple deficits? Whatever the component of the nerve targeted and whatever the mechanism, inherent neuropathies should stay on our list.

    NMJ. We come to the terminal branches of each nerve interfacing with muscle. Myasthenia is here. Our patient has no fatigue or daily fluctuations in strength. The presence of normal sensation fits the diagnosis, but the density of CN III and VI motor deficits without any other pharyngeal or neck muscle deficit is odd. If and when myasthenia presents with near paralysis of eye motion, we expect other NMJ units of the pharynx and neck to be involved.

    A toxin-disrupting ACH release needs to be considered if this were an acute presentation. It is rapidly progressive, and sites other than III and VI are soon involved. Patients lose their ability to swallow, hold up their head, or breathe. ACH release rather than reception is involved, so deprived synaptic ganglia are also affected They are the vehicle by which autonomic changes can accompany somatic weakness. Dilated pupils, dry mouth, tachycardia, intestinal ileus, urinary retention may be present at some point in botulism.

    Muscle. Myopathies focused on the orbit do exist. But what about inflammation singling out extraocular muscles? Our first answer is here. Over-read of his head CT demonstrated enlarged medial rectus muscles bilaterally. He would transition into atrial fibrillation with rapid ventricle response. He was never febrile or diaphoretic. He had no proptosis or goiter, but his thyroid functions tests showed primary hyperfunction.

    Graves ophthalmopathy. Derived from antibodies directed against TSH receptors that cross-react with orbital connective tissue. Lymphocyte and fibroblast activity results in enlarged, dysfunctional, and eventually fibrosed extraocular muscles. No sensory findings or pupillary disturbance. Most patients, however, have some degree of proptosis or conjunctival injection or goiter. By all accounts, ours did not.

    Ptosis being uncharacteristic for thyroid ophthalmopathy, ACH receptor antibody testing was still performed, and returned strongly positive. The diagnosis now became dual: Graves ophthalmopathy associated with ocular myasthenia gravis. A literature search later demonstrated these two autoimmune conditions can coexist.

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