Ophthalmoplegia

 

Thyroid myopathies: Several thyroid associated myopathies exist: 1) chronic thyrotoxic myopathy, 2) infiltrative ophthalmoplegia (Graves ophthalmoplegia), 3) myasthenia gravis associated with hypothyroidism or diffuse toxic goiter, 4) periodic paralysis associated with toxic goiter, and 5) muscle hypertrophy and slow contraction/relaxation associated with myxedema.

Graves ophthalmoplegia is often characterized by proptosis, most commonly weakness of inferior  and medial recti muscles, lid retraction, and orbital pain. The ophthalmoplegia starts unilateral. Pupillary and ciliary muscles are spared. There two phases, the inflammatory and fibrotic phase. Since we are dealing with an autoimmune disorder, associated ocular myasthenia gravis, SLE and pernicious anemia can be found. Antithyroperoxidase and antithyroglobulin antibodies are often found. MRI with fat suppression T1-weighted images of the orbit and orbital apex shows swollen muscles. The lack of sensory abnormalities in the trigeminal V1 and V2 dermatoma distinguishes the condition from a cavernous sinus syndrome.

 

Cavernous sinus syndrome: This syndrome is characterized by pain associated with ophthalmoplegia with sensory loss in first and/or second trigeminal dermatoma. In the posterior portion of the sinus in addition to the ocular nerves the ophthalmic and maxillary branches are affected, while in the anterior part (giving way to superior orbital fissure), only the ocular nerves and the ophthalmic branches of the trigeminal nerve is affected.

 

Retrocavernous compressive lesions: These include infraclinoid aneurysms and tumors (often meningioma).

 

Myasthenia gravis (MG): The prevalence of MG in the general population is around 0.1. MG is a heterogeneous autoimmune disorder with regard to age of onset of disease, serum titers of anti-AchR antibodies, and severity of clinical symptoms. The disease predominates in women (affected twice as much as men) and most commonly peaks in the 2nd - 3rd decades, while the peak age in man occurs at later age 5th - 6th decade. In 5% of patients, MG is associated with other autoimmune diseases such as autoimmune thyroiditis, RA, SLE and pernicious anemia. In a large majority of patients (80‑90%) suffering from MG, these autoantibodies are found in the serum. MG is a monophasic illness, which begins relatively acutely in most patients (often following surgery, trauma, infection or pregnancy). The hallmark of MG is fluctuating weakness and muscle fatigability, particularly of ocular muscles (initially 40% and eventually 85%). Bulbar symptoms (dysphagia or dysarthria), leg weakness and generalized weakness with fatigue and muscle pain (low back pain) are found each in about 10% of patients. The pure ocular form of MG is observed in 15‑20% of patients. About 10-15% of MG patients have a thymoma. Two tests are of immediate diagnostic help in MG: the most direct confirmatory study is the edrophonium (Tensilon) test (sensitivity 80‑90%) and the repetitive supramaximal nerve stimulation (3 Hz) of the median nerve, which reveals a decremental response of the CMAP amplitude: in about 50% of MG patients a decrement (>10% decrease in CMAP amplitude of the 5th potential vs. 1st potential) to repetitive nerve stimulation is found. However in patients with pure ocular or mild generalized weakness the test is less likely to be positive. With regards to the edrophonium test, one or preferably two reliable endpoints (ptosis, dysconjugate gaze,...) must be taken as reference. Anti-AchR antibodies are found in 70-85% of all patients with generalized MG and around 50% of patients with the ocular form. The levels of the anti-AchR antibodies do not predict the severity or clinical course of the patient. Anti-AchR antibodies are almost invariable found in patients with both MG and associated thymoma. Patients with thymoma-associated MG, late age at disease onset (mean 65 years) and with intermediate titers of anti-AchR antibodies have high prevalence (55%) of anti-titin antibodies and anti-muscle-specific tyrosine kinase. Ryanodine receptor and anti-titin antibodies present in 70% and 95% of thymoma and 14% and 58% of late onset MG, respectively. The long‑term natural course of MG is highly variable. Generalization usually develops within the first year of the disease while spontaneous long-lasting remission occurs in 10‑15% of cases, usually in the first two years of the disease. Thymectomy is generally recommended for thymoma, moderate to severe MG inadequately controlled with pyridostigmine, and those patients <55 years. An estimated 75% of MG patients will benefit from thymectomy, and the intervention appears to be most efficient the first two years of the disease. Thymectomy is classically a long-term therapy and its effect may not be apparent until after 1 year. Thymectomy appears to increase the likelihood of long-term remission and possibly reduces the long-term exposure to immunosuppressive drugs. 80% of patients will respond favorable response to steroids. Corticosteroids (1mg/kg/d in 3 divided doses e.g. 20 mg tid or 120 mg alternate days) are used in patients with moderate to severe disabling symptoms that are refractory to pyridostigmine and require hospitalization due to risk of early exacerbation (first few days of therapy and lasting about 3-4 days or 2 weeks). However transient initial severe exacerbation (10% of patients) requiring mechanical ventilation or tube feeding may occur after 1 - 3 weeks. Maximum dose should be maintained until complete remission is accomplished (about 3 months), than tapering (5-10%/month) can begin. Steroid sparing can be envisaged with azathioprine (initially 1 mg/kg/day to a maintenance dose of 2-3 mg/kg/day). Short-term effects (1-2 months) are achieved with plasmapheresis and IVIg. Improvement starts within a few days after the onset of the treatment and is meaningful after 14 days, persisting at 1 month. Mostly patients with severe disease benefit from IVIg. In patients with Osserman classification grade > 2 plasmapheresis (5 sessions on alternate day basis over 1 week, each session removing 2.5-4 L of plasma to be replaced by 5% albumin in saline (ml/ml) including 1 L of fresh frozen plasma pre-thymectomy)) is indicated pre-thymectomy. Parameters such as fibrinogen, coagulation factors, calcemia should be monitored. Anticholinergic therapy should be continued tilt the morning of the intervention (1 mg iv or im neostigmine = 30 mg pyridostigmine po, e.g 1 mg iv q4h). Prednisolone 20 mg w or w/o cyclophosphamide 50 mg can be added if required pre-thymectomy. The post-operative dose of pyridostigmine is generally 25-50% of the pre-operative dose.  In acute cases, monitoring should be done by respiratory rate, pulse oximetry, FVC (intubation if FVC<15 ml/kg), arterial blood gases every 2 hours. Cranial neuropathies (diabetes and botulism, mitochondrial disorders, hypothyroidism, myopathies or MND), Wernicke encephalopathy, MFS, ALS, SMA, LEMS and drug-induced MG need to be excluded in the differential diagnosis. Congenital MG should always be considered in patients with seronegative MG, as in those cases there is a high prevalence of autoimmune conditions like thyroid disease, polymyositis, SLE, RA and pernicious anemia.

 

Internuclear ophthalmoplegia

 

Infranuclear vs. supranuclear nerve palsies:

 

Oculomotor palsy: pupil-sparing (medical III) - lesions are nuclear, fascicular, radicular (subarachnoidal space and tentorial edge), nerve (cavernous sinus and superior orbital fissure) lesions vs. non pupil-sparing (surgical III).