Progressive external bilateral ophthalmoplegia

In general, bilateral chronic ophthalmoplegia can be observed in processes at the supranuclear, nuclear (at the level of the brainstem), radicular, axonal (neural) and muscular levels. However, in practice, bilateral ophthalmoplegia most often indicates a muscular level of damage or (less often) a brainstem localization of damage. The intermediate level (neural), as a rule, is unilateral. Moreover, muscular damage is characterized by a chronically progressive course (myopathy). Bilateral damage to the oculomotor nerves at the nuclear level in the brainstem area is more often (but not exclusively) observed in acute processes leading to a comatose state.

There are detailed classifications of bilateral progressive external ophthalmoplegia (PEO) syndrome, built mainly on the genetic principle and not very convenient for a practicing physician. It is important to emphasize that most forms of isolated bilateral progressive ophthalmoplegia are caused by ocular myopathy of various genetic origins, that is, processes at the most peripheral muscle level. Bilateral ophthalmoplegia caused by damage at the neural or neuronal level (damage to the oculomotor nerves on both sides or their nuclei in the brainstem) is extremely rare and is observed in the picture of hereditary degenerative (less often - metabolic) disorders against the background of other massive neurological symptoms.

Main reasons:

1. Kearns-Sayre mitochondrial encephalomyopathy (ophthalmoplegia plus).
2. Oculopharyngeal muscular dystrophy with autosomal dominant or autosomal recessive inheritance.
3. Congenital myopathies: central core disease, nemaline, myotubular and others.
4. Congenital myasthenia gravis (myasthenia gravis).
5. PNO with hypogonadism.
6. PNO in neurological diseases:
   • abetalipoproteinemia,
   • spinocerebellar ataxia,
   • amyotrophic lateral sclerosis (rare),
   • sensorimotor neuropathy in paraproteinemia,
   • progressive supranuclear palsy, other neurological diseases.

The most clinically significant forms are those that begin in young and adulthood. Among them, mitochondrial forms and, especially, Kearns-Sayre disease are most common. The mitochondrial defect in this disease is not limited to muscle tissue, but extends to the central nervous system and internal organs.

Obligatory manifestations of Kearns-Sayre syndrome include:

1. external ophthalmoplegia;
2. pigmentary degeneration of the retina;
3. cardiac conduction disorders;
4. increased protein content in the cerebrospinal fluid.

The first symptoms usually appear in childhood or adolescence (rarely in adults) as slowly increasing ptosis; this is followed by symptoms of ophthalmoparesis with intact pupils. Ophthalmoparesis slowly progresses to ophthalmoplegia. Uniform involvement of all external eye muscles means that strabismus and diplopia are rarely observed. When attempting to look up, the head is thrown back and the frontal muscles contract (Hutchinson face). In addition to the extraocular muscles, the orbicularis oculi muscle is often involved, creating difficulties in both opening and closing the eyes, which may resemble myasthenia gravis or myotonic dystrophy. Other facial muscles, as well as the masseter, sternocleidomastoid, deltoid, or peroneal muscles, are variably involved in about 25% of cases. Cerebellar ataxia, spastic paraparesis, dementia, deafness and other symptoms (“ophthalmoplegia plus”) may be present.

The absence of myotonia, cataracts, and endocrine disorders distinguishes progressive external ophthalmoplegia from myotonic dystrophy (which the ptosis may resemble). More extensive forms of Kearns-Sayre syndrome may resemble the facio-scapulohumeral form of muscular dystrophy. A characteristic feature of Kearns-Sayre syndrome is that ptosis and oculomotor disorders precede involvement of other muscles.

Optional symptoms: damage to visceral organs (heart, liver, kidneys, endocrine glands - "oculocraniosomatic syndrome").

Oculopharyngeal muscular dystrophy with autosomal dominant inheritance, associated with chromosome 14, is characterized by late onset (usually after 45 years) and manifests itself mainly by slowly progressive bilateral ptosis and dysphagia. Thus, in addition to ptosis (ophthalmoplegia does not develop), dysphagia develops and the voice changes. Severe dysphagia sometimes leads to severe cachexia. In some families, weakness of the muscles of the shoulder and pelvic girdles joins in the late stages. "Oculopharyngodistal myopathy" has been described. The nuclei of the cranial nerves and the nerves themselves are histologically unchanged. The level of CPK is normal; EMG is changed only in the affected muscles.

Finally, families have been described in which progressive external ophthalmoplegia was transmitted from generation to generation together with symptoms of hypogonadism. Some other hereditary variants of progressive external ophthalmoplegia are also possible.

Progressive bilateral external ophthalmoplegia in neurological diseases has been described in several situations. Abetaliproteinemia (Bassen-Kornzweig disease) is an autosomal recessive disease characterized by an almost complete absence of beta-lipoprotein (and therefore, impaired absorption of fats and vitamin E) and manifested already in infants in the first year of life by steatorrhea (fatty stools), growth retardation, retinal degeneration (decreased vision and blindness), acanthocytosis and neurological symptoms indicating predominant damage to the cerebellum and peripheral nerves. Slowly progressive ophthalmoparesis may occur.

Ophthalmoplegia as a rare symptom has also been described in other neurological diseases, including hereditary spastic paraplegia, spinocerebellar degenerations (eg, Machado-Joseph disease), sensorimotor polyneuropathy (in paraproteinemia). Ophthalmoplegia is rare in progressive spinal amyotrophy and even rarer in amyotrophic lateral sclerosis.

Chronic bilateral ophthalmoplegia may be observed in brainstem glioma, chronic meningitis. Among the rare forms are ophthalmoplegia in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE - mitochondrial neurogastrointestinal encephalomyopathy) and mitochondrial encephalomyopathy with ophthalmoplegia, pseudoobstruction and polyneuropathy (MEROP - mitochondrial encephalomyopathy with ophthalmoplegia, pseudoobstruction and polineuropathy), subacute necrotizing encephalomyelopathy (Leigh disease), vitamin E deficiency.

Among other causes of PNO, progressive supranuclear palsy should be mentioned, which may eventually lead to complete ophthalmoplegia, but the latter is revealed against the background of extrapyramidal, pyramidal and sometimes mental (dementia) disorders.

Supranuclear ophthalmoplegia is also characteristic of Whiple's disease (weight loss, fever, anemia, steatorrhea, abdominal pain, arthralgia, lymphadenopathy, hyperpigmentation; in the neurological status, slowly progressive memory loss or dementia, hypersomnia, supranuclear ophthalmoplegia, ataxia, epileptic seizures, myoclonus, oculomasticatory myorhythmia).

Progressive external ophthalmoplegia can sometimes be observed in myasthenia gravis (congenital and juvenile), ophthalmopathy in thyrotoxicosis (thyrotoxic ophthalmopathy), in chronic inflammation in the orbit, and congenital myopathies.

If the pupils do not react to light with ophthalmoplegia, then it is more correct to call this syndrome not external, but complete (total) ophthalmoplegia. It is often acute, but we are not discussing acute total bilateral ophthalmoplegia in detail here. Its main causes are: pituitary apoplexy, botulism, midbrain hematoma, pretectal infarction, Wernicke's encephalopathy, Guillain-Barré syndrome, cavernous sinus syndrome with a tumor or inflammatory process in this localization, myasthenia.

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