Ординатура / Офтальмология / Английские материалы / Essentials in Ophthalmology Pediatric Ophthalmology Neuro-Ophthalmology Genetics_Lorenz, Borruat_2008

276Chronic Progressive External Ophthalmoplegia

deletions has been Southern blot analysis from muscle DNA (Fig. 15.8). However, low levels of multiple deletions cannot be detected by South­ ern blot analysis. Thus, more sensitive techniques such as long-range polymerase chain reaction (PCR) are necessary in order not to overlook pa­ tients (Deschauer et al. 2003). However, due to the highly polymorphic nature of the mtDNA there is also a risk of false-positive results (De­ schauer et al. 2004). Moreover it is important to know that low levels of mtDNA deletions are also observed in ageing. In general, deletions of mtDNA are detectable only in muscle and not in blood. However, with sensitive PCR techniques it is sometimes possible to detect single deletions in blood. In contrast to deletions, point mutation of the mtDNA, e.g., the 3243A>G mutation, can be detected in blood more easily. But levels of mu­ tant DNA are generally higher in muscle than in blood (Deschauer et al. 2000).

If multiple deletions of mtDNA are detected, a screening for the nuclear gene of intergenomic

15

Fig. 15.8.  Detection of deletions of mtDNA by South­ ern blot analysis: Lane 1, normal control; lane 2, single deletion of mtDNA; lane 3, multiple deletions of mt­ DNA

communication defects should be performed. However, there are many different mutations in these genes and only few laboratories are per­ forming diagnostic sequencing of the nuclear genes at the moment (e.g., Medizinisch Gene­ tisches Zentrum Munich, Germany; Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne, UK; HUSLAB, Laboratory of Molecular Genetics, Helsinki, Finland; Medi­ cal Genetics Laboratories, Huston, Texas, USA). If there is recessive inheritance of CPEO, there are two frequent POLG1 mutations that should be tested first (A467T and W748S) (Horvath et al. 2006).

Summary for the Clinician

■Diagnosis of CPEO requires a close collaboration between ophthalmologist, neurologist, and laboratory investiga­ tors.

■Laboratory testing should include mea­ surement of lactate not only at rest but also during mild bicycle exercise.

■Usually a limb muscle biopsy is necessary for confirming the diagnosis of CPEO, showing histological and biochemical mitochondrial abnormalities.

■Molecular genetic analysis is not only important for genetic counseling; in­ creasingly molecular genetic testing from blood can confirm a diagnosis thus avoiding muscle biopsy.

15.5 Treatment

15.5.1 Pharmacological Therapy

In general supplementation with vitamins and co­ factors has been shown not to be effective (Baker and Tarnopolsky 2003). However, in patients with proven coenzyme Q deficiency, supplemen­ tation with coenzyme Q can result in remarkable improvement as shown in a patient with Ke­ arns-Sayre syndrome (KSS): cachexia, ataxia and tremor disappeared but ophthalmoplegia and retinopathy were unchanged after 2 years of treat­ ment (Zierz et al. 1989). Coenzyme Q supple­

mentation might also be helpful in patients with normal coenzyme Q levels due to its anti-oxida­ tive effect, since defects of the respiratory chain can result in an increased production of reactive oxygen species. In patients with KSS reduced levels of folinic acid were measured in cerebro­ spinal fluid and there is a report of a remarkable improvement after high-dose supplementation with folinic acid in a child with KSS (Pineda et al. 2006). Allogeneic stem cell transplantation was used in two patients with MNGIE syndrome to restore TP activity and to reduce the thymidine level. One patient improved and the other patient died of disease progression and sepsis 3 months after transplantation (Hirano et al. 2006).

15.5.2 Symptomatic Treatment

Ptosis cannot only impair vision but it can also be a cosmetic problem and the subject of embarrass­ ment for younger patients. However, surgery for ptosis should be recommended only if the visual axis is obscured since there is a risk of complica­ tions due to corneal exposure in cases of post­ operative lagophthalmos. The preferred surgical technique is frontalis muscle suspension, avoid­ ing levator palpebrae muscle resection, because this ensures better protection of the cornea. Lid height can be adjusted if necessary (Bau and Zi­ erz 2005; Wong et al. 2002).

Generally, corneal exposure symptoms are treated with lubricants. Some patients with pto­ sis get on well with “eyelid crutches” mounted on their glasses. Fresnel prisms can be helpful if there is diplopia, especially in patients with poor convergence. However, it is often difficult or im­ possible to suppress diplopia with prisms in the presence of incomitant strabismus. When specta­ cles are prescribed, the motility deficits should be taken into account (e.g., no bifocals in impaired downgaze) (Bau and Zierz 2005).

Extraocular muscle surgery in cases of strabis­ mus with diplopia is recommended only in care­ fully selected patients. Because of the progressive nature of the disease, the benefit might be only temporary. Deviation should be stable for sev­ eral months before operation. Resection as well as recession can be used depending on results of forced ductions at the time of surgery (Wallace et al. 1997).

15.5  Treatment 277

Heart conduction blocks should be checked at frequent intervals because timely placement of a pacemaker can be lifesaving (Nitsch et al. 1990). Endurance training to reduce exercise intolerance is safe and efficient (Jeppensen et al. 2006; Taivas­ salo et al. 2006). In treatment of seizures valproic acid should be avoided since it can trigger hepatic failure in patients with POLG1 defects (Horvath et al. 2006). Amplification aids can help against hearing loss. If necessary, cochlear implants can be safely and successfully installed (Sinnathuray et al. 2003). In patients with dysphagia due to incomplete opening of the upper esophageal sphincter (cricopharyngeal achalasia) myotomy can help (Kornblum et al. 2001). Diabetes mel­ litus should be treated in the standard way. How­ ever, metformin should be avoided because this drug can cause lactic acidosis (Walker et al. 2005). During surgery and anesthesia patients with mi­ tochondrial disorders need special care because certain drugs can inhibit the respiratory chain in vitro (e.g., propofol and midazolam) and malig­ nant hyperthermia has been reported in single cases, thus trigger agents (e.g., succinylcholine and inhalation anesthetics) should be avoided if possible (Shipton and Prosser 2004).

15.5.3 Gene Therapy

Due to the complex genetics of mitochondrial disorders different strategies toward gene therapy are under current development, albeit at an early stage. One promising strategy is to reduce the ra­ tio of mutant to wild-type mitochondrial genomes (“gene shifting”) due to inhibition of the replica­ tion of mutant genomes. Based on the observa­ tion that satellite cells of the muscle contain lower levels of mutant mtDNA compared to mature muscle fibres, two studies have been performed. Bupivacaine was injected in the levator palpebrae muscles of patients with CPEO to induce muscle necrosis, which activates satellite cells. However, no improvement of ptosis was observed (Andrews et al. 1999). Also high-intensity exercise stimu­ lates satellite cells and was shown to be effective in a single patient (Taivassalo et al. 1999).

Maternal transmission of mtDNA point muta­ tions can be prevented by nuclear transplantation. After in vitro fertilization of an oocyte carrying a mtDNA mutation the pronucleus is transferred

278

15

Chronic Progressive External Ophthalmoplegia

into an enucleated normal donor oocyte. The re­ sulting embryo has the nuclear genomes of the parents but mainly the mitochondrial genome of the donor women, thus showing only very low levels of heteroplasmy well below the threshold. This approach was successful in mice (Sato et al. 2005) and has been approved for human experi­ ments in the UK (Brown et al. 2006).

Summary for the Clinician

■In general, only symptomatic treatment is presently available. Correction of the gene defects is not yet possible.

■Supplementation with vitamins and cofactors is rarely effective. However, patients with proven coenzyme Q defi­ ciency may improve from supplementa­ tion with coenzyme Q and patients with Kearns-Sayre syndrome can improve with folinic acid supplementation.

■Lid surgery should preferably be fronta­ lis suspension and not levator palpebrae resection because this ensures better protection of the cornea.

■Because of the progressive nature of the disease, strabismus surgery is recom­ mended only in carefully selected pa­ tients with diplopia. Prisms can be also helpful.

■Timely placement of a pacemaker can be lifesaving.

■Endurance training can reduce exercise intolerance.

15.6 Differential Diagnosis

15.6.1Oculopharygeal Muscular Dystrophy

Another inherited myopathy (with autosomaldominant trait) leading to external ophthalmo­ plegia is oculopharyngeal muscular dystrophy (OPMD). These patients also present with severe ptosis but ocular motility is usually less severely impaired than in CPEO. Moreover, in contrast to CPEO, age of onset is typically after the age

of 40 and nasal speech and dysphagia are more frequent than in CPEO. Similarly to CPEO, many patients with OPMD also show proximal limb weakness. Distal muscle weakness was also observed in a few families, defining a distinct disease called oculopharyngodistal myopathy (Satayoshi and Kinoshita 1977). Genetically, OPMD is due to an elongation in the PABPN1 gene within a repeat region showing additional GCG or GCA triplets. This elongation can be easily detected by PCR in patients with OPMD (Müller et al. 2006).

15.6.2 Myasthenic Syndromes

Myasthenic syndromes are disorders due to de­ fective neuromuscular transmission due to either autoimmune processes (myasthenia gravis and Lambert-Eaton syndrome) or hereditary defects of the synaptic system (congenital myasthenic syndromes). Myasthenic syndromes are frequent and are an important differential diagnosis that should not be overlooked because they are treat­ able. Ptosis and restricted eye movements may be the predominant feature or even the sole feature (ocular myasthenia). Typically, ptosis fluctu­ ates and double vision is frequent in contrast to CPEO. Similarly to CPEO, patients suffer from exercise intolerance.

Myasthenia gravis is frequently due to autoan­ tibodies against the acetylcholine receptor. A few years ago it was shown that the so-called sero­ negative myasthenia without antibodies against acetylcholine receptors is caused by antibod­ ies against the muscle specific tyrosine kinase (MuSK) in half of the cases (Hoch et al. 2001). Similar to acetylcholine-receptor-positive my­ asthenia gravis, MuSK-positive myasthenia gra­ vis can occur as ocular myasthenia with weak­ ness sparing muscles of the limbs (Hanisch et al. 2006b). MuSK antibody testing is now available in many laboratories.

Lambert-Eaton syndrome is a paraneoplastic myasthenic syndrome due to antibodies against voltage-gated calcium channels. Congenital myasthenic syndromes, which can also become manifest in later life, are due to mutations in at least ten different genes that play a role in neuro­ muscular transmission (Müller et al. 2007).

15.6.3Congenital Fibrosis

of the Extraocular Muscles

Another rare inherited disorder leading to weak­ ness of the extraocular muscles is congenital fibrosis of the extra ocular muscles (CFEOM), which is not a myopathy, but results from a dys­ innervation of the extraocular muscles leading to a secondary fibrosis. There are different forms of CFEOM associated with various gene defects that have autosomal dominant or autosomal recessive inheritance. In contrast to CPEO the disease is usually present at birth and is non-progressive in general. Progression was only rarely observed (Hanisch et al. 2005).

15.6.4 Ocular Myositis

External ophthalmoplegia can also be caused by ocular myositis. Inflammation is due to an autoimmune disorder or results from infection, e.g., herpes zoster (Krasnianski et al. 2004). In contrast to CPEO typically the onset is acute and there is associated pain. Enlargement of the muscles can be seen with a high-resolution CT or more precisely with MRI.

15.6.5 Endocrine Ophthalmopathy

Endocrine ophthalmopathy can present with external ophthalmoplegia. However, typically there is no ptosis but proptosis and widening of the palpebral fissure. Muscle enlargement can be observed by CT or MRI, similar to ocular myo­ sitis.

References 279

15.6.7Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disorder with weakness predominantly of the facial and shoul­ der girdle muscles, rarely associated with exter­ nal ophthalmoplegia (Krasnianski et al. 2003).

15.6.8 Congenital Myopathies

This group of myopathies is defined by distinc­ tive and characteristic structural abnormalities in skeletal muscle (e.g., central nuclei, nemaline rods, multicores, and tubular aggregates). Al­ though onset is often at birth, there are also lateonset forms with no or only mild progression of limb weakness. Rarely, the limb girdle myopathy is associated with ophthalmoplegia (Beyenburg and Zierz 1993; Jones and North 1997). In con­ trast to mitochondrial CPEO the external oph­ thalmoplegia in these diseases is usually not the prominent manifestation.

Summary for the Clinician

■The two most important differential di­ agnoses of CPEO are oculopharyngeal muscular dystrophy (OPMD) and myas­ thenia.

■OPMD can be easily identified by mo­ lecular genetic testing.

■Myasthenia should not be overlooked because it is treatable.

15.6.6 Myotonic Dystrophy

Myotonic dystrophy is an autosomal dominant repeat disorder with predominant weakness of the distal limb muscles in type 1 and proximal mus­ cles in type 2. Both forms show myotonia that is characterized by slowing of relaxation of muscle contraction. Ptosis is typically observed in many patients with type 1, rarely also with ophthalmo­ plegia (Yamashita et al. 2004), but not in patients with type 2. Cataract is frequent in both types.

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284 Treatment of Specific Types of Nystagmus

Core Messages

■The most common etiologies of acquired pendular nystagmus (APN) are lesions due to multiple sclerosis or infarctions at different sites of the brainstem (inferior olive, medial vestibular nucleus, red nucleus in the rostral midbrain). It has been hypothesized that APN may arise from instability of the neural integrator for eye movements. Patients receiving APN treatment should start with memantine or gabapentin as an alternative. If side-effects occur at higher dosages, a combination of both drugs can be useful.

16.1 Introduction

The ocular motor system holds images stable on the fovea. A direct result of the inability to maintain stable foveal vision is acquired or congenital nystagmus. It causes decreased visual acuity, blurred vision, and the illusion that the observed world is moving (i.e., oscillopsia). Abnormal eye movements may also interfere with spatial localization and the ability to perform accurate limb movements. For these functions the vestibular system and the vestibulo-ocular reflex (VOR)

16 play an important role. The VOR connects the peripheral vestibular end-organs, the semicircular canals, with their appropriate pair of eye muscles by a three-neuronal arc (Fig. 16.1) [9]. This three-neuronal reflex arc makes compensatory eye movements possible during rapid head and body movements.

Some acquired nystagmus syndromes have a peripheral or central vestibular origin and are caused by lesions along the neuronal pathways that mediate the VOR. These pathways travel from the peripheral labyrinth over the vestibular nuclei in the medullary brainstem to the ocular motor nuclei (III, IV, VI) and the supranuclear integration centers in the pons and midbrain (interstitial nucleus of Cajal, INC; and rostral interstitial nuclei of the medial longitudinal fasciculus, riMLF). Another branch runs over the posterolateral thalamus up to the multisensory

vestibular areas in the temporoparietal cortex, such as the parietoinsular vestibular cortex ( ), retroinsular areas, areas in the superior temporal gyrus, the inferior parietal lobe, and the precuneus as well as the anterior cingulum. These cortical areas mediate the perception of head/ body position and motion in space. Descending pathways travel from the vestibular nuclei along the medial and lateral vestibulospinal tract into the spinal cord bilaterally to mediate postural control. In addition, there are also pathways to the vestibulo-cerebellum and the hippocampus. Thus, disorders of the VOR are characterized not only by ocular motor deficits, but also by disorders of perception due to impaired vestibulocortical projections of the VOR and by disorders of postural control due to impaired vestibulospinal projections of the VOR.

For the clinician it is often useful for a topographical diagnosis to identify the specific abnormalities of eye movements, since lesion site and etiology may influence the therapy. Although a lot is known about the anatomy, physiology, and pharmacology of the ocular motor and vestibular systems, treatment options for certain specific ocular motor syndromes remain limited. Treatments based on pharmacologic mechanisms are in general preferred. However, since most drug treatments are based only on case reports and a few controlled treatment trials with a small number of patients, all treatment recommendations have to be classified as class C [52].

16.2Peripheral Vestibular

and Ocular Motor Disorders

16.2.1Acute Peripheral Vestibulopathy, Vestibular Neuritis

An acute episode of severe rotational vertigo is usually accompanied by horizontal-rotatory spontaneous nystagmus toward the affected side, a tendency to fall to the normal side, and severe nausea and vomiting. It gradually resolves over days to weeks. The cause is an acute peripheral vestibulopathy, the second most common cause of vertigo after benign paroxysmal positional vertigo [9]. Its etiology may be bacterial labyrin-