Ocular myasthenia gravis - IOVS

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Ocular myasthenia gravis
                                                                Kermit E. Osserman

                              The symptoms, clinical classification, diagnosis and differential diagnosis, and treatment of
                              myasthenia gravis of the extraocular muscles.

                       M.    .yasthenia gravis is a disorder charac-
                       terized by fatigability and abnormally
                                                                                these muscles or evidence of any central
                                                                                nervous system lesion.1
                       rapid exhaustion, with loss of strength in                  Since mild myasthenia gravis often re-
                       muscles under voluntary control and a re-                mains undetected, and occasionally ful-
                       turn of strength, at least in part, after a              minating cases may die undiagnosed, esti-
                       period of rest or administration of anti-                mation of the true incidence of this disease
                       cholinesterase drugs.                                    is difficult. An educated guess would place
                          The term myasthenia gravis comes from                 the incidence in the United States at one
                       the Greek mys (muscle) plus asthenia                     in 20 to 30 thousand. Sex and age distribu-
                       (weakness), and from the Latin gravis                    tion of myasthenia has been remarkably
                       (heavy), and implies a marked or severe                  similar in major groups of patients ana-
                       muscle weakness. This weakness does not                  lyzed8; incidence in female to male subjects
                       necessarily have to be "gravis" to be                    is a 3:2 ratio. However, the greatest inci-
                       "myasthenia." Undoubtedly, because of the                dence in women is in the third decade in
                       mild character of the symptomatology in                  life whereas in men it is in the sixth or
                       some cases, many remain undiagnosed and                  seventh decade. Onset may be at any age
                       untreated.1                                              from birth to the ninth decade.
                          Pathophysiology of myasthenia gravis
                       has been demonstrated at the neuromus-                   Symptoms
                       cular junction, and whether this be pre-                    One of the commonest signs of myas-
                       synaptic or postsynaptic has not been                    thenia gravis is unilateral or bilateral ptosis.
                       settled at the present time, although evi-               Frequently ptosis shifts from one eye to
                       dence leans toward the former.- There is                 the other and when this is seen it is pathog-
                       a lack of correlation between prominent                  nomonic of this disease.1 Occasionally the
                       weakness and abnormal physiologic re-                    upper lid is so retracted that the eye is kept
                       sponses of certain involved voluntary mus-               extremely wide open and patient is unable
                       cles and any demonstrable pathology of                   to close the eye completely. This phe-
                                                                                nomenon is always unilateral, the other
                                                                                lid being ptosed. This is seen in treated
                                                                                cases. Although ptosis may be the only
                       From the Department of Medicine, Myasthenia              evident sign of myasthenia gravis, systemic
                         Gravis Clinic and Research Laboratory of The
                         Mount Sinai Hospital, New York, N. Y.
                                                                                examination may reveal unsuspected weak-
                       This work was supported by a grant from The
                                                                                ness or fatigability in muscles other than
                         Tillie Lewis Foundation.                               those obviously involved. In most patients
                                                                          277

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278 Osserman                                                             Investigative Ophthalmology
                                                                                                                  ]une 1967

                       ptosis is accompanied by diplopia and            Clinical classification
                       blurring of vision. These ocular signs and          Symptomatology at onset does not neces-
                       symptoms, especially ptosis, are made            sarily indicate eventual total involvement.
                       worse by bright light. In about 70 per cent      Classification of the individual patient
                       of patients, one or another of the eye symp-     should be dynamic, with initial classifica-
                       toms described above will mark the onset         tion revised as the disease progresses. As
                       of myasthenia, and after a period of time        a result of careful study of over 800 pa-
                       they will be seen in at least 90 per cent of     tients, a Clinical Classification has been
                       all patients. Frequently after the onset of      developed which takes into account not
                       eye symptomatology, other striated muscle        only initial symptomatology, age at onset,
                       weaknesses will be apparent in the form          and sex, but also for progress of the dis-
                       of myasthenic facies caused by weakness          ease. In addition to its prognostic value,
                       of facial muscles. This is responsible for the   this classification is a guide for selection of
                       snarl which may develop when myasthenic          therapy. According to age at onset, pa-
                       patients are asked to smile or show their        tients are divided into pediatric and adult
                       teeth. As a meal progresses, weakness of         groups as follows.1-5
                       jaw muscles may cause difficulty in chew-           Pediatric group. The pediatric myas-
                       ing and dysphagia, which frequently re-          thenia gravis group includes neonatal and
                       sults in nasal regurgitation of fluids. Diffi-   juvenile patients.
                       culty in speech in the form of dysarthria,          Neonatal group. Neonatal myasthenia
                       characterized by a nasal "twang," is often       gravis occurs only in infants bom of myas-
                       heard. When starting to speak the voice          thenic mothers and is a self-limited condi-
                       is relatively clear and the speech is easy       tion lasting no more than six weeks. It is
                       to understand; as speech continues, volume       probably caused by transmission of an
                       of voice and clarity of speech decrease.         etiologic factor across the placental barrier.
                       Respiratory distress may be seen in some         Progression to juvenile myasthenia has been
                       cases. This may be either inspiratory or         reported in only one instance.1
                       expiratory depending upon muscle groups             Juvenile group. Unlike the neonatal form,
                       involved. In milder cases, respiratory dis-      clinical myasthenia gravis is not present in
                       tress occurs only during exercise. A rela-       the mothers of these children. The juvenile
                       tively uncommon sign of myasthenia gravis        form may develop at any time from
                       is a longitudinal furrowing of the tongue        birth to puberty, and tends to be perma-
                       called "myasthenic tongue."                      nent. In those infants in whom the disease
                           The skeletal muscles most frequently in-     begins at birth, there may be an apparent
                       volved are those of neck, shoulder, and          confusion with the neonatal form but the
                       hip girdles. Proximal leg muscles are            mother's status and permanence of the
                       affected more often than distal ones; ex-        defect soon define the actual classification.
                       tensors of upper extremities are involved        Siblings and close relatives of juvenile
                       more frequently than the flexors. These          myasthenia patients may also have myas-
                       symptomatologies are asymmetric in most          thenia gravis. Ophthalmoplegia with severe
                       adult patients.                                  ptosis, bilateral, partial or complete, is
                           Early atrophic changes of involved mus-      common in this group and is often resistant
                       cle groups do occur and do not rule out          to drug therapy. Symmetrical limb involve-
                       diagnosis of myasthenia gravis. Ocular           ment is also frequently present. The nature
                       pain, headache, paresthesias,1 and other         and degree of the myasthenic defect indi-
                       sensory changes have been noted at one           cate inclusion of these patients into the
                       time or another in about 14 per cent of          more descriptive divisions of the adult
                       patients.1 The pain becomes more severe          groups below.
                       as the day progresses, but it usually re-           Adult group. Adult myasthenia gravis
                       sponds to rest or anticholinesterase medica-     patients have been divided into four
                        tion.                                           groups.

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                           Group I. Ocular myasthenia. This is a         correlated with disuse and not associated
                        localized form frequently limited to only        with any demonstrable lesions of central
                        one eye and characterized by ptosis and          and peripheral nervous systems. Electro-
                        diplopia. This group has an excellent prog-      myography of involved muscle groups re-
                        nosis and, if there, is no spread of myas-       veals a characteristic myopathic pattern.
                        thenic involvement to other muscle groups
                        within two years of onset, the disease usu-       Diagnosis
                        ally remains nonprogressive. Of 833 myas-            Diagnosis of myasthenia gravis is simple
                        thenic patients, 21 per cent are in this          when the patient presents classical symp-
                        group.                                            toms; however, diagnosis early after onset
                           Group HA. Mild generalized myasthenia          of a mild form may be difficult, and a high
                        grams. This form is characterized by slow         degree of awareness of myasthenia gravis
                        onset, frequently ocular, gradually spread-       is necessary. Of utmost importance is dili-
                        ing to skeletal and bulbar musculature.           gence in eliciting the following details
                       The respiratory muscles are spared. The            when obtaining the patient's history: onset
                       response to drug therapy is good and the           of weakness and its diurnal variation; effect
                       mortality rate is very low.                        of rest; influence of menstrual cycle, infec-
                           Group 1IB. Moderate generalized myas-          tion, and emotional stress; response to medi-
                       thenia grams. This form has a gradual              cations; tolerance of average and unusual
                       onset with frequent ocular presentation,           physical activity; possible history of remis-
                       progressing to more severe generalized in-         sions followed by exacerbations. Shift of
                       volvement of the skeletal and bulbar mus-         ptosis from one eye to the other is almost
                       culature. Dysarthria, dysphagia, and poor         pathognomonic of myasthenia gravis. The
                       mastication are more prevalent than in            possibility of neurotic asthenia which may
                       Group IIA. The respiratory muscles are            closely resemble myasthenia gravis can be
                       not involved. The response to drug therapy        excluded by critical and objective assess-
                       is less satisfactory and the patient's activi-    ment of alleged weakness.
                       ties are restricted, but the mortality rate           The basal state (nonmedicated) is essen-
                       is low.                                           tial for thorough physical and neurologic
                          Group III. Acute fulminating myasthenia        examination. In mild cases, physical activ-
                      grams. This form has a rapid onset of              ity may be necessary to provoke muscle
                      severe bulbar and skeletal muscle weakness         weakness. Although routine laboratoiy tests
                      with early involvement of respiratory mus-         usually have no diagnostic value in myas-
                       culature. Progression of the disease is           thenia gravis, such studies as chest radiog-
                      usually complete within six months. The            raphy (with tomography if indicated),
                      percentage of thymomas is highest in this          thyroid evaluation, lupus erythematosus
                      group. The response to drugs is poor, and         preparations, and immunologic testing of
                      the incidence of myasthenic, cholinergic,         sera may be helpful. An enlarged thymus
                      and mixed crises is high; the mortality rate      is a common finding.1
                      is also high.                                         Most diagnostic doubts can be eliminated
                          Group IV. Late severe myasthenia gravis.      through the use of pharmacologic tests,
                      In this form, severe myasthenia gravis            reparative or provocative, with or without
                      develops at least two years after onset of        electromyography and ergography/' Drugs
                      Group I or Group II symptoms. Progression         in current use are edrophonium chloride
                      of myasthenia gravis may be either grad-           (Tensilon), neostigmine (Prostigmin), d-
                      ual or sudden. This group has the second          tubocurarine (curare), and decametho-
                      highest percentage of thymomas. The re-           nium. Quinine is no longer advocated as a
                      sponse to drug therapy and the prognosis          provocative test because of attendant
                      are poor.                                         hazards.
                          Some patients in Groups II and IV may             To detect false-positive responses to drug
                      demonstrate localized muscle atrophy, not         tests, parallel tests should be performed

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280 Osserman                                                             In uestigative   Ophthulmolngy
                                                                                                                       June 1967

                         with a placebo, preferably in a double-
                         blind fashion.
                            If weakness is experienced in the pharyn-
                         geal constrictors, fluoroscopic examination
                         during swallowing of a contrast medium
                         before and after administration of an anti-
                         cholinesterase drug often has diagnostic
                         value.
                            Edrophonium chloride test. Osserman
                         and Kaplan0 developed the edrophonium
                         chloride test for my asthenia gravis which,
                                                                        Fig. 1. Patient with oculobulbar myasthenia gravis.
                         in its present form,7 is performed as fol-     Left, before injection of edrophonium chloride.
                         lows: the patient's muscle strength is         Right, relief of ptosis and better facial expression
                         evaluated both subjectively and objectively,   30 seconds after injection of edrophonium chloride.
                         measuring the width of the palpebral fis-      {Reprinted from Osserman, K. E.: Myasthenia
                         sure and the range of extraocular muscle       Gravis, New York, 1958, Grune & Stratton, Inc.,
                                                                        p. 95.)
                         movements. For the latter, the red-glass
                         or red-bar tests are helpful. Skeletal mus-
                         cles involved in the myasthenic process        placebo. Either 20 mg. of nicotinic acid,
                         are tested by using the dynamometer and        200 mg. of calcium chloride, or 0.3 to 0.4
                         the ergograph. Vital capacity is measured      mg, of atropine will be suitable for this
                         with a ventilation meter, and chewing and      purpose. Advantages of the edrophonium
                         swallowing are observed. Following a 4         chloride test are: it can be repeated with-
                         to 6 minute rest period, 2 mg. of edropho-     in 10 minutes; its action is rapid and tran-
                         nium chloride is injected intravenously and    sient, enabling both physician and patient
                         muscle strength is again evaluated within      to observe repeatedly the effects of anti-
                         30 to 90 seconds. If an inadequate response    cholinesterase medication; muscarinic side-
                         results from this dose, increments up to 8     reactions are less frequent and less severe
                         mg. of edrophonium chloride should be          than after neostigmine, and they disappear
                         tried after a 2 minute delay. If the 2 mg.     rapidly.
                         dose gives a cholinergic response, the test       Edrophonium chloride tonometry. Recent
                         should be repeated 30 minutes later with       reports indicate that increased tension in
                         a dose of 0.5 to 1.0 mg. Subjective com-       the eyeball of the myasthenic patient is
                         plaints of diplopia may remain unchanged       found by tonometry when edrophonium
                         after edrophonium chloride testing al-         chloride is administered.s>9 To date, at The
                         though the examiner may be able to dem-        Mount Sinai Hospital, New York, we have
                         onstrate that the original weak muscle is      not evaluated this use of edrophonium.
                         corrected by edrophonium, and a previ-            Neostigmine methylsulfate test. With
                         ously uninvolved muscle is weakened by         the introduction of neostigmine, adminis-
                         a cholinergic response. This type of reac-     tration of this drug became the basic pro-
                         tion to edrophonium is a positive test for     cedure in diagnosis.10 It may be given in
                         my asthenia gravis. The edrophonium chlo-      one of two ways: (1) intramuscular injec-
                         ride test in a patient with oculobulbar        tion of 1.5 mg. of neostigmine methyl-
                         myasthenia gravis is illustrated in Fig. 1.    sulfate alone or combined with 0.6 mg. of
                         If one suspects that weakness is functional    atropine sulfate or, (2) intravenous injec-
                         or the result of other muscular or central     tion of 0.5 mg. of neostigmine methyl-
                         nervous system diseases rather than myas-      sulfate. The commonest means of testing
                         thenia gravis, one should pair the edropho-    with this drug is the intramuscular route.
                         nium chloride injection in a double-blind      The patient is given an injection and re-
                         fashion with intravenous injection of a        examined at 5 to 10 minute intervals for

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                       45 to 50 minutes, with both subjective and      the evidence of abnormality of the motor
                       objective improvement or lack of it being       unit which it reveals is or is not compatible
                       noted. The same observations are carried        with the clinical diagnosis under considera-
                       out with intravenous testing; however, the      tion. Electromyographic results must be in-
                       response starts within one to two minutes.      tegrated with results of other tests, clinical
                       False-negative results with this test may       examination, and history in arriving at a
                       occur because of the size of the dose: the      diagnosis. However, electromyography is
                       patient may be sensitive to neostigmine         not a necessary routine for diagnosis. Phar-
                       and with the dosage used the weakness           macologic tests usually are reliable and are
                       of the disease may be replaced with the         not difficult to perform in clinic or office.
                       weakness of overdepolarization. This test       The real value of electromyography is seen
                       cannot be repeated with increasing dosages      when other tests produce equivocal results
                       at the same visit; therefore, testing with a    or when objective tests are needed because
                       different dosage must await a subsequent        of difficulty in interpreting clinical data,
                       visit.                                          even though compared with a placebo
                          Curare test. Occasionally, in a patient      test.1
                       with mild, generalized myasthenia gravis,          Bremen1'1 has developed a technique
                       information obtained from the edrophoni-        combining electromyography without stim-
                       um or neostigmine test may be confusing.        ulation and the edrophonium test. This
                       When this occurs, additional information        technique requires subconjunctival inser-
                       may be obtained by using cZ-tubocura-           tion of fine gauge, concentric electrodes
                       rine.11'n- Because persons with myasthenia      directly into extraocular muscles with the
                       gravis are very sensitive to very small doses   use of only topical anesthesia. This is a
                       of d-tubocurarine, utmost caution is neces-     simple, practical procedure devoid of
                       sary: this test should be used only in those    harmful effects; the only complication is
                       cases in which definite diagnoses cannot        the occasional occurrence of a sub-
                       be obtained with edrophonium and neo-           conjunctival ecchymosis, which is a cos-
                       stigmine tests. When performing this test,      metic blemish of brief duration. Muscle
                       it is imperative to have at hand drugs and      action potentials are suitably amplified,
                       equipment necessary for respiratory resus-      displayed on dual-beam oscilloscopes, and
                       citation and also physicians thoroughly         recorded with moving film photography.
                       competent in their use.1                        Utilization of electromyography to evalu-
                          Decamethonium test. In myasthenia            ate drug action has revealed a striking and
                       gravis there is resistance of clinically non-   characteristic muscle response even though
                       involved muscles to intravenous adminis-        gross improvement in motility may not be
                       tration of decamethonium. Because severe        evident.
                       respiratory depression may develop during          In the past decade, immunologic studies
                       the decamethonium test, the same safe-          have shown that an antibody may be found
                       guards necessary for the curare test should     in the sera of 40 per cent of myasthenic
                       be provided. In normal subjects, decame-        patients. Weiner and Osserman15 have
                       thonium produces marked reduction in            found this antibody in 32 per cent of Group
                       height of action potential and considerable     I ocular myasthenia patients studied. Al-
                       muscle weakness. Subsequent injection of        though this test at present cannot be used
                       anticholinesterase (e.g., edrophonium) in-      as a completely diagnostic procedure, it
                       creases generalized weakness. In myasthe-       lends support to clinical and phannacologic
                       nic subjects, relatively large doses of dec-    observations.
                       amethonium cause little or no reduction
                       in height of action potential or strength of    Differential diagnosis
                       noninvolved muscles.13                            Isolated ocular symptoms, either ptosis
                          Electromyography aids in diagnosis when      or diplopia, occur in many neurologic dis-

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282 Osserman                                                           Investigative Ophthalmology
                                                                                                                June 1967

                        orders. Characteristic of strabismus seen       eurysiri; A bruit heard over the eye is char-
                        as a congenital or heredodegenerative pro-       acteristic of aneurysm. If there is dimin-
                        cess is the static, nonprogressive nature of    ished comeal sensation in the involved eye,
                        the ocular sign from birth on. But even this    this diagnosis becomes a probability and
                        need not be an absolute differentiation. A      myasthenia gravis is excluded. In cranial
                        patient has been seen who had congenital        neuropathies associated with diabetes,
                        strabismus of the external type superim-        syphilis, diphtheria, and the so-called
                        posed upon which myasthenia developed;          Guillian-Barre syndrome, the total clinical
                        its effects were limited to an increase in      picture is essential for differentiation of
                        the degree of external rotation of the left     these conditions from myasthenia gravis. If
                        eyeball and demonstrable only by the re-        myasthenia is still suspected, response of
                        sponse of the eyeball to anticholinesterase     symptoms to anticholinesterase medication
                        medication. Congenital ptosis of the lids       again becomes the diagnostic feature. In
                        is perhaps most often confused with my-         multiple sclerosis, ocular symptoms are
                        asthenia gravis, but this, too, is a disturb-   most often accompanied by nystagmus, and
                        ance exhibited at birth and nonprogressive      true nystagmus is rarely seen in myasthenia
                        in nature. In these cases familial history,     gravis. Nystagmus caused by multiple scle-
                       the static nature of the ptosis, the history     rosis results most often from involvement
                        of its presence since birth, as well as nega-   of the median longitudinal bundle, with
                       tive responses to anticholinesterase medica-     resultant horizontal and vertical nystagmus
                       tion serve to differentiate the condition        diagnostic of involvement of the brain-
                       from myasthenia gravis.                          stem. Temporal pallor of the optic disks is
                           Involvement of oculomotor, trochlear,        commonly seen in multiple sclerosis. Of
                       or abducens nerves by any number of              course, if there is evidence of central ner-
                       processes, including infections, trauma,         vous system involvement, the diagnosis is
                       and neoplasm, produces characteristic ocu-       multiple sclerosis.
                       lar palsies which do not have the fluctuat-         Unilateral ptosis as an isolated sign or
                       ing characteristics of myasthenia gravis.        symptom may be congenital, or due to in-
                       Myasthenic involvement of external ocular        volvement of the ocular sympathetic nerves
                       muscles may closely simulate any of the          or the oculomotor nerve, or it may be my-
                       ocular palsies. It has been said that, when      asthenic in origin. Congenital ptosis, as
                       myasthenia gravis discretely involves one        previously described, exists from birth and
                       eye in a manner which produces what ap-          does not vaiy. Involvement of ocular sym-
                       pears to be a typical third nerve palsy, a       pathetic nerves produces a Homer's syn-
                       differential point of significance is absence    drome, in which case ptosis is accompanied
                       of involvement of the pupil. Since periph-       by ipsilateral miosis, enophthalmos, and
                       eral involvement of the oculomotor nerve         diminished sweating over the same side of
                       is almost invariably accompanied by an           the head and face. Ptosis produced by third
                       internal as well as external ophthalmople-       nerve palsies is accompanied by dilatation
                       gia, this is used as a distinguishing char-      of the pupil as well as specific ocular pal-
                       acteristic. There are reports in the litera-     sies related to involvement of the third
                       ture of isolated cases of myasthenia gravis      nerve. In these cases, the eye is commonly
                       involving the ciliary muscle. In such rare       deviated externally because of unopposed
                       instances, ultimate differentiation may de-      pull of the external rectus muscle. Diag-
                       pend upon response to anticholinesterase         nosis of myasthenia gravis is confirmed by
                       medication.                                      the response of the ptosis to anticholin-
                           When diplopia and/or ptosis are ac-          esterase medication.
                       companied by localized headache over the            Weakness exclusively in the limbs may
                       involved eye or by pain in the eye, one          resemble that present in muscular dystro-
                       must think seriously of an intracranial an-      phy, motor neuropathies, or amyotonia con-

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                        genita. Symptoms of chronic fatigue may          gastric distress including nausea, abdom-
                        mimic those of myasthenia gravis, but re-       inal cramps, diarrhea, and fasciculations)
                        sponse to specific testing is different. En-    which are pronounced and sometimes diffi-
                        docrine disorders and the "Eaton-Lambert-       cult to control even with atropine sulfate.
                        Rooke syndrome" also may simulate myas-         Because atropine sulfate obscures early
                        thenia gravis. No therapeutic test is abso-     signs of incipient overdosage it should not
                       lutely pathognomonic. Hysteria can simu-         be used routinely. Neostigmine bromide is
                        late almost any symptomatology known.           available as a 15 mg. scored tablet and
                        False-positive or false-negative edrophoni-     usually is prescribed for use eveiy two to
                        um or curare tests can result in errors in      three hours. Dosage is variable, not only
                       diagnosis. Proper testing with placebos in       between patients but also for the same pa-
                       the former usually precludes this error.         tient on the basis of stress from physical
                       However, Schwab and Perlo10 reported a           activity, menses, infection, or emotional
                       group of patients having a variety of neu-       trauma. While no specific dose can be
                       rologic syndromes who had definite false-        recommended, it usually is safe to start a
                       positive reactions to edrophonium and neo-       new patient on one tablet three times a
                       stigmine testing. Rare false-negative re-        day.
                       sults occur when either negligible objective        Pyridostigmine (Mestinon) bromide. This
                       response is noted or overdosage with the         drug is an analogue of neostigmine and
                       test drug causes a cholinergic reaction. To      more effective in relieving myasthenia
                       rule out false-negative responses, any syn-      symptoms in small .muscles innervated by
                       drome of muscle weakness, not accom-             cranial nerves, particularly those involved
                       panied by alteration of tendon reflexes, in      in ptosis, diplopia, and dysarthria. Its di-
                       which there is some improvement of               urnal duration of action is approximately
                       strength after administration of correct         half an hour longer than that of neostig-
                       amounts of neostigmine or edrophonium           mine. However, one of the chief advan-
                       should be considered to be myasthenia           tages of pyridostigmine is its longer noc-
                       gravis. A history of remissions in the past     turnal action, obviating administration dur-
                       or evidence of thymic abnormality tends         ing the night and enabling even the pa-
                       to confirm the diagnosis. A positive edro-      tient with dysphagia to swallow the first
                       phonium or neostigmine test serves to con-      dose in the morning. Another salient ad-
                       firm the clinical impression derived from       vantage of pyridostigmine over neostig-
                       history and physical examination. When          mine is its smoother action, low incidence
                       tests are properly performed with placebos      of muscarinic side-effects, and resultant
                       and mechanical and electrical measure-          marked decrease in need for routine use
                       ments are used, the diagnosis rarely re-        of atropine sulfate. Although the range of
                       mains in doubt.                                 therapeutic and toxic levels of pyridostig-
                                                                       mine is much greater than that of neostig-
                       Treatment                                       mine, the usual side-reactions do occur with
                          Pharmacologic therapy depends upon a         overdosage. Most patients using pyridostig-
                       group of relatively short-acting potent anti-   mine are satisfied with the sustained feel-
                       cholinesterases.                                ing of well-being throughout the day.
                          Choice of drugs.                             Pyridostigmine bromide is available as a
                          Neostigmine bromide. This drug has           ^-scored 60 mg. tablet, usually replace-
                       been used effectively for three decades. It     able tablet-for-tablet with neostigmine, and
                       is not habit forming; the requirement de-       prescribed every three to four hours in
                       creases if myasthenia remits. Its two dis-      most cases. Prolonged-action pyridostig-
                       advantages are short duration of action         mine bromide is available as a scored
                       (approximately two hours) and side-effects      "Timespan" tablet containing 180 mg.,
                       (sweating, salivation, lacrimation, and epi-    which has the immediate effect of a reg-

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284 Osserman                                                             Investigative Ophthalmology
                                                                                                                  June 1967

                       ular 60 ing. tablet. Its slow release of pyri-   termined. They may be used in combina-
                       dostigmine produces a duration of action         tion with oral neostigmine or pyridostig-
                       approximately 2 to 2V2 times that of a reg-      mine, but never with ambenonium, as there
                       ular pyridostigmine tablet. Its primary ad-      is a marked synergism with the latter,
                       vantage is its production of extended noc-       which may cause cholinergic crisis.1 s
                       turnal relief; frequently it is prescribed for      Combinations. When a single drug will
                       the last dose of the day, regardless of which    not effect adequate control, some patients
                       drug may be used throughout the day.             may be treated more satisfactorily with
                          Ambenonium (Mytelase) chloride. This          combinations of anticholinesterase drugs.
                       drug is a bis molecule and is wholly differ-     Pyridostigmine and ambenonium are more
                       ent in structure from neostigmine or pyri-       effective in predominately bulbar involve-
                       dostigmine. Its effect on involved pe-           ment, whereas neostigmine and ambeno-
                       ripheral muscles is excellent and results in     nium are better for control of peripheral
                       more sustained increase in strength. For         muscular weakness. Combined drug ther-
                       bulbar myasthenia ambenonium is mid-             apy should be reserved for patients with
                       way between pyridostigmine and neostig-          relatively stable myasthenia and of proved
                       mine in value. While its action is definitely    intelligence in handling their own drug
                       longer than that of neostigmine, and per-        dosages.
                       haps slightly longer than that of pyrido-           Adjuvant drugs. In isolated cases, use of
                       stigmine for diurnal use, its nocturnal ef-      ephedrine sulfate and potassium salts still
                       fect is the same as that of regular pyrido-      meets with some favor and results in occa-
                       stigmine. It has fewer toxic side-effects        sional improvement. Ephedrine sulfate, 25
                       than neostigmine, but more than pyrido-          mg. three times a day, gives an increase in
                       stigmine, and they differ in nature. More        strength to some patients not fully con-
                       prominent are central nervous system side-       trolled with anticholinesterase therapy
                       effects such as headache. Other early signs      alone. Potassium salts in liquid form, 15
                       of overdosage are fasciculations and mus-        mEq. three times a day, may also be help-
                       cular weakness. Gastrointestinal side-reac-      ful. Instead of potassium salts, intracellular
                       tions are less common, but they do appear        potassium-sparing drugs such as spirono-
                       later when overdosage is imminent. For the       lactone (Aldactone-A), 25 mg. four times
                       patient on a respirator, ambenonium has          a day, or triamterene (Dyrenium), 100
                       the distinct advantage of causing less bron-     mg. twice a day, may be employed. Thus,
                       chial secretions than do other anticholin-       ephedrine sulfate and any one of the three
                       esterase drugs. Ambenonium chloride is           adjuvants affecting potassium may be used
                       available as scored tablets of 10 and 25 mg.     separately or together in addition to the
                       Approximately 6 mg. of ambenonium chlo-          basic treatment of anticholinesterase medi-
                       ride is equivalent to 15 mg. of neostigmine      cations. If no improvement is evident, ad-
                       bromide or 60 mg. of pyridostigmine bro-         juvant drug therapy should be discon-
                       mide. Ambenonium should be started cau-          tinued.
                       tiously with a 5 mg. dose and gradually             Thymectomy and radiotherapy are not
                       increased to therapeutic levels.                 indicated in the treatment of ocular myas-
                          Instillations of strong, long-lasting anti-   thenia, and the use of adrencorticotropic
                       cholinesterases such as echothiophate io-        hormone (ACTH) has not proved to be of
                       dide (Phospholine iodide) have been ad-          value in this form of the disease.19
                       vocated for treatment of ptosis and extra-
                       ocular muscle weakness. When effective,          Edrophonium test in management
                       these drugs usually relieve ptosis better          In drug management of the myasthenic
                       than diplopia.17 These long-lasting anti-        patient7' -° there are three ways to deter-
                       cholinesterases should not be administered       mine optimal dosage for the selected drug:
                        unless red-cell esterase activity can be de-    (1) use of empiric dosage by means of

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Volume 6                                                                 Ocular myasthenia gravis 285
                       Number 3

                       clinical judgment; (2) use of the edro-                    ages according to a table of equivalents
                       phonium chloride test, and (3) use of in-                  (Table I).
                       travenous titration with pyridostigmine                       After the patient has been started on an
                       bromide or neostigmine methylsulfate. Ex-                  anticholinesterase drug by either of the
                       treme caution is required because of the                   above methods, dosage regulation can be
                       serious hazard involved in the intravenous                 accomplished by performing an edrophoni-
                       titration.                                                 um test one hour after the patient has
                          When the diagnosis of myasthenia gravis                 taken his treatment drug. Three possible
                       is established, treatment with one of the                  responses are presented in Table II.
                       anticholinestera.se drugs is started. One                    If improvement of muscle strength follows
                       may empirically prescribe a tablet for use                 administration of edrophonium, the oral
                       at specific intervals, usually three times a               dosage may be increased by one quarter
                       day, and observe duration of action, im-                   to one half of a tablet. If the patient be-
                       provement in striated muscle strength, and                 comes worse, the oral dosage should be
                       occurrence of side-effects. The dosage is                  decreased by one fourth to one half of a
                       gradually increased until the patient ob-                  tablet. If the patient shows no change in
                       tains maximal improvement with minimal                     strength, the dosage is adequate and should
                       side-reactions.                                            not be adjusted at that time. If the response
                          For intravenous titration one gives small               is adequate but the patient is still poorly
                       increments of pyridostigmine or neostig-                   controlled, use of adjuvant drugs or possi-
                       mine at 2 minute intervals until maximal                   ble reassessment of therapy should be con-
                       improvement is obtained. This intravenous                  sidered.
                       dose can then be translated into oral dos-                    In management, there are variations in
                                                                                  amounts of edrophonium chloride used.
                                                                                  One must differentiate between dosages
                                                                                  recomended for diagnostic testing and
                       Table I. Table of equivalents                              dosages required for regulation and con-
                                                           Intra-
                                                                                  trol of treatment medications.7 Our recom-
                                                          venous     Oral         mended test dosage for regulation of the
                                                            dose    dose          required amount of anticholinesterase drug,
                                   Drug                    (mg.)    (mg.)         based on thousands of tests, is 0.2 ml. (0.2
                       Pyridostigmine bromide                                     mg.) of edrophonium chloride administered
                         (Mestinon)                         2.0       60          intravenously one hour after intake of the
                       Pyridostigmine bromide
                         (Timespan)                         2.0      180          oral treatment drug. With this small dose,
                       Neostigmine methylsulfate                                  edrophonium per se causes little interference
                         (Prostigmin)                       0.5      —            in reaction; effects observed clearly deline-
                       Neostigmine bromide                  —        15
                       Ambenonium (Mytelase)                                      ate a response based on the oral drug admin-
                         chloride                           —          6          istered one hour earlier. Other investi-

                       Table II. Responses to edrophonium test
                                                                                        Myasthenic     Adequate   \ Cholinergic
                        Muscle strength (ptosis, diplopia, dysphonia, dysphagia,      Improvement    No change     Worse
                          dysarthria, respiration, limb strength)
                        Fasciculations (orbicularis oculi, facial muscles, limb       Absent         Present or   Present or
                          muscles)                                                                     absent       absent
                        Side-reactions (pallor, lacrimation, diaphoresis, salivation, Absent         Minimal      Severe
                          abdominal cramps, nausea, vomiting, diarrhea,
                          headache)

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286 Osserman                                                             Inoestigative Ophthalmology
                                                                                                                  June 1967

                        gators have recommended doses of 3, 4,          edrophonium testing and (2) those whose
                        and even 10 mg. At times, with these high-      ptosis responds better than does the extra-
                        er doses, certain areas of muscle weakness      ocular muscle weakness, thereby giving
                        are improved while other striated muscles       prominence to the more disabling aspect
                        become weaker. Thus, the test is difficult      of their problem. In these patients, resort
                        to interpret. However, such a dichotomy         to mechanical aids is helpful. Dark glasses
                        will occasionally result even with the use      may help to relieve ptosis; a plastic or wire
                        of 0.2 ml. (2.0 mg.). In such instances, it     lid crutch attached to the eyeglass frame
                        is the safer course to consider the current     may be worn to correct the ptosis. It may
                        drug dose to be adequate rather than risk       be advisable to use an eye patch or opaque
                       possible cholinergic weakness by increasing      corneal lens to obscure the vision of one
                       the oral dosage. Only rarely does increas-       eye and thus relieve the diplopia. Prism
                       ing the dose of edrophonium chloride to 4       lenses may be prescribed to correct mild
                       or 5 mg. give additional information.           degrees of extraocular muscle weakness;
                           In some myasthenia gravis patients it is    however, the degree of prism needed varies
                       important to compare the results of the         with the patient's myasthenic condition,
                       edrophonium test with those of a placebo        which often varies with time of day and
                       injection. The physician must be acutely        activity. Thus, prisms are rarely successful
                       aware of the fact that the myasthenic pa-       in relieving diplopia.
                       tient quickly learns to differentiate the          Various operations have been performed
                       effects of edrophonium and placebo.             to correct ptosis and diplopia. In myasthe-
                          The edrophonium test can be used to          nia gravis, surgery is not justified, because
                       determine the frequency as well as the          the patient's condition changes with time.
                       quantity requirement of anticholinesterase      Unless edrophonium testing and ocular
                       medication, although this use is not im-        electromyography indicate that the muscle
                       portant in the patient who is easily con-       involved shows little evidence of response
                       trolled. Where regulation is difficult, espe-   to neuromuscular treatment drugs, surgical
                       cially in the seriously ill myasthenic pa-      procedures may prove to be a handicap.
                       tient, edrophonium testing should be per-
                       formed at the end of a dose period to avoid         REFERENCES
                       administration of oral medication before        1. Osserman, K. E.: Myasthenia gravis, New
                       the patient demonstrates a clear myasthe-          York, 1958, Gnine & Stratton, Inc.
                                                                       2. Whipple, H. E., Editor: Myasthenia gravis,
                       nic response.                                      Ann. New York Acad. Sc. 135: 1966.
                          The frequency of management edropho-         3. Perlo, V. P., Poskanzer, D. C , Schwab, R. S.,
                       nium tests for the patient admitted to hos-        Viets, H. R., Osserman, K. E., and Cenkins,
                       pital for regulation should vary from a            G.: Myasthenia gravis: evaluation of treat-
                       daily basis to every two or three days.            ment in 1355 patients, Neurology 16: 431,
                                                                          1966.
                       Changes in oral medication usually do not       4. Harvey, A. M.: Some preliminary observa-
                       show their full effect in less than 24 to 48       tions on the clinical course of myasthenia
                       hours. Because of possible differences in          gravis before and after thymectomy, Bull,
                       drug requirements during the day, it is            New York Acad. Med. 24: 8, 1948.
                       advisable to test oral dosages administered     5. Osserman, K. E., Foldes, F. F., and Genkins,
                                                                          G.: Myasthenia gravis, in Cheymol, J., editor:
                       during different periods.                          International Encyclopedia of Pharmacology
                          In Group I (myasthenia with ptosis and/         and Therapeutics, XIV, London, 1967, Per-
                       or diplopia), if edrophonium testing re-           gamon Press, Ltd.
                       sults in complete relief of symptomatology,     6. Osserman, K. E., and Kaplan, L. I.: Rapid
                       anticholinesterase drugs should be started.        diagnostic test for myasthenia gravis, j . A.
                                                                          M. A. 150: 265, 1952.
                       However, two types of patients are not          7. Osserman, K. E., and Genkins, C.: Critical
                       candidates for drug therapy: (1) those             reappraisal of the use of edrophonium (Ten-
                       who have negligible improvement with               silon) chloride tests in myasthenia gravis and

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                       Number 3

                             significance of clinical classification, Ann.     15. Weiner, L. B., and Osserman, K. E.: Corre-
                             New York Acad. Sc. 135: 312, 1966.                    lation of presence of immunofluorescence in
                        8.   Kornblueth, W., Jampolsky, A., Tamler, E.,            serums with clinical findings in myasthenia
                             and Marg, E.: Contracture of the oculorotary          gravis, Ann. New York Acad Sc. 135: 644,
                             muscles and the intraocular pressure, Am. J.          1966.
                             Ophth. 49: 1381, 1960.                            16. Schwab, R. S., and Perlo, V. P.: Syndromes
                        9.   Giaser, j . S., Miller, G. R., and Gass, J. D.        simulating myasthenia gravis, Ann. New York
                             M.: The edrophonium tonogram test in myas-            Acad. Sc. 135: 350, 1966.
                             thenia gravis, Arch. Ophth. 76: 368, 1966.        17. Leopold, I. H., Hedges, Jr., T. R., Montana,
                       10.   Viets, H. R., and Schwab, R. S.: Thymectomy           J., Krishna, N., and Beckett, S.: Local ad-
                             for myasthenia gravis, Springfield, 111., 1961,       ministration of anticholinesterase agents in
                             Charles C Thomas, Publisher.                          ocular myasthenia gravis, Arch Ophth. 63:
                       11.   Bennett, A. E., and Cash, P. T.: Curare as a          544, 1960.
                             diagnostic test for myasthenia gravis—curari-     18. Osserman, K. E., Cohen, E. S., and Genkins,
                             zation as an etiologic clue in the disease, Tr.       C.: Phospholine iodide: an anticholinesterase
                             Am. Neurol. A. 68: 102, 1942.                         drug of new structure. Preliminary report in
                       12.   Rowland, L. P., Aranow, H., and Hoefer, P.            the treatment of myasthenia gravis, in Viets,
                             F. A.: Observations on the curare test in the         H. R., editor: Myasthenia gravis, Second In-
                             differential diagnosis of myasthenia gravis, in       ternational Symposium, Springfield, 111., 1961,
                             Viets, H. R., editor: Myasthenia gravis, Sec-         Charles C Thomas, Publisher, p. 58.1.
                             ond International Symposium, Springfield, 111.,   19. Mount, F. W.: Corticotropin in treatment of
                             1961, Charles C Thomas, Publisher, p. 411.            ocular myasthenia, Arch. Neurol. 1: 114,
                       13.   Churchill-Davidson, H. C , and Richardson,            1964.
                             A. T.: Neuromuscular transmission in myas-        20. Osserman, K. E., Kaplan, L. I., and Besson,
                             thenia gravis, Am. J. Med. 19: 691, 1955.             G.: Studies in myasthenia gravis:. endrophoni-
                       14.   Breinin, G. M.: Electromyography: a tool in           um chloride (Tensilon) test as a new ap-
                             ocular and neurologic diagnosis of myasthenia         proach to management, J. Mt. Sinai Hosp.
                             gravis, Arch. Ophth. 57: 161, 1957.                   20: 165, 1953.

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