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Periodic Alternating Nystagmus
PERIODIC ALTERNATING NYSTAGMUS A DALE G.
REPORT OF E I G H T CASES
DAVIS, M.D.,
AND J. LAWTON S M I T H ,
M.D.
Miami, Florida Periodic alternating nystagmus is infreguently recognized in this country. Towle 1 counted only 40 cases in the world literature, and of these, but three were in English. Only one case has appeared in the American oph thalmic literature.2 The following is a report of eight cases of periodic alternating nystag mus, a description of its characteristic na ture, and an etiologic differential diagnosis. C A S E REPORTS
Case 1—This 38-year-old black woman was hos pitalized because of leiomyomata of the uterus. Neuro-ophthalmic consultation was requested be cause of abnormal eye movements. On ocular exam ination the corrected visual acuity was 20/25 in both eyes. The pupils reacted 2 + to light, and there was a 4 + reaction to near. The slit lamp, fundus, and visual field findings were normal. Motility examination revealed classic periodic al ternating nystagmus. This was manifested by a hor izontal, jerk-type nystagmus whose amplitude grad ually increased to a maximum, and then similarly abated. This phase lasted 110 seconds and was followed by a 20-second quiet interlude during which there was no nystagmus. A similar sequence then followed with the rapid phase in the opposite direction. The amplitude of the oscillations in creased when she looked into the direction of the rapid phase, and decreased when she looked into the direction of the slow phase. This cycle repeated it self over and over again. Of interest was the fact that the horizontal nystagmic movements were also present in vertical gaze. During the height of the oscillations the patient's visual acuity decreased and she experienced oscillopsia. The past history revealed that at the age of 16 years she had delivered a stillborn fetus and several months later a serological test for syphilis was re active. She was treated for this with penicillin at age 16 and again at age 20. At the age of 30 years a progressive neurologic disease began which was unFrom the Department of Ophthalmology, Uni versity of Miami School of Medicine, Bascom Palmer Eye Institute, Miami, Florida. This investi gation was supported in part by Public Health Ser vice Special Fellowship 1F03EY 47,263-01 of the National Eye Institute. Reprint requests to J. Lawton Smith, M.D., Bas com Palmer Eye Institute, 1638 N.W. 10th Avenue, Miami, Florida 33136.
remitting. In 1961 she began to note aching pains in her legs and began having difficulty seeing. An opti cian told her she had "jumping eyes." There was an insidious onset of difficulty in walking and paresthesia in the extremities. Hearing loss began on the left. She was hospitalized in 1963 and thought to have multiple sclerosis. By 1967 she required a walker, and began having difficulty with bladder and bowel control. One year prior to admission she obtained a wheelchair. Neurologic examination revealed motor weak ness in the lower extremities, and a mild dystaxia of the upper extremities. Skull x-ray examination and a cervical myelogram were normal. Blood tests for syphilis revealed a weakly reactive VDRL and a 2 + reactive FTA-ABS test. COMMENT
This 39-year-old woman had a stillborn fetus at the age of 16 years, and shortly thereafter was found to have a reactive sero logical test for syphilis. She was treated for this with penicillin at the ages of 16 and 20 years. I n the past 10 years she developed progressive spastic paraplegia and periodic alternating nystagmus. She also had lightning pains in the right upper extremity, involve ment of sphincters, and a hearing loss in the left ear. T h e impression was neurosyphilis with myelitis and periodic alternating nys tagmus. A three-month course of ampicillin and probenecid (Benemid) was advised. Case 2—A 49-year-old white man was referred with a chief complaint of "attacks of blurred vi sion." At the age of 44 years he noted the onset of episodes of blurred vision and oscillopsia which would last for five to 30 seconds. These increased in frequency to approximately 100 a day. The patient also noted clumsiness in walking and slurring of his speech for the past 18 months. Three years previ ously neurologic examination, lumbar puncture, bi lateral carotid and right vertebral arteriograms were normal. A trial of corticosteroids was of no help. On examination the visual acuity in the right eye was 20/25 and in the left eye 20/30. The visual fields and ocular fundi were normal. Electronystagmography demonstrated periodic alternating nystag mus with rapid phase to the right followed by a nystagmus with the rapid phase to the left. When 757
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TABLE 1 ELECTKONYSTAGMOGRAPHIC DATA FROM CASE 2
Rapid Phase to the Right
Duration (seconds) Frequency/second
Right Gaze
Primary Gaze
134 3
111 3
the rapid phase was to the right, in right gaze the duration of the nystagmus lasted 134 seconds with an oscillation of three beats per second, in primary gaze the nystagmus persisted at 111 seconds at three beats per second, and in left gaze persisted for 81 seconds, at a rate of 1.8 beats per second. When the fast phase of the nystagmus was to the left, in right gaze the direction of each episode of nystagmus was 91 seconds with a frequency of 1.8 per second, and in primary gaze the duration was 108 seconds with a frequency of 2.2 per second, and in left gaze the duration was 113 seconds with a frequency of 4 per second (Table 1). Optokinetic responses had no effect on the nys tagmus in any direction. However, cold caloric re sponses had a definite effect in that irrigation of the ear with ice water abolished the nystagmus and re versed its direction. Neurologic examination revealed mild dysarthria, vertical ocular dysmetria, modest abnormality in heel-to-shin testing, some imbalance in walking heel-to-toe, and some dyssynergy on foot patting and pivoting. Skull x-ray films, electroencephalogram, serum F T A - A B S test, and spinal fluid examination were normal. A trial of meclizine HC1 (Antivert), isoxsuprine HC1 (Vasodilan), and carbamazepine (Tegretol) showed no improvement. Diphenylhydantoin sodium (Dilantin) decreased the duration of the cycle by 30 seconds with a slight slowing of oscillations in the rapid phase to the left and a shorter period of crescendo in the rapid phase to the right. A repeat examination two years later revealed no change. The clinical impression was periodic alternating nystagmus probably due to demyelinizing disease. Case 3—A 21-year-old black woman was hospi talized with the chief complaint of headaches, nau sea, and vomiting of 10 days' duration. Three days prior to admission she noted blurred vision and hor izontal diplopia. Two days before admission severe vertigo and a staggering gait developed. This pa tient had sickle cell anemia since the age of three years requiring numerous transfusions, and had suffered bouts of abdominal and joint pain. On admission she was lethargic and markedly ataxic. Spinal fluid examination revealed a normal opening pressure but a pleocytosis of 330 leukocytes/ml 3 , 15% polymorphonuclear leukocytes, 85% mononuclear leukocytes, and a protein of 77
Left Gaze 81 1.8
Rapid Phase to the Left Right Gaze 91 1.8
Primary Gaze 108 2.2
Left Gaze 113 4
mg%. The impression was viral encephalitis and sickle cell anemia. On neuro-ophthalmic examination the visual acuity was 20/60 in both eyes. There was a left blepharoptosis, a slight left hypertropia, and anisocoria, with the left pupil slightly larger than the right. Both pupils reacted well to light but there was a slight Marcus Gunn pupil phenomenon on the left. The optokinetic responses were right 1 + , left 1-f, up 3 + , and down nil. The fundi showed slight optic nerve pallor on the left. The most striking eye finding was periodic alter nating nystagmus. An electronystagmogram showed disorganized, short, rapid saccades rather than a well-organized nystagmus. The periodic alternating nystagmus appeared as follows: left-beating nys tagmus was 75 seconds per cycle at 28 to 35 beats per 10 seconds. There was a 10 to 15 second rest period, followed by a right-beating nystagmus of 110 seconds per cycle with 35 to 40 beats every 10 seconds. The left-beating nystagmus could be virtu ally eliminated by extreme right gaze, and the right-beating nystagmus could be reduced, though not eliminated, by extreme left gaze. The nystag mus could be increased by stimulating the visual at tention, and diminished by having the patient stare at a blank wall. The nystagmus continued with the eyes closed. The nystagmus could be modified by the optokinetic drum, although not eliminated or re versed. T h e direction of the rapid phase could be reversed by irrigation of the left ear with cold wa ter (30°C) during the left-beating nystagmus, and during right-beating nystagmus the rapid phase could be reversed to left-beating nystagmus by a similar irrigation into the right ear. The patient was treated with whole blood for the hematologic problem, and the spinal fluid cleared in the succeeding three weeks. There was a gradual improvement in the patient's severe truncal ataxia. A 10-day course of corticosteroids gave no im provement. The impression was postinfectious or viral meningoencephalitis with periodic alternating nystag mus and sickle cell disease with aplastic crisis. Case 4—A 70-year-old white man complained of "a hemorrhage in the back of my left eye." Seven years previously the patient suffered a vitreous hemorrhage in the right eye with a permanent loss of vision. Tow months previously he noted a loss of vision in the left eye. A general medical examina-
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PERIODIC ALTERNATING
tion and a blood glucose test were normal. H e was told that he had a macular hemorrhage. This was followed by some resorption, and another episode of bleeding from the same area, with a marked visual loss. On examination the patient demonstrated peri odic alternating nystagmus. The cycles were ap proximately 90 to 120 seconds. During the oscilla tions the patient experienced a vertiginous sensation and an illusion of movement correlated with the di rection of the rapid phase. There was past-pointing which practically disappeared during the rest peri ods. Cold calorics demonstrated unequivocal inter ruption and reversal of the nystagmus. A general neurologic examination was normal. No ocular, cranial, or carotid bruits were heard, and the patient's mental status and speech were un inhibited. All cerebellar functions and all reflexes were intact. The impression was periodic alternating nystag mus following loss of all vision on an intraocular basis. Case 5—A 72-year-old black man was seen dur ing a survey of a population with known late syphi lis. The patient was totally deaf and had gradually lost all vision in both eyes 20 years previously. This visual loss occurred over a two-year period. He had no light perception in either eye since that time. Examination revealed anisocoria, with the right pupil larger; neither pupil reacted to light. The ocular fundi revealed extreme primary optic atro phy in both eyes, with bilaterally narrowed arterioles and choroidal sclerosis. There was marked pig mentary clumping along the inferior vessels of the left eye. Applanation pressure was 17 mm H g in both eyes. Motility examination revealed periodic alternat ing nystagmus. T h e rapid phase to the right oc curred for 45 seconds, followed by a rest phase of 10 seconds, and then a rapid phase to the left of 40 seconds. A neurologic examination revealed shoulder girhle atrophy with fasciculations across the shoulders and into the forearms. The fasciculations were also noted in the calves. The deep tendon reflexes were all active and the plantor responses were neutral to extensor at times. The patient's gait was unsteady, and he was unsteady in the Romberg position. A serum V D R L was reactive 1:16, and a T P I and F T A - A R S test were reactive. The impression was a syphilitic amyotrophic lat eral sclerosis-like picture with primary optic atro phy, total amaurosis, deafness, and periodic alter nating nystagmus. Case 6—A 34-year-old white man was referred for evaluation for nystagmus surgery. At the age of eight months he was first noted to have move ments of his eyes and head which had persisted thereafter. Although he had difficulty reading, he was able to learn words by recognition rather than by reading single letters. In this manner, he had achieved a Ph.D. degree. The family history was negative.
NYSTAGMUS
759
On examination the corrested visual acuity was 20/70 in each eye. There was 70 prism diopters of exotropia. The slit-lamp examination revealed a scleralization of the limbus and an anterior inser tion of Schwalbe's line at the temporal limbus of each eye. There was a periodic alternating nystagmus with the minimal position of nystagmus just to the right of primary gaze. This varied with the direction of the nystagmus. Thus, with the rapid phase to the right, the nystagmus was less with the head turned to the right, and increased with the head turned to the left. The nystagmus occurred in one direction for approximately 90 seconds, then slowed and nearly came to a stop. The nystagmus would then build up to a crescendo, with the rapid phase to the left for approximately 90 seconds. During the nystagmus to the left, the oscillations were dampened by turning the head to the left, and increased by turning the head to the right. The optokinetic responses were intact although asymmetrical (right 1 + , left 2-3+, up 1 + , and down 3 + ) . When the nystagmus re versed its direction the optokinetic responses were also reversed (right 2-3+, left 1 + , up 1 + , down
3+).
Neurologic examination was essentially normal with the exception of a minimal decrease in motor power in the right upper extremity, somewhat brisker reflexes in the right upper extremity, and atypical plantar responses. There were no abnormal cerebellar signs and the caloric responses were nor mal. An audiogram was normal, and serum VDRL, F T A - A B S , and T P I tests were non-reactive. The patient did not respond to trials on carbamazepine (Tegretol), trimethobanzamide HC1 (Tigacol), meclizine HC1 (Antivert), nicotinyl alcohol (Roniacol), or isoxsuprine HC1 (Vasodilan). A follow-up examination five years later re vealed that the patient's clinical picture was un changed. The impression was congenital periodic al ternating nystagmus. Case 7—A 23-year-old black man was well until March 8, 1969, when, while on patrol in Viet Nam, he sustained multiple shell fragment wounds to the head, extremities, and left leg. One fragment en tered the face on the right side, lodging in the left occipital area. A bifrontal craniotomy was per formed on the day of the injury. Cerebrospinal fluid rhinorrhea developed and a culture of the spinal fluid grew out Pseudomonas aeruginosa 12 days af ter the injury. The patient was treated with antibi otics and the cerebrospinal fluid rhinorrhea subsided after four days. On March 21, 1969, a peripheral blood smear revealed Plasmodium falciparum, and the patient was treated with antimalarial therapy. H e was then transferred to the Walter Reed Army Hospital for continued care. Upon examination the patient was found to be quadriparetic, more marked on the right, with a left peroneal nerve palsy. Spinal fluid examination re vealed a clear fluid with a lymphocytosis. The pa tient was started on a course of intravenous ampi-
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cillin. A repeated spinal fluid examination revealed a lymphocytosis, as well as a polymorphonuclear re sponse, and gramicidin was added to the therapy. The quadriparesis increased, and was accompanied by a right hemisensory hypesthesia, hypalgesia, ataxic gait, scanning speech, dysmetria, and inten tion tremor of all extremities. A right lateral and a rotary nystagmus was first noted. The patient was then transferred to the Miami Veterans Administration Hospital on July 1, 1969, where he underwent extensive speech and physical therapy. In October, 1969, he had an episode of sta tus epilepticus with right-sided seizures responding to diphenylhydantoin sodium (Dilantin) and diazepam (Valium). In February, 1970, the patient was examined by Dr. Noble J. David and classic periodic alternating nystagmus was first noted. This persisted for sev eral months. Upon re-examination in November, 1970, the periodic alternating nystagmus had cleared. The impression was postencephalitic periodic al ternating nystagmus. Case 8—A 40-year-old white man was referred because of a decrease in his vision in both eyes from 20/60 to 20/200. The patient had albinism and had always had poor vision and nystagmus. The past history and family history were negative. The ocular examination revealed the visual acu ity to be 20/200 in both eyes. The external exami nation revealed albinism, with diaphanous irides and albinotic fundi. Closer inspection of the nystagmus revealed it to be of a periodic alternating nature, with typical characteristics. Because of the paient's hypermetropia and in creasing age the visual change was explained on a presbyopic basis. The impression was albinism with congenital periodic alternating nystagmus. DISCUSSION
Periodic alternating nystagmus is a hori zontal or horizontal-rotary jerk-type nystag mus whose amplitude first increases and then decreases over a one- to six-minute period. This is followed by a quiet interlude of four to 20 seconds, and thereafter a similar se quence occurs but in the opposite direction. This cycle repeats itself over and over again. Periodic alternating nystagmus may last for years, or may disappear spontaneously. The amplitude, frequency, and speed of the nys tagmus are influenced by fatigue, emotion, sleep, and alertness, but the cycle is charac teristic for each individual. During the height of the oscillations, the visual acuity is decreased and there is oscillopsia. The ampli tude of the oscillations is increased when
OCTOBER, 1971
gaze is directed towards the side of the rapid phase, and dampened when gaze is directed away from the rapid phase. Optokinetic re sponses have a minimal effect on the nystag mus. However, cold caloric responses can abolish the nystagmus and reverse its direc tion. Duke-Elder3 stated that periodic alternat ing nystagmus was a very rare condition. As of April, 1970, there were 40 reported cases in the world literature,1 since the phenome non was first recognized by Borries4 in 1920 in a case associated with a labyrinthine fis tula. Since that report, periodic alternating nystagmus has been described in a wide vari ety of clinical conditions (Table 2 ) . Among these include cases associated with chronic otitis media,5"9 cerebral concussion or basal skull fracture,7'10"12 vertebrobasilar artery insufficiency,13 encephalitis,8'14"16 syphilitic optic atrophy,9*17 multiple sclerosis,18"19 cerebellar disease,1'9,20"21 posterior fossa le sions,9'22 Friedreich's ataxia,2 tumor of the corpus callosum,20 and congenital occur rence.23 It is evident that several of the eight cases in this report (Table 3) had etiologic diag noses similar to those seen in Table 2. Thus, both Cases 3 and 7 presented with encephali tis. Of interest was the fact that the periodic alternating nystagmus persisted in the for mer, but cleared within nine months in the latter. Two of the cases presented with total TABLE 2 CONDITIONS ASSOCIATED WITH PERIODIC ALTERNATING NYSTAGMUS
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
Chronic otitis media Cerebral trauma Vertebrobasilar artery insufficiency Encephalitis Syphilitic optic atrophy Multiple sclerosis Cerebellar disease Posterior fossa lesions Friedreich's ataxia Tumor of the corpus callosum Congenital
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PERIODIC ALTERNATING TABLE 3
CLINICAL IMPRESSION IN EIGHT CASES OK PERIODIC ALTERNATING NYSTAGMUS
1. Syphilitic myelitis 2. Demyelinizing disease with cerebellar involve ment 3. Encephalitis with cerebellar involvement 4. Total amaurosis secondary to vitreous hemor rhage 5. Total amaurosis secondary to syphilitic optic atrophy 6. Congenital 7. Encephalomyelitis 8. Congenital, associated with albinism
amaurosis. Case 5 had bilateral syphilitic op tic atrophy, whereas Case 4 developed peri odic alternating nystagmus two to three weeks following a vitreous hemorrhage. Cases 1 and 5 both had syphilis. Cases 6 and 8 should be considered congenital. Case 8 was remarkable since the patient was a universal albino, but without the usual searching nystagmus seen characteristically in such individuals. There is no previous rec ord in the literature of periodic alternating nystagmus associated with albinism. The pathophysiology of periodic alternat ing nystagmus has not been firmly estab lished. Duke-Elder 3 stated that the phenome non was most probably a central vestibular disturbance but that the mechanism was not clear. Kestenbaum9 also indicated a central vestibular mechanism as the cause of this form of nystagmus. Kornhuber 19 proposed a central vestibular disturbance following a le sion in the tegmentum. He stated that the nystagmus was caused by a bilateral lesion of parts of the rostral paramedian reticular formation of the pontomesencephalic teg mentum. Towle 1 reported the first case of periodic alternating nystagmus studied neuropathologically and found an arachnoid cyst caudal to the cerebellum, displacing the cerebellum upward, with medullary compression. His second case24 studied neuropathologically was found to hae a midline posterior fossa (Arnold-Chiari variant) lesion. These two
NYSTAGMUS
761
cases have strengthened the hypothesis that a central vestibular disturbance is present in periodic alternating nystagmus. The fact that periodic alternating nystagmus may oc cur on a congenital basis as well as following blindness due to ocular disease does not nec essarily rule out the presence of a concomi tant central vestibular lesion. It is our feeling that periodic alternating nystagmus is not as rare as it has been previ ously reported. Because of its characteristic nature it can be easily recognized merely by studying all cases of nystagmus over a more prolonged period of time than is usual, and comparing right and left lateral gaze on re peated occasions. Three of our eight cases have been recognized in the past six months. It is important to recognize this peculiar form of nystagmus because of its known etiologic factors. These include demyelinizing disease, neurosyphilis, encephalitis, blind ness, congenital anomaly, and albinism. Their recognition may often obviate the ne cessity for extensive neurologic studies. A careful history should be taken, inquir ing as to onset, exacerbations, and remis sions. A complete ophthalmic and neurologic examination, including examination of the serum FTA-ABS test and spinal fluid are suggested as the initial workup in these cases. SUMMARY
Periodic alternating nystagmus is a charac teristic neuro-ophthalmic motility disturb ance. Horizontal nystagmus with the rapid phase to the right is followed periodically by left-beating nystagmus. This pattern recurs at regular intervals. This entity is present in vertical gaze, and is an exception to the gen eral rule that horizontal nystagmus on upgaze or downgaze points to congenital nystagmus. Periodic alternating nystagmus is associated with certain clinical conditions; it is impor tant to recognize this peculiar form of ny stagmus because known etiologic factors in clude demyelinizing disease, neurosyphilis, encephalitis, blindness, congenital anomaly,
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and albinism. Diphenylhydantoin sodium ( D i l a n t i n ) t h e r a p y m e r i t s f u r t h e r t r i a l s in r e d u c i n g oscillopsia in t h i s d i s o r d e r . ACKNOWLEDGMENTS
We thank Dr. Noble J. David for Case 4 and Dr. J. Donald M. Gass for Case 8. REFERENCES
1. Towle, P. A., and Romanul, F . : Periodic alter nating nystagmus: First pathologically studied case. Neurology 20:408, 1970. 2. Gorman, W. F., and Brock, S.: Periodic alter nating nystagmus in Friedreich's ataxia. Am. J. Ophth. 33 :860, 1950. 3. Duke-Elder, S.: System of Ophthalmology, vol. 4. The Neurology of Vision. Motor and Opti cal Anomalies. St. Louis, C. V. Mosby, 1949, p. 4231. 4. Borries, G. V . : Periodisch alternierender nys tagmus bei labyrinthfistel. Int. Zbl. Laryng. 36:308, 1920. 5. Borries, G. V . : Vasculare labyrinthfistel symptome. Mschr. Ohrenheilk. 57:443, 1923. 6. Kestenbaum, A . : Periodisch umschlagender nystagmus. Klin. Mb!. Augenheilk. 84:552, 1930. 7. Ohm, J . : Periodisch umschaltender nystagmus. Arch. Ohr. Nas. Kehlkopfheilk. 145 :462, 1938. 8. Forssman, G., and Henrikkson, N. G.: Nys tagmus alternans. Practica Oto Rhino Laryng. 20: 235, 1958-1959. 9. Kestenbaum, A . : Clinical Methods of Neuro Ophthalmologic Examination. New York, Grune and Stratton, 1961, p. 381. 10. Van Rossem, A.: Nystagmus alternans. Zbl. Hals. Nas. Ohrenheilk, 13:479, 1929.
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11. Duensing, F., and Pfander, F . : Reizwiderstandsfahiger (dominanter) und reizabhangiger nystagmus alternans nach hirntrauma. Arch. Ohr. Nas. Kehlkopfheilk. 168:349, 1956. 12. Gramowsky, K. H., and Unger, E . : Traumatisch bedingter nystagmus alternans. H N O 13:22. 1965. 13. Toglia, J. U.: Periodic alternating nystag mus. Arch. Otolaryng. 88:148, 1968. 14. Cantele, G., and Grahe, K.: Nystagmus alter nans. Arch. Ohr. Nas. Kehlkopfheilk. 137:174, 1933. 15. Ohm. J.: Der Nystagmus alterans in der Begutachtung. Arch. Ohr. Nas. Kehlkopfheilk. 170: 584, 1957. 16. Bodo, G. Y., and Ozvath, K.: Electronystagmographic recording of alternating nystagmus. Ful. Orr. Gegeggogyaszat. 4:8, 1958. 17. Buys, E . : Un cas de nystagmus spontane direge alternativement vers la droite et vers la gauche. J. Neurol. ( B r u x . ) . 32:715, 1932. 18. Boenninghaus, H. G.: Nystagmus alternans. Arch. Ohr. Nas. Kehlkopfheilk. 155:605, 1949. 19. Kornhuber, H. H . : Der periodisch alternierende nystagmus (nystagmus alternans) und die enthenimung des vestibiilaren systems. Arch. Ohr. Nas. Kehlkopfheilk. 174:182, 1959. 20. Cerny, T . : Nystagmus alternans. Csl. Otolar yng. 7:331, 1958. 21. Kornhuber, H. H.: Optokinetischer nach nys tagmus, vestibulaere nebererragbarkeit und periodischer nystagmus alternans. Klin. Wschr. 40:549, 1962. 22. Barth, H . : "Ober den nystagmus alternans. Ztschr. Laryng. Rhinol. 34:600, 1955. 23. Garcia Vaquero Garrido, E., and Gutierrez Luco, E.: Un caso de nistagmo espontaneo alternante. Rev. Esp. Oto-Netiro-oftal. 15:468, 1956. 24. Towle, P. A . : Personal communication.
REPORT OF E I G H T CASES
DAVIS, M.D.,
AND J. LAWTON S M I T H ,
M.D.
Miami, Florida Periodic alternating nystagmus is infreguently recognized in this country. Towle 1 counted only 40 cases in the world literature, and of these, but three were in English. Only one case has appeared in the American oph thalmic literature.2 The following is a report of eight cases of periodic alternating nystag mus, a description of its characteristic na ture, and an etiologic differential diagnosis. C A S E REPORTS
Case 1—This 38-year-old black woman was hos pitalized because of leiomyomata of the uterus. Neuro-ophthalmic consultation was requested be cause of abnormal eye movements. On ocular exam ination the corrected visual acuity was 20/25 in both eyes. The pupils reacted 2 + to light, and there was a 4 + reaction to near. The slit lamp, fundus, and visual field findings were normal. Motility examination revealed classic periodic al ternating nystagmus. This was manifested by a hor izontal, jerk-type nystagmus whose amplitude grad ually increased to a maximum, and then similarly abated. This phase lasted 110 seconds and was followed by a 20-second quiet interlude during which there was no nystagmus. A similar sequence then followed with the rapid phase in the opposite direction. The amplitude of the oscillations in creased when she looked into the direction of the rapid phase, and decreased when she looked into the direction of the slow phase. This cycle repeated it self over and over again. Of interest was the fact that the horizontal nystagmic movements were also present in vertical gaze. During the height of the oscillations the patient's visual acuity decreased and she experienced oscillopsia. The past history revealed that at the age of 16 years she had delivered a stillborn fetus and several months later a serological test for syphilis was re active. She was treated for this with penicillin at age 16 and again at age 20. At the age of 30 years a progressive neurologic disease began which was unFrom the Department of Ophthalmology, Uni versity of Miami School of Medicine, Bascom Palmer Eye Institute, Miami, Florida. This investi gation was supported in part by Public Health Ser vice Special Fellowship 1F03EY 47,263-01 of the National Eye Institute. Reprint requests to J. Lawton Smith, M.D., Bas com Palmer Eye Institute, 1638 N.W. 10th Avenue, Miami, Florida 33136.
remitting. In 1961 she began to note aching pains in her legs and began having difficulty seeing. An opti cian told her she had "jumping eyes." There was an insidious onset of difficulty in walking and paresthesia in the extremities. Hearing loss began on the left. She was hospitalized in 1963 and thought to have multiple sclerosis. By 1967 she required a walker, and began having difficulty with bladder and bowel control. One year prior to admission she obtained a wheelchair. Neurologic examination revealed motor weak ness in the lower extremities, and a mild dystaxia of the upper extremities. Skull x-ray examination and a cervical myelogram were normal. Blood tests for syphilis revealed a weakly reactive VDRL and a 2 + reactive FTA-ABS test. COMMENT
This 39-year-old woman had a stillborn fetus at the age of 16 years, and shortly thereafter was found to have a reactive sero logical test for syphilis. She was treated for this with penicillin at the ages of 16 and 20 years. I n the past 10 years she developed progressive spastic paraplegia and periodic alternating nystagmus. She also had lightning pains in the right upper extremity, involve ment of sphincters, and a hearing loss in the left ear. T h e impression was neurosyphilis with myelitis and periodic alternating nys tagmus. A three-month course of ampicillin and probenecid (Benemid) was advised. Case 2—A 49-year-old white man was referred with a chief complaint of "attacks of blurred vi sion." At the age of 44 years he noted the onset of episodes of blurred vision and oscillopsia which would last for five to 30 seconds. These increased in frequency to approximately 100 a day. The patient also noted clumsiness in walking and slurring of his speech for the past 18 months. Three years previ ously neurologic examination, lumbar puncture, bi lateral carotid and right vertebral arteriograms were normal. A trial of corticosteroids was of no help. On examination the visual acuity in the right eye was 20/25 and in the left eye 20/30. The visual fields and ocular fundi were normal. Electronystagmography demonstrated periodic alternating nystag mus with rapid phase to the right followed by a nystagmus with the rapid phase to the left. When 757
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TABLE 1 ELECTKONYSTAGMOGRAPHIC DATA FROM CASE 2
Rapid Phase to the Right
Duration (seconds) Frequency/second
Right Gaze
Primary Gaze
134 3
111 3
the rapid phase was to the right, in right gaze the duration of the nystagmus lasted 134 seconds with an oscillation of three beats per second, in primary gaze the nystagmus persisted at 111 seconds at three beats per second, and in left gaze persisted for 81 seconds, at a rate of 1.8 beats per second. When the fast phase of the nystagmus was to the left, in right gaze the direction of each episode of nystagmus was 91 seconds with a frequency of 1.8 per second, and in primary gaze the duration was 108 seconds with a frequency of 2.2 per second, and in left gaze the duration was 113 seconds with a frequency of 4 per second (Table 1). Optokinetic responses had no effect on the nys tagmus in any direction. However, cold caloric re sponses had a definite effect in that irrigation of the ear with ice water abolished the nystagmus and re versed its direction. Neurologic examination revealed mild dysarthria, vertical ocular dysmetria, modest abnormality in heel-to-shin testing, some imbalance in walking heel-to-toe, and some dyssynergy on foot patting and pivoting. Skull x-ray films, electroencephalogram, serum F T A - A B S test, and spinal fluid examination were normal. A trial of meclizine HC1 (Antivert), isoxsuprine HC1 (Vasodilan), and carbamazepine (Tegretol) showed no improvement. Diphenylhydantoin sodium (Dilantin) decreased the duration of the cycle by 30 seconds with a slight slowing of oscillations in the rapid phase to the left and a shorter period of crescendo in the rapid phase to the right. A repeat examination two years later revealed no change. The clinical impression was periodic alternating nystagmus probably due to demyelinizing disease. Case 3—A 21-year-old black woman was hospi talized with the chief complaint of headaches, nau sea, and vomiting of 10 days' duration. Three days prior to admission she noted blurred vision and hor izontal diplopia. Two days before admission severe vertigo and a staggering gait developed. This pa tient had sickle cell anemia since the age of three years requiring numerous transfusions, and had suffered bouts of abdominal and joint pain. On admission she was lethargic and markedly ataxic. Spinal fluid examination revealed a normal opening pressure but a pleocytosis of 330 leukocytes/ml 3 , 15% polymorphonuclear leukocytes, 85% mononuclear leukocytes, and a protein of 77
Left Gaze 81 1.8
Rapid Phase to the Left Right Gaze 91 1.8
Primary Gaze 108 2.2
Left Gaze 113 4
mg%. The impression was viral encephalitis and sickle cell anemia. On neuro-ophthalmic examination the visual acuity was 20/60 in both eyes. There was a left blepharoptosis, a slight left hypertropia, and anisocoria, with the left pupil slightly larger than the right. Both pupils reacted well to light but there was a slight Marcus Gunn pupil phenomenon on the left. The optokinetic responses were right 1 + , left 1-f, up 3 + , and down nil. The fundi showed slight optic nerve pallor on the left. The most striking eye finding was periodic alter nating nystagmus. An electronystagmogram showed disorganized, short, rapid saccades rather than a well-organized nystagmus. The periodic alternating nystagmus appeared as follows: left-beating nys tagmus was 75 seconds per cycle at 28 to 35 beats per 10 seconds. There was a 10 to 15 second rest period, followed by a right-beating nystagmus of 110 seconds per cycle with 35 to 40 beats every 10 seconds. The left-beating nystagmus could be virtu ally eliminated by extreme right gaze, and the right-beating nystagmus could be reduced, though not eliminated, by extreme left gaze. The nystag mus could be increased by stimulating the visual at tention, and diminished by having the patient stare at a blank wall. The nystagmus continued with the eyes closed. The nystagmus could be modified by the optokinetic drum, although not eliminated or re versed. T h e direction of the rapid phase could be reversed by irrigation of the left ear with cold wa ter (30°C) during the left-beating nystagmus, and during right-beating nystagmus the rapid phase could be reversed to left-beating nystagmus by a similar irrigation into the right ear. The patient was treated with whole blood for the hematologic problem, and the spinal fluid cleared in the succeeding three weeks. There was a gradual improvement in the patient's severe truncal ataxia. A 10-day course of corticosteroids gave no im provement. The impression was postinfectious or viral meningoencephalitis with periodic alternating nystag mus and sickle cell disease with aplastic crisis. Case 4—A 70-year-old white man complained of "a hemorrhage in the back of my left eye." Seven years previously the patient suffered a vitreous hemorrhage in the right eye with a permanent loss of vision. Tow months previously he noted a loss of vision in the left eye. A general medical examina-
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tion and a blood glucose test were normal. H e was told that he had a macular hemorrhage. This was followed by some resorption, and another episode of bleeding from the same area, with a marked visual loss. On examination the patient demonstrated peri odic alternating nystagmus. The cycles were ap proximately 90 to 120 seconds. During the oscilla tions the patient experienced a vertiginous sensation and an illusion of movement correlated with the di rection of the rapid phase. There was past-pointing which practically disappeared during the rest peri ods. Cold calorics demonstrated unequivocal inter ruption and reversal of the nystagmus. A general neurologic examination was normal. No ocular, cranial, or carotid bruits were heard, and the patient's mental status and speech were un inhibited. All cerebellar functions and all reflexes were intact. The impression was periodic alternating nystag mus following loss of all vision on an intraocular basis. Case 5—A 72-year-old black man was seen dur ing a survey of a population with known late syphi lis. The patient was totally deaf and had gradually lost all vision in both eyes 20 years previously. This visual loss occurred over a two-year period. He had no light perception in either eye since that time. Examination revealed anisocoria, with the right pupil larger; neither pupil reacted to light. The ocular fundi revealed extreme primary optic atro phy in both eyes, with bilaterally narrowed arterioles and choroidal sclerosis. There was marked pig mentary clumping along the inferior vessels of the left eye. Applanation pressure was 17 mm H g in both eyes. Motility examination revealed periodic alternat ing nystagmus. T h e rapid phase to the right oc curred for 45 seconds, followed by a rest phase of 10 seconds, and then a rapid phase to the left of 40 seconds. A neurologic examination revealed shoulder girhle atrophy with fasciculations across the shoulders and into the forearms. The fasciculations were also noted in the calves. The deep tendon reflexes were all active and the plantor responses were neutral to extensor at times. The patient's gait was unsteady, and he was unsteady in the Romberg position. A serum V D R L was reactive 1:16, and a T P I and F T A - A R S test were reactive. The impression was a syphilitic amyotrophic lat eral sclerosis-like picture with primary optic atro phy, total amaurosis, deafness, and periodic alter nating nystagmus. Case 6—A 34-year-old white man was referred for evaluation for nystagmus surgery. At the age of eight months he was first noted to have move ments of his eyes and head which had persisted thereafter. Although he had difficulty reading, he was able to learn words by recognition rather than by reading single letters. In this manner, he had achieved a Ph.D. degree. The family history was negative.
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On examination the corrested visual acuity was 20/70 in each eye. There was 70 prism diopters of exotropia. The slit-lamp examination revealed a scleralization of the limbus and an anterior inser tion of Schwalbe's line at the temporal limbus of each eye. There was a periodic alternating nystagmus with the minimal position of nystagmus just to the right of primary gaze. This varied with the direction of the nystagmus. Thus, with the rapid phase to the right, the nystagmus was less with the head turned to the right, and increased with the head turned to the left. The nystagmus occurred in one direction for approximately 90 seconds, then slowed and nearly came to a stop. The nystagmus would then build up to a crescendo, with the rapid phase to the left for approximately 90 seconds. During the nystagmus to the left, the oscillations were dampened by turning the head to the left, and increased by turning the head to the right. The optokinetic responses were intact although asymmetrical (right 1 + , left 2-3+, up 1 + , and down 3 + ) . When the nystagmus re versed its direction the optokinetic responses were also reversed (right 2-3+, left 1 + , up 1 + , down
3+).
Neurologic examination was essentially normal with the exception of a minimal decrease in motor power in the right upper extremity, somewhat brisker reflexes in the right upper extremity, and atypical plantar responses. There were no abnormal cerebellar signs and the caloric responses were nor mal. An audiogram was normal, and serum VDRL, F T A - A B S , and T P I tests were non-reactive. The patient did not respond to trials on carbamazepine (Tegretol), trimethobanzamide HC1 (Tigacol), meclizine HC1 (Antivert), nicotinyl alcohol (Roniacol), or isoxsuprine HC1 (Vasodilan). A follow-up examination five years later re vealed that the patient's clinical picture was un changed. The impression was congenital periodic al ternating nystagmus. Case 7—A 23-year-old black man was well until March 8, 1969, when, while on patrol in Viet Nam, he sustained multiple shell fragment wounds to the head, extremities, and left leg. One fragment en tered the face on the right side, lodging in the left occipital area. A bifrontal craniotomy was per formed on the day of the injury. Cerebrospinal fluid rhinorrhea developed and a culture of the spinal fluid grew out Pseudomonas aeruginosa 12 days af ter the injury. The patient was treated with antibi otics and the cerebrospinal fluid rhinorrhea subsided after four days. On March 21, 1969, a peripheral blood smear revealed Plasmodium falciparum, and the patient was treated with antimalarial therapy. H e was then transferred to the Walter Reed Army Hospital for continued care. Upon examination the patient was found to be quadriparetic, more marked on the right, with a left peroneal nerve palsy. Spinal fluid examination re vealed a clear fluid with a lymphocytosis. The pa tient was started on a course of intravenous ampi-
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cillin. A repeated spinal fluid examination revealed a lymphocytosis, as well as a polymorphonuclear re sponse, and gramicidin was added to the therapy. The quadriparesis increased, and was accompanied by a right hemisensory hypesthesia, hypalgesia, ataxic gait, scanning speech, dysmetria, and inten tion tremor of all extremities. A right lateral and a rotary nystagmus was first noted. The patient was then transferred to the Miami Veterans Administration Hospital on July 1, 1969, where he underwent extensive speech and physical therapy. In October, 1969, he had an episode of sta tus epilepticus with right-sided seizures responding to diphenylhydantoin sodium (Dilantin) and diazepam (Valium). In February, 1970, the patient was examined by Dr. Noble J. David and classic periodic alternating nystagmus was first noted. This persisted for sev eral months. Upon re-examination in November, 1970, the periodic alternating nystagmus had cleared. The impression was postencephalitic periodic al ternating nystagmus. Case 8—A 40-year-old white man was referred because of a decrease in his vision in both eyes from 20/60 to 20/200. The patient had albinism and had always had poor vision and nystagmus. The past history and family history were negative. The ocular examination revealed the visual acu ity to be 20/200 in both eyes. The external exami nation revealed albinism, with diaphanous irides and albinotic fundi. Closer inspection of the nystagmus revealed it to be of a periodic alternating nature, with typical characteristics. Because of the paient's hypermetropia and in creasing age the visual change was explained on a presbyopic basis. The impression was albinism with congenital periodic alternating nystagmus. DISCUSSION
Periodic alternating nystagmus is a hori zontal or horizontal-rotary jerk-type nystag mus whose amplitude first increases and then decreases over a one- to six-minute period. This is followed by a quiet interlude of four to 20 seconds, and thereafter a similar se quence occurs but in the opposite direction. This cycle repeats itself over and over again. Periodic alternating nystagmus may last for years, or may disappear spontaneously. The amplitude, frequency, and speed of the nys tagmus are influenced by fatigue, emotion, sleep, and alertness, but the cycle is charac teristic for each individual. During the height of the oscillations, the visual acuity is decreased and there is oscillopsia. The ampli tude of the oscillations is increased when
OCTOBER, 1971
gaze is directed towards the side of the rapid phase, and dampened when gaze is directed away from the rapid phase. Optokinetic re sponses have a minimal effect on the nystag mus. However, cold caloric responses can abolish the nystagmus and reverse its direc tion. Duke-Elder3 stated that periodic alternat ing nystagmus was a very rare condition. As of April, 1970, there were 40 reported cases in the world literature,1 since the phenome non was first recognized by Borries4 in 1920 in a case associated with a labyrinthine fis tula. Since that report, periodic alternating nystagmus has been described in a wide vari ety of clinical conditions (Table 2 ) . Among these include cases associated with chronic otitis media,5"9 cerebral concussion or basal skull fracture,7'10"12 vertebrobasilar artery insufficiency,13 encephalitis,8'14"16 syphilitic optic atrophy,9*17 multiple sclerosis,18"19 cerebellar disease,1'9,20"21 posterior fossa le sions,9'22 Friedreich's ataxia,2 tumor of the corpus callosum,20 and congenital occur rence.23 It is evident that several of the eight cases in this report (Table 3) had etiologic diag noses similar to those seen in Table 2. Thus, both Cases 3 and 7 presented with encephali tis. Of interest was the fact that the periodic alternating nystagmus persisted in the for mer, but cleared within nine months in the latter. Two of the cases presented with total TABLE 2 CONDITIONS ASSOCIATED WITH PERIODIC ALTERNATING NYSTAGMUS
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
Chronic otitis media Cerebral trauma Vertebrobasilar artery insufficiency Encephalitis Syphilitic optic atrophy Multiple sclerosis Cerebellar disease Posterior fossa lesions Friedreich's ataxia Tumor of the corpus callosum Congenital
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CLINICAL IMPRESSION IN EIGHT CASES OK PERIODIC ALTERNATING NYSTAGMUS
1. Syphilitic myelitis 2. Demyelinizing disease with cerebellar involve ment 3. Encephalitis with cerebellar involvement 4. Total amaurosis secondary to vitreous hemor rhage 5. Total amaurosis secondary to syphilitic optic atrophy 6. Congenital 7. Encephalomyelitis 8. Congenital, associated with albinism
amaurosis. Case 5 had bilateral syphilitic op tic atrophy, whereas Case 4 developed peri odic alternating nystagmus two to three weeks following a vitreous hemorrhage. Cases 1 and 5 both had syphilis. Cases 6 and 8 should be considered congenital. Case 8 was remarkable since the patient was a universal albino, but without the usual searching nystagmus seen characteristically in such individuals. There is no previous rec ord in the literature of periodic alternating nystagmus associated with albinism. The pathophysiology of periodic alternat ing nystagmus has not been firmly estab lished. Duke-Elder 3 stated that the phenome non was most probably a central vestibular disturbance but that the mechanism was not clear. Kestenbaum9 also indicated a central vestibular mechanism as the cause of this form of nystagmus. Kornhuber 19 proposed a central vestibular disturbance following a le sion in the tegmentum. He stated that the nystagmus was caused by a bilateral lesion of parts of the rostral paramedian reticular formation of the pontomesencephalic teg mentum. Towle 1 reported the first case of periodic alternating nystagmus studied neuropathologically and found an arachnoid cyst caudal to the cerebellum, displacing the cerebellum upward, with medullary compression. His second case24 studied neuropathologically was found to hae a midline posterior fossa (Arnold-Chiari variant) lesion. These two
NYSTAGMUS
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cases have strengthened the hypothesis that a central vestibular disturbance is present in periodic alternating nystagmus. The fact that periodic alternating nystagmus may oc cur on a congenital basis as well as following blindness due to ocular disease does not nec essarily rule out the presence of a concomi tant central vestibular lesion. It is our feeling that periodic alternating nystagmus is not as rare as it has been previ ously reported. Because of its characteristic nature it can be easily recognized merely by studying all cases of nystagmus over a more prolonged period of time than is usual, and comparing right and left lateral gaze on re peated occasions. Three of our eight cases have been recognized in the past six months. It is important to recognize this peculiar form of nystagmus because of its known etiologic factors. These include demyelinizing disease, neurosyphilis, encephalitis, blind ness, congenital anomaly, and albinism. Their recognition may often obviate the ne cessity for extensive neurologic studies. A careful history should be taken, inquir ing as to onset, exacerbations, and remis sions. A complete ophthalmic and neurologic examination, including examination of the serum FTA-ABS test and spinal fluid are suggested as the initial workup in these cases. SUMMARY
Periodic alternating nystagmus is a charac teristic neuro-ophthalmic motility disturb ance. Horizontal nystagmus with the rapid phase to the right is followed periodically by left-beating nystagmus. This pattern recurs at regular intervals. This entity is present in vertical gaze, and is an exception to the gen eral rule that horizontal nystagmus on upgaze or downgaze points to congenital nystagmus. Periodic alternating nystagmus is associated with certain clinical conditions; it is impor tant to recognize this peculiar form of ny stagmus because known etiologic factors in clude demyelinizing disease, neurosyphilis, encephalitis, blindness, congenital anomaly,
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and albinism. Diphenylhydantoin sodium ( D i l a n t i n ) t h e r a p y m e r i t s f u r t h e r t r i a l s in r e d u c i n g oscillopsia in t h i s d i s o r d e r . ACKNOWLEDGMENTS
We thank Dr. Noble J. David for Case 4 and Dr. J. Donald M. Gass for Case 8. REFERENCES
1. Towle, P. A., and Romanul, F . : Periodic alter nating nystagmus: First pathologically studied case. Neurology 20:408, 1970. 2. Gorman, W. F., and Brock, S.: Periodic alter nating nystagmus in Friedreich's ataxia. Am. J. Ophth. 33 :860, 1950. 3. Duke-Elder, S.: System of Ophthalmology, vol. 4. The Neurology of Vision. Motor and Opti cal Anomalies. St. Louis, C. V. Mosby, 1949, p. 4231. 4. Borries, G. V . : Periodisch alternierender nys tagmus bei labyrinthfistel. Int. Zbl. Laryng. 36:308, 1920. 5. Borries, G. V . : Vasculare labyrinthfistel symptome. Mschr. Ohrenheilk. 57:443, 1923. 6. Kestenbaum, A . : Periodisch umschlagender nystagmus. Klin. Mb!. Augenheilk. 84:552, 1930. 7. Ohm, J . : Periodisch umschaltender nystagmus. Arch. Ohr. Nas. Kehlkopfheilk. 145 :462, 1938. 8. Forssman, G., and Henrikkson, N. G.: Nys tagmus alternans. Practica Oto Rhino Laryng. 20: 235, 1958-1959. 9. Kestenbaum, A . : Clinical Methods of Neuro Ophthalmologic Examination. New York, Grune and Stratton, 1961, p. 381. 10. Van Rossem, A.: Nystagmus alternans. Zbl. Hals. Nas. Ohrenheilk, 13:479, 1929.
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11. Duensing, F., and Pfander, F . : Reizwiderstandsfahiger (dominanter) und reizabhangiger nystagmus alternans nach hirntrauma. Arch. Ohr. Nas. Kehlkopfheilk. 168:349, 1956. 12. Gramowsky, K. H., and Unger, E . : Traumatisch bedingter nystagmus alternans. H N O 13:22. 1965. 13. Toglia, J. U.: Periodic alternating nystag mus. Arch. Otolaryng. 88:148, 1968. 14. Cantele, G., and Grahe, K.: Nystagmus alter nans. Arch. Ohr. Nas. Kehlkopfheilk. 137:174, 1933. 15. Ohm. J.: Der Nystagmus alterans in der Begutachtung. Arch. Ohr. Nas. Kehlkopfheilk. 170: 584, 1957. 16. Bodo, G. Y., and Ozvath, K.: Electronystagmographic recording of alternating nystagmus. Ful. Orr. Gegeggogyaszat. 4:8, 1958. 17. Buys, E . : Un cas de nystagmus spontane direge alternativement vers la droite et vers la gauche. J. Neurol. ( B r u x . ) . 32:715, 1932. 18. Boenninghaus, H. G.: Nystagmus alternans. Arch. Ohr. Nas. Kehlkopfheilk. 155:605, 1949. 19. Kornhuber, H. H . : Der periodisch alternierende nystagmus (nystagmus alternans) und die enthenimung des vestibiilaren systems. Arch. Ohr. Nas. Kehlkopfheilk. 174:182, 1959. 20. Cerny, T . : Nystagmus alternans. Csl. Otolar yng. 7:331, 1958. 21. Kornhuber, H. H.: Optokinetischer nach nys tagmus, vestibulaere nebererragbarkeit und periodischer nystagmus alternans. Klin. Wschr. 40:549, 1962. 22. Barth, H . : "Ober den nystagmus alternans. Ztschr. Laryng. Rhinol. 34:600, 1955. 23. Garcia Vaquero Garrido, E., and Gutierrez Luco, E.: Un caso de nistagmo espontaneo alternante. Rev. Esp. Oto-Netiro-oftal. 15:468, 1956. 24. Towle, P. A . : Personal communication.