Article abstract

Paralysisof horizontalgaze, pendular nystagmus, and progressivescoliosis were manifestations of an autosomal recessive genetic disease in four siblings. Bilateral facial myokymia with continuous facial contraction developed in the oldest patient. Electromyographicexaminationof his facial muscles after facial nerve block at the stylomastoid foramen showed absence of all muscle potentials, consistent with a supranuclear origin of the myokymia. Normality of convergence, vertical gaze, and pupillary constrictor reflex activity assured integrity of midbrain ocular motor function. Absence of horizontal vestibulo-ocular reflexes signified involvementof the pontine tegmenturn in this distinctive heredofamilial syndrome.

Familial paralysis of horizontal gaze Associated with pendular nystagmus, progressive scoliosis, and facial contraction with myokymia JAMES A. SHARPE, M.D., J. L. SILVERSIDES, M.D., and R. D. G. BLAIR, M.D.

P

aralysis of horizontal saccadic, pursuit, and vestibular eye movements is usually acquired from lesions in the pons. It can be a congenital, nonprogressive disorder, either sporadic1,*or familial, that is isolated or associated with facial palsy in Mobius' ~yndrome.~J This report documents paralysis of lateral gaze, pendular nystagmus, and progressive scoliosis in a family. The oldest patient acquired bilateral facial myokymia and continuous facial contraction. The results of electromyographic examination of his facial muscles and the ocular motor manifestations implicate supranuclear involvement in the pons.

Clinical data. Family study. Four siblings with paralysis of horizontal gaze and their family were examined in Kingston, Jamaica, in 1971 and 1973. The family was Chinese of Hakka extraction. Figure 1 shows the

From the Neuro-ophthalmology Unit, Division of Neurology, Toronto Western Hospital,and the Department of Medicine, University of Toronto. This study was supported in part by Medical Research Council of Canada grants ME 5509, MA 5404 (Dr.Sharp). Presentedin partatthe Neuro-ophthalmologySymposium of the University of Miami, Miami Beach, January 9. 1975. Received for publication March 7, 1975. Reprint requests should be addressed to Dr. Sharp at Toronto Western Hospital, 399 Bathurst Street, Toronto, Ontario, Canada.

pedigree. Consanguinity could not be detected. The parents believed that all the children had full eye movements in early childhood. In 1974, two of the affected patients (111-3, 111-4) and three of their brothers (111-6, 111-8, 111-9)emigrated to Toronto, where they were examined at the Neuro-Ophthalmology Clinic, Toronto Western Hospital. A Jamaican physician first documented gaze paralysis in one brother (111-3, figure l), whom he examined for scoliosis in early adolescence. Examination of the other children showed scoliosis and horizontal gaze palsy in two (111-4 and 111-7). The same physician reported that the youngest child (111-10) had full eye movement when first examined at age 2. By his fourth year, this boy had early scoliosis and partial limitation of lateral gaze. In 1973, when he was 14, his horizontal eye movements were paralyzed. We found pendularnystagmus in all fourofthe propositi and in one brother (111-8) who did not have gaze paralysis or scoliosis. Milner, Clegg, and WeatheralP identified genetically independent disorders of hemoglobin synthesis in this family. One brother (111-8, figure l), his father (11-2). an uncle (11-3), and six children, not shown in figure 1, had an abnormal elongated alpha chain structure, named hemoglobin Constant Spring after the road in Kingston where the family lived. Other family members, including the propositi, had alpha-thalassemia- 1 trait or NEUROLOGY 25: 1035-1040,Novsmbsr1975 1035

Familial paralysis of horizontal gaze

III

4 scoLlosls c]0

GAZE PARALYSIS, NYSTAGMUS,

[I0 Hb CONSTANT SPRING

00

DEAD

II - - - :

/-.\

NOT EXAMINED, REPORTED TO BE NORMAL

‘-’

1 I

I

CLASSICAL oc THALASSEMIA TRAIT THALASSEMIA TRAIT

NORMAL

---1

0 x

NYSTAGMUS

Figure 1. Pedigree of family.

beta-thalassemia trait. Inheritance of both an alpha-thalassemia- 1 trait and hemoglobin Constant Spring produced clinical manifestations of hemoglobin H disease in one brother (111-8) and two cousins, previously reported in detail. The abnormal hemoglobins assorted independently. It was apparent that the hematologic abnormalities were not connected with the neuro-ophthalmic disorder reported here The propositi. Case 1. In a 30-year-old man (111-3, figure 1) progressive scoliosis of the thoracic spine developed after age 10 and required spinal fusion at age 1 3 . His mother stated that his gestation and birth were normal and that eye movements were full in early childhood. A physician detected absence of lateral gaze in early adolescence, and the patient then realized that he turned his head to look to either side. He never experienced illusionary movement of the environment. He had worn glasses for nearsightedness since age 1 1 . For 3 years before our examination in Jamaica in 1973, he had a tight pulling sensation of his face, mainly about the left side of the mouth. For about 2 years, he had been aware of involuntary flickering movements of his face. The patient was admitted to the neurology service of the Toronto Western Hospital in November 1974. General physical examination showed severe thoracic scoliosis convex to the left. Neurologic examination revealed normal intellectual function. Muscle tone, strength and coordination were normal. Tendon reflexes were active, the jaw jerk was brisk, and the patient had unsustained clonus of both ankles. Superficial reflexes were normal, and plantar reflexes were flexor. There were no sensory deficits. The visual acuity in each eye was 20/80 with correction for myopic astigmatism, and near vision was Jaeger 2 bilaterally. Color vision and the visual fields were normal. His pupils were 5 mm and briskly reactive to light and near stimuli. The cornea and ocular media were normal on slit lamp examination. 1036 NEUROLOGY November 1975

Fundoscopy showed myopic crescents at the disks and enhanced visibility of choroidal vessels. The maculae and peripheral retinae were normal. Lateral gaze was absent. Vertical pursuit was saccadic but upward, and downward excursion of the eyes was full. Caloric and rotational vestibular stimulation and oculocephalic maneuvers did not overcome the paralysis of lateral gaze. Full lateral excursion of each eye was accomplished only by passive forced duction. The patient had horizontal pendular nystagmus of very low amplitude in all positions of vertical gaze. The oscillations were not always obvious on inspection of the eyes, but fundoscopy showed them to be continuous. Small-amplitude head oscillations occurred during maximal visual effort. Convergence was normal, and it damped the nystagmus. His facial muscles were contracted, with deepening of the nasolabial folds, retraction of the angle of the mouth, and inconstant narrowing of the palpebral fissures. The facial contraction was consistently more evident on the left side (figure 2). Small vermiform movements occurred randomly over both sides of the face and platysma, and less frequent larger flickering movements undulated over the brow and lower face. These involuntary movements did not involve specific groups of facial muscles, nor did they produce an organized pattern of facial movement. Voluntary and emotional movements were full and without weakness, abnormal synkinesis, or associated movements. He had normal salivation, lacrimation, and taste. There was no ptosis. Hearing and the fifth, ninth, tenth, eleventh, and twelfth cranial nerves were normal. E l ~ c ~ r o m y o g r u p h yElectromyographic . examination of the facial muscles was performed with concentric bipolar needle electrodes. During attempted complete relaxation, continuous, spontaneous muscle potentials were recorded from facial muscles on either side. These potentials were indistinguishable from normal motor unit potentials. Superimposed on this continuous low-amplitude interference pattern of distant motor units were intermittent bursts of repetitive muscle potentials (figure 3 ) . These rhythmic motor units had discharge rates of 15

Figure 2. Case 1. Facialcontraction with the patient at rest, showing retraction of angle of mouth on the left side with mild narrowing of palpebral fissure. to 65 per second and occurred at intervals of 1 to 8 seconds with burst durations of 1 to 4 seconds. Each motor unit potential showed a stereotyped pattern of repetition that was asynchronous with adjacent repetitive motor unit potentials or those recorded in facial muscles on the opposite side. There was no change in the pattern of the spontaneous discharges with

initiation of voluntary movement. Voluntary and mimetic facial movements were full clinically, but on needle electrode examination, a reduced number of motor units we= active during maximal effort. Voluntary motor unit potentials were normal in amplitude and duration in all facial muscles. Facial nerve stimulation at the angle of the jaw showed a normal latency (2.2 msec), and the amplitudes of the muscle action potentials were normal (9 mv) bilaterally. Intravenously administered diazepam (10 mg) produced no change in the vermiform facial movements or in the rhythmic periodic muscle activity recorded on the electromyogram. Lidocaine (Xylocaine@)infiltration of the left facial nerve at the level of the stylomastoid foramen stopped the myokymia and contraction. Needle electrode examination of left facial muscles showed no evidence of denervation (figure 4). All spontaneous and voluntary muscle potentials were absent for the duration of the block (1 hour). Skull x-rays were normal, without evidence of basilar impression. X-rays of - the spine showed extensive rotary scoliosis, extending from the sixth cervical level to the upper lumbar vertebrae. No underlying abnormalities of the vertebrae were present. Pneumoencephalography and computerized axial tomography showed normal brain stem and cerebellar size and contour. An electroencephalogram was normal. Audiograms showed no impairment of hearing. The cerebrospinal fluid had two white cells per milliliter and a protein concentration of 14 mg per 100 ml. An electrocardiogram was normal. Hemoglobin was 12.4gmper l00m1, andreticulocyteswere0.6percent. The white blood cell count was 6,300 per milliliter with a normal differential count, and platelets were normal. Peripheral blood films showed erythrocyte microcytosis, hypochromia, and bizarre poikilocytes. Hemoglobin electrophoresis showed hemogIobin A and increased hemoglobin A2 and hemoglobin F consistent with beta-thalassemia trait. The VDRL test was negative. Serum enzymes, calcium, and phosphorus were normal, as were urinalysis and urinary amino acid chromatography. Case 2. A 28-year-old man (111-4, figure 1 ) was not aware of

Figure 3. Electromyogram from orbicularis oris showing rhythmic repetitive motor unit potentials occurring spontaneously.

I

20msec

Figure 4. Electromyograrn from orbicularis oris after facial nerve block.

10 m sec NEUROLOGY November 1975 1037

Familial paralysis of horizontal gaze

Figure 5. Case 2. Upward (a) and downward (c) gaze is full. Convergence is normal (e). Attempted lateral gaze to right (d) and left (9 shows substituted convergence.

impairment of lateral gaze until age 12, but his siblings noticed impaired eye movements after his eighth year; he had to turn his head to look to the side. At the time of our examinations in 1971 and 1973, lateral eye movements were absent. One year later, the patient crossed his eyes when lateral gaze was tested with his head fixed. However, he habitually preferred to turn his head. He never had facial twitching. He had worn glasses for myopia since age 12. He denied oscillopsia. Curvature of the spine began at age I0 and progressed despite insertion of a Harrington rod at age 23. General physical examination in November 1974 showed severe thoracic scoliosis convex to the right. Neurologic examination was normal apart from the cranial nerve findings. The patient exhibited slowness in starting volitional and emotional movements of his face, particularly on the right side. Once initiated, facial movement and strength were full. No spontaneous movements or abnormal synkinesis of the face was present. Distance visual acuity was 20/40 with -2.5 spherical correction in each eye, and near acuity was Jaeger 1. Color vision and the visual fields were normal. Fundoscopy showed onlv myopic crescents of the disks. The patient had paralysisof lateral gaze. Attempted fixation to either side produced convergence, pupillary constriction, and accommodation instead of lateral gaze (figure 5). Ocular retraction did not accompany this substituted convergence. Cold caloric irrigation of either ear and oculocephalic maneuvers did not overcome the lateral gaze palsy. Full abduction was achieved by forced duction under topical anesthesia. Upward and downward gaze was full, but vertical pursuit was saccadic. Convergence amplitudes were normal. He had conjugate horizontal oscillations of the eyes in all positions of vertical gaze. Head oscillations occurred during intense efforts to fixate. Convergence in forward and attempted lateral gaze stopped the nystagmus. Optokinetic stimulation to either side produced convergence without nystagmus. Vertical optokinetic responses were reduced. Skull x-rays were normal. X-rays of the spine showed

1038 NEUROLOGY November 1975

scoliosis with curvature extending from the fifth cervical to the first lumbar vertebra and a Harrington rod between T3 and L1. No defects of vertebral structure were present. Audiograms and an electrocardiogram were normal. Hemoglobin was 12.2 gm per 100 ml, white cell count was 3,000, and platelets were normal. Peripheral blood films showed hypochromia, bizarre poikilocytes, and target cells. Hemoglobin electrophoresis showed a pattern of beta-thalassemia trait identical to that in case 1. Chromosomal analysis of peripheral white cells by trypsin banding was normal. Case 3. In a 23-year-old woman (111-7, figure I ) , scoliosis began after age 8. She had paralysis of lateral gaze that was complete when examined in Jamaica in 1973. Its precise duration could not be determined. Her parents thought that her eye movements were full in early childhood. General physical examination showed severe thoracic scoliosis. Her intellect was normal. The corrected visual acuity was 20120 in each eye. Pupillary reactions were normal. The visual fields were full and the fundi were normal, apart from myopic crescents at the disks. Lateral gaze was absent. Vertical excursions and convergence were normal. The patient had horizontal pendular nystagmus of low amplitude in all positions of vertical fixation. Facial movements were normal, without contraction or myokymia. Neurologic examination was otherwise normal. Case 4. In the youngest child (111-10, figure l ) , age 14, mild scoliosis had developed in his fourth year. A physician reported normal lateral eye movements at age 2 and some impairment of lateral gaze at age 4. Examination in 1971 and 1973 showed severe scoliosis convex to the left. Distance visual acuity was 20/60 in the right eye and 20/40 in the left eye with correction for high myopia. Near visual acuity and pupillary reactions were normal. The fundi showed myopic crescents, with no other degenerative changes. Gaze was absent in both horizontal directions. Vertical gaze and convergence were full. Lateral eye movements were not elicited by doll’s head maneuvers. He had low amplitude, horizontal pendular nystagmus in forward, upward, and downward gaze. Facial movements were normal, and there were no other neurologic abnormalities.

A 22-year-old brother (111-8, figure 1) had nystagmus, first detected in 1971. He did not have oscillopsia. Distance visual acuity was 20/25 in each eye with correction for myopic astigmatism, and near acuity was Jaeger 1. Gaze was full in all directions, and convergence was intact. His nystagmus was horizontal in all positions of fixation and pendular through a wide neutral zone. On extreme lateral gaze, he had jerk nystagmus in the direction of deviation. The null region of best visual acuity and minimum nystagmus intensity was straight ahead. The nystagmus stopped during convergence. Optokinetic nystagmus was impaired in both lateral directions. Vertical optokinetic responses were normal. This patient did not have scoliosis, and neurologic examination was normal.

Discussion. Paralysis of horizontal gaze, pendular nystagmus, and scoliosis in four members of this Chinese family were expressions of a genetic disease. Absence of these abnormalities in three antecedent generations and involvement of patients of both sexes indicated an autosomal recessive pattern of inheritance. Dretakis and Kondoyannis' recently reported a syndrome of progressive scoliosis, ophthalmoplegia, and horizontal nystagmus in siblings of two Greek families. In one family, mental deficiency was noted, and in both, upward and downward gaze was mildly restricted, in contrast to our patients. Despite minor phenotypic variation, that disorder appears to be nosologically identical to the syndrome described here. The lateral gaze paralysis was complete when we first examined these patients. Earlier medical history6 and the parents' testimony notwithstanding, the ophthalmoplegia may have been present at birth and not detected until childhood or adolescence. The facial contraction and myokymia in the oldest patient and the scoliosis in all four patients were, however, acquired and progressive manifestations that distinguish this disorder from congenital, nonprogressive syndromes of horizontal gaze paralysis. 1-4 All four of the propositi had scoliosis that progressed after childhood and adolescence. None had signs of segmental spinal neuromuscular involvement to specify a neurogenic mechanism. Familial studies of progressive scoliosis without recognized neuromuscular cause have implicated autosomal dominant o r multifactorial i n h e r i t a n ~ e . ~In? this ~ family, both the scoliosis and the ocular motor disorder were pleiotropic effects of autosomal recessive inheritance. Facial myokymia and associated continuous facial contraction were progressive for three years in the oldest patient (case 1). The intensity of facial contraction was variable on the right side but persistent on the left. Continuous facial contraction and myokymia are uncommon phenomena that are usually associated with multiple scIerosis1° o r pontine neoplasms. l - l C o m p u t e r i z e d axial t o m o g r a p h y a n d pneumoencephalography did not show evidence of a structural brain stem lesion in our patient. Electrophysiologic evidence has suggested a central

origin for this facial dyskinesia." It could result from an irritative process affecting the facial nuclei o r intramedullary axons. Andermann et all proposed oscillating depolarization of somatodendritic membranes of facial motor neurons. Sethi, Smith, and Kalyanaraman' provided compelling evidence for its supranuclear origin in a pathologic study of facial myokymia from metastatic tumor in the pons that spared the facial nucleus and fascicle. Electromyographic examination in our patient demonstrated asynchronous bursts of periodic muscle potential on both sides of the face. A background of continuous potentials from distant motor units was the electromyographic correlate of sustained facial contraction. Abolition of all muscle potentials after peripheral facial nerve block as demonstrated by Tenser and Corbett" and in our case is consistent with a supranuclear disturbance of facial innervation. Absence of fibrillation potentials implied integrity of the facial nuclei and axons. The slowness of initiation of facial movement and decreased number of motor units active during maximal contraction suggested defective recruitment of motor neurons. O'Conner, Wynn, Perry, and DaviesI4 postulated that isolation of facial motor neurons caused the continuous facial contraction. Degeneration of supranuclear inhibitory and excitatory fibers or interneurons may be responsible for the facial contraction and myokymia in case 1. T h e f o u r p r o p o s i t i had horizontal pendular nystagmus in all positions of vertical gaze. The nystagmus impaired distance visual acuity. Convergence damped the nystagmus and improved near acuity in each case. We could not establish the duration of nystagmus in these patients. Pendular nystagmus was the only neurologic disorder in one brother (111-8, figure 11, in whom we could observe eye movements through full excursions. The nystagmus did not exhibit binocular disparity of direction and amplitude or vertical components often apparent in acquired pendular nystagmus from brain-stem disease. l 5 Neither he nor the propositi had oscillopsia. The oscillations were characteristic of congenital nystagmus. This patient was old enough to have the gaze palsy and scoliosis manifested in four of his siblings. We attribute their absence to delayed or reduced expressivity of the same pleiotropic genes that afflicted the propositi. The gaze paralysis can be explained by bilateral involvement of the paramedian pontine reticular formation that mediates ipsilateral pursuit and saccadic eye movements. l 6 9 I 7 Failure of vestibular stimulation to move the eyes laterally signified disruption of the vestibulo-ocular reflex arc at the level of the caudal paramedian pontine reticular formation.18y19 Convergence with pupillary constriction and accommodation was substituted for horizontal version in case 2 . The patient used cross fixation to look to either side. Substitution of convergence can occur in congenital gaze paralysis1 or in gaze paralysis acquired from pontine lesions.20J1 Retraction of the nonfixating convergent eye, sometimes evident in the congenital form, was not present in case 2. Sparing vertical gaze, pupillary NEUROLOGY November 1975 1039

Familial paralysis of horizontal gaze

constrictor reflex activity, upper lid function, and convergence assured normality of midbrain ocular motor function. Neurologic system degenerations can produce predominant involvement of the brain stem reticular formation and supranuclear ophthalmoplegia. 2 2 Progressive supranuclear palsy exemplifies such a disorder with early paresis of vertical eye movements.23 The syndrome described here may be explained by degeneration in the pontine tegmentum. This familial disorder differs from all the neurodegenerative diseases associated with external ophthalmoplegia wherein ocular movements are symmetrically impaired. 2 4 Horizontal gaze paralysis, pendular nystagmus, progressive scoliosis, and facial contraction with myokymia are distinctive features of a unique heredofamilial syndrome. Acknowledgments Dr. D. M. C. Sutton and Dr. D. Pantalony performed the hematologic examinations. Professor J. S. R. Golding, of the University of the West Indies, provided historical information. REFERENCES 1. Zweifach PH, Walton DS, Brown RH: Isolated congenital horizontal gaze paralysis. Arch Ophthalmol 81 345-350,1969

2.Taumer R, Schellenbeck R, Schmidt D: Kongenitale bilaterale horizontale Blinckparese mit erhaltener konvergenz. Albrecht von Graefes Arch Klin Ophthalmol 187299-309,1973 3.Francois J: Congenital ophthalmoplegias. In Brunette JR, Barbeau A (Editors): Progress in Neuro-Ophthalmology. Amsterdam, Exerpta Medica Foundation, 1969,vol 2,pp 387-421 4.Van Allen MW, Blodi FC: Neurologic aspects of the Mbbius syndrome. Neurology (Minneap) 10:249-259, 1960 5. Danis P: Les paralysies oculo-faciales congenitales. Ophthalmologica 110:113-137, 1945 6.Milner PF, Clegg JB, Weatherall DJ: Haemoglobin H disease due to a unique haemogbbin variant with an elongated alpha chain. Lancet 1 :729-732, 1971

1040 NEUROLOGY November 1975

7.Dretakis EK, Kondoyannis PN: Congenital scoliosis associated with encephalopathy in five children of two families. J Bone Joint Surg (Am)

56A11747-I750,1974 8. Riseborough EJ, Wynne-Davies R: A genetic survey of idiopathic scoliosis in Boston, Massachusetts. J Bone Joint Surg (Am) 55A:

974-982, 1973 9.Filho NA, Thompson MW: Genetic studies in scolbsis. J Bone Joint Surg (Am) 53A:199,1971 10. Andermann F, Cosgrove JBR, Lloyd-Smith DL, et al: Facial myokymiain multiple sclerosis. Brain 8431-44, 1961 11. Tenser RB, Corbett JJ: Myokymia and facial contraction in brain stem

glioma. An electromyographic study. Arch Neurol 30:425-427,1974 12.Sogg RL, Hoyt WF, Boldrey E: Spastic paretic facial contracture. Neurology (Minneap) 13:607-612, 1963 13. Sethi PK, Smith BH. Kalyanaraman K: Facial myokymia: A clinicopathological study. J Neurol Neurosurg Psychiatry 37:745-749,

1974 14.OConnor PJ, Wynn Parry CB, Davies R: Continuous muscle spasm in intramedullaty tumours of the neuraxis. J Neurol Neurosurg Psychiatly

29510-314,1966 15. Aschoff JC, Conrad B, Kornhuber HH: Acquired pendular nystagmus with oscillopsia in multiple sclerosis: A sign of cerebellar nuclei disease. J Neurol Neurosurg Psychiatry 37570-577,1974 16. Daroff RB, Hoyt WF: Supranuclear disorders of ocular control systems in man: Clinical, anatomical and physiological correlations. In Bach-Y-Rita P, Collins CC, Hyde JE (Editors): The Control of Eye Movements. New York, Academic Press, Inc, 1971,pp 175-235 17.Keller E L Participation of medial pontine reiicular formation in eye movement generation in monkey. J Neurophysiol 37316-332,1974 18.Cohen B, Komatusuraki A, Bender MB: Electrooculographic syndrome in monkeys after pontine reticular formation lesions. Arch Neurol

18:7&92, 1968 19. Sharp JA, Rosenberg MA, Hoyt WF, et al: Paralytic pontine exotropia. Neurology (Minneap) 24:1076-1081, 1974 20. Burian HM, Van Allen MW, Sexton RR, et al: Substitution phenomena in congenital and acquired supranuclear disorders of eye movement. Trans Am Acad Ophthalmol Otolaryngol 693105-1114,

1965 21. Kestenbaum A: Clinical Methods of Neuro-ophthalmologic Examination. New York, Grune & Stratton, Inc, 1961,p 330 22.Neumann MA: Pathologyof the reticular formation. In Minkler J (Editor): Pathology of the Nervous System. New York, McGraw-Hill Book Company, vol 1, pp 696-707,1968 23.S e e k JC, Richardson JC, Olszewski J: Progressive supranuclear palsy. Arch Neurol 10333-359,1964 24.Drachman DA: Ophthalmoplegia plus. Arch Neurol 18:654-674, 1968

Familial paralysis of horizontal gaze: Associated with pendular nystagmus, progressive scoliosis, and facial contraction with myokymia JAMES A. SHARPE, J. L. SILVERSIDES and R.D.G. BLAIR Neurology 1975;25;1035 DOI 10.1212/WNL.25.11.1035 This information is current as of November 1, 1975 Updated Information & Services

including high resolution figures, can be found at: http://www.neurology.org/content/25/11/1035.full.html

Citations

This article has been cited by 7 HighWire-hosted articles: http://www.neurology.org/content/25/11/1035.full.html##otherarticles

Permissions & Licensing

Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions

Reprints

Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus

Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 1975 by the American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.