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Show Journal of Neuro- Ophthalmology 15( 2): 63- 69, 2995. © 1995 Raven Press, Ltd., New York Editorial Uhthoff and His Symptom John B. Selhorst, M. D., and Robert F. Saul, M. D. At the turn of the last century, Wilhelm Uhthoff was a renowned clinical neuro- ophthalmologist, and probably the first clinician whose entire career was devoted to this discipline. His achievements are among those that mark the commencement of contemporary neuro- ophthal-mology. Uhthoff's symptom of visual loss with exercise is most frequently associated with optic neuritis. The symptom carries a major risk for recurrence of optic neuritis and development of multiple sclerosis. This study and its companion in this publication show that, independently, a metabolic byproduct of exercise increases in body temperature or causes a reversible conduction block in demyelinated optic nerves and result in temporary loss of vision. Key Words: Uhthoff's symptom- Exercise- Hyperthermia- Pattern visual evoked potentials- Conduction block. While conducting a study to determine the effect of hyperthermia on pattern visual evoked potentials ( PVEPs), which is reported in another part of this journal, we wondered if exercise had the same or a different effect on PVEPs as did increased temperature. This curiosity was inspired by several patients who told us about their blurry vision with exercise, a s y m p t om that was d e s c r i b e d by Uhthoff > 100 years ago ( 1). As the study of hyperthermia progressed, we were frequently asked, " Who was Uhthoff?" " Why is his symptom important?" and " What causes it to occur?" Consequently, we delved into the past, and we performed PVEPs on four p a t i e n t s in whom changes in vision, temperature, and metabolism were carefully recorded during exercise- induced visual loss. Although briefly reported before ( 2,3), the historical perspective of Wilhelm Uhthoff's accomplishments, the relevance of his symptom to current clinical practice, and the importance of the exercise- induced PVEP changes warrant further attention. Manuscript received December 2, 1994. From The Departments of Neurology and Ophthalmology ( J. B. S.), Saint Louis University Health Sciences Center, St. Louis, Missouri; and Geisinger Medical Center ( R. F. S.), Danville, Pennsylvania, U. S. A. Address correspondence and reprint requests to Dr. John B. Selhorst, Department of Neurology, 3635 Vista at Grand Blvd., St. Louis, MO 63110- 0250, U. S. A. HISTORY OF WILHELM UHTHOFF Uhthoff was born in 1853 in Warin, which is in the German province of Mecklenburg, near the Black Sea ( 4). He was one of 10 children. Because the custom at that time was to obtain higher education at various universities, Uhthoff's premedi-cal studies were obtained in Tubingen and Gottin-gen. His uncle, who was a pediatrician, inspired him to enter medicine. He earned his medical degree in Berlin, where he became closely acquainted with the renowned pathologist, Rudolf Virchow. He remained in Berlin, which at the time was the cultural and scientific center of central Europe. In 1878, Uhthoff began his training in ophthalmology 63 64 }. B. SELHORSTAND R. F. SAUL in the private clinic of Professor Schoeler. Uhthoff soon became his chief resident. In his memoirs, he wrote that he worked 12- to 14- h days, 7 days a week, which helped him repay the loans he took for his education. Uhthoff had a natural curiosity and penchant for investigating clinical material. As a young ophthalmologist, he championed the role of ophthalmoscopy in the diagnosis of systemic disease and he experimented with fluorescein. Despite his demanding schedule, he studied the relationship between illumination and visual acuity at Helm-holtz's Institute of Physics. His lifetime interest in neuro- ophthalmology was engendered when he was appointed as a consultant to Westphal's neurology clinic in Berlin's Charite Hospital. Inspired by Westphal, a cadre of curious and later well-known neurologists attended this clinic. Among them was Hermann Oppenheim, who became a leader of German neurology at the turn of the century and whose textbook on neurologic disorders underwent seven editions ( 5). Other neurologists who attended this clinic made contributions that are well known to many current clinicians: Wallenberg ( lateral medullary infarction), Thomsen ( myotonia congenita), and Mobius ( congenital bulbar paralysis, ophthalmoplegic migraine) ( 6). A similar consulting relationship developed in London between the ophthalmologist, Marcus Gunn, and the neurologists at the National Hospital, Hughlings- Jackson, and Gowers. In Paris, too, the relationship between the eye and the brain was bridged by Henri Parinaud, who served Charcot and his collaborators at the famed Salpetriere. Early on, Uhthoff distinguished himself as a tireless worker and astute clinician. Many of his observations were original or important collaborative reports in a time when deductive clinical diagnosis was flourishing. Today, components of these contributions often reappear in our medical literature. His initial publications were straightforward, e. g., in 1885, he described the ocular signs accompanying facial palsy. In the same year, during a swirl of ophthalmologic interest in topical cocaine, he was the first to suggest that cocaine would be useful as a pharmacologic test for Horner's syndrome ( H. Stanley Thompson, personal communication). In 1886, he reported on the occasional benignity of sixth nerve palsies. Subsequently, his works became more detailed. In 1887, he wrote about 250 cases of alcoholic amblyopia. During this period, he recognized an association between optic neuritis and multiple sclerosis. In a 1890 paper titled, " Examinations of Disturbances of the Eye Occurring in Multiple Sclerosis" ( 1), he detailed his collaboration with Gnauck, a neurologist, with whom he examined 100 patients. In three patients, he noted that physical exertion and fatigue caused a desaturation of color vision. The phenomenon that today bears his name is best recognized in a fourth patient ( XVIII). After having the patient walk around his examining room, Uhthoff demonstrated a decrease in vision from 6/ 200 and 1/ 6 in the right and left eyes to 4/ 200 and 14/ 200, respectively. In the same paper, he also described patients with internuclear ophthalmoplegia and horizontal gaze palsy. In 1890, Uhthoff was appointed a full professor of ophthalmology at Marburg. With much of the material being brought from Berlin, a monumental study was published in 1893, in which the eye signs of 2,500 patients with neurosyphilis were delineated. In subsequent years, Uhthoff became more prolific. Among his papers are those concerning color scotomas, choroidal metastases, pho-topsias with retinal detachment, optic atrophy subsequent to encephalitis, visual field defects occurring with migraine and vascular cerebral infarctions, binasal hemianopia resulting from a pituitary tumor, and the evolution of optic atrophy in tower skull. In 1896, Uhthoff was named professor of ophthalmology in Breslau. He had gained a reputation for being a meticulous investigator who had little regard for speculation. His daily rounds were renowned for his extensive efforts to account for all signs and symptoms. Moreover, his compassionate and considerate manner with patients and polite words for associates were widely acknowledged. During these years, he assiduously collected pathological specimens with clinical correlations, a habit which suggests the early influence of Virchow. These specimens were used effectively in his lectures to students and residents and in later publications. His didactic skills were complimented by a visiting American ophthalmologist who referred to him as the best teacher in all of Europe. He remained in Breslau despite subsequent petitions from Vienna, Bonn, and Berlin ( 3,5). By the turn of the last century, Uhthoff was widely recognized in the field of ophthalmology. In the first English textbook of neuro- ophthalmology, The Eye and Nervous System, by Posey and Spiller ( 1906), Uhthoff is cited more than 30 times ( 7). He joined the editorial board of Klinische Monatsblatter and, with Axenfeld, is credited with raising its standards ( 8). In 1914, he was invited to England as the Bowman lecturer ( 9). In his address, he detailed his experience with patients having papilledema from cerebral tumors. In those / Neuro- Ophthalmol, Vol. 15, No. 2, 1995 UHTHOFF AND HIS SYMPTOM 65 days, 38% of such patients were blind or had severe loss of vision before death. He also allowed that the optic nerve sheath splitting procedure of de Wecker and others was ineffective because the discharge of cerebrospinal fluid was not permanent. He considered the period in Breslau his most satisfying ( Fig. 1). His work there culminated in the publication in 1915 of his 775- page treatise, Eye Symptoms in Diseases of the Nervous System, which was a well- illustrated, separate volume in the Graefe- Saemich Handbuch. Later in his career, Uhthoff was named chairman of the German Ophthalmologic Congress. He died in 1927. Not surprisingly, in his eulogy, Bielschowsky ( 4), a professor of ophthalmology at Breslau, referred to Wilhelm Uhthoff as the " true originator" of clinical neuro- ophthalmology. UHTHOFF'S SYMPTOM Uhthoff's symptom was unappreciated for many years. However, in the post- World War I era, interest developed in fever therapy for neurosyphilis and multiple sclerosis, and this effort brought attention to the reversible effect of high temperatures on the nervous system. Then, in 1947, Franklin and Brickner ( 10) described a woman who reported blurred vision after swimming. In 1951, Guthrie ( 11) documented loss of vision during a hot bath test that was used to induce signs of multiple sclerosis. In the following year, a deleterious effect of exercise and increased temperature on symptoms of multiple sclerosis was reported ( 12). In 1955, Edmund and Fog ( 13) described 11 patients who complained of blurry vision with exercise and who lost vision after being placed in an air- heated barrel. Subsequently, heat was commonly used to induce added focal neurologic dysfunction and assist in the diagnosis of multiple sclerosis ( 14,15). In 1961, Ricklefs ( 16) first acknowledged Uhthoff's original description when reporting a patient who lost vision with exercise. Additional reports of Uhthoff's symptom soon followed in the literature ( 17- 19). More often, the reversible effect of exercise and elevated temperature on vision was referred to interchangeably and assumed to be causally related. In many clinical studies, complaints of transient visual loss are recorded as they occur singly with exercise, heat, fatigue, or anxiety or in combination with each other. Uhthoff's symptom is an uncommon presenting complaint. When it does occur, a mild degree of optic atrophy is usually present ( 19). The symptom is occasionally bilateral. In some patients it develops as early as 30 s after onset of exercise. For example, one of our patients reported the symptom after running from one end of a basketball court to the other, and a second patient said that his vision blurred after lightly jogging only 200 feet. Generally, obscured vision persists for only several minutes after exercise ceases, but occasionally it lasts for 5= h ( 18). When a history of transient blurring of vision is regularly sought from patients who have optic neuritis, Uhthoff's symptom is commonly detected. McAlpine and Compston ( 12) reported momentary loss of vision in one third of patients, and Edmund and Fog ( 13) obtained a similar history in 25% of patients. Perkin and Rose ( 20) reported transiently blurred vision in 33% of 125 patients; in 11% of these patients, the blurred vision occurred with exercise. In a prospective study, transient vi- FIG. 1. Wilhelm Uhthoff ( seated, center) with his assistants in Breslau. On his left is his nephew, Karl August Uhthoff. / Neuw- Ophthalmol, Vol. 15, No. 2, 1995 66 ], B. SELHORST AND R. F. SAUL sual loss was reported in 49% of 81 patients, of which 52% had been associated with exercise ( 20). Clearly, Uhthoff's symptom is very commonly associated with optic neuritis. Sometimes it develops during an acute attack, but mostly it appears after recovery from optic neuritis. Infrequently, Uhthoff's symptom is reported in other optic neuropathies as well. These include compression by tumor or Friedreich's ataxia ( 14), Leber's hereditary optic neuropathy ( 22), chloramphenicol optic neuropathy ( 23), and posterior ciliary artery insufficiency from internal carotid artery occlusion or giant cell arteritis ( 24). Some colleagues have also noted the symptom in patients with dysthyroid eye disease. In our experience, the phenomenon continues only temporarily for several months to several years. This resolution suggests remyelina-tion or repair of denuded optic nerve fibers by some other process. Unfortunately, the symptom is sometimes halted by further demyelination of the optic nerve. Surprisingly, exogenous factors have also been shown to transiently improve vision. This inverse phenomenon has been corroborated by recovery of the PVEP with simultaneous reduction of tympanic membrane temperature after ingestion of ice water ( 25). Reversal of the conduction block shown by PVEP and an increase in visual acuity have also been documented after ingestion of warm, dark beer ( 26); in this report, the causal nature of this improvement, i. e., temperature or alcohol, could not be established. In a recent Boston study of 81 patients with optic neuritis ( 21), PVEPs showed conduction delays whether or not Uhthoff's symptom was present. However, magnetic resonance imaging ( MRI) scans were abnormal in 87% of the 40 patients with Uhthoff's symptom. It is pertinent that within 3.5 years, the patients with Uhthoff's symptom had a 53% incidence of multiple sclerosis, identified by combined clinical, laboratory, and MRI criteria. Thus, as a presenting complaint or as a sequela of optic neuritis, this symptom is an important risk for multiple sclerosis. Also in this study, 47% of the patients having Uhthoff's symptom had a recurrence of optic neuritis. This tendency to recur has been suggested in earlier reports of Uhthoff's symptom ( 18,19). PATHOPHYSIOLOGY OF UHTHOFF'S SYMPTOM With approval from the institutional review board for human research, PVEPs were performed on four consenting patients who gave a history of Uhthoff's symptom ( 3). Black and white checkerboard patterns of 15 min were used. Resting near visual acuities were recorded, and temperatures were measured both orally and at the tympanic membrane ( 27). Tympanic thermometry provides a real- time index of the temperature of blood in the carotid artery that supplies both the optic nerve and tympanic membrane. The patients then pedaled a lightly loaded ergometer bicycle while serial PVEPs, visual acuities, and temperature were obtained. Venous pH and lactic acid samples were also drawn as measures of muscle metabolism. Control PVEPs were obtained from stimulation of eight eyes of four normal subjects. The principal positive peak ( P2) of their PVEPs showed little change in amplitude during longer more strenuous exercise. All four patients had a definite diagnosis of multiple sclerosis. Each had recovered from a previous monocular attack of optic neuritis. Their visual acuities ranged from 20/ 20 to 20/ 30. The P2 in each patient had significantly (> 3SD) longer latencies and smaller amplitudes than those of normal subjects. After the patients began exercising, P2s decreased in amplitude. At the time blurry vision was first noticed, bicycling time ranged from 4 to 5 min in two patients to 12 and 13 min in the other two patients. Visual acuities decreased to 20/ 40- 20/ 60 and were attended by a complete loss of P2 in three patients. These changes in two patients are shown in Figs. 2 and 3. The fourth patient had severe attenuation of P2. Simultaneous increases in tympanic membrane temperatures were absent in one patient and were only 0.1 C in the other three patients. In three patients, decreases in venous pH averaged 0.03 U, and the mean increase in lactic acid was 2.9 mEq/ ml. With cessation of exercise, vision recovered in < 5 min in three patients and after 15 min in the fourth patient. The restoration of vision was accompanied by an approximate return in the P2 amplitude to its pre-exercise state. The four unaffected eyes of these four patients had reductions of less than one third of the preexercise P2 amplitude and no loss in visual acuity. Persson and Sachs ( 28) measured oral temperatures and PVEP after completion of 10 min bicycling that induced a reduction of vision in eight patients. They noted attenuation or complete loss in P2 amplitudes and a mean change of only 0.1° C in the oral temperatures. In four patients, there was no recorded increase or a lower temperature. Proposed pathophysiologic mechanisms for Uhthoff's phenomenon have included hyperthermia, vascular insufficiency, and altered metabo- / Neuw- Ophtltalmol, Vol. 15, No. 2, 1995 UHTHOFF AND HIS SYMPTOM 67 Patient 2 15' Pattern VEP LEFT EYE RIGHT EYE TM 37.4° C PH 7.40 LA 1.0 VA 20/ 20 VA 20/ 20 TM 37.5° C pH 7.39 LA 3.9 TM 37.4° C pH 7.40 LA 1.4 Pre- Exercise 7 min - 12 min STOP Posl- Exercise - 5 min - 15 min FIG. 2. An effect of exercise, independent of temperature, is demonstrated by the progressive decrease and then loss of P2 amplitude, 4 min after initiation of bicycle pedaling. At the same time that vision in the left eye decreased to 20/ 40, there was no change in temperature but a decrease in venous pH and an increase in lactic acid. Furthermore, the conduction block was reversed, and visual acuity was restored, despite a O. TC increase in temperature after cessation of exercise. lism ( 28), but temperature increases in our patients and those of Persson and Sachs ( 28) were very minimal or absent. Persson and Sachs concluded that the pathophysiologic mechanism for visual impairment could not be determined because their study lacked registration of central temperature. The tympanic thermister used in our patients, however, showed that the effect of central temperature was negligible. Moreover, in one of our patients ( Fig. 2), vision improved after cessation of exercise despite the persistence of a 0.1° C increase in blood temperature. Furthermore, higher tem- Patient 15 Pattern VEP FIG. 3. P a t t e r n visual evoked potentials were obtained from alternate eyes while the patient bicycled for 15 min. At 12 and 20 min, P2 amplitude was not discernible. Visual acuity in the left eye was reduced with only a 0.1° C increase in temperature while venous pH and lactic acid increased. Visual Acuity 20/ 20 Tympanic Membrane 37. 3° C Respiration 14/ min pH 7.43 Lactic Acid mE/ L 3.9 jaV 20/ 40 373° C 37.3° C 7.4I 6,0 20/ 20 374° C 37.4° C 37.4° C 28/ min LE RE bfln'v LE 4 bMM^& m^ s t BEGIN EXERCISE 9 10 II 12 13 14 min SSI t SI OP / Neuro- Ophthalmol, Vol. 15, No. 2, 1995 68 ]. B. SELHORST AND R. F. SAUL perature increases apparently are usually required to induce neurologic dysfunction. In the companion study of hyperthermia and PVEPs in six similarly selected patients, loss of vision and similar reductions in P2 amplitudes required temperature increases of 1.3°- 2.1° C ( mean 1.6° C). In an earlier report on hyperthermia by Nelson and McDowell ( 29), less precise oral temperatures were obtained at the onset of neurologic symptoms. In 14 patients, average oral temperature increases were 0.7° C ( range of 0.17°- 1.5° C). Several additional clinical factors argue against an exclusively causal role for hyperthermia in patients having Uhthoff's symptom. First, the rapid onset of visual loss « £ 30 s after light exercise is initiated in too short a time to raise optic nerve temperature. Second, not all patients who report visual loss with hyperthermia have Uhthoff's symptom and vice versa. Impaired blood supply is also an unlikely cause of Uhthoff's symptom because patients with such a condition primarily have demyelinating optic nerve disease and rarely vascular disease. Furthermore, the repeated, stereotyped visual loss with exercise and full recovery of vision is unlike the progressive nature of vascular insufficiency characteristic of cerebrovascular disease. Finally, retinal vasospasm has not been observed in patients with Uhthoff's symptom ( 18). Because multiple sclerosis is so common in patients with Uhthoff's symptom, it is reasonable to assume that a denuded internodal segment is the underlying structural component of this phenomenon. Demyelination of a portion of the optic nerve is also possible in all the other optic neuropathies associated with Uhthoff's symptom. The lack of convincing increases in temperature and the findings of decreased pH and increased lactic acid suggest that a byproduct of metabolism alters denuded internodal segments within the optic nerve to produce Uhthoff's symptom. Nerve conduction is ordinarily maintained by a substantial safety factor in which the action current exceeds by five to seven times the threshold required to propagate an impulse ( 30). The demyelinated optic nerve with good vision, especially one with conduction delays evident by PVEP, is a compensated optic nerve that very likely functions with a reduced action current and lower safety factor. Presumably, in patients with Uhthoff's symptom, the metabolic effect of exercise promotes ionic leakage across the demyelinated segment. Depletion of sodium, the principal intra- axonal ion, would reduce the action current further, decrease the safety factor to < 1.0, and cause conduction to fail. If a sufficient population of axons is affected, a reduction in P2 amplitude is recorded; and if most of the macular axons are involved, loss of vision and block of the P2 amplitude occur, as shown in Figs. 2 and 3. With the clearing of the byproducts of exercise, ionic leakage ceases, and conduction is restored. Similar involvement of motor axons could explain the debilitating fatigue experienced by many patients with multiple sclerosis. Because these symptoms may not always be due to hyperthermia, but rather, may be attributable to some effect of metabolism, they may be amenable to pharmacologic treatment. It is hoped that development of pharmacologic agents such as 4- aminopy-ridine ( 31), which improve central conduction, will ameliorate or eliminate such troubling symptoms. Acknowledgment: Dr. Brian Weinshenker shared his collaborative findings with Dr. Alain Parent on the life of Wilhelm Uhthoff. He also led us to Uhthoff's grand-nephew, Dr. Hans K. Uhthoff, a well- published orthopedic surgeon in Ottawa, Canada, who provided Uhthoff's memoirs for review and the photograph from his clinic in Breslau. The late Dr. David G. Cogan gave encouragement and assistance. Dr. H. Stanley Thompson also wrote to offer his familiarity with Uhthoff's contributions on the pupil. In Richmond, Virginia, Dr. Juer-gen Hubert, an anesthesiologist, and Ursula Jones, a loyal neighbor, gave their time to translate various articles from their native German into English. We especially thank Dr. Stephen K. Burger, a neurology resident with an invaluable and ready command of the German language, and the Department of Neurology at the Medical College of Virginia for providing the facilities, time, and support to carry out this study. Mary Althage typed the manuscript, and Mary Selhorst was manuscript editor. REFERENCES 1. Uhthoff W. Untersuchungen uber die bei der multiplen Herdsklerose vorkommenden Augenstorungen. Arch Psy-chiat Nervenker 1890; 21: 55- 116,303- 410. 2. Selhorst JB, Saul RF, Waybright EA. Optic nerve conduction: opposing effects of exercise and hyperventilation. Trans Am Neurol Assoc 1982; 106: 1- 4. 3. Selhorst JB. Uhthoff and his symptom. Neurology 1982; 32: 193. 4. Bielshowsky A. Gedachtnisrede auf Wilhelm Uhthoff. Med Klin 1927; 50: 1954- 6. 5. McHenry LC: Garrison's history of neurology. Springfield, 1L: Charles C Thomas. 1964: 302. 6. Simmerling E. Wilhelm Uhthoff. Arch Psychiatr Nervenkr 1927; 81: 293- 6. 7. Posey WC, Spiller WG. The eye and nervous system. Philadelphia: J. B. Lippincott, 1906. 8. Heine. Wilhelm Uhthoff. Munch Med Wochenschr 1927; 23: 981- 2. 9. Uhthoff W. Ophthalmic experiences and consideration on the surgery of cerebral tumors and tower skull. Trans Oph-thal Soc UK 1914; 34: 47- 123. 10. Franklin CR, Brickner RM. Vasospasm associated with multiple sclerosis. Arch Neurol Psychiatry 1947; 58: 125- 62. 11. Guthrie TC. Visual and motor changes in patients with multiple sclerosis: a result of induced changes in environmental temperature. Arch Neurol Psychiatry 1951; 65: 437- 51. J Ncuro- Ophthalmol, Vol. 15, No. 2, 1995 UHTHOFF AND HIS SYMPTOM 69 12. McAlpine D, Compston N. Some aspects of the natural history of disseminated sclerosis. Q ] Med 1952; 21: 135- 67. 13. Edmund J, Fog T. Multiple sclerosis- visual and motor instability. Arch Neurol Psychiatry 1955; 73: 316- 23. 14. Nelson DA, Jeffreys WH, McDowell F. Effects of induced hyperthermia on some neurological diseases. Arch Neurol Psychiatry 1958; 79: 31- 9. 15. Davis FA. The hot bath test in the diagnosis of multiple sclerosis. / Mount Sinai Hosp NY 1966; 33: 280- 2. 16. Ricklefs G. Uber das Uhthoffsche Symptom bei multipler Sklerose. Klin Monatsbl Augenheilkd 1961; 139: 385- 90. 17. Earl CJ. Some aspects of optic atrophy. Trans Ophthal Soc UK 1964; 84: 215- 26. 18. Goldstein JE, Cogan DG. Exercise and the optic neuropathy of multiple sclerosis. Arch Ophthalmol 1964; 72: 168- 76. 19. Thomson DS. Blurring of vision on exercise. Trans Ophthal Soc UK 1966; 86: 479- 92. 20. Perkin GD, Rose FC. Uhthoff s syndrome. Br / Ophthalmol 1976; 60: 60- 3. 21. Scholl GB, Song H- S, Wray SH. Uhthoff's symptom in optic neuritis: relationship to magnetic resonance imaging and development of multiple sclerosis. Ann Neurol 1991; 30: 180- 4. 22. Smith JL, Hoyt WF, Susac JO. Ocular fundus in acute Leber's optic neuropathy. Arch Ophthalmol 1973; 90: 349- 54. 23. Godel V, Nemet P, Lazar M. Chloramphenicol optic neuropathy. Arch Ophthalmol 1980; 98: 1417-^ 21. 24. Raymond LA, Sacks JG, Choromokos E, et al. Short posterior ciliary artery insufficiency with hyperthermia ( Uhthoff's symptom). Am J Ophthalmol 1980; 90: 619- 23. 25. Scherokman BJ, Selhorst JB, Waybright EA, et al. Improved optic nerve conduction with ingestion of ice water. Ann Neurol 1985; 17: 418- 9. 26. Alvarez SL, Jacobs NA, Murray IJ. Visual changes mediated by beer in retrobulbar neuritis- an investigative report. Br I Ophthalmol 1986; 70: 141- 6. 27. Benzinger M. Tympanic thermometry in surgery and anesthesia. ] AMA 1969; 209: 1207- 11. 28. Persson HE, Sachs C. Visual evoked potentials elicited by pattern reversal during provoked visual impairment in multiple sclerosis. Brain 1981; 104: 369- 82. 29. Nelson DA, McDowell F. Effects of induced hyperthermia on patients with multiple sclerosis. / Neurol Neurosurg Psychiatry 1959; 22: 113- 6. 30. Tasaki I. Nervous transmission, Springfield, IL: Charles C Thomas, 1953: 42- 14. 31. Davis FA, Stefoski D, Rush J. Orally administered 4- ami-nopyridine improves clinical signs in multiple sclerosis. Ann Neurol 1990; 27: 186- 92. / Neuro- Ophthalmol, Vol. 15, No. 2, 1995 |
