History of Neuro-Ophthalmology

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Hania Pawlowski, Dina Abdelsalam

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Neuro-ophthalmology grew from early attempts to link the eye and brain, evolving steadily through major anatomical and optical discoveries. It became a true subspecialty in the 20th century, largely shaped by Frank Walsh and the clinicians who refined diagnostic understanding.

Early History

Ancient Greek philosophers are among the first to debate vision theories. Karanjia et al. proposes that Socrates (469-399 BCE) was among the first who pondered the nature of vision citing “Allegory of the Cave”, in which Socrates argues that perception cannot be entirely trusted and it can be altered by filters of the mind. His student, Plato (427-347 BCE), formalized the emission theory, which states that the eyes emit “finger-like” projections that touch the environment. Aristotle (384-322 BCE), Plato’s student, questioned how small projections from the eye could emit to distant mountains. However, the emission theory gained traction and mathematical credibility from Euclid (325-265 BCE), who provided the first optical ray tracing, showing rays of light reflected to and from the eyes. Around the same time, Herophilos of Alexandria (344-289 BCE) stated that sense functions did not come from the heart, but rather linked the eye with the brain and provided the first description of the optic nerve and chiasm.

Roman and Greek physician, Galen of Pergamon (129-216 CE), was the first to provide significant anatomical observations in relation to vision. Through his work on gladiators, Galen was able to describe cranial nerves III, IV, and VI. He connected the anatomy and physiology, believing that the optic nerves were hollow and carried resonating waves to the brain’s three ventricles corresponding to perception, reasoning, and memory. This established the fundamental concept of a physical connection between the eyes and the brain.

Early Arabic philosophers, like Ya’qub ibn Ishaq al-Kindi (800–870 CE), favored a combined emission-intromission theory. In his book on Optics, al-Kindi postulated that the eye sends out light to the observed object, which then reflects light back into the eye. It was not until Abu Ali al-Hassan ibn al-Haytham (Latinized to Alhazen) (965-1040 CE), who advanced and marked the onset of neuro-ophthalmology. He created an early visual representation of the eye and optic pathway, depicting the lens as the photoreceptor and the optic nerve as a hollow tube. Ibn al-Haytham taught that images are first formed by the lens and then flow through the optic nerves, which join at the optic chiasm, where images from each eye unite, before diverging to the ‘ultimum sentiens’, though it is not clear where this is. He further explained that both eyes perceive one image since both lenses have one corresponding point within the ‘positio consimilis’. Ibn al-Haytham understood that imaging occurs in the eye but did not recognize the inverted image on the retina.

The Renaissance and the Rise of Anatomical Science

The understanding of vision changed dramatically during the Renaissance. Leonardo da Vinci (1452-1519 CE) not only rejected the emission theory, but also proposed a new revolutionary idea: the eye functions like a camera obscura and the visual system generates “spirits” and goes behind the eye to three cerebral rooms.5 The three rooms described as, the room of ‘representation’, the room of ‘reasoning’, and the room of ‘memory’. Da Vinci’s later work demonstrated a deep understanding of anatomy, with drawings which illustrated both lateral ventricles and the passageways to the third and fourth ventricles.

Andreas Vesalius (1514 - 1565 CE), the father of modern anatomy and a predecessor of neuroscience, disproved Galen’s observations that optic nerves were hollow. Vesalius correctly demonstrated that they were solid fiber bundles, which terminated at the thalamus. This paved the way for more accurate understandings of the visual pathway.

In the 17th century, Johannes Kepler (1571-1630) questioned whether we see with the brain or the eye, and discovered the pathway of the light to the retina, though he did not understand how the reversed retinal image was consciously perceived as upright.

Thomas Willis (1621 - 1675) and William Briggs (1650-1704) provided more detail regarding Vesalius’ findings. They showed that the eyes provided input to the brain through the optic nerves.

In 1704, Isaac Newton (1643-1727) hypothesized a partial crossing of optic fibers at the chiasm. This theory was later confirmed by Bernhard von Gudden (1824-1886) in 1880 through pathological examination.

The 19th and Early 20th Centuries: The Era of Specialization

The understanding of the brain's anatomy was significantly advanced in the 19th century, with neurology and ophthalmology emerging as distinct specialties.

One of the earliest insights into the cortex's layered structure was by Francesco Gennari (1752-1797 CE), a pioneer in neuroanatomy. Gennari identified a unique extra layer in the visual cortex, now known as the Stripe of Gennari. Later, it was Marie-Jean-Pierre Flourens (1794-1867) who advanced Willis and Briggs findings further, demonstrating through animal experiments that ablating the visual cortex led to vision loss. Eventually, Pierre Gratiolet (1815-1865 CE) dissected the brain to reveal connections of the optic tracts (Gratiolet radiations) and how they link to the lateral geniculate nucleus and the pretectum. These discoveries helped define the visual pathway as a complex and multilayered system rather than simple connection.

One of the turning points in ophthalmology during this period was the invention of the ophthalmoscope by Hermann von Helmholtz (1821-1894) in 1851, which allowed clinicians to directly view the optic disc and retina, and gave them the ability to correlate specific eye findings with neurological diseases for the first time. The physical ability to see the eye greatly advanced the connection between the eye and the brain. In fact, Albrecht von Graefe (1828-1894 CE) was the first to detect bilateral papilledema in patients with brain tumors. His cousin, Alfred Graefe, along with Dutch ophthalmologist, Frans Cornelius Donders (1818-1889 CE), would be among the first to discuss and postulate convergence, accommodation, and strabismus. However, it was two Americans, William C. Posey (1866-1934 CE) and William C. Spiller (1863-1940 CE), who coedited the book The Eye and the Nervous System, who set the literary foundation and tradition for American neuro-ophthalmology.

Hughlings Jackson (1835-1911 CE) was another pioneer neurologist, who recognized the importance of the routine examination of the fundus using the ophthalmoscope. He argued that a physician may not be able to diagnose neurological disease without it, and even noted that severe headaches warranted an ophthalmic examination.

A monumental contribution to the field came from Hermann Wilbrand (1851-1935), whose extensive nine-volume work co-written with Alfred Sanger, Neurologie des Auges, meticulously connected clinical findings with pathological specimens. Wilbrand’s work provided the first documentation that a lesion anywhere along the postchiasmal visual pathway could cause homonymous hemianopia.

Around the same time, Johann Freidrich Horner (1834-1886) together with physiologist Claude Bernanrd (1813-1878) described sympathetic denervation of the eye which would later become known as Horner’s syndrome.

The anatomy of the retina and its outputs were largely unknown until 1906 Nobel Prize winner in Physiology and Medicine, Santiago Ramon y Cajal (1852-1934), composed detailed drawings based of the retina and demonstrated that the nervous system is composed of individual neurons rather than a single continuous network.

Several military engagements, which allowed for casualty examinations, played a significant role in advancing neuro-ophthalmology. During the American Civil War, Silas Weir Mitchell (1829-1914) studied neurological injuries in soldiers. Similarly, during World War I, British neurologist Gordon Holmes (1876-1965) studied the relationship between bullet wounds to the occipital lobe and specific visual defects, demonstrating the organization of the visual cortex.

This era established a foundational knowledge base that paved the way for the specialty's formalization in the 20th century.

The Modern Era and the Birth of Neuro-Ophthalmology

The modern era of neuro-ophthalmology is fundamentally defined by the founder of neuro-ophthalmology, Frank Burton Walsh (1895-1978). It was Walsh who transformed a loosely connected set of observations into a true subspecialty. While working at the Wilmer Eye Institute at the Johns Hopkins Hospital, Walsh detailed extensive clinical cases and collaborated extensively with neurologists and neurosurgeons, eventually leading to what became the “bible” of the specialty, Clinical Neuro-Ophthalmology (first edition 1947). This book became the definitive reference, both summarizing and defining the field.

Soon after, Walsh approached William F. Hoyt of University of California San Francisco to help expand his book to a three-volume edition, known as Walsh and Hoyt’s Clinical Neuro-Ophthalmology (1969). Hoyt’s influence extended far beyond the text– he went on to train more than 70 fellows, many of whom became leaders and mentors in neuro-ophthalmology.

Around the same time, David G. Cogan (1908-1993) of Harvard was another rising figure in neuro-ophthalmology. Cogan is best known for his study on the relation of motor disturbances caused by lesions of the central nervous system. His Neurology of the Ocular Muscles (1948) and Neurology of the Visual System (1966) bridged clinical practice with basic laboratory science, while his leadership at the National Eye Institute advanced the specialties scientific credibility. One of Cogan’s trainees, J. Lawton Smith, went on to carry Cogan’s enthusiasm and energy to other institutions. At Bascom Palmer, Lawton Smith, along with colleagues Joel Glaser (1938-2011), Norman Schatz (1936-2024), and Noble “Nobby” David (1927-2011) created a dynamic center for neuro-ophthalmology.

The second half of the 20th century saw the rise of several other influential figures who broadened the field. Simmons Lessell (1933-2016) was renowned for his eloquence in writing, teaching, and mentorship. Lessell combined wit, vitality, and probing questions that challenged and inspired his learners. Lessel blended his training in neurology and ophthalmology to produce more than 200 articles, chapters, and reviews including descriptions of toxic optic neuropathies, palinopsia, and cerebral achromatopsia among others. In 2003, he was awarded the joint American Academy of Ophthalmology/North American Neuro-Ophthalmology Society Hoyt Award. Other influential William F. Hoyt Awardees include: Jonathan Trobe (who became a “teacher of teachers” at Michigan, memorializing the pioneers of the field through his Legacy series), Neil Miller at Wilmer (who assumed Walsh’s chair and continued to anchor Hopkins as a center of scholarship),1, and Nancy Newman at Emory and Alfredo Sadun in Los Angeles (extended the reach of American neuro-ophthalmology with landmark work on genetic optic neuropathies and mitochondrial disease) – they all extended the reach of American neuro-ophthalmology with landmark work.

Neuro-Ophthalmology Today

The establishment of neuro-ophthalmology as a distinct subspecialty was a gradual process, thanks to the tireless work of all distinguished figures mentioned in the article. Imaging technologies like the MRI and OCT, combined with advances in genetics and molecular biology, have shifted our understanding of complex etiologies, and improved both diagnosis and management.

In the present era, there is an increasing supportive role of diagnostic tests – advances in neuroimaging protocols, electrodiagnostics, pupillometry, and mobile applications have added new layers of precision to clinical practice. However, the subspecialty also faces pressing challenges: the demand for neuro-ophthalmalges is growing faster than the workforce, raising urgent questions about training, sustainability, and access to care.

Together, these shifts signal a transformation from a discipline once defined by description and careful observation to one characterized by intervention, innovation, and multidisciplinary integration, while remaining faithful to its clinical roots of meticulous history-taking, examination, and mentorship.