Neuroanatomy, Edinger–Westphal Nucleus (Accessory Oculomotor Nucleus)


The Edinger-Westphal (EW) nucleus, which is part of the oculomotor nuclear complex (ONC), was first described in the literature in the 17th century.[1] Recently, it has been discovered that two different cell populations within the EW nucleus[2] – and, in fact, it subdivides into the EW preganglionic (EWpg) population and the EW nucleus centrally projecting (EWcp) population. However, the accepted nomenclature for these two groups varies.[1][2]

The EWpg is what is thought of as the classic ONC—sending parasympathetic nerve fibers toward the eye. It is located in the midbrain immediately dorsal to the oculomotor nucleus near the level of the superior colliculus, which is why it is often included in the overarching term oculomotor complex.[3] The EWcp population of cells (the non-preganglionic EW cells), also referred to as the subgriseal paramedian midbrain neuronal stream to reflect their actual path, differ in function from the EWpg nucleus.[4][5] However, the name subgriseal paramedian midbrain neuronal stream has not found favor in the literature due to the complexity of the name and the belief that the EW nucleus consisted of only one cell type. These two bodies of cells, while both referred to as the EW nucleus and intermingled from a structural standpoint in the midbrain, have fundamentally different roles in function.

Structure and Function

The EWpg nucleus houses choline acetyltransferase-positive cell bodies responsible for the parasympathetic innervation of the eye.[6] The EWpg nucleus is comprised of preganglionic cell bodies that track along the course of the oculomotor nerve (cranial nerve III) toward the postganglionic ciliary bodies.[6] These cell bodies participate in the light reflex pathway that leads to pupillary constriction when the retina has exposure to light.[6][7] The EWpg nucleus receives input from the locus ceruleus in response to the light hitting the retina, which then prompts the nucleus to send a forward signal that synapses at the postganglionic cells of the ciliary ganglion (CG).[6] This synapse between the EWpg nerve fibers and the ciliary ganglion postganglionic cell bodies is a nicotinic synapse with acetylcholine as the neurotransmitter.[6]

In response to the signal from the EWpg, the postganglionic ciliary bodies relay the signal along their axons by way of the ciliary nerves towards the eye. This relay leads to the innervation of the sphincter pupillae (causing miosis) and ciliary muscles (ocular accommodation). The constriction of the pupil moderates the amount of light the retina is exposed to, which is the efferent limb of the pupillary light reflex. Additionally, the contraction of the ciliary muscles leads to the relaxation of the zonular fibers, allowing for increased convexity of the lens and, subsequently, an increase in refractive power and accommodation.[6]

Since the discovery of the two cell populations of the EW nucleus, the function of the EWcp has been a subject of ongoing research. The EWcp is located medial and dorsal to the OCN in the midbrain and is comprised of a collection of peptidergic neuron cell bodies.[6][2][8] It is known that a large population of these cells are urocortinergic neurons, which are positive for the neuropeptide urocortin-1 (part of the corticotropin-releasing factor family) and negative for choline acetyltransferase.[4] These differ immunohistochemically from the cholinergic parasympathetic neurons of the EWpg, which are choline acetyltransferase positive. The EWcp nucleus significantly contributes to the amount of urocortin-1 neuropeptide in the brain.[9] Studies have shown that this nucleus is involved in stress adaptation, anxiety, and pain.[10] However, it is thought that the response to stress by the EWcp nucleus is separate from that of the hypothalamic-pituitary-adrenal (HPA) axis.[11]


Nucleogenesis in the brain during embryologic development is a subject of ongoing research. The thought is that brain nuclei develop as part of neuromeres and arcs (distinct columns of cells in the brain with high levels of acetylcholinesterase).[12] As part of the midbrain, the EW nucleus develops with the midbrain arc, which is under the control of the homeobox genes Sonic Hedgehog and FGF8.[12] Post-mortem studies in neonates who suffered prenatal hypoxia have shown there to be an expression of urocortin-1 from the EWcp as early as 34 weeks gestation—demonstrating both the development of the EW nucleus at this age and specifically the EWcp role in stress response.[8]

Blood Supply and Lymphatics

While there is not a single blood supply to the EW nucleus, it receives its blood supply via vessels that feed the midbrain and brainstem. These blood vessels are part of the vertebrobasilar circulation and include the basilar artery, superior cerebellar artery, and posterior cerebral artery [13]. The posterior cerebral artery (PCA) is intimately related to the midbrain after originating from the bifurcation of the basilar artery within the interpeduncular cistern. Thereafter, it is anatomically divided into four segments. The first segment (P1) extends from the origin of the PCA to the junction with the posterior communicating artery.

The second segment (P2) is characterized by an anterior and posterior part (P2A and P2P). The P2A begins at the end of the P1 and extends to the most lateral aspect of the cerebral peduncle. The P2P then continues onwards to the posterior edge of the lateral midbrain. The P3 part of the artery extends until the origin of the parieto-occipital sulcus, and the P4 parts are the branches that occupy this sulcus and the calcarine sulcus.[14] Although the P2P segment of the PCA lies closest to the dorsal part of the midbrain occupied by the Edinger-Westphal nucleus, the arterial branches that supply that part of the midbrain, in fact, branch from the P1 and P2A segments of the PCA.[15] Specifically, these are the long and short circumflex arteries (from P1) and the medial posterior choroidal artery (from P2A).[15]

The lymphatic drainage of the brain consists of the perivascular pathway (basement-membrane drainage system), glymphatic pathway, cerebrospinal fluid drainage via meningeal lymphatic vessels, and cervical lymph drainage routes.[16]


The EWpg nucleus projects parasympathetic preganglionic neurons, which synapse on the postganglionic ciliary bodies.[6][7] The axons of the postganglionic ciliary bodies are the short ciliary nerves that innervate the sphincter pupillae and the ciliary muscles of the eye.[6] The EWcp nucleus sends projections to the interpeduncular nucleus (a component of the limbic midbrain), lateral hypothalamus, lateral septum, raphe, and preganglionic sympathetic neurons in the spinal cord; however, these projections are not explicitly named nerves.[5] 

While the oculomotor nucleus is a separate complex, the preganglionic projections to and postganglionic projections from the ciliary ganglion do course along CN III.[6] The oculomotor nucleus houses the motor neurons that innervate the superior, inferior, and medial recti as well as inferior oblique and levator palpebrae ocular muscles.[3]


As discussed above, the short ciliary nerves innervate the sphincter pupillae (miosis) and the ciliary muscles (lens accommodation secondary to zonular fiber relaxation).[6] Thus, pathology affecting the Edinger-Westphal nucleus is often clearly evident on clinical examination, as discussed later.

Physiologic Variants

Much of the information we know today about the EW nucleus was originally studied in monkeys, mice, and birds. For instance, cellular morphology in pigeons differs from mice and human morphology, which have similar patterns of distribution of urocortin-1 positive neurons of the EWcp.[4] However, more opportunity remains for the variations in cell populations in the EW nucleus to be studied in humans.

Surgical Considerations

Brainstem and midbrain surgery are technically highly challenging procedures, and careful avoidance of damage to the numerous critical structure in this region is paramount to ensure as patients have as good as the possible quality of life following surgery.[17] The EW nucleus is situated in the dorsal part of the midbrain, or the tectum, at the level of the superior colliculus.[18] It lies laterally to the periaqueductal grey matter on either side of the aqueduct of Sylvius.[19] 

In adults, gliomas (malignant primary central nervous system tumors) are rare, constituting only 2% of brain malignancy in this population. The mean age of onset is in the sixth decade, and surgical treatment is often challenging and without the possibility of achieving total resection of the tumor. Adjuvant chemotherapy and radiotherapy are often employed, which has improved survival rates, but the overall median survival is still poor at 13.5 months.[20]

Clinical Significance

Alzheimer Disease

One clinical implication of the EW nucleus is its association with Alzheimer disease. Being that there are more than 5.4 million Americans estimated to be affected by Alzheimer disease and that this neurodegenerative disease is one of the leading causes of death in the United States, this relationship could prove to be an important finding in the understanding of the disease.[21] Degenerative changes in the early course of the disease are known to affect the hippocampus and entorhinal cortex, but another early target is the neurons of the EW nucleus.[22][21] The density of the dendritic spines of the EW neurons was significantly reduced in the post-mortem analysis of AD-affected brains compared to unaffected age-matched controls.[22]  This finding clinically correlates with exaggerated pupillary responses to cholinergic antagonists seen early on in the course of the disease in individuals with Alzheimer disease, and being that the EW nucleus is an early target of degeneration, this response could be a useful tool in the early clinical diagnosis of Alzheimer disease.[22]

Weber Syndrome

Weber syndrome is a rare brainstem infarct syndrome characterized by occlusion of one of the paramedian branches of the basilar artery or posterior cerebral artery. The resulting infarction affects the oculomotor nucleus and the cerebral peduncle.[18] Owing to these structures being involved, the clinical presentation typically consists of a combination of oculomotor nerve palsy (the ipsilateral eye deviated inferolaterally, with diplopia and ptosis) and concurrent contralateral hemiplegia. Despite the debilitating consequences of the presenting symptoms, with aggressive control of vascular risk factors (i.e., hypertension), a good clinical recovery can be achieved.[23]

Benedikt Syndrome

Benedikt syndrome (otherwise known as paramedian midbrain syndrome) is the name given to the rare clinical syndrome resulting from the infarction of branches from the posterior cerebral artery that supplies oculomotor nerve fascicles and the red nucleus.[18] The red nucleus is a primitive subcortical relay between the cerebellum and the spinal cord allowing for control of purposeful motor movements and is involved via the rubrospinal and olivocerebellar tracts.[24][25] Similarly to Weber syndrome, the principal etiology is vascular, although traumatic and infectious cases have been reported in the literature.[26] The clinical presentation consists of ipsilateral oculomotor nerve palsy (the ipsilateral eye deviated inferolaterally, with diplopia and ptosis), along with contralateral ataxia and intention tremor. In patients with residual tremor following optimal medical management of the vascular risk factors, deep brain stimulation targeting both the thalamic ventral intermediate nucleus and the contralateral lenticular fasciculus have been trialed with good results reported in small case series.[27][28]

Other clinical considerations would include the presence of structural lesions that could lead to the compression of the nucleus. These lesions include tumors, aneurysms, and impaired CSF outflow leading to cerebral aqueduct enlargement.

Other Issues

Many of the issues regarding the understanding of the EW nucleus involve the discovery of the EWcp, which changed the classic definition of the EW nucleus, as it was solely associated with parasympathetic control of the eye for decades. With time and more research, the terminology of the EWpg and EWcp will gain recognition and acceptance throughout the scientific community.

(Click Image to Enlarge)
Midbrain anatomy
Midbrain anatomy
Image courtesy S Bhimji MD

(Click Image to Enlarge)
Midbrain cross sectional anatomy
Midbrain cross sectional anatomy
Image courtesy S Bhimji MD

(Click Image to Enlarge)
Edinger-Westphal Nucleus, optic nerve, afferent pathway,  pretectal nucleus, optic tract, red nucleus, lateral geniculate nucleus, posterior commissure, nerve with parasympathetic fibers.
Edinger-Westphal Nucleus, optic nerve, afferent pathway, pretectal nucleus, optic tract, red nucleus, lateral geniculate nucleus, posterior commissure, nerve with parasympathetic fibers.
Illustration by Emma Gregory

(Click Image to Enlarge)
Pupil non-sparing third nerve palsy
Pupil non-sparing third nerve palsy
Contributed by Sunil Munakomi, MD
Article Details

Article Author

Madeline B. Heiland Hogan

Article Author

Suriya Subramanian

Article Editor:

Joe M Das


12/26/2022 11:41:45 AM



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