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  • Updated 06.29.2020
  • Released 07.07.1997
  • Expires For CME 06.29.2023

Olfactory bulb agenesis, hypoplasias, and dysplasias

Introduction

This article includes discussion of olfactory bulb agenesis, hypoplasias, and dysplasias and olfactory hypoplasias and agenesis. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

In this article, the author describes olfactory bulb agenesis and dysgenesis and also reviews the embryology, maturation, neuropathology, and clinical diagnosis and manifestations. The olfactory bulb is still immature but functional in the term neonate. It is a reservoir of progenitor “stem” cells capable of neuronal differentiation in the adult as well as in the fetus. Complete agenesis of the olfactory tract results in congenital anosmia. Olfactory reflexes in the neonate and preterm infant can be tested as early as 28 weeks’ gestation using a nonirritant aromatic substance, such as peppermint (infantile olfactory reflexes). Fetuses perceive odors in the amniotic fluid that circulate through the nasal passages in the late second and third trimesters. Agenesis of the olfactory bulbs (arrhinencephaly) is a constant feature in alobar and semilobar holoprosencephaly but also can occur as an isolated minor cerebral malformation without other dysgeneses. At times it is asymmetrical. In septo-optic-pituitary dysplasia the olfactory bulbs often are hypoplastic. In Kallmann syndrome, there is hypogonadism with delayed or absent puberty; associated neurologic findings may be present, such as ataxia, impaired hearing, eye movement disorders, or mental handicap. Diagnosis is confirmed by MRI, and molecular studies can reveal genetic mutations. Dysgenesis, rather than agenesis, of the histological architecture of the olfactory bulbs occurs in some genetic syndromes and particularly in postzygotic somatic mutations such as tuberous sclerosis complex and hemimegalencephaly. Multiple genetic factors are essential in normal olfactory bulb ontogenesis. Supernumerary olfactory bulbs are rarer than agenesis but documented and associated with impaired olfaction. Fusion of olfactory bulbs may occur in some cases in which the bulb appears unilaterally absent on gross examination.

Key points

• Agenesis of the olfactory bulbs (arrhinencephaly) may occur as an isolated defect, as a component of holoprosencephaly (regardless of the genetic etiology) associated with other cerebral malformations, or as a component of Kallmann syndrome with endocrinopathies.

• Agenesis or hypoplasia of 1 or both olfactory bulbs at times occurs in isolation without other CNS anomalies or with other focal defects such as hypoplasia of the ipsilateral optic nerve and in septo-optic-pituitary dysplasia.

• The clinical feature is anosmia, but patients rarely complain of this because it is congenital rather than acquired after they had experienced a sense of smell; the deficit is nonprogressive.

• It can be diagnosed by MRI of the olfactory bulbs following clinical demonstration of absent olfaction bilaterally; neuropathological confirmation is demonstrated at autopsy, though olfactory agenesis is not a cause of death.

• Olfactory reflexes are present at birth (after 32 weeks gestation) and can be tested as part of the neurologic exam in neonates and young infants by using an aromatic, non-irritative test substance that does not stimulate the pain endings of the trigeminal nerve in the nasal mucosa; responses are sucking or arousal withdrawal.

• The principal well-documented olfactory dysplasias are the presence of a deep longitudinal sulcus on the inferior surface with synaptic glomeruli lining the neural tissue on either side (hemimegalencephaly), megalocytic and dysplastic neurons (tuberous sclerosis and hemimegalencephaly), fusion of the 2 olfactory bulbs, and delayed maturation of expression of neuronal proteins and synapse formation.

• Olfactory bulb agenesis should be distinguished from acquired causes of anosmia, such as fracture of the cribriform plate in head trauma, tumors, granulomas and other lesions of the olfactory bulbs or tracts, olfactory groove meningioma, vascular anomalies associated with a persistent fetal olfactory artery, and olfactory impairment due to chemotherapy or other drugs.

• Multiple genetic mutations and deficiencies of transcription factors and cell adhesion molecules are associated with olfactory agenesis, but usually with other CNS anomalies.

• Supernumerary olfactory bulbs occur rarely.

• Some olfactory auras in focal epilepsy may originate in the olfactory bulb and can only be mediated by the amygdala, insula, or entorhinal cortex.

Historical note and terminology

Perception of odorous soluble molecules is the earliest special sense to develop both phylogenetically and ontogenetically. Even simple medusae (jellyfish) and polyps (hydra) that poses only a simple nerve net without a brain or even a ganglion can perceive and distinguish molecules in surrounding sea water as attractants (ie, food) or adversive elements (ie, potentially harmful) and react accordingly, as noted as early as 1849 by the famous English biologist of his era, Thomas Huxley (63). Human fetuses also perceive odors dissolved in amniotic fluid. Whether these primitive perceptions are best classified as olfactory or gustatory (taste) is a difficult distinction. Both fetuses and preterm neonates distinguish different types of both pleasant and unpleasant odors (89; 145; 156; 102).

The cranial nerves were numbered I to XII by Sömmerring in 1791, but the human olfactory nerve had been described half a century earlier by Winslow in 1733. In ancient times Alcmaeon of Croton (c490-430 B.C.), the father of Greek medicine, first postulated that “channels” (ie, passages, ducts) connected sense organs of the head (nose, eyes, ears, tongue) with the brain, and he is attributed to have first described the olfactory and optic nerves, as reported by Aristotle’s successor Theophrastus (c327-287 B.C.) and later also acknowledged by Galen in the 2nd century A.D. (168).

The first report of anosmia associated with hypogonadism was in 1856 (97). In 1918 Blakeslee described specific anosmia for either pale pink or red verbenas, but not for both, in a group of healthy people (21), and a few reports have since appeared describing familial congenital anosmia in otherwise mainly asymptomatic people (99; 94; 161). In addition, there have been occasional descriptions of "sporadic cases of Kallmann syndrome," in which isolated congenital anosmia is also present (58). In a seminal paper on the genetic aspects of primary eunuchoidism, Fritz Kallmann and colleagues described 36 males and 12 females in whom the condition was associated with combinations of anosmia, color blindness, synkinesis, and mental handicap (67). Subsequent clinical descriptions have permitted better delineation of the syndrome and its association with aplasia or hypoplasia of the olfactory bulbs and tracts (163; 101; 180; 58). A study that investigated isolated congenital anosmia without chromosomal disorders (02) compared the MRI appearances of the frontobasal structures of 16 patients with controls. In half the patients there was bilateral hypoplasia of the olfactory bulbs, and in the remainder there were combinations of hypoplasia and aplasia of the bulbs. Descriptions of anosmia and olfactory aplasia as 1 component of the holoprosencephalies represent the other extreme of the spectrum (50; 91). Isolation of the Kallmann syndrome gene in X-linked Kallmann syndrome has expanded our insight into this syndrome of anosmia and hypogonadism (92; 126). Septo-optic-pituitary dysplasia is a frequent cerebral malformation and is often accompanied by olfactory bulb hypoplasia or even aplasia (153; 18).

Olfaction and taste are functionally closely related despite the wide separation of their neuroanatomical receptive centers in the olfactory bulb and lower brainstem, respectively (148). Even the simplest marine animals with only a primitive nerve network and no central nervous system, such as medusa (jellyfish) and polyps (hydra, sea anemones, etc.), perceive molecules dissolved in the water as either threatening, resulting in retraction of tentacles, or food, resulting in feeding behaviors. In humans, postnatal respiration is essential for smell, and retronasal olfaction is dependent on expiration and also refines perception of taste for chocolate and other flavors, even accompanied by EEG changes (104). Olfaction is an important aspect of wine tasting and distinguishing foods.

There are no published consensus criteria of the definition of a “cranial nerve.” The following is a suggested working definition for sensory cranial nerves: a) peripheral nerves; b) arising from neurons in the peripheral nervous system that possess dendritic receptors for specific sensory stimuli; c) include a ganglion at some point along the nerve (eg, trigeminal gasserian, semilunar ganglion, facial geniculate ganglion, vestibular/cochlear spiral ganglion, glossopharyngeal jugular or Müller ganglion, vagal jugular, nodose ganglion); and d) enter the brain, not the spinal cord (151). By these simple criteria, the olfactory is a true cranial nerve, even though its dispersed axons do not become compacted until they reach the olfactory bulb to form layer 1 of this structure. Though the olfactory nerve lacks a compact ganglion along its course, unique synaptic glomeruli on the ventral surface of the olfactory bulb, facing the cribriform plate of the ethmoid bone through which individual olfactory nerve fibres pass, are connections between primary olfactory axons and dendrites of mitral and tufted cells (148); these glomeruli serve the same function, hence, an olfactory ganglionic equivalent is incorporated into the olfactory bulb as layer 2 of the bulb (151). Ironically, the accessory olfactory bulb, a transitory fetal structure in humans, has peripheral ganglia like those of other sensory cranial nerves but lacks synaptic glomeruli because it is fused to the principal olfactory bulb far from the cribriform plate because the accessory bulb is fused to the principal olfactory bulb dorso-medially far from the cribriform plate (134; 135). Many residents and attending pediatric neurologists hold the premise that the olfactory nerve is not a “true” cranial nerve, but objective neuroanatomical criteria dispel this unjustified notion in comparing the olfactory with lower sensory cranial nerves. The olfactory bulb and tract are still immature at birth with incomplete synaptogenesis and no myelination, yet already are functional to perceive olfaction from about 28 weeks’ gestation.

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