Aging and Disorders of the Eye

Scott E. Brodie , in Brocklehurst's Textbook of Geriatric Medicine and Gerontology (Seventh Edition), 2010

LACRIMAL APPARATUS

The lacrimal apparatus consists of the lacrimal glands, which secrete the tears, and the lacrimal sac and ducts, which convey the tears into the nasal cavity. Secretory function of the lacrimal glands declines with age, and many elderly individuals develop "dry eye" syndrome. (This nonspecific reduction in tear production is much more common than the full-fledged Sjögren syndrome, which is an autoimmune disease process affecting both salivary and lacrimal secretion. 12 ) Paradoxically, many tear-deficient patients complain of excess tearing, because the chronically irritated eyes may stimulate reflex tear production. Dry eyes are treated with artificial tear eyedrops, as often as needed. Some patients respond well to topical treatment with cyclosporin A. 13 In patients whose eyes dry out overnight, lubricant ointment at bedtime may be helpful. In severe cases, small silicone plugs may be placed to obstruct the lacrimal puncta, 14 or surgical occlusion of the lacrimal puncta may be performed, in order to conserve the available tears.

Obstruction of the lacrimal ducts also leads to epiphora. Uncomplicated mechanical stenosis may occasionally be relieved with simple probing, but severe cases (often following bacterial infection of the lacrimal sac) are treated surgically: a dacryocystorhinostomy is performed to anastomose the mucosa of the nasal cavity to the lacrimal sac through an osteotomy made in the lacrimal bone. 15

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Ocular Toxicity of Chemical Warfare Agents

Patrick M. McNutt , Tracey L. Hamilton , in Handbook of Toxicology of Chemical Warfare Agents (Second Edition), 2015

The eye and the accessory visual structures (e.g., the conjunctiva, lacrimal apparatus, and eyelids) are arguably the most important sensory organ of the body. It is estimated that 75% of perception and cognition incorporates visual information. The ocular structure is highly complex, containing a variety of tissues with distinct functions that are critically dependent on the structural and cellular environment for proper function. Consequently, any injury that interferes with vision can be extremely disruptive, incapacitatiing or even life-threatening. Due in large part to its exposed location and intricate internal structure of the eye, it is highly sensitive to injury by a wide array of chemical warfare agents (CWAs). Ocular manifestations caused by exposure to CWAs can range from mild conjunctivitis to corneal ulceration and loss of vision. The severity of response is highly dependent on a combination of dose, agent, and environmental conditions and is mediated through the specific interactions of each agent with the physiological and biochemical environment of the eye. In some cases, the recovery from intoxication may be significantly influenced by the regenerative capacity of individual ocular tissues. This chapter discusses what is known about the toxicological and toxicokinetic effects of ocular exposure to a wide array of traditional CWAs, including several biological toxins.

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Ocular diseases

In Diagnostic Techniques in Equine Medicine (Second Edition), 2009

Appearance of the eye and adnexa

The general appearance of the eye and the adnexa (globe, eyelids, lacrimal apparatus, orbit and paraorbital areas) should be assessed and the symmetry of each side compared. Abnormal elevations, depressions or deviations of the skull or soft tissues of the head should be evaluated. In particular, it is important to check that the depth of the supraorbital fossa is normal and symmetrical bilaterally ( Fig. 15.7). Swelling in this region may indicate a retrobulbar or orbital space-occupying lesion. The quantity and quality of ocular or nasal discharges should be evaluated for increased or decreased tear production (associated with inflammation), and tear overflow (epiphora) from blockage of the lacrimal drainage system. Purulent discharge may be associated with infection.

The angle of the upper eyelashes with respect to the cornea should be examined. Normally they should be at almost 90°to the cornea (Fig. 15.8 (Plate 14)). Downward deviation may indicate enophthalmos (backward displacement of the eye into the orbit) due to ocular pain. Enophthalmos may be normal in ponies. Alternatively, an upward deviation may indicate exophthalmos (abnormal protrusion of the eye).

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OCULOPLASTICS

In Moorfields Manual of Ophthalmology, 2008

Background

Broad groups of eyelid injury are recognized, but any combination may occur:

▪

Lacerating trauma.

Uncomplicated:

±

lid margin laceration.

Complicated by injury to : levator complex, lacrimal apparatus, globe, orbit, sinuses, cranium.

±

retained lid or orbital foreign body (FB).

▪

Blunt trauma (contusion, avulsion of lid).

▪

Chemical injury.

History

A carefully documented history is often medicolegally important. Note the following:

▪

The time and nature of an alleged assault or FB, as well as the distance and trajectory.

▪

Whether parts or all of the FB have been recovered.

▪

Other ocular symptoms.

▪

ENT symptoms including epistaxis and CSF rhinorrhoea.

Examination

▪

Record VA.

▪

Accurately document or preferably photograph the extent of any wound, noting if it is partial or full thickness. Note any involvement of the lid margin(s), lacrimal drainage apparatus, or posterior lamella.

▪

Exclude anterior segment, (p. 205), posterior segment (p. 551), and orbital injury (p. 101).

Investigations

Imaging is chiefly to exclude bony injury, retained FB, gas, and pus. A plain skull X-ray is quick and readily available but ultrasound and CT may be appropriate. Avoid MRI if metal FBs are suspected.

General principles of repair

▪

Most systemic and ocular injuries take priority over eyelid repair.

▪

Extensive lid, globe, orbital, and even intracranial injury may occur through a small eyelid laceration.

▪

Primary canalicular repair is easier within 24 hours of injury, but other lid injuries may wait 48 hours. Provide antibiotic cover if repair is delayed.

▪

Involve paediatricians if children are injured. Nonaccidental injury, though uncommon, should be considered. Children with traumatic ptosis are at risk of amblyopia and may require urgent brow suspension.

▪

Provide tetanus toxoid cover.

▪

Animal bites may be closed primarily but cover with a suitable oral antibiotic, e.g. co-amoxiclav 375 mg t.d.s. p.o..

▪

Corneal protection is a key objective in any repair.

▪

Repair under general anaesthesia unless there is limited injury to the lid alone.

▪

Thoroughly clean all dirty wounds.

▪

Do not discard tissue unless necrotic or infected.

▪

Primary repair aims to approximate tissue planes – posterior lamella, tarsus and skin. Complex procedures (e.g. skin grafting) are undertaken secondarily.

▪

Avoid vertical shortening as tissue contracture leads to ectropion.

▪

In most situations use a standard 2-1-1 knot: draw the suture in opposite directions with each throw and tie knots anteriorly to avoid corneal abrasion.

▪

Use deep 5/0 absorbable sutures to draw planes together and anchor tissues. Skin sutures should not bear tension.

▪

Skin: Use 7/0 Vicryl continous, or 6/0 Vicryl interrupted ± 6/0 Nylon continuous. Use a rapidly absorbing suture in children (e.g. Vicryl rapide).

▪

Tarsus: Use 5/0 Vicryl × 2–3.

▪

Grey line and lash line: Use buried 7/0 Vicryl.

▪

Remove skin sutures at 1 week.

▪

Avoid silk sutures.

Specific injuries

▪

Lid margin: Repair using the same principles as a pentagon wedge excision (see page 10).

▪

Levator palpebrae complex: thoroughly clean the wound and approximate corresponding tissue as accurately as possible. Do not extend the wound to identify further structures because spontaneous resolution of the ptosis may occur, up to 6 months post-injury and the ptosis may in part be due to a neuropraxia.

▪

Medial canthal tendon: even in cases of avulsion, a residual stump of deep tissue may often be grasped with toothed forceps, and approximated to the medial cut end of the tarsus using a 5/0 suture (absorbable or nonabsorbable) on a fish-hook or half-circle needle.

▪

Canaliculus: controversy exists regarding the repair of injury to a single canaliculus, as adequate tear drainage may occur via the healthy fellow canaliculus, and the failure rate is high due to ring contracture. However, if repair is undertaken, a monocanalicular self-retaining silicone stent may be placed (shorten the stent before insertion). Identification of the cut proximal end of the canaliculus within the wound is aided by application of 10% epinephrine on a cotton bud (the transected end appears as a pale ring), or by syringing through the fellow canaliculus with fluorescein or air. The bell-shaped end of the stent fits in the punctal ampulla flush with the punctum. The stent does not require suturing and may easily be removed at 2–3 weeks as epithelialization occurs within a few days. The presence of a stent will not prevent tissue contracture, which occurs over many months. This technique avoids the use of the pigtail probe, which, depending on the design of the probe and the experience of the surgeon, may lead to injury of the healthy canaliculus. Alternatively, if sufficient distal canaliculus is present, this can be opened along its posterior surface by a few millimetres, and marsupialized into the conjunctival sac with an 8/0 absorbable suture. Where both canaliculi are injured, repair by an experienced surgeon is indicated. A silicone rod may be used and tied in the nose. The risk of failure is high. If subsequent dacryocystorhinostomy with retrotubes fails, a Lester Jones tube may be indicated.

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Basic Diagnostic Techniques

David J. Maggs , in Slatter's Fundamentals of Veterinary Ophthalmology (Fourth Edition), 2008

SCHIRMER TEAR TEST

The Schirmer tear test (STT) is a semiquantitative method of measuring production of the aqueous portion of the precorneal tear film. It must be performed before application of any topical solutions, because these would artificially but temporarily raise the STT value. In addition, some topical solutions exert a more protracted inhibitory effect. For example, topically applied anesthetics or parasympatholytic drugs used to induce mydriasis, and local anesthetics, both will reduce STT values. Finally, manipulative procedures such as corneal or conjunctival scrapings, flushing of the lacrimal apparatus, and potentially even application of bright lights to an inflamed eye will result in artificially elevated STT values. For these reasons, if the STT is to be performed, it should be done as the first component of the ophthalmic examination.

The test is performed with sterile, individually packaged strips of absorbent paper with a notch 5 mm from one end. Each strip is folded at the notch and hooked over the middle to lateral third of the lower lid for 60 seconds (Figure 5-3). The distance from the notch to the end of the moist part of the paper is measured immediately on removal of the strip from the eye. This is the STT 1, which measures basal and reflex tearing, including that due to corneal stimulation provided by the test strip itself. That is why the STT strip should be placed in the middle to lateral region of the lower eyelid, where it can gently contact the corneal surface. If it is placed more medially, the third eyelid can protect the cornea and reduce STT 1 results. In normal dogs, the STT 1 result should exceed 15 mm in 1 minute. Readings of less than 10 mm in 1 minute are considered diagnostic for keratoconjunctivitis sicca. Values between 10 and 15 mm in 1 minute are considered highly suggestive of keratoconjunctivitis sicca, particularly if appropriate clinical signs are present.

The reported range for STT results in normal cats is 3 to 32 mm in 1 minute with a mean of 17 mm in 1 minute. However, experience suggests that lower readings than the reported mean can be expected in a clinical setting. This is probably due to autonomic control of secretion and short-term alterations in tear flow due to stress in the examination room. Values should still be recorded in cats but should be interpreted with caution and always in conjunction with clinical signs. Commercial strips are often unsuitable for horses if left in place for 60 seconds because of greater tear production in this species, which quickly saturates the entire strip. Some recommend broader strips, but these must be prepared in a very uniform manner. Rather, it is probably better to leave a standard strip in place for only 30 seconds in this species. STT results are also published for a number of exotic species (see Chapter 20).

For measurement of the STT 2, corneal sensation is abolished with topical anesthetic, and lower test values result because the afferent limb of the reflex path is blocked and reflex secretion by the lacrimal and nictitans glands is reduced. The STT 2 has not received widespread clinical application in animals but is sometimes referred to in texts and research studies.

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Fungal infections of the eye

Golnaz Javey , ... Victor L. Yu , in Clinical Mycology (Second Edition), 2009

Dacryocystitis and canaliculitis

Anatomy

The lacrimal outflow system begins with the pinpoint opening, the punctum, in the medial upper and lower eyelids (Fig. 30-14). The superior and inferior puncta are the proximal openings of the respective superior and inferior canaliculi, delicate duct structures intimate with the medial canthal tendon. The upper and lower canaliculi merge, in most individuals, into a short common canaliculus before entering the lacrimal sac. Tears exit from the sac down the nasolacrimal duct and empty into the nasal passage in the inferior meatus. The constant contraction and relaxation of the orbicularis oculi during normal blinking account for the intraluminal pressure changes that move the tears from the eye into the nose. An anatomic obstruction in the lacrimal outflow system, usually in the nasolacrimal duct, predisposes the patient to tear stasis and infection of the lacrimal sac, also known as dacryocystitis. 131 Dacryocystitis is the most common infection of the lacrimal apparatus.

Epidemiology

Fungal dacryocystitis accounts for 5% of all acquired dacryocystitis, and 14% of cases of congenital dacryocystitis. 132-134 Women are affected more frequently with all forms of dacryocystitis than men, probably because of anatomically narrower nasolacrimal ducts. 128 It most commonly affects individuals in their 50s or 60s. Recent or past midfacial trauma, particularly nasoethmoid fracture, predisposes the patient to nasolacrimal obstruction and dacryocystitis. Other risk factors include dacryolith formation, and nasal or paranasal sinus disease. Allergy or chronic inflammation of the nasal mucosa impedes outflow from the duct, worsening stasis and increasing the risk of dacryocystitis.

Mycology

Fungi implicated in dacryocystitis include species of Acremonium, Aspergillus, Candida, Paecilomyces, Rhizopus, and dermatophytes. Candida albicans and A. niger are the fungi most frequently isolated. 133,135 Aspergillus, Candida, Paecilomyces, Rhinosporidium seeberi, and dermatophytes can cause a chronic granulomatous dacryocystitis. 136,137

Clinical manifestations

Dacryocystitis typically presents with erythema, induration, and sensation of pressure in the medial canthus. Because of retrograde regurgitation of the infected matter from the lacrimal sac to the ocular cul-de-sac, the eye may be red and the eyelids edematous. Preseptal cellulitis may be seen particularly with rupture of a distended lacrimal sac (Fig. 30-15). Fistula formation, when it occurs, usually involves the skin overlying the inferior medial orbit (Fig. 30-16).

Pain frequently is severe and may localize to the glabellar region due to irritation of the supratrochlear nerve. Dacryocystitis should be considered in patients presenting emergently with acute pain in the lower forehead, particularly with a history of tearing, fullness and/or tenderness in the medial canthus. However, the infection is more often indolent and the pain mild.

Canaliculitis presents with unilateral conjunctivitis, mucopurulent discharge form the puncta, pouting of the punctum, and focal inflammation over the involved canaliculus. It is not a common ocular adnexal infection and most often is caused by Actinomyces and infrequently by fungi.

Treatment

Initial treatment of dacryocystitis is oral antimicrobial therapy. If the lacrimal sac is distended, needle aspiration with a 16 or 18-gauge needle can be used to eliminate the associated discomfort and prevent fistula formation, and the aspirate can be submitted for culture. Hospitalization is rarely necessary except in debilitated or pediatric patients. In patients with recurrent dacryocystitis or those not responding to oral therapy, surgical drainage of the infected sac combined with dacryocystorhinostomy is indicated. If the infection recurs after dacryocystorhinostomy, dacryocystectomy may be warranted, as a nidus of infection can persist in the sac or duct remnant or both. One study demonstrated notably better results with combined surgical and medical treatment, with an 80% cure rate, versus medical treatment alone, with a 10% cure rate. 138 Infants are typically treated by probing of the lacrimal duct, sometimes in conjunction with silicone intubation of the lacrimal system to maintain patency.

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Eye and related structures

J. Ruberte , ... L. Mendes-Jorge , in Morphological Mouse Phenotyping, 2017

Eyelids and Lacrimal System

The eyelids ( Fig. 14-2 ) together with the lacrimal fluid (tears) are responsible for cleaning the anterior surface of the eye and preventing it from drying out. There are two eyelids, the upper and lower, whose borders form the palpebral fissure on the surface of the eyeball. The free border of the eyelid is known as palpebral margin and has two edges, the anterior palpebral limbus and the posterior palpebral limbus. Special hairs known as eyelashes or cilia have their origin in the anterior palpebral limbus. The eyelids join to form the lateral and medial ocular angles. In the medial angle of the eye is found the lacrimal caruncle, which is poorly developed in mice ( Fig. 14-2 ). The anterior surface of the eyelid is lined with thin skin, formed of 7 to 12 layers of keratinocytes. The posterior surface of the eyelid is covered by the palpebral conjunctiva, which is reflected in the fornix to form the bulbar conjunctiva. The conjunctiva is a stratified epithelium of keratinocytes and caliciform mucosal cells (goblet cells) with mucin accumulations ( Fig. 14-2 ). Generally, conjunctival keratinocytes, unlike skin keratinocytes, generally do not become cornified. In the region of the fornix, the conjunctiva forms several folds and the number of goblet cells is greater. The bulbar conjunctiva is thicker than the palpebral conjunctiva. Inside the eyelids, there is a fascia of connective tissue that forms the tarsus in the vicinity of the palpebral margin ( Fig. 14-2 ). Several tubule-alveolar sebaceous glands, the Meibomian's or tarsal glands, are associated with the tarsus. Its secretion lubricates the movement of the eyelids.

Figure 14-2. Eyelids. A) Lateral view of head of an ICR mouse. B) Lateral view of eye of a C57BL/6 mouse. C) Sagittal section of upper and lower eyelids. Hematoxylin-eosin stain (20X). D) Magnification of lower eyelid. Masson's trichrome stain (100X). E and F) Palpebral conjuctiva. Hematoxylin-eosin stain (400X).

1: Upper eyelid; 2: Lower eyelid; 3: Lid margin; 4: Anterior palpebral limbus; 5: Posterior palpebral limbus; 6: Posterior surface of eyelid; 7: Anterior surface of eyelid; 8: Eyelashes; 9: Palpebral fissure; 10: Lateral palpebral commissure; 11: Medial palpebral commissure; 12: Lacrimal caruncle; 13: Palpebral conjunctiva; 14: Conjunctival fornix; 15; Bulbar conjuctiva; 16: Stratified epithelium; 17: Caliciform mucosal cells (goblet cells); 18: Tarsus; 19: Tarsal gland; 20: M. orbicularis oculi; 21. M. levator palpebrae superioris.

The lacrimal apparatus consists of glands, which produce tears, and their conductive pathways ( Figs. 14-3 to 14-8 ). The mouse has three lacrimal glands that are very developed: the orbital, the extraorbital and the gland of the third eyelid or the Harderian gland. The orbital lacrimal gland, as its name suggests, is located in the dorsotemporal region of the orbit, below the upper eyelid ( Fig. 14-3 ). The extraorbital lacrimal gland is similar in size to the parotid gland and is situated in contact with its rostral border. The extraorbital gland is subcutaneous and is located laterally to the m. temporalis and m. masseter and the zygomatic arch ( Figs. 14-3 and 14-4 ). From a histological point of view, the orbital and extraorbital lacrimal glands are serous tubulo-alveolar glands and both glands are covered by a fibrous capsule. The alveoli are larger and less densely packed than the acini of the parotid gland. The cuboidal cells of the alveoli have a granular and basophilic cytoplasm with a basally-located nucleus. The excretory ducts of the glands, which drain into the conjunctival sac, also have a simple cuboidal epithelium ( Fig. 14-3 ).

Figure 14-3. Orbital and extraorbital lacrimal glands. A) Superficial dissection of head. Left lateral view. B) Extraorbital lacrimal gland. Hematoxylin-eosin stain (200X). C and D) Orbital lacrimal gland. Hematoxylin-eosin stain (200X and 400X, respectively).

1: Orbital lacrimal gland; 2: Extraorbital lacrimal gland; 3: Parotid gland; 4: Eyeball; 5: M. temporalis; 6: M. masseter; 7: Ventral buccal branch (facial nerve); 8: Dorsal buccal branch (facial nerve); 9: Apex of nose; 10: Auricle; 11: Alveolus; 12: Secretory ducts.

Figure 14-4. Ultrasound images of lacrimal glands. A) Rostrocaudal section passing through the ramus of mandible. B) Dorsoventral section passing through the lateral palpebral commissure. C) Dorsoventral section passing through the ramus of mandible.

1: Extraorbital lacrimal gland; 2: Orbital lacrimal gland; 3: Lacrimal gland of third eyelid (harderian gland); 4: M. masseter; 5: M. temporalis; 6: Ramus of mandible; 7: Zygomatic arch; 8: Eyeball; 9: Lateral palpebral commissure; 10: Skin.

Figure 14-5. Lacrimal gland of third eyelid. A) Dissection of orbits. Dorsal view. Parietal and temporal bones were removed. B) Histological section. Hematoxylin-eosin stain (40X). C and D) Magnetic resonance images. Horizontal and transverse sections, respectively.

1: Lacrimal gland of third eyelid; 2: Dorsal lobe; 3: Ventral lobe; 4: Optic nerves; 5: Eyeball; 6: M. rectus dorsalis; 7: M. obliquus ventralis; 8: Nasal septum; 9: Ethmoidal labyrinth; 10: Olfactory bulb; 11: M. pterygoideus lateralis; 12: M. temporalis.

Figure 14-6. Structure of lacrimal gland of third eyelid. A, C and D) Albino ICR female mouse. A: Hematoxylin-eosin stain (400X). C: Confocal laser microscope image (400X). Autofluorescence (red) and nuclei counterstained with SYTOX Green. D: Confocal laser microscopy image transmission mode (400X). B) Pigmented C57BL/6 male mouse. Hematoxylin-eosin stain (400X).

1: Aveolus; 2: Epithelial cells; 3: Myoepithelial cell; 4: Porphyrin.

Figure 14-7. Third eyelid. A) Dissection of medial angle of eye. B) Histological section. PAS-hematoxylin stain (100X).

1: Third eyelid; 2: Cartilage of third eyelid; 3: Semilunar fold of conjunctiva; 4: Cornea; 5: Lacrimal caruncle; 6: Lacrimal canaliculus; 7: Upper eyelid; 8: Lower eyelid; 9: Caliciform mucosal cells (goblet cells); 10: Ventral lobe of lacrimal gland of third eyelid.

Figure 14-8. Ultrasound images of lacrimal gland of third eyelid. A) Oblique transverse section. B) Oblique horizontal section.

1: Lacrimal gland of third eyelid; 2: Eyeball; 3; Upper eyelid; 4: Lower eyelid.

The gland of the third eyelid or Harderian gland is found exclusively in animals that have a nictitating membrane. In the mouse, the gland of the third eyelid is large and occupies most of the orbit ( Figs. 14-5 to 14-8 ). It is shaped like a hollow hemisphere with its concave portion in contact with the posterior surface of the eyeball. Two lobes can be distinguished, the dorsal and ventral, the latter being the largest. The optic nerve passes between the two lobes, leaving the eyeball to connect to the brain. The Harderian gland is tubulo-alveolar in nature and produces an oily secretion, which is dissolved in routine histology, causing the vacuolated appearance of alveolar cells ( Fig. 14-6 ). The third eyelid gland accumulates a dark brown autofluorescent pigment within the alveoli, which has been identified as porphyrin. This pigment is more common in females than in males. Despite mice have a large Harderian gland, its function is unclear. As a lacrimal gland, its function in the lubrication of the cornea is recognized, although it also has been linked to the synthesis of melatonin outside the pineal gland, pheromone production, immune response and even temperature regulation, because it has been shown that porphyrin is involved in temperature control in mice. The nictitating membrane, or third eyelid, is located in the medial angle of the eye and is covered by the semilunar fold of the conjunctiva. In the mouse, the third eyelid also has a lamina of hyaline cartilage that gives it consistency ( Fig. 14-7 ).

Tears drain through the lacrimal points of the caruncle. These points are continuous with the lacrimal canaliculi and lacrimal sac that ultimately empty into the nasolacrimal duct and nasal cavity, where tears evaporate ( Figs. 6-4 , 6-13 and 14-7 ).

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Neuroteratology of Autism

Patricia M. Rodier , in Handbook of Developmental Neurotoxicology, 1998

III Thalidomide Exposure and Autism

In 1994, a teratologic study with key information about the origin of autism was published. Miller and Strömland had initiated a study of the effects of thalidomide exposure on eye motility in the population of thalidomide victims in Sweden. That prenatal exposure to thalidomide had cranial nerve effects had been known since the mid-1960s (d'Avignon and Barr, 1964) and the authors of the new study hoped to use this sample with a high incidence of rare forms of strabismus to learn more about them. In particular, the well-documented time table of somatic malformations associated with thalidomide offered the chance to determine when the embryo is susceptible to brainstem injuries leading to eye motility problems (Miller, 1991). To the surprise of the investigators, first one, then another, and another of their subjects was observed to have a syndrome of global behavioral anomalies. In the end, 5 of about 100 subjects were determined to have autism (Strömland et al., 1994). Compared to a rate of approximately 1/1,000 in Sweden, this is a highly significant increase in the incidence of the disorder. However, the morphologic evaluation of all cases suggested an even greater effect: All the cases with autism had a pattern of physical anomalies that indicated exposure during a very narrow window of embryonic life, between gestational days (GD) 20–24. In fact, the members of the sample with evidence of such early exposure numbered only 15, making the rate of autism during the critical period 33%.

Like children with Joubert syndrome, the thalidomide-exposed cases of autism had malfunctions of several motor cranial nerves. The neurologic abnormalities observed in the five thalidomide autistic cases included the following: three cases of Duane syndrome, a failure of cranial nerve (CN) VI (abducens) to innervate the lateral rectus muscle of the eye with subsequent reinnervation of the muscle by CN III (oculomotor) (Hotchkiss et al., 1980); four cases of Moebius syndrome, a failure of the CN VII (facial) to innervate the facial muscles, often associated with other cranial nerve symptoms (May, 1986 ); and two cases of abnormal lacrimation, a failure of the neurons of the superior salivatory nucleus (CN VII) to innervate the lacrimal apparatus with subsequent misinnervation of the structure by neurons that normally supply the submandibular glands ( Ramsey and Taylor, 1980). One patient had gaze paresis, suggesting malfunction of CN III (oculomotor).

Each patient had hearing deficits and ear malformations. The auditory symptoms do not necessarily indicate an injury to CN VIII, which carries auditory and vestibular information, because there is no way to exclude the possibility of damage located at more central stations along the sensory pathways. In addition, thalidomide-induced malformations of the external ear are known to be associated with malformations of the middle and inner ear (d'Avignon and Barr, 1964). Thus, peripheral injury is a possibility in the thalidomide-induced auditory deficits.

Are the neurologic and physical features of the thalidomide cases representative of many cases of autism, or are these patients atypical? The literature on autistic cases of unknown etiology suggests that the features of the thalidomide cases are not rare. In a study of eye motility in autism, 7 of 34 cases had strabismus, and 31 of 34 cases had abnormal optokinetic nystagmus (Scharre and Creedon, 1992). In a review of studies of brainstem auditory responses in patients with autism, although hearing deficits were an exclusionary criterion in most studies, nonetheless, 35–50% of the cases tested had evidence of peripheral hearing deficits (Klin, 1993). Furthermore, victims of Moebius syndrome (congenital diplegia of the facial muscles and lateral rectus) have a high rate of autism—about 30% (Gillberg and Steffenberg, 1989; Strömland and Miller, 1997). Minor external terata are seen in a significant proportion of children with autism, the most common and most discriminating between autism and mental retardation being low-set, malformed, and, especially, posteriorly rotated ears (e.g., Walker, 1977; Rodier et al., 1997). Thus, there is nothing new about the idea that people with autism have neurologic defects and malformations indicative of very early injury to the brainstem. What is new is the idea that these associations may be the critical in understanding the origin of the disease.

Obviously, the importance of the thalidomide study does not lie in its ability to tell us what causes autism. Very few cases could have been exposed to thalidomide, which was removed from the market long ago. Rather, this study establishes the principle that exogenous insults can cause autism, and that the critical period for insult is in the third and fourth week of intrauterine life. Furthermore, because almost no neurons have begun to form at this time, the critical period predicts that autism does not arise from direct injury to the forebrain or even to the cerebellum. These form too late to have been exposed to the teratogen (Bayer et al., 1993). Instead, the initiating injury must be confined to the brainstem tegmentum. Secondary effects, of course, might follow from the initial injury, and malfunctions of areas undamaged by the initial insult might occur because of distortion of normal input from the damaged hindbrain.

Days 20–24 of gestation fall at the stage when the human neural tube is closing (Streeter, 1948). This is the period when the first neurons appear in all vertebrates, and in each species most are destined to form motor nuclei of cranial nerves (Taber-Pierce, 1973; Bayer et al., 1993). Thus, the cranial nerve motor symptoms and the time of exposure in the thalidomide cases are consonant with the hypothesis that thalidomide interfered with neuron production for the cranial nerve motor nuclei. Whether it had this effect by a cytotoxic action or by disrupting the pattern formation of the rhombomeres from which the neurons arise is not known. We know nothing about the neuroanatomy of the thalidomide cases except what we can guess from their symptoms and the critical period. Indeed, the teratology literature contains not even one study of the effects of thalidomide on the CNS in humans or animals. Furthermore, because previous studies of neuroanatomy in autism typically have focused on the forebrain, there was no evidence at the time of the thalidomide study to answer the question of whether other people with autism have alterations of the cranial nerve nuclei.

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