Aim: To describe the clinical spectrum of achiasmia, a congenital disorder of reduced relative decussation at the optic chiasm.
Methods: A retrospective case note and patient review of nine children (four boys). Achiasmia was defined by the combination of a characteristic asymmetry of the monocular visual evoked potential (VEP) response to flash and neuroimaging showing reduced chiasmal size.
Results: Three of the children had an associated skull base encephalocele with agenesis of the corpus callosum. In two patients achiasmia was associated with septo-optic dysplasia. Three patients had no neuroimaging abnormalities other than reduced chiasmal size and have no known pituitary dysfunction. One child had multiple physical deformities but the only brain imaging abnormality was reduced chiasmal size.
Conclusions: Some children with disorders of midline central nervous system development, including septo-optic dysplasia and skull base encephaloceles, have congenitally reduced chiasmal decussation. Reduced relative decussation may co-exist with overall chiasmal hypoplasia. Children with an apparently isolated chiasmal decussation deficit may have other subtle neurological findings, but our clinical impression is that most of these children function well.
Statistics from Altmetric.com
- NDRFFS, non-decussating retinal fugal fibre syndrome
- VEP, visual evoked potential
- non-decussating retinal fugal fibre syndrome
- septo-optic dysplasia
- NDRFFS, non-decussating retinal fugal fibre syndrome
- VEP, visual evoked potential
- non-decussating retinal fugal fibre syndrome
- septo-optic dysplasia
The optic chiasm, shaped liked the letter X, is named after the Greek letter chi (χ). Decussation of retinal fibres at the chiasm appears to be the evolutionary “default pathway” and the amount of ipsilateral projection correlates with binocular specialisation.1,2 Clinically, most cases are due to acquired abnormalities caused by compression, trauma, or inflammation. In some individuals, decussation of retinal ganglion cell axons at the chiasm is selectively reduced during development.3,4 Abnormal decussation could be the result of disruption in molecular mechanisms that guide midline axonal crossing. This is an area of active molecular genetic research. Signalling pathways have been identified that produce an achiasmic phenotype—for instance, retinal axons do not decussate in Pax-2 deficient mice, entering the ipsilateral optic tract instead.5,6 When Pax-2 is blocked, Sonic hedgehog expression at the ventral midline is prolonged.7 Other molecular pathways implicated in midline attraction or avoidance of retinal ganglion cell axons include CD44 (a surface bound adhesion molecule),8 Zic2 (a zinc finger transcription factor),2 and the Ephrins.9–11 An alternative to the molecular genetic paradigm is a vascular disruption sequence; during embryogenesis branches of the anterior cerebral artery supply the chiasm, anterior hypothalamus, and septum pellucidum.12 In humans, chiasmal decussation of nerve fibres and development of the contralateral optic radiation has been reported despite unilateral optic nerve aplasia.13
Abnormalities of decussation can be revealed by hemispheric asymmetry of monocular visual evoked potentials (VEP).4,14 In humans, both reduced (in achiasmia)15,16 and excess (in albinism)17 decussation correlate with nystagmus. However, a VEP asymmetry does not necessarily predict readily visible nystagmus—as shown in albinism.14,18 Significant asymmetry of the monocular VEP response is not always found in albinism with nystagmus.19,20
Complete absence of the chiasm (chiasmal aplasia) may not be associated with other significant CNS abnormalities: a girl with bilateral microphthalmos, bilateral aplasia of the optic nerves, chiasm and tracts had no other apparent abnormalities and was developing normally up to the age of 3.5 years.21 Also, aplasia of the chiasm was associated only with optic nerve hypoplasia and polymicrogyria.22
The term “non-decussating retinal fugal fibre syndrome” (NDRFFS) has been used to describe isolated absence of chiasmal crossing.23 There is an animal model—a strain of Belgian sheep dogs with absent chiasmal decussation and the combination of horizontal and seesaw nystagmus.24 The clinical features of NDRFFS are combined horizontal and seesaw nystagmus, an achiasmic VEP pattern, absence of endocrine abnormalities, normal visual fields, and normal foveal reflexes.15,23 To our knowledge, the state of their optic discs on ophthalmoscopy has not been photographically detailed in the literature3,15,23,25–27 but is described as normal.25–27 Head “shudder” or “tremor”, torticollis, and alternating esotropia have been reported in at least three of four reported patients with the combined horizontal and seesaw nystagmus of NDRFFS.15,26 Nystagmus in patients with a range of chiasmal disorders may be classically “seesaw”, but nystagmus is not necessarily present and may be of many less specific types.
There are other cases in which reduced chiasmal decussation does not fall within the strict criteria of NDRFFS. A retrospective case note and patient review was undertaken to define better the clinical spectrum of achiasmia.
From the records of the Great Ormond Street Hospital (GOSH) Ophthalmology Department, nine children (four boys) aged 4–14 years were identified with a diagnosis of achiasmia. All of these children had previously been clinically examined and had undergone clinically appropriate neuro-imaging and VEP studies. One patient had died before the start of this study, three were re-examined at routine follow up visits to GOSH, one (who had been previously evaluated at GOSH) was reviewed locally by a paediatric ophthalmologist, and four were reviewed specially at GOSH. Inclusion criteria were presence of nystagmus, VEP documentation of consistent positive contralateral crossed asymmetry to flash,16 and reduced chiasmal size on neuroimaging. Where appropriate, VEPs and eye movement studies were repeated.
Data on ocular motility, strabismus, refraction, and visual acuity were recorded and the anterior segment and fundi were examined in all cases. Whenever possible, eye movements, fundus photographs, and formal visual fields were recorded. All previous hospital notes were reviewed.
The study was approved by the Great Ormond Street Hospital and the Institute of Child Health (University College London) research ethics committee
VEPs to flash16 were recorded from three occipital electrodes—one placed 2–3 cm above the inion and two placed midway between the inion and mastoid process. Simultaneously, flash electroretinograms were recorded from skin electrodes placed along the inferior eyelid margin.
Eye movement recording
Quantitative measurements of eye movements were made with an infrared limbus tracking system (Skalar Medical, Delft, The Netherlands). Horizontal movements were recorded from the right eye and vertical movements were recorded from the left eye. A chin rest was used to stabilise the head and the subject was asked to fixate on a red LED light subtending a quarter of a degree of visual angle. The eye movement recordings were calibrated by asking the subjects to fixate additional positions spaced ±15 degrees apart horizontally and ±5 degrees apart vertically. Video recordings of eye movements were also made to facilitate interpretation of the quantitative eye movement recordings.
All previous brain neuroimaging results were reviewed to confirm reduced chiasmal size and to review other associated brain deformities.
The case records and clinical examination results of the nine children are shown in table 1. The appearance of the optic nerves and relevant neuroimaging is shown in figs 1–9: fundus photographs were not available for cases 2 and 4 and only one fundus was available for case 9. All patients had a characteristic pattern of monocular VEP asymmetry to a flash of light (the VEPs for case 1 are shown in fig 1I and for case 6 in fig 6G).16 Three of the children had a skull base encepahalocele and agenesis of the corpus callosum (cases 6, 7 and 8). In two patients achiasmia was associated with septo-optic dysplasia, a combination of absent septum pellucidum, optic nerve hypoplasia, and hypopituitarism12 (cases 4 and 5). Three children had no neuroimaging abnormalities other than reduced chiasmal size and have no known pituitary dysfunction (cases 1, 2 and 3); however, one had mild Asperger syndrome and one had subclinical epileptiform seizure activity. One child had multiple deformities including microtia, hemifacial microsomia, oesophageal atresia, and hydronephrosis; the only brain imaging abnormality was reduced chiasmal size (case 9).
Corrected acuities varied widely: one eye had 0.1 LogMAR, the others between perception of light and 0.5, 10 eyes had between 0.5 and 0.6. Eight patients had a best corrected binocular acuity of at least 0.6 LogMAR (table 1). All children had normal colour vision as tested with Ishihara colour plates. Stereo acuity as tested with Titmus fly and/or TNO stereo acuity tests was recorded as absent in all patients. No specific pattern of nystagmus was common to the study patients. The sample includes pure horizontal, rotary, and compound rotary or circumrotary and horizontal nystagmus (table 1). Further details can be seen on the video available on the journal website (http://bjo.bmjjournals.com/supplemental)
Our patients seem mostly to fall into three subtypes: type A (three patients) with isolated achiasmia on neuroimaging, type B (two patients) with septo-optic dysplasia, and type C (three patients) with skull base encephalocele and agenesis of the corpus callosum (table 1). One patient (case 9) did not fit into any of these groups.
Definition and classification of achiasmia
There is probably some chiasmal hypoplasia whenever there is optic nerve hypoplasia. In most of these cases, normal proportions of retinal ganglion cell axons have been directed ipsilaterally and contralaterally but, overall, are fewer in number. The optic chiasm in achiasmia is not just hypoplastic but it has the essential absence or relative lack of crossing fibres; thus, optic nerve hypoplasia and achiasmia may co-exist (figs 5A and B, 6A and B, 7B). The term “achiasmia” may strictly suggest an absence of the chiasm but, for clarity, it is used here to identify the essential abnormality of crossing fibres. Complete absence of the chiasmal structure, often associated with optic nerve aplasia, is thus not achiasmia; the term “chiasmal aplasia” is more appropriate.21,22
The definition of achiasmia is therefore not as strict as NDRFFS (defined above). The criteria for diagnosis are positive contralateral asymmetry of the monocular VEP response to flash (figs 1I and 6G) and neuroimaging showing reduced chiasmal size (figs 1G, 2, 3A and B, 4, 5C, 6E, 8D, and 9B). Although nystagmus was part of the inclusion criteria for this study, it may not be a constant feature of achiasmia—just as the excess decussation in albinism is not inevitably associated with clinical nystagmus.18
To our knowledge, four patients (all female) have been reported with NDRFFS.15,23,26 A fifth female has been described with isolated achiasmia but she only has horizontal nystagmus.25 The male:female ratio in our mixed group of patients with achiasmia is 4:5. One of three patients with isolated chiasmal deficit (our type A) is male (case 1). Another (case 9) who had an isolated small chiasm on neuroimaging but other associated facial and visceral problems is also male.
From our small sample and those in the literature, some general patterns appear to emerge. While the numbers of patients with this rare finding are small, we feel that there may be three main groups of patients with achiasmia:
Type A: reduced decussation with optic nerves of normal appearance on clinical examination.25,26 A small chiasm may be the only abnormality on the brain MRI scan. This group appears to overlap with NDRFFS. There may be seesaw23 or purely horizontal25 nystagmus, and the visual fields appear to be normal.23 In our patients, cases 1 and 3 had normal formal visual fields, case 2 (who was 4 years old) had behaviourally normal fields. Abnormal head posture, strabismus,26 and other subtle neurological abnormalities (mild autism in case 1 and subclinical epileptiform temporal lobe activity in case 2) may be present.
Type B: reduced decussation in combination with chiasmal hypoplasia and the midline defects of septo-optic dysplasia,16,28 a combination of absent septum pellucidum, optic nerve hypoplasia, and hypopituitarism (cases 4 and 5).12
Type C: reduced decussation and chiasmal hypoplasia in association with clefting disorders and encephaloceles of the skull base (cases 6, 7, and 8). Agenesis of the corpus callosum was present in all three of our patients with basal encephaloceles. The association of corpus callosum agenesis, morning glory disc, and optic nerve staphylomas with skull base encephaloceles has been previously reviewed.29
One patient in our series (case 9) did not fit into any of the above categories. This child suffered from multiple facial (microtia, hemifacial microsomia), visceral (oesophageal atresia, hydronephrosis), and developmental problems in addition to an isolated small chiasm; the MRI scan was otherwise normal.
Visual fields in achiasmia
Congenitally reduced chiasmal decussation need not be associated with visual field defects. The visual field may be abnormal due to optic nerve hypoplasia (case 6, fig 2) but does not necessarily have a bitemporal hemianopia pattern such as that seen with traumatic shearing of the chiasm.30–32
In cases 1 and 3 the appearance of the optic nerves and formal visual field testing were normal (figs 1C and D, 3E and F) The finding of normal visual fields in association with an isolated small chiasm on neuroimaging has been reported previously.15,23,27 A full visual field is consistent with studies of the lateral geniculate body (LGN) in the canine model of isolated achiasmia: misdirected nasal fibres form ipsilateral mirror image maps in those LGN layers that normally would have received nasal fibres from the contralateral eye.33 The optic discs may appear normal in achiasmia.25–27 The size of the optic nerves, density of axons, and total number of axons do not differ between achiasmic mutant and normal dogs, but the area centralis of the achiasmic dogs is smaller and has a lower peak ganglion cell density than that of normal dogs.34
Seesaw nystagmus and achiasmia
Seesaw nystagmus was described by Maddox in 1914.35 There is a conjugate torsional component and a dysconjugate vertical component. Both eyes rotate clockwise and then counterclockwise. The intorting eye rises while the extorting eye falls. However, the definition of seesaw nystagmus has not remained strict over time. In 1946 Rucker36 described seesaw nystagmus in a patient with vertical and torsional movements in the left eye (as described by Maddox), but only vertical movement in the right eye. Jensen described seesaw nystagmus as a “rare disjunctive form of vertical nystagmus in which the eyes perform opposed vertical movements”, but did not specify a necessary torsional component.37
Disorders of the mesencephalon,38–40 chiasmal trauma,30,31 and chiasmal compressive lesions41,42 are associated with seesaw nystagmus. Achiasmia is a recent addition to the differential diagnosis of seesaw nystagmus.43
In initial reports the pattern of nystagmus in achiasmia was limited to the combination of congenital horizontal and seesaw nystagmus.43,44 However, purely horizontal nystagmus may be present in achiasmia, as illustrated by cases 1, 2 and 9 in this study and in a previous case report.25 Combined horizontal and torsional nystagmus also appears to be consistent with achiasmia as illustrated by cases 4 and 7.
Conclusions and general observations
Certainty of the diagnosis of achiasmia can only be achieved by a combination of MRI scanning and VEPs. A number of our original sample of patients with VEP features of contralateral crossed positivity had to be excluded because the study was too noisy and/or was not reproducible on subsequent testing. It is also not possible to determine if there is complete absence of decussation on the MRI scan; this would require extremely thin sections.
Despite the wide spectrum of midline congenital CNS malformations in our achiasmic patients, most function well; five of the nine patients attend mainstream schools and are not behind their age matched peers. One (case 1) participates in junior golf competitions; another (case 6) performs well in arts and crafts. Other reports corroborate our finding of a high level of functioning in these children.15,26,27
Full visual fields3,23,27,44 and ophthalmoscopically normal optic discs25–27 are consistent with achiasmia, as shown by our cases 1 and 3. There does not appear to be any single pattern to the nystagmus: it may be rotary, seesaw, or purely horizontal. Subtle neurological problems may co-exist with “isolated” forms, as reported elsewhere15,26 and in our cases 1 and 2.
Achiasmia appears to be rare, but a portion of children diagnosed with “idiopathic congenital motor nystagmus” may have reduced decussation as part of the underlying abnormality—especially since VEPs and MRI scans are often not performed when the appearance of the nystagmus is “classic”.
Relatively reduced decussation affects a subset of children with developmental abnormalities that include midline facial defects, basal encephaloceles, midbrain defects, pituitary and hypothalamic defects, alone or in combination. Whenever there is reason to suspect congenital chiasmal maldevelopment, VEPs, MRI scans, endocrine assessment, and visual follow up until mature are recommended.
A video sequence accompanies this article.
Files in this Data Supplement:
- [view video] - Horizontal movements were recorded from the right eye and vertical movements were recorded from the left eye. A chin rest was used to stabilise the head and the subject was asked to fixate on a red LED light subtending a quarter of a degree of visual angle. The eye movement recordings were calibrated by asking the subjects to fixate additional positions spaced ±15 degrees apart horizontally and ±5 degrees apart vertically. Video recordings of eye movements were also made to facilitate interpretation of the quantitative eye movement recordings.
There is a publisher error in the author list of this paper. The name of the ninth author is incorrect, and should read:
Competing interests: none declared
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.