Antenatal Bilateral Thalamic Injury

Overview

A fetus may survive an acute episode of intrauterine asphyxia in severity equivalent to postnatal prolonged bradycardia or asystoly, and then, during pregnancy or at birth, show signs of an established brain lesion. The hallmark of this disorder is the combined presence of necrosis and gliosis in diencephalon, striatum, cerebellum and brainstem. In some, necrosis in deep gray matter is associated with leukomalacia or matrix destruction. Other mechanisms of prenatal brain damage must be excluded: primary haemorrhage with secondary ischaemia, fetal infection, any genetic (e.g. metabolic) condition or embryonic anomaly. Survival with milder degrees of this problem may, in the absence of neonatal encephalopathy, be a cause of cerebral palsy. The presence of symmetrical thalamic lesions with a consonant clinical picture establish a tentative diagnosis of this entity.

Sequence of clinical events

Clinical presentation: polyhydramnios, signs of fetal distress (with a typical paradox between decreased or even absent heart beat variation and a normal scalp pH), pulmonary hypoplasia, a small to normal occipitofrontal circumference, fixed limb contractures due to neurogenic muscle atrophy (often initially diagnosed as "arthrogypoid syndrome" or "Pena-Shokeir syndrome"), hypertonia and tendon hyperreflexia from birth, early seizures, cranial pareses (facial diplegia, swallowing or sucking problems, ophthalmoplegia, tongue fasciculations, stridor), signs of hypothalamic dysfunction (temperature instability), abdominal fasciculations. The mortality rate associated with diffuse antenatal brain ischaemia is high. Potential causes are all mechanisms jeopardizing oxygenation and/or perfusion to the fetus. It is often only on repeated history taking that a clue to the cause of a so-called birth asphyxia is found in pregnancy-related problems. The absence of growth retardation in more than 3/4 of the cases does not suggest a role for an underlying chronic maternal or placental problem.

Causes and risk factors

A high percentage (> 30 %) of stillbirths presents with histological arguments for established damage to white matter (increased number of hypertrophied astrocytes or pure presence of GFAP-positive cells). Hypothetic mechanisms underlying gliotic leukomalacia of the third trimester are: intermittent umbilical cord compression, smoking, fetal endotoxinaemia, excessively recurrent Braxton-Hicks contractions and placental ischaemia (with or without pre-eclampsia). Placental ischaemia may present as genuine infarction or, in less explicit cases, as accelerated villous maturation. A rare cause of in utero brain ischaemia is villitis of unknown aetiology, where in third trimester for unexplained reasons an inflammatory infiltrate in the placenta is associated with subacute placental dysfunction (Boog et al. 2007).

Antenatal onset thalamic hyperechogenicity

Mitochondrial disorders usually affect striatum as well if they damage thalamus. Molybdenum cofactor deficiency may need to be ruled out, although (sub)cortical injury is typical of that disorder. Symmetrical infantile thalamic degeneration (Ambler and O'Neil 1975) was described in a term boy with delayed onset of spontaneous respiration for one minute following uneventful pregnancy and delivery. At three weeks gasping and increasing apnoea finally led to late neonatal death. A screen for aminoacidopathy, fetal infection and meningeal inflammation was unrewarding. His brain, of normal weight (390 g) appeared macroscopically normal. Severe neuron loss and astrogliosis were restricted to thalamus and hypothalamus. Neurons affected contained basophilic cytoplasmic globules, staining positive with von Kossa and PAS. Electron microscopy described these globular bodies of variable shape and size as being surrounded by a single smooth membrane and filled with linear spicules typical of calcium apathite crystals. Although pushed aside the nuclei, endoplasmic reticulum and mitochondria were still present and appeared unaffected. Similar descriptions were by Abuelo et al. 1981 and Rosales and Riggs 1962. Whether or not this is a distinct disorder or a post-ischaemic event remains unclear. Hyperoxaluria may present in infancy with crystal deposition in thalamus (Ardemani et al. 2017).

Typical cases: antenatal bilateral thalamic injury

Persistent hyperchoic changes in thalamus (from day 1) and limited T1 hypersignal in thalamus without acute diffusion restriction. Negative infectious and metabolic diagnostic tests. Courtesy dr Agut, Sant Joan de Deu Barcelona

Two term infants with hypertonia and lowered consciousness from birth and difficult swallowing

The combination of the clinical picture and these "subtle" sonographic changes allow for a tentative diagnosis of this often misjudged clinical picture. In case of hypoxic-ischaemic insult in the last days before delivery, the imaging substrate may be more deceptive: absent brain swelling and no luxury perfusion. Recent haemorrhage may be hyperechoic in such instance. Ischaemic matrix injury may also be seen in the hyperechoic, pre-cystic stage. ∆∆ Symmetrical thalamic injury can be seen in neonatal pyruvate utilisation and mitochondrial disorders; those conditions cause infarction with cavitation of pallidum, hypothalamus or brainstem tegmentum. With antepartum asphyxia no focal calcification is seen anterior to the fourth ventricle as sometimes seen in Möbius syndrome.

Typical behaviour of thalamus on ultrasound

Term infant (day one) with seizures within the hour following caesarean section for unexplained fixed fetal heart rate and reduced fetal movements; normal umbilical artery pH, no anaemia; the cause of this asphyxial event was unknown; this child died in the neonatal period.

First week: shrunken hyperechoic thalamus

Hyperechoic brainstem tegmentum

Sonographic observations of established in utero global forebrain ischaemia are scarce (Eicke et al. 1992, Pols et al. 2019). In personal observations echogenicity of white matter appeared normal. Both lateral and the third ventricles were moderately widened, in sagittal section the otherwise virtual third ventricle is too well visualized. Thalamus appears atrophic, with cystic germinolysis in the caudothalamic groove in some. Both thalami are moderately hyperechoic, striata are not (thalamus is a graveyard of encrusted neurons in these infants). Ischaemic zones in the dorsal brainstem and thalamus accordingly may be seen on MRI: gliotic zones in the dorsal part of the brainstem and ventrolateral thalamus may have high signal in T1-weighted sequences. Under the anterior fontanelle there can be an arachnoid space of more than 4 mm wide, pointing to global atrophy.

Recent antepartum asphyxia

Antepartum asphyxia at 31w, caesarean section for loss of beat to beat variation on CTG and no fetal movements for 24 hours; if relatively recent, MRI may show changes in diffusion as on these images taken on day two.

Hyperechoic thalamus on day 1

Hypersignal on T1 in caudate, putamen, pallidum and ventrolateral thalamus

Diffusion restriction in putamen and thalamus

Typical MR changes in the first week

GA 36w, MRI day 6, polyhydramnios, intubation for Pierre-Robin sequence. Courtesy A Dereymaker, UZ Leuven.

Typical old antepartum event

Neonatal parasagittal sonogram and MRI (at 1 month for axial T1W MRI, at 3 months for brainstem sections) of a term infant whose mother suffered cardiac arrest at 28 weeks of gestation (courtesy Dr Speer, Banerjea and Speer 2001). Neat gliosis and calcification are striking in the ventrolateral thalamic nuclei; within the brainstem there are areas of gliosis and tissue loss lateral to the medial lemnisci.

Histopathology: sequence of events

Onset and duration of histopathological changes
Feature	Onset	Duration
edema/sponginess	6-12 h	3-4 d
neuronal karyorrhexis	24-36 h	± 10 d
astroglia		3-6 d
- astroglial reaction	12-24 h	years (peak activity 3-5 d)
- gemistocytic reaction	6 d	weeks
microglial reaction	< 1 d	months (peak activity 4-5 d)
endothelial proliferation	< 1 d	weeks
new capillaries	7 d
neuronal ferrugination	8-10 d	years
cavitation - microcavitation, liquefaction	8 d
cavitation - macrocavitation	10-14 d	permanent
cavitation - cystic germinolysis	7 d	months

Differential diagnosis

Injury to thalamus in the newborn is diverse. Focal injury to thalamus (often symmetrical) can occur in some inborn errors of metabolism like mitochondrial disorders (typically the Leigh phenotype) and primary hyperoxaluria type I (Ardemani et al. 2017). The oxalate crystal deposition in thalamus may be similar to the cases reported on apathite crystals by Ambler and O'Neil 1975. Unilateral rare lesions may also present in thalamus. Thalamus can be affected as part of extensive brain destruction by postinfectious haemophagocytosis. Vascular anomalies may present in thalamus: bleeding from a choroidal AVM can extend into thalamus, and on rare occasion a DVA is observed in thalamus.

Primary hyperoxaluria

A 2-month-old infant was admitted, and was diagnosed with renal failure; abdominal ultrasound images revealed enlarged and hyperechoic kidneys; additionally, on CUS hyperechoic changes of thalami were noted, reminiscent of perinatal hypoxic-ischaemic brain damage; however, MRI of the brain did not show any abnormal signal intensities compatible with asphyxia. The hyperechoic appearance of deep grey matter, was therefore not due to asphyxiated brain damage but seemed related to the deposition of oxalate salts; macular crystals were detected at ophthalmoscopy.

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