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Brainstem dysgenesis: Concept

Brainstem dysgenesis (BSD) is a generic or umbrella term that we proposed in 2003 to describe all patients with congenital dysfunction of CN and decreased muscle tone due to prenatal lesions or malformations of the BS [2,10]. The origin of the BSD can be genetically determined in some patients and it may be present in isolation or be part of a more extensive polimalformative syndrome. In most cases BSD is due to prenatal destructive or disruptive lesions of vascular origin. Depending on the vessels involved and the magnitude of the lesion, clinical consequences range from intrauterine death to mild involvement of one or several cranial nerves. There is recent literature recognizing an amalgam between destructive and developmental processes in the injured fetus because a destructive process that occurs in a rapidly developing tissue may cause both a derangement of subsequent development and injury to an already-developed structure; the less vigorous reactive cellular response to tissue destruction during early development makes it difficult to distinguish developmental (genetically determined) lesions from destructive lesions [22].

 According to our experience and the literature review, disruptive accidents occurring early in gestation are the most common cause of BSD, and thus the recurrence risk is minimal [9,10,11]. Clinical findings in some BSD patients may coincide with those described in well-recognized dysmorphological syndromes (e.g., Duane, Möbius, and Pierre Robin), if this is the case, the eponym indicates the predominant location of the BS lesion. Clinical manifestations in the majority of patients with BSD do not fit into any of the aforementioned syndromes, in these circumstances the term BSD should be followed by a detailed description of each patient’s clinical findings and the BS segment presumably involved see (Figure 1).

Brain stem dysgenesis: classification

Continuous advances in developmental biology, molecular genetics, and neuroimaging have conducted to an increased interest in developmental disorders of the embryonic midbrain and hindbrain and all this amount of information has led to rather sophisticated developmental/genetic classifications of brainstem malformations [23, 24]. We have proposed two alternative and complementary BSD classifications. A) From an etiologic point of view three main categories are considered: a) acquired (destructive o disruptive); b) genetically determined; and c) dysmadurative. It should be noted that disorders within each of the first two groups can present without involvement of other organs or systems or with malformations (syndromic) other organs or systems. (Table I) B) Based on severity of the disorder (in our experience not two BSD patients present with identical clinical manifestations), we have proposed four clinical forms:  1) Lethal forms, associated with respiratory failure and death occurring in the first few months of life [25,26,27]; 2) Severe or diffuse forms which include those patients with hypotonia and involvement of multiple cranial nerves, mild pyramidal signs, temporo-mandibular ankyloses (TMA), and feeding problems, in some of them, the CFZS could be entertained [3, 11, 28]; 3) Moderate or intermediate forms, some of which match the descriptions of MS or PRS, and 4) Mild or Restricted forms, which have isolated bilateral involvement of one of the cranial nerves reflecting the disrupted segment of the BS. For each of the last three described BSD forms there are asymmetrical or even unilateral variants for which the disruptive vascular cause is the most likely origin [29].

Clinical manifestations
Neonatal period

Bilateral VII CN involvement, muscle hypotonia and feeding difficulties are the most common presenting clinical signs of newborns (NB) with BSD. The most commonly affected CN in decreasing order of frequency are the 7th, 9th, 10th, 5th, 12th, 6th, 4th and 3rd. The decreased muscle tone in this group of patients is often associated with signs of pyramidal tract involvement (increased deep tendon reflexes, jaw jerk and Achilles clonus), probably due to concomitant corticospinal and spinocerebellar tract involvement at the BS level (30).

Feeding problems and swallowing dysfunction varies from patient to patient depending on the extent of the lesion.  In NB with intermediate or restricted BSD forms in which there is mild facial involvement and intact swallowing mechanisms, tube feeding can be discontinued once muscle hypotonia improves. Some NB, particularly those presenting with lesions located in the caudal portion of the BS, may suffer from swallowing difficulties, respiratory problems, esophageal motility dysfunction and cardiac arrhythmia which, sometimes, are the cause of death. It is worth mentioning that heart rate problems are occasionally detected during the practice of conventional EEG or during sleep EEG recordings [1,31,32].  Profuse oral secretions and choking episodes are quite common in this group of NB with diffuse forms of BSD and require frequent oropharyngeal suctioning of secretions or, in some instances, it is necessary to place a continuous nasopharyngeal suction catheter. It must be taken into account that poor handling of saliva alone can cause repeated silent micro-aspiration and lead to chronic lung injury [3].

Associated congenital anatomical malformations found in NB with BSD such are: TMA, cleft palate, retro-micrognathia, associated or not to glossoptosis, can cause severe airway problems. Mandibular growth may be impaired or retarded, owing to trigeminal nerve involvement, [1,3,28,32] and results in varying degrees of micrognathia. TMA is a common and often over-looked clinical finding in NB or infants with BSD and often associates with retro-micrognathia and, its proposed cause is intrauterine paresis of mandibular muscles due the aforementioned 5th CN involvement. We have not found specific descriptions of TMA after reviewing different cohorts reported under the name unrestricted or expanded MS, PRS or CFZS [8,13,14,33], however, considering the clinical descriptions on those publications, TMA was present in a considerable number of the reported patients. Recently, Pasetti and cols. have published an infant diagnosed of CFZS with TMA (28) and Hong et al. [34] have reported and infant with BSD, TMA and oculomotor apraxia.  This last clinical combination (muscle hypotonia, facial diplejía, TMA and oculomotor apraxia and mild pyramidal signs) has been found in a total of 8 patients (10); we have later reported another patient  [30] and consulted on another two infants with similar phenotype. It would be most interesting to know if other colleagues around the world have cared for patients with a comparable form of BSD (see comment to ref. 34).

BSD in the NB, as mentioned earlier, can be associated to malformations in other organs or systems which can divert attention from the BS as being part of the syndrome. The “Athabascan brainstem dysgenesis syndrome” was the first report to call attention upon BS involvement as part of a polymalformative syndrome and distinguish it from MS [35]. Some years later, Athabascan syndrome was proved to be caused by a defect of the HOXA1 gene [16] and gave us arguments to use the term BSD to designate all the patients with disordered BS development.  As a general rule, BS involvement as part of a genetic /syndromic disorder tents to be diffuse and therefore severe, whereas those caused by disruptive lesions involve predominantly the Rombencephalon. Finally, a multidisciplinary team approach to manage BSD in the neonatal period has been recently reported to improve its management and prognosis [30,34].  

Clinical Follow-up (Natural history)

Muscle tone tends to improve with the passage of time and does not appear to be a significant clinical problem after 3 years of age in most instances.  After the first few months of age facial diplegia, feeding difficulties, poor handling of oral secretions, dysarthria, and signs of pyramidal tract involvement, including a brisk jaw jerk are the most common clinical findings. Adequate respiratory function is a prerequisite for successful oral food intake. Initially, feeding may be via nasogastric tube (NGT) until the airway is assessed and appropriate management is determined. TMA and an anteriorly positioned larynx can make mask ventilation and endotracheal intubation extremely difficult. Securing a patent airway may prove a very difficult task and