A neuropathological study of familial dysautonomia (Riley-Day syndrome) in siblings

Abstract

Riley, Day, Greeley, and Langford (1949) described the clinical features of a disturbance of the autonomic nervous system manifested by skin blotching, fluctuations in blood pressure, erratic temperature control, disturbances of the swallowing reflex, hyperhidrosis, and diminished or absent lacrimation. Additional signs of neurological involvement included incoordination, relative insensitivity to pain, diminished deep tendon reflexes, emotional lability, and disturbances of the gastrointestinal tract with episodes of severe vomiting.While this widespread involvement of the nervous system was evident clinically, attempts to elucidate the histopathology and pharmacopathology have met with only partial success. The aetiology and pathogenesis of this condition remains obscure. Aring andEngel (1945a, 1945b) reported clinical and pathological studies in a patient who had 'hypothalamic attacks' and at necropsy an old cystic lesion was found in the thalamus. These authors postulated repeated paroxysms of hypothalamic overactivity because of disruption of corticohypothalamic association tracts described by Magoun (1939) which coursed through a cystic degenerative lesion of the dorsomedial and lateral nuclei of the right thalamus. The clinical descriptions of the 'hypothalamic attacks' are those of dysautonomia.In a more recent necropsy study of a typical case of dysautonomia, Cohen and Solomon (1955) found the pons and medulla grossly smaller than normal due to alterations in the reticular formation. No aetiological clues could be found. These authors believed that the pathological changes had occurred in tracts similar to those described by Magoun (1939) The two cases in siblings reported here are significant in that the abnormalities described by Cohen and Solomon (1955), and to some extent by Aring and Engel (1945a), were present. In addition, changes in the dorsal longitudinal bundle in the brain-stem, spino-thalamic tracts of the cord and medulla, ascending dorsal columns, and spinocerebellar tracts were found. Also included in the report is a detailed study of significant changes in autonomic ganglia and peripheral nerves. MATERIALS AND METHODSThe brains of both cases and the spinal cord of case 1 were fixed in 10% neutral formalin. Other tissues were fixed in both Zenker's solution and 10% neutral formalin. An extensive dissection was carried out on case I and eyes, muscles, lacrimal glands, tongue, vagus, peroneal, femoral nerves, brachial plexus, and autonomic nerve chains were all sampled and placed in both fixatives. Autonomic ganglia from the coeliac plexus and the thoracic and pelvic regions were taken. The brain in case 2 was coronally sectioned and embedded in both celloidin and paraffin. The brain and spinal cord in case 1 were similarly cut and embedded only in paraffin. The brains and cord were sectioned subserially and stained using multiple histopathological techniques (Weil, haematoxylin and eosin, Holzer, Nile blue sulphate, Luxol fast blue, Bielschowsky, and Bodian preparations). Tests for melani...

Pathological Confirmation of Optic Neuropathy in Familial Dysautonomia

“…Neuropathological findings of the disease include brainstem, pontine, medullary, and spinal atrophy with neuronal depletion in dorsal root (sensory) and sympathetic ganglia, as well as reduced numbers of small myelinated and nonmyelinated (sensory) axons of peripheral nerves (8)(9)(10)(11)(12).…”

Obstructive Sleep-Disordered Breathing Is More Common than Central in Mild Familial Dysautonomia

“…34 However, absence of REM sleep may also be due to brain pathology described in FD patients. [11][12][13][14][15][16][17] The scarce autopsies of FD patients showed spongiform degeneration of the reticular formation, particularly in the medulla, pons, and mesencephalon, but also pathology in other brain regions including the cerebellum or frontal and parietal lobes.…”

“…[52][53][54] Among the parameters possibly changing the sensitivity of central chemoreflex receptor neurons are alterations in the descending cortical input, pulmonary vagal feedback, and feedback from arterial baroreceptors or peripheral chemoreceptors. 53 In FD patients, cerebral pathology [11][12][13]17 may compromise central chemoreceptor neuron function, while impaired afferent impulses from pulmonary receptors, [11][12][13]16,37 peripheral chemoreceptors, 4 and baroreceptors 19 may further contribute to deficient central respiratory control and decreased controller gain, i.e., decreased chemoresponsiveness with reduced ventilatory responses to hypoxia or hypercapnia. 52 Finally, Maayan et al reported that the loop gain, i.e., the measure of the stability or instability of the ventilator control system 54 may change in FD patients during sleep and may thus critically destabilize respiration.…”

“…37 Even though the parasympathetic nervous system is less severely compromised in FD than is the sympathetic system, 13 central processing of impulses from pulmonary and lower airway vagal afferents reaching the nucleus of the solitary tract 51 might be altered in FD patients due to their inherent brainstem pathology. [11][12][13]16 Thus, many different pathomechanisms may contribute to obstructive events in FD patients.…”

“…5 While obstructive apneas can be treated with continuous positive airway pressure (CPAP), this treatment is less successful in central sleep apneas. 9,10 In FD patients, the pathology with central and peripheral autonomic dysfunction, 2,4,[11][12][13][14][15][16][17][18][19] kyphoscoliosis, 20 and craniofacial abnormalities 21 may give rise to both central and obstructive sleep apneas.…”