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

Riley, Day, Greeley, and Langford (1949) described the clinical features of a disturbance of the auto- nomic nervous system manifested by skin blotching, fluctuations in blood pressure, erratic temperature control, disturbances of the swallowing reflex, hyperhidrosis, and diminished or absent lacrimation.Ad- ditional signs of neurological involvement included incoordination, relative insensitivity to pain, dimin- ished 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 and Engel (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) in cats.These tracts arise in the lateral hypothalamus and descend to preganglionic sympathetic neurons of the spinal cord.In the medulla, these tracts are situated largely in the lateral reticular formation.Recently Riley (1957) presented a comprehensive review of this condition.He reviewed t'1ree new cases.In one case there were multiple brain abscesses, presumably secondary to an aspiration type pneu- monia.In the other cases abnormalities of the central nervous system were sought using the Cohen and Solomon (1955) criteria.but none were found.No note was made of any examination of the peripheral nervous system.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 spino- cerebellar 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 melanin, iron, lipofuscin and periodic acid- Schiff (P.A.S.)-positive materials were done on tissue sections of autonomic ganglia using methods described by Pearse (1960).CASE REPORTS CASE 1 The clinical details of this case have been exten- sively treated in another context by Linde (1956).The following is only a brief clinical abstract: J.S., a 2-year-old Jewish girl, was noted on the second day of life to have hypotonia, hypertension, poor colour, 131 by