Faculty Bibliography

Background: The arterial baroreflex buffers blood pressure to prevent it from rising or falling excessively. Afferent baroreflex failure occurs in patients with genetic or acquired lesions of the afferent (sensory) baroreceptor nerves relaying information to the brain or within the central connections of the medulla. Patients with afferent baroreflex failure have extremely volatile high and quite low pressures. Review of the literature reveals that acquired forms of afferent baroreflex failure have never been described in children or young adults. Aim: To define the cause, clinical spectrum, and treatment of acquired baroreflex failure in children and young adults. Methods: We prospectively studied consecutive pediatric and young adult patients (<30 years old) who were diagnosed with afferent baroreflex failure. Each patient underwent a detailed clinical history, neurological examination, autonomic testing, plasma catecholamine measurements, and ambulatory blood pressure monitoring. Results: We identified 6 patients (3 males and 3 females; age range: 11-28 years old). All presented with severe, labile hypotension with syncope and hypertension often accompanied by headache, and flushing. Office blood pressure ranged from a maximum of 198/138 to 143/90 mmHg and a minimum of 70/40 to 102/68 mmHg. Plasma norepinephrine levels failed to increase appropriately during head-up. On ambulatory monitoring, 24-h systolic blood pressure standard deviation was markedly exaggerated (from 17.5 to 20.8 mmHg). In all cases, patients had excessive pressor and tachycardic responses to cognitive arousal (mental-arithmetic). The underlying causes of the afferent baroreflex failure included surgery and radiotherapy of head or neck cancer (n = 4), posterior reversible leukoencephalopathy (n = 1), and Moebius syndrome (n = 1). Conclusions: Acquired afferent baroreflex failure should be considered in children and young adults with otherwise unexplained labile hypertension, particularly in those with a history of head or neck cancer

Our genome encodes for all proteins in the body and controls our biological functions. Mutations in DNA sequences that encode for proteins highly expressed in nerve tissue can result in specific lesions within the autonomic pathways. Mutations that result in a deficiency in a protein important for the survival of autonomic neurons at key developmental stages are usually expressed at birth or in early childhood. Hereditary sensory and autonomic neuropathies (HSAN) are a group of inherited diseases with insensitivity to pain. There are currently 6 major HSAN subtypes and at least 12 known gene-causing mutations. The severity of autonomic involvement is most profound in types 3 and 4, which are both autosomal recessive, but their autonomic phenotypes are distinctly different. Genetic mutations that result in the overexpression of proteins expressed in autonomic neurons typically present later in life and follow a more degenerative course. Familial amyloid polyneuropathies are a group of disorders caused by deposits of amyloid fibrils, most commonly due to mutations within the transthyretin (TTR) gene. This results in a length-dependent sensorimotor and autonomic neuropathy affecting unmyelinated and small myelinated fibers. The most common auto-nomic features are orthostatic hypotension, erectile dysfunction and gastrointestinal dysmotility, and can sometimes be a presenting sign. Genetic factors may also play a role in susceptibility to neurode-generative diseases. A recent genome wide association study found several genes that may emerge as genetic players in synucleinopathies including multiple system atrophy. For now, clinical trials are underway to explore whether modifying gene expression can influence the survival of autonomic neurons in HSAN3 and transthyretin-related hereditary amyloidosis. In the future, it may be possible to modify our future risk of developing an autonomic disorder with genetic therapy

Introduction: Familial dysautonomia (FD) is a rare autosomal recessive disorder caused by a point mutation in the IKBKAP gene, resulting in reduction of the IkappaB Kinase-associated protein/Elongator protein 1 (IKAP/ELP1). ELP1 is a transcriptional regulator that targets downstream genes involved with cell migration, stability and survival. We hypothesized that ELP1-associated abnormalities may increase the incidence and prevalence of neoplasia and cancer in FD. Methods: Retrospective chart review of the New York University FD Patient International Registry, which contains standardized clinical information on patients with genetically confirmed FD since 1970. We identified cases with neoplasia or cancer, and reviewed their demographics, tumor type and age at diagnosis. Results: At the time of writing, of the 674 patients with FD reviewed, we identified 25 cases of neoplasia, which included 12 cases of cancer. The prevalence of neoplasia in the FD population was 3.7% and the prevalence of cancer was 1.8%. Average age at cancer diagnosis was 29 years, significantly younger than in the general population (66 years). Additionally, 16% of all neoplasia were tumors derived from neural crest cells. There was no association between growth hormone treatment and the prevalence of neoplasia or cancer. Conclusions: Patients with FD have higher rates of neoplasia and cancer than previously reported in the literature. Overall, the FD population develops cancer and tumors at a much younger atypical age than the general population. Our results suggest that ELP1 plays an important role in tumor genesis and may explain the high prevalence of neoplasia and cancer in patients with FD

PURPOSE: To report the use of intranasal dexmedetomidine, an alpha2-adrenergic agonist for the acute treatment of refractory adrenergic crisis in patients with familial dysautonomia. METHODS: Case series. RESULTS: Three patients with genetically confirmed familial dysautonomia (case 1: 20-year-old male; case 2: 43-year-old male; case 3: 26-year-old female) received intranasal dexmedetomidine 2 mcg/kg, half of the dose in each nostril, for the acute treatment of adrenergic crisis. Within 8-17 min of administering the intranasal dose, the adrenergic crisis symptoms abated, and blood pressure and heart rate returned to pre-crises values. Adrenergic crises eventually resumed, and all three patients required hospitalization for investigation of the cause of the crises. CONCLUSIONS: Intranasal dexmedetomidine is a feasible and safe acute treatment for adrenergic crisis in patients with familial dysautonomia. Further controlled studies are required to confirm the safety and efficacy in this population.

Objective: To determine if administration of a muscarinic agonist can stimulate the secretion of tears in patients with familial dysautonomia (FD). Background: FD is frequently referred to as a disease with no tears, but the underlying reason for this alacrima is unknown. Normally, nerves in the cornea stimulate the production of tears from lacrimal glands in the eye. Whether the absent/reduced tears in FD is due to denervation or an abnormality in the lacrimal glands themselves is unclear. Design/Methods: We applied pilocarpine (4%, a parasympathetic M3 receptor agonist), topically to the eyes of 16 patients with genetically confirmed FD to stimulate the tear secretion directly in the lacrimal glands bypassing the nerve pathways. We assessed corneal sensitivity using a Cochet-Bonnet esthesiometer. Tear volume was estimated with the Schirmer test (a scaled paper strip placed in the lower eyelid and the length of moisture measured after 5 minutes). Schirmer's test was performed four times: at baseline; 30-minutes after instillation of normal saline (placebo, 2 drops); at 30-minutes; and 3-hours after pilocarpine instillation (2 drops). Results: Basal tear secretion was 6.3 +/- 2.6 mm (mean +/- SD), and 6.9 +/- 3.0 mm 30 min after placebo (p=0.395). Thirty minutes after the instillation of piloparpine, tear volume more than doubled to 19.6 +/- 8.3 mm (p<0.001); and the increased tear production persisted at 3 hours (12.6 +/- 5.1 mm; p<0.001). There was a significant positive correlation between corneal sensitivity and tear secretion at baseline (p<0.0001; R2=0.74). Conclusions: Patients with FD have functional lacrimal glands, which can be stimulated with an M3 agonist to produce tears. Basal tear secretion was directly related to corneal sensitivity. The findings suggest for the first time that tear production in patients with FD can be restored pharmacologically

BACKGROUND: Multiple system atrophy (MSA) is a rare, adult-onset, rapidly progressive fatal synucleinopathy that primarily affects oligodendroglial cells in the brain. Patients with MSA only rarely have visual complaints, but recent studies of the retina using optical coherence tomography (OCT) showed atrophy of the peripapillary retinal nerve fiber layer (RNFL) and to a lesser extent the macular ganglion cell layer (GCL) complex. METHODS: We performed a literature review and meta-analysis according to the preferred reporting items for systematic reviews and meta-analyses guidelines for studies published before January 2017, identified through PubMed and Google Scholar databases, which reported OCT-related outcomes in patients with MSA and controls. A random-effects model was constructed. RESULTS: The meta-analysis search strategy yielded 15 articles of which 7 met the inclusion criteria. The pooled difference in the average thickness of the RNFL was -5.48 mum (95% CI, -6.23 to -4.73; p < 0.0001), indicating significant thinning in patients with MSA. The pooled results showed significant thinning in all the specific RNFL quadrants, except in the temporal RNFL quadrant, where the thickness in MSA and controls was similar [pooled difference of 1.11 microm (95% CI, -4.03 to 6.26; p = 0.67)]. This pattern of retinal damage suggests that MSA patients have preferential loss of retinal ganglion cells projecting to the magnocellular pathway (M-cells), which are mainly located in the peripheral retina and are not essential for visual acuity. Visual acuity, on the other hand, relies mostly on macular ganglion cells projecting to the parvocellular pathway (P-cells) through the temporal portion of the RNFL, which are relatively spared in MSA patients. CONCLUSION: The retinal damage in patients with MSA differs from that observed in patients with Parkinson disease (PD). Patients with MSA have more relative preservation of temporal sector of the RNFL and less severe atrophy of the macular GCL complex. We hypothesize that in patients with MSA there is predominant damage of large myelinated optic nerve axons like those originating from the M-cells. These large axons may require higher support from oligodendrocytes. Conversely, in patients with PD, P-cells might be more affected.

Study Objectives: Sudden unexpected death during sleep (SUDS) is the most common cause of death in patients with familial dysautonomia, an autosomal recessive disease characterized by sensory and autonomic dysfunction. It remains unknown what causes SUDS in these patients and who is at highest risk. We tested the hypothesis that SUDS in FD is linked to sleep-disordered breathing. Methods: We retrospectively identified patients with familial dysautonomia who died suddenly and unexpectedly during sleep and had undergone polysomnography within the 18-month period prior to death. For each case, we sampled one age-matched surviving subject with familial dysautonomia that had also undergone polysomnography within the 18-month period prior to study. Data on polysomnography, EKG, ambulatory blood pressure monitoring, arterial blood gases, blood count, and metabolic panel were analyzed. Results: Thirty-two deceased cases and 31 surviving controls were included. Autopsy was available in 6 cases. Compared with controls, subjects with SUDS were more likely to be receiving treatment with fludrocortisone (odds ratio; 95% confidence interval) (OR 29.7; 4.1-213.4), have untreated obstructive sleep apnea (OR 17.4; 1.5-193) and plasma potassium levels < 4 mEq/L (OR 19.5; 2.36-161), but less likely to use non-invasive ventilation at night (OR 0.19; 0.06-0.61). Conclusions: Initiation of non-invasive ventilation when required, and discontinuation of fludrocortisone treatment may reduce the high incidence rate of SUDS in patients with familial dysautonomia. Our findings contribute to the understanding of the link between autonomic, cardiovascular, and respiratory risk factors in sudden unexpected death during sleep.

Clinical data suggest that optic neuropathy and retinal ganglion cell loss are the main cause of visual decline in patients with familial dysautonomia, but this has not previously been confirmed by pathological analyses. We studied retinas and optic nerves in 6 eyes from 3 affected patients obtained at autopsy. Analyses included routine neurohistology and immunohistochemistry for neurofilaments, cytochrome c oxidase (COX), and melanopsin-containing ganglion cells. We observed profound axon loss in the temporal portions of optic nerves with relative preservation in the nasal portions; this correlated with clinical and optical coherence tomography findings in 1 patient. Retinal ganglion cell layers were markedly reduced in the central retina, whereas melanopsin-containing ganglion cells were relatively spared. COX staining was reduced in the temporal portions of the optic nerve indicating reduced mitochondrial density. Axonal swelling with degenerating lysosomes and mitochondria were observed by electron microscopy. These findings support the concept that there is a specific optic neuropathy and retinopathy in patients with familial dysautonomia similar to that seen in other optic neuropathies with mitochondrial dysfunction. This raises the possibility that defective expression of the IkB kinase complex-associated protein (IKAP) resulting from mutations in IKBKAP affects mitochondrial function in the metabolism-dependent retinal parvocellular ganglion cells in this condition.