Faculty Bibliography

Familial dysautonomia (FD) is a rare neurological disorder caused by a splice mutation in the IKBKAP gene. The mutation arose in the 1500s within the small Jewish founder population in Eastern Europe and became prevalent during the period of rapid population expansion within the Pale of Settlement. The carrier rate is 1:32 in Jews descending from this region. The mutation results in a tissue-specific deficiency in IKAP, a protein involved in the development and survival of neurons. Patients homozygous for the mutations are born with multiple lesions affecting mostly sensory (afferent) fibers, which leads to widespread organ dysfunction and increased mortality. Neurodegenerative features of the disease include progressive optic atrophy and worsening gait ataxia. Here we review the progress made in the last decade to better understand the genotype and phenotype. We also discuss the challenges of conducting controlled clinical trials in this rare medically fragile population. Meanwhile, the search for better treatments as well as a neuroprotective agent is ongoing.

BACKGROUND: Orthostatic hypotension (OH) is a sustained fall in blood pressure on standing which can cause symptoms of organ hypoperfusion. OH is associated with increased morbidity and mortality and leads to a significant number of hospital admissions particularly in the elderly (233 per 100,000 patients over 75 years of age in the US). OH can be due to volume depletion, blood loss, large varicose veins, medications, or due to defective activation of sympathetic nerves and reduced norepinephrine release upon standing (i.e., neurogenic OH). METHODS AND FINDINGS: Literature review. Neurogenic OH is a frequent and disabling problem in patients with synucleinopathies such as Parkinson disease, multiple system atrophy, and pure autonomic failure, and is commonly associated with supine hypertension. Several pharmacological and non-pharmacological therapeutic options are available. CONCLUSIONS: Here we review the epidemiology, diagnosis, and management of neurogenic OH, and provide an algorithm for its treatment emphasizing the importance of removing aggravating factors, implementing non-pharmacologic measures, and selecting appropriate pharmacological treatments.

Objective: The purpose of this study was to determine the predictors of the improvement in orthostatic symptoms with atomoxetine. Background: We previously reported that the norepinephrine transporter inhibitor, atomoxetine, improves upright blood pressure and pre-syncopal symptoms as measured by the orthostatic hypotension symptom assessment (OHSA) in patients with neurogenic orthostatic hypotension (nOH). Design/Methods: Our sample size consisted of 101 autonomic failure patients with nOH who participated in clinical trials (NCT00223691, NCT1316666) conducted in two national referral centers for autonomic disorders (Vanderbilt Autonomic Dysfunction Center and NYU Langone Medical Center Dysautonomia Center). The analyses was performed in patients with symptomatic nOH defined as item-1 OHSA (lightheadedness) equal or more than four points. Seated blood pressure was measured in three occasions before and 60 minutes after receiving 18 mg of atomoxetine. Standing blood pressure at 1, 3, 5 and 10 minutes and OHSA questionnaire was collected before and after the atomoxetine dose. Multiple linear regression was used to test for overall linear relations between the dependent variable (OHSA score after atomoxetine) and independent variables (baseline OHSA score, age, diagnosis, baseline supine norepinephrine levels) and to assess the significance of these relations after adjustments for each covariate. Results: 47 patients (47%) met criteria for symptomatic nOH. The average age at the time of evaluation was 67+/-9 years, 47 % were males. 55% were diagnosed as pure autonomic failure, 30% as multiple system atrophy, 11% as Parkinson disease and 4% were patients with nOH of unknown etiology. Adjusted R2 for this model was 0.3, only supine norepinephrine levels (P=0.047) accurately predicted orthostatic symptoms following atomoxetine after adjusting for baseline OHSA, age and specific diagnosis. Conclusions: Supine baseline norepinephrine levels predict the improvement in symptoms produced by atomoxetine in patients with symptomatic nOH

Objective: To define which factors predict the pressor response to droxidopa in patients with neurogenic orthostatic hypotension (nOH). Background: Droxidopa, a synthetic norepinephrine precursor, was recently approved to treat symptomatic nOH. The dosage required to elicit a pressor response is variable. It is unknown which factors predict the magnitude of the pressor response to droxidopa. Design/Methods: We prospectively evaluated the BP response to increasing doses of droxidopa in patients with nOH. BP supine and after 3-min standing was measured before and 1-hour after 100 mg of droxidopa orally. Dosage was progressively increased until i) complete relief of symptoms, ii) supine systolic BP >180 mmHg, iii) occurrence of side effects, or iv) a dose of 600mg was reached. Results: Sixteen subjects with nOH (6 with Parkinson disease, 5 with pure autonomic failure -PAF-, 3 with autoimmune autonomic ganglionopathy -AAG-, and 2 with multiple system atrophy) were included. Mean BP was 126+/-28/72+/-11 mmHg supine and 89+/-19/53+/-15 mmHg after 3-min standing (fall of 37/18 mmHg). Mean plasma norepinephrine supine was 192+/-216 pg/ml. Maximum droxidopa dose was 212+/-102 mg (range: 100-400 mg). Droxidopa increased BP to 148+/-53/90+/-13 mmHg supine and 135+/-38/66+/-16 mmHg after 3-min standing (p<0.001). Plasma norepinephrine levels were inversely correlated with higher systolic BP after-3 min standing following droxidopa treatment (R2=0.42; p=0.023). Four patients (3 with AAG, 1 with PAF) with very low plasma norepinephrine levels (<90 pg/ml) experienced transient nausea, vomiting, and abdominal pain during titration with dosages of 200 mg. In these patients, treatment with 100 mg/day was effective and well tolerated. Diagnosis did not predict response to droxidopa. Conclusions: Lower plasma norepinephrine levels are associated with a greater pressor response to droxidopa in nOH. This response is probably related to the degree of denervation supersensitivity. Norepinephrine levels may be useful to predict appropriate dosing of droxidopa in the clinical setting

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

Objective: To describe three cases with acute autonomic and sensory neuropathy (AASN). Background: AASN is considered a very rare variant of immune-mediated acute peripheral neuropathy or ganglionopathy. Only a few cases have been documented in the literature so far. Design/Methods: Case series. Results: Three previously healthy subjects (11-year-old male; 11-year-old female; 37-year-old female), all of Asian ancestry, presented with acute and severe sensory and autonomic deficits shortly after a brief gastrointestinal or respiratory febrile illness. Autonomic disturbances included vomiting, diarrhea, anhidrosis, abdominal cramps, neurogenic pain, dry mouth and eyes, non-reactive mid-sized pupils, and dizziness upon standing and syncope. Sensory disorders included decreased perception for all sensory modalities with widespread patchy distribution and significant sensory ataxia. Impaired motor control with dysphagia was interpreted as reduced muscle power and prompted an early diagnosis of Guillain-Barre syndrome. Symptoms progressed for a few days and later stabilized. Neurological examination revealed very depressed or absent deep tendon, corneal, and gag reflexes with preserved muscle power. Corneal exam showed paracentral and inferior corneal opacities due to exposure keratopathy and dry eye. Nerve conduction studies showed extremely reduced or absent sensory nerve action potentials with normal motor nerve conduction and F waves. Cardiovascular autonomic evaluation showed decreased heart rate variability, orthostatic hypotension without compensatory tachycardia and very low or absent plasma norepinephrine levels. Spinal cord MRI showed extensive T2 hyperintensities of the posterior cords. Patient #1 had positive anti-sulfatide antibodies. One year after onset, recovery of sensory impairment was poor, and autonomic dysfunction was ameliorated with symptomatic treatment. Conclusions: This is the second largest case series ever reported of patients with AASN, an immune-mediated disorder mostly affecting Asian subjects. Patients are usually misdiagnosed, which delays the start of appropriate therapy

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.

Current consensus diagnostic criteria for multiple system atrophy (MSA) consider dementia a non-supporting feature, although cognitive impairment and even frank dementia are reported in clinical practice. Mini-Mental State Examination (MMSE) is a commonly used global cognitive scale, and in a previous study, we established an MSA-specific screening cut-off score <27 to identify cognitive impairment. Finally, MSA neuroimaging findings suggest the presence of structural alterations in patients with cognitive deficits, although the extent of the anatomical changes is unclear. The aim of our multicenter study is to better characterize anatomical changes associated with cognitive impairment in MSA and to further investigate cortical and subcortical structural differences versus healthy controls (HC). We examined retrospectively 72 probable MSA patients [50 with normal cognition (MSA-NC) and 22 cognitively impaired (MSA-CI) based on MMSE <27] and compared them to 36 HC using gray- and white-matter voxel-based morphometry and fully automated subcortical segmentation. Compared to HC, MSA patients showed widespread cortical (bilateral frontal, occipito-temporal, and parietal areas), subcortical, and white-matter alterations. However, MSA-CI showed only focal volume reduction in the left dorsolateral prefrontal cortex compared with MSA-NC. These results suggest only a marginal contribution of cortical pathology to cognitive deficits. We believe that cognitive dysfunction is driven by focal fronto-striatal degeneration in line with the concept of "subcortical cognitive impairment".