1. Ng FL, Lobo MD Department of Clinical Pharmacology The William Harvey Research Institute Barts and The London School of Medicine BHS Annual Scientific Meeting 14th September 2011 Complex Labile Hypertension: A Life On Hold

2. Referral from University Hospital Galway Mr JK, 48 year old male, Construction Worker Frequent paroxysms of flushing Uncontrolled hypertension for 14 months –Minute-to-minute lability on intra-arterial monitoring –Surges on standing, activity and alerting factors Collapses postulated secondary to hypotension

3. Admission to Royal London Worsening symptoms over preceding two years –Flushing, sweating with nausea –Palpitations –Paraesthesia of fingertips –Severe headaches –Early morning epistaxis –Collapses –Erectile dysfunction –Nocturia –Sensations of heat in the body –Lethargy

4. Additional history Other Past Medical History –Pneumonia aged 33 Current Medications –Clonidine 450 micrograms tds –Prazosin 1mg bd –Metoprolol75mg tds –No drug intolerances Ex-smoker Nil EtOH since on medications No recreational drugs or over the counter medications

5. Examination BMI 28.4 kg/m 2 Absent left radial pulse with previous arterial line Otherwise unremarkable BP (mmHg)Pulse (bpm) Supine141/6570 Standing166/97104

6. Initial management plan Initially withhold medication Bed rest and non-invasive monitoring Specialist investigations: –Autonomic testing –Autoimmune profile and anti-neuronal auto-antibodies –Urinary metanephrines and plasma catecholamines –MRI brainstem –Whole body PET FDG Scan

9. SympatheticDeep target organ sympathetic failure Postganglionic sympathetic failure Normal muscle and cardioaccelerator function ParasympatheticMinimal resting cardiac vagal tone Attenuated carotid massage response BaroreflexPeripheral baroreflex failure CutaneousPartial thermoregulatory failure BrainstemMarked abnormal spontaneous activity Autonomic Testing

10. Autoimmune profile ANAPositive 1/640, speckled pattern Anti-Scl-70Positive Anti-Jo-1Negative Anti-RNPNegative Anti-Sm Negative Anti-RoWeak positive Anti-LaNegative Anti-ds DNANegative Anti-neuronal antibodies Negative

11. Further investigations Clinical Neurophysiology –No abnormalities MRI Brainstem –No evidence of brainstem abnormalities Positron Emission Tomography –No evidence of malignancies Skin punch biopsy histology –No evidence of small fibre neuropathy

12. Summary 48 year old gentleman with –Progressive symptoms associated with paroxysmal hypertension, symptomatic hypotension and autonomic dysfunction –Testing confirming widespread autonomic dysfunction –Autoimmune profile suggestive of scleroderma/UCTD Diagnoses –Extreme blood pressure lability due to dysautonomia –Autoimmune small fibre neuropathy secondary to underlying scleroderma/UCTD

13. Management BP control and stability achieved through strict bedrest Diazepam was initiated to attenuate alerting responses Methyldopa and clonidine patches improved symptoms Discharged with: –Clonidine patch100 micrograms/day –Methyldopa1g at 08:00, 1g at 16:00, 500mg at 20:00 –Diazepam5mg at 09:00, 5mg at 14:00, 3mg at 22:00

15. Commentary...

16. Results of autonomic testing... Parasympathetic function reduced Generalised failure of Sympathetic function to deep and cutaneous targets Denervation Hypersensitivity to phenylephrine Poor BP stability during orthostasis (SBP varied by 112 mm Hg) However: normal resting supine BP (MAP 92.4 mm Hg) and normal muscle sympathetic tone during isometric exercise

17. What do the tests mean? The patient is not hypertensive per se but has very poor BP stability The responsible neurons are small, thinly myelinated or unmyelinated fibres No evidence of large fibre peripheral neuropathy

19. Further plans Repeat skin punch biopsy of Left leg Thermal Threshold testing Nail fold capillaroscopy Rheumatology review Adjustment of antihypertensive medications to better control BP surges Consideration of IV γ-globulin therapy to arrest immune- mediated neuropathy