AChE Inhibitor May Finesse Baroreflex Problems Common to Ganglionopathies

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One of the most common symptoms of autonomic neuropathy is orthostatic hypotension (OH). It is treatable; however, the only FDA-approved therapeutic agent for OH, midodrine, causes supine hypertension. This hypertension occurs to a greater degree and for a longer period than bouts of OH, explained Philip A. Low, MBBS, MD, during a plenary session at the 59th Annual Meeting of the American Academy of Neurology (AAN), held in Boston, April 28 to May 5.

What should be done to get to the root of the barore- flex problems seen in neurogenic neuropathies? In his presentation at the AAN meeting, Low, who is the Robert D. and Patricia E. Kern Professor of Neurology and director of the Autonomic Disorders Program Project at the Mayo Clinic College of Medicine in Rochester, Minnesota, focused on the conditions associated with ganglionopathy.

During his presentation at the AAN meeting, Low reviewed published research, primarily his and his colleagues', demonstrating that certain autonomic neuropathies-specifically autoimmune autonomic ganglionopathies (AAGs)-are linked to seropositivity for ganglionic acetylcholine receptor (AChR) antibodies¹ and that enhancing sympathetic ganglionic transmission through acetylcholinesterase (AChE) inhibition has a beneficial effect on standing blood pressure without compromising supine blood pressure.² Low's "take-home" message is that the AChE inhibitor pyridostigmine appears to ameliorate OH in certain dysautonomic patients without causing supine hypertension.²

"AAG is associated with the A3 AChR antibody and has clinical phenotypes ranging from pandysautonomia syndrome to selective pseudomotor impairment anhidrosis to pure adrenergic failure to heart rate involvement in postural orthostatic tachycardia syndrome [POTS]," explained Low. "The antibody suppresses membrane currents and sympathetic neurons. By enhancing neuroganglionic transmission [through AChE inhibition], it is possible to improve neurogenic OH without aggravating supine hypertension. Improvements in OH result in improvements in symptoms, and improvements appear to be sustained," he said.

Clinical phenotypes of AAG discussed by Low included pandysautonomia, pure autonomic failure, chronic idiopathic anhidrosis (CIA), and POTS.

Pandysautonomia. Back in 1983,³ Low and colleagues described pandysautonomia as a neuroinflammatory immune disorder characterized by parasympathetic and sympathetic dysfunction. "This disorder is associated with high antibody titers. Patients have Adies pupil, sicca complex of the eyes and mouth, and widespread autonomic failure with severe effects of the cholinergic system, with sudomotor failure, neurogenic bladder and bowel, and severe OH-so they truly have a pan-autonomic neuropathy," commented Low in his presentation at the AAN meeting.

In a study⁴ of 18 patients with autoimmune autonomic neuropathy in which Low was involved, more than 50% of the patients with symptoms of pandysautonomia had high levels (more than 1.0 nmol/L) of autonomic ganglionic AChR antibodies. Although only patients who were seropositive for ganglionic AChR antibodies were included in the study, Low and his team demonstrated that the higher the antibody titers, the greater the autonomic dysfunction.

Pure autonomic failure. Unlike patients with pandysautonomia, patients with pure autonomic failure have low levels of antibody titer, explained Low. The primary feature is severe OH. "If you measure plasma catecholamines, the plasma epinephrine is extremely low, typically less than 50 µg/mL, indicating that there are very few surviving functioning postganglionic adrenergic neurons," said Low. "Patients do have some cholinergic involvement but it is more restrictive. They can have some bladder involvement and they can show widespread anhidrosis."

CIA. Described by Low and colleagues in 1985,⁵ CIA is associated with moderate antibody titers. The primary symptom is the inability to sweat. "Patients have subacute onset and have autonomic failure confined to the sudomotor system. Heat intolerance is a major concern. Patients do not have adrenergic failure, however. If you were to do a biopsy, you would see a heavy infiltrate with inflammatory lymphocytes in the ecrine sweat gland," Low explained.

POTS. In 1993, Schondorf and Low described POTS as a mild form of acute autonomic neuropathy.⁶ Patients have a low antibody titer, orthostatic intolerance, and mild tachycardia. "These are all young people. One in 6-or 15%-will have antibody titers in relatively low levels. Fifty percent will show evidence of distal sudomotor denervation."

The finding that POTS has neuropathic and autoimmune features was recently confirmed by members of Low's team at the Mayo Clinic.⁷ They looked at 153 patients, most (86.8%) of whom were women. About 50% had sudomotor abnormalities and 35% had significant adrenergic impairment, leading the investigators to conclude that POTS had a neurogenic basis in at least half of the patients in the study. Ganglionic AChR antibody was detected in 14.6% of the patients. Twenty-nine percent of patients were hyperadrenergic, and at least 29% were hypovolemic, according to the researchers.

TREATING GANGLIONOPATHIC OH

"If you use different doses of midodrine, you can dose-dependently improve standing blood pressure. Unfortunately, midodrine's effect on supine blood pressure is consistently greater than its effect on standing blood pressure. Also, it lasts longer. This is a major shortcoming of the only available drug for OH," remarked Low. Low and his team began to work with pyridostigmine, which inhibits AChE at the ganglion, to achieve stability of baroreflexes in all positions in patients with ganglionopathy-associated OH.

The team started with a prospective open-label study that included 8 men and 6 women² who had evidence of neurogenic OH. The patients' blood pressure was measured 1 hour before and 1 hour after receiving 60 mg of pyridostigmine.

"The drug had no effect on supine blood pressure but significantly improved standing blood pressure," reported Low. Mean supine blood pressure before the therapeutic dose was 98.4 mm Hg. An hour after dosing, it was 102.0 mm Hg. Mean standing blood pressure before dosing was 75.8 mm Hg. An hour after dosing, it rose to 85.5 mm Hg.

The researchers then embarked on a double-blind placebo-controlled study⁸ involving 58 patients with neurogenic OH that compared pyridostigmine alone with the agent in combination with low-dose (either 2.5 or 5 mg) midodrine. Blood pressure and heart rate were measured at baseline and each hour after treatment for up to 6 hours. Results similar to those of the open-label study were seen. "Pyridostigmine alone or in combination with low-dose [5 mg] midodrine had no effect on supine blood pressure but significantly improved standing blood pressure," noted Low. The drug's effect peaked at 4 hours and then subsided.

"More recently, we investigated whether the drug would improve heart rate in POTS," explained Low. "We performed a prospective open-label study of 18 patients with POTS. There was a significant improvement in supine and especially in standing heart rate and baroreflex-sensitive norepinephrine regeneration."

Low concluded that it was clear from his years of research that neurogenic OH can be improved and baroreflexes stabilized by addressing pathology at the level of the ganglion and applying therapeutic strategies that enhance neuroganglionic transmission.

References:

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