Orthostatic hypotension is a common presentation in older adults; however paraneoplastic autonomic neuropathy is very rare but often underdiagnosed in older people presenting with orthostatic hypotension.
Orthostatic hypotension may be caused by primary or secondary autonomic failure or occur in the absence of autonomic dysfunction (usually drug-induced). Orthostatic hypotension affects 6% of the general population; however, it is seen much more frequently in the older population and studies report a prevalence of 10-30%. Older patients are less likely to have a causative disease or factors found, with 40% diagnosed as idiopathic orthostatic hypotension.1
Neurological paraneoplastic syndromes are uncommon, and autonomic paraneoplastic syndrome is particularly rare. It can also be seen in conjunction with subacute sensory neuronopathy, which is the most common type of neurological paraneoplastic syndromes.2
This article reviews its incidence, clinical presentation, diagnosis and management and illustrates case discussion for the readers to help day-to-day correlation with geriatric clinical practice.
Authors used MESH terms ‘paraneoplastic autonomic neuropathy’, ‘paraneoplastic neuropathy’, ‘postural hypotension’, ‘orthostatic hypotension’, ‘older adults’, ‘elderly’ and ‘old age’ to search PubMed, Medline and Ovid from 1970 to 2018, as well as relevant online educational articles and textbooks.
Patients frequently present with symptoms of autonomic failure prior to the discovery of malignancy. Symptoms may include profound orthostatic hypotension in euvolemic patients, intestinal pseudo-obstruction, loss of pupillary light reflex and other dysautonomias (dry eyes, urinary incontinence, erectile dysfunction and dry skin). These autonomic symptoms often present alongside other paraneoplastic syndromes, and as such may be overlooked in favour of better-recognised syndromes.3
Patients can present with chronic intestinal pseudo-obstruction, which is the only autonomic syndrome to be considered a classical paraneoplastic syndrome.4 Recurrent episodic hypotension and bradycardia has also been reported in the literature.4
Clinical progression can be acute or subacute, and progressive debilitating symptoms often leave the patient bedbound.5
Pathogenesis remains unclear, but the autoimmune model is widely accepted. Tumours express intracellular or surface antigens identical to neuronal antigens, which may be recognised by the immune system as foreign. Onconeuronal antibodies then develop and an immune response may target various sites of the central and peripheral neurological system.6
Cytotoxic T cells have a key role in neuronal cell death.7 Autonomic failure occurs when the autoimmune process causes sufficient damage to sympathetic and parasympathetic ganglions. Interestingly, the histology of the tumour affects how frequently antigens are expressed and if an immune response is mounted. Some tumours will always express onconeuronal antigens, but the immune system will only sometimes mount a response. There are other tumours where antigens are rarely expressed but an immune response is always mounted.6
Well characterised onconeuronal antibodies include Anti-Hu, Anti-Yo and Anit-CV2/CRMP5. Detection of Anti-ganglionic acetylcholine receptor antibodies directed against nicotinic acetylcholine receptors expressed on sympathetic and parasympathetic ganglia are most specific to autonomic failure.4
These antibodies cause specific inhibition of synaptic transmission in autonomic ganglia and can be associated with other neurological disorders including autoimmune autonomic ganglionopathy and chronic autoimmune dysfunction. Anti-Hu is the second most common to cause autonomic failure and is positive in 25% of patients with paraneoplastic dysautonomia.
Antibodies may be detected in patients with no diagnosis of cancer, even after an extensive investigation. A possible explanation is that the immune attack by onconeuronal antibodies also controls the growth of the tumour.6
International expert classification (2004) can be used in cases of suspected paraneoplastic syndrome. Based on the presence or absence of cancer, the presence of well-characterised antibodies and type of clinical syndrome it distinguishes between ‘definite’ and ‘probable’ paraneoplastic neuropathy.2
Significant overlap exists between the clinical picture and paraneoplastic syndromes of various autoantibodies; hence a panel of autoantibodies should be tested (Achr-ganglionic neuronal antibody; anti-Hu antibody; anti-neutrophil nuclear antibodies 1, 2 and 3; antineuronal antibody; anti –NMDA receptor antibody; anti-VGCC antibody).
Autonomic nervous function tests can be used to confirm autonomic dysfunction. They usually show the absence of heart rate response, abnormal Valsalva and cold pressor response. Adrenocorticotropic hormone stimulation test, serum serotonin, histamine, VDRL test, urinary 5-HIAA level and serum norepinephrine are other useful supportive investigations.
The clinical symptoms along with positive antibodies are often suggestive of a specific primary cancer.6
Imaging should be performed to look for primary malignancy or metastases, dependent on the primary malignancy suspected. If none is found the workup should be repeated at 3-6 months. Serological markers of malignancies eg CEA, PSA, AFP, CA125, CA19-9) can be helpful. PET CT can be used diagnostically in patients highly suspicious for PNS when all other diagnostic tests are negative.3
There is no specific management for paraneoplastic autonomic neuropathy; however, treatment of associated cancer or immunosuppression can improve symptoms. Symptomatic management of autonomic failure in these cases is the same as for idiopathic autonomic failure. Serial antibody titres are unhelpful in predicting response to treatment or neurological outcome.8
Neurological damage is frequently irreversible but there are reports of improvement in autonomic function following chemotherapy and plasma exchange.9,10 Chronic intestinal pseudo-obstruction responds well to palliative treatment with repeated neostigmine dosage.11
Prognosis is dependent on age, tumour and disease spread, but autonomic paraneoplastic disease is noted to have the worst prognosis of all paraneoplastic syndromes.3
An 86-year-old male was admitted with collapse and transient loss of consciousness lasting thirty seconds, preceded by presyncope whilst seated, and accompanied by urinary incontinence. In addition, he had experienced significant anorexia, lethargy and weight loss in the previous year. He was on hormonal treatment for locally invasive carcinoma of the prostate (stage T4 Nx Mx, Gleason 4+5=9), and was a smoker with a 35-pack year history. He was on numerous antihypertensive and diuretic therapies. Clinical examination revealed a cachectic, clubbed man with bruising secondary to recent blackouts, a significant symptomatic postural drop in his blood pressure between supine and standing, and urinary retention. Neurological examination demonstrated just mild global weakness and no extra-pyramidal signs; cognition was intact.
His electrocardiogram (ECG) showed sinus rhythm, and plain radiographic imaging of the chest was normal. Blood testing revealed a normocytic anaemia, and hyponatraemia (sodium 117mmol/L on admission); this did not improve following the withdrawal of his bendroflumethiazide and was later confirmed as Syndrome of Inappropriate Anti-Diuretic Hormone (SIADH). Thyroid function, vitamin B12, folate, serum cortisol, serum catecholamine, prostate-specific antigen (PSA) and carcinoembryonic antigen (CEA) tests were all within normal parameters.
Despite the withdrawal of all culprit medication, fitting of full-length compression hosiery and instigation of fludrocortisone therapy, his significant and debilitating postural hypotension persisted, and severe autonomic dysfunction was confirmed on testing. In light of his normal catecholamine profile, smoking history and constitutional symptoms, secondary paraneoplastic autonomic failure was considered. Paraneoplastic antibodies (detailed above) demonstrated a positive anti-Hu result. Computed tomography (CT) of the chest revealed a mass lesion later confirmed as stage IV lung cancer on biopsy. In view of his frailty and poor performance status, he was palliated and discharged home, where he died two months after his initial admission.
X-Ray Chest reported as normal
CT chest showing stage 4 carcinoma
Our patient did not respond to normal therapeutic measures and his resting catecholamine profile was normal (although we could not measure stress-induced catecholamine levels: an appropriate rise in catecholamines in the erect posture), so secondary autonomic failure was considered. Catecholamine levels are low in primary autonomic failure and baroreceptor failure, these patients are also unable to mount endogenous catecholamine surge following stress.
Paraneoplastic autonomic neuropathy is probably under diagnosed and under reported in older adults hence available literature is sparse. Geriatricians should consider this diagnosis in refractory postural hypotension secondary to autonomic failure. Noradrenaline/catecholamine profile (normal and stress-induced) can help to differentiate primary versus secondary autonomic failure.
Amanda Stafford, The Royal Bournemouth Hospital, Dorset
Divya Tiwari, Centre for Postgraduate Medical Research and Education, Bournemouth University, Dorset
11. Calvert X et al. Repeated neostigmine dosage as palliative treatment for chronic colonic pseudo-obstruction in a patient with autonomic paraneoplastic neuropathy. Gastroenterology 2003, 98(3); 708-9