Autonomic Disorders

Question 1

Treatment algorithm for patients with orthostatic hypotension

Answer 1

Question 2

Examples of medications that may cause or exacerbate orthostatic hypotension

Answer 2

Question 3

Selected drugs for orthostatic hypotension

Answer 3

Question 4

Plasma catecholamine levels in MSA and PAF

Answer 4

Plasma catecholamine levels are low in both multiple system atrophy and PAF

Question 5

Dysautonomia in Guillain Barre syndrome: percentage and most common clinical findings

Answer 5

The prevalence of autonomic dysfunction ranges from 38 to 70 percent of patients with GBS

most frequent autonomic symptoms

*Ileus

*Hypertension

*Hypotension

*Fever

*Tachycardia or bradycardia

*Urinary retention

Question 6

Which antibody is commonly found in acute pandysautonomia

Answer 6

Antibodies to ganglionic acetylcholine receptor α3 subunit (41%)

(distinct from neuromuscular junction α1 subunit)

Question 7

Paraneoplastic syndromes with prominent autonomic involvement

Answer 7

A) Lambert Eaton myasthenic syndrome

B) Subacute sensory neuronopathy

C) Paraneoplastic autonomic neuropathy

D) Enteric neuronopathy

Question 8

Subacute sensory neuronopathy: pathogenesis and clinical findings

Answer 8

Selective involvement of the dorsal root ganglia, referred to as sensory neuronopathy, results in a particularly disabling form of sensory loss with prominent sensory ataxia.

The sensory deficits of paraneoplastic subacute sensory neuronopathy typically begin with loss of vibratory sensation and joint position sense, followed by impairment in pain and temperature sensation
Patients initially complain of pain or the sensation of “pins and needles” or “electric shocks.” The symptoms may initially affect one extremity, but in a few weeks or months, they usually progress to involve other extremities, the face, the abdomen, or the trunk.
In a subset of patients, hyperalgesia and spontaneous pain remain the prominent symptoms, and sensory ataxia is mild or even absent

On neurologic examination, there is usually moderate to severe involvement of all sensory modalities. These sensory deficits frequently lead to prominent ataxia, which is exacerbated by eye closure and associated with pseudoathetoid movements of the fingers and extremities. Other neurologic findings may include sensorineural hearing loss, diminished taste sensation, and symmetric or asymmetric reduction or loss of deep tendon reflexes.

As in other paraneoplastic disorders, symptoms typically predate the discovery of a tumor. The association with pain may erroneously lead to the diagnosis of radiculopathy or polyneuropathy

Question 9

Sensory neuronopathy diagnosis

Answer 9

Neurophysiologic studies usually show reduced or absent sensory potentials with normal or borderline motor nerve conduction velocities.
Abnormal motor conduction velocity with axonal and demyelinating features may occur, complicating the differential diagnosis between peripheral nerve and dorsal root ganglia involvement.
Neurophysiologic features that can help distinguish sensory neuronopathy from peripheral nerve disorder include at least one absent or three low (<30 percent of normal) sensory action potentials in the arms with fewer than two abnormal motor nerve conduction studies (NCS) in the legs

The cerebrospinal fluid may be normal but often shows moderate pleocytosis, increased protein, intrathecal synthesis of immunoglobulin G (IgG), and oligoclonal bands.

Histologic examination reveals a mononuclear cell infiltrate in the dorsal root ganglia that is probably immune mediated, neuronal degeneration, and proliferation of the satellite cells.
There is also a variable involvement of the dorsal and ventral nerve roots, and secondary demyelination of the spinal cord dorsal columns
Sural nerve biopsy shows a reduction in myelinated fiber density with depletion of large fibers most prominent in those with more severe sensory ataxia

Question 10

Paraneoplastic antibodies in sensory neuronopathy and associated tumors

Answer 10

Approximately 80 percent of patients with paraneoplastic subacute sensory neuronopathy have small cell lung cancer (SCLC), usually in association with anti-Hu antibodies.
Many of these patients progress to paraneoplastic encephalomyelitis.
Some patients have anti-CRMP5 antibodies, directed against antigens present on peripheral nerves, often in conjunction with anti-Hu antibodies.
If both antibodies are present, a mixed axonal and demyelinating sensory motor neuropathy may be superimposed on subacute sensory neuronopathy.
Well-characterized paraneoplastic antibodies such as anti-Hu and anti-CRMP5 are almost always detectable in serum; only in rare instances will the CSF reveal antibodies undetected in serum

Aside from SCLC, other tumors associated with subacute sensory neuronopathy include
* breast
* prostate
* colon cancers
* lymphoma
* uterine sarcoma

Thus, tumor screening with CT and/or FDG-PET should be performed in patients with suspected paraneoplastic sensory neuronopathy

Question 11

Differential diagnosis of cisplatin and paraneoplastic sensory neuronopathy

Answer 11

Cisplatin neuropathy and paraneoplastic sensory neuronopathy can usually be distinguished by the fact that cisplatin produces a large fiber neuropathy affecting position and vibration sense almost exclusively and sparing pain and temperature sense, whereas the paraneoplastic disorder affects all sensory modalities.

Question 12

Sensory neuronopathy etiology

Answer 12

• Paraneoplastic
• autoimmune disorders (eg, Sjögren’s disease, celiac disease, autoimmune hepatitis)
• infections (eg, Epstein-Barr virus, HIV, varicella-zoster)

Question 13

Paraneoplastic sensory neuronopathy treatment

Answer 13

Treatment with glucocorticoids, plasma exchange, and intravenous immune globulin (IVIG) is usually ineffective, although there are a few reported exceptions to this general rule

In one report, the combination of IVIG plus cyclophosphamide and methylprednisolone resulted in disease stabilization in 2 of 10 patients with anti-Hu antibody-associated paraneoplastic sensory neuronopathy

Early diagnosis and treatment of the tumor is likely the best approach to stabilize (or improve) the neurologic symptoms.

Question 14

Clinical manifestations of diabetic autonomic neuropathy

Answer 14

Question 15

Techniques for the diagnosis of diabetic autonomic neuropathy

Answer 15

Question 16

Amyloidosis related polyneuropathy: clinical findings

Answer 16

Length-dependent mixed sensory and motor peripheral neuropathy and/or autonomic neuropathy may occur and are prominent features in some of the heritable amyloidoses (called familial amyloidotic polyneuropathy) and in AL amyloidosis.
Symptoms of numbness, paresthesia, and pain are frequently noted, as in peripheral neuropathy of many other causes.
Compression of peripheral nerves, especially the median nerve within the carpal tunnel, can cause more localized sensory changes.
Symptoms of bowel or bladder dysfunction and findings of orthostatic hypotension may be due to autonomic nervous system damage.

Question 17

Major forms of systemic amyloidosis

Answer 17

Major forms include:

● AL amyloid – AL amyloid, caused by a plasma cell dyscrasia, is due to deposition of protein derived from immunoglobulin light chain fragments.
AL amyloidosis usually complicates lower-grade plasma cell clones but can occur in association with multiple myeloma or, much less often, Waldenström macroglobulinemia, non-Hodgkin lymphoma, or chronic lymphocytic leukemia

● ATTR (transthyretin) amyloid – ATTR amyloid may occur as a “wild-type” (ATTRwt) associated with aging or as mutant proteins (ATTRv or hATTR [where v indicates a variant and h indicates hereditary; these were formerly termed ATTRm, to indicate a mutant protein]) associated with familial neuropathy and/or cardiomyopathy

● AA amyloidosis – AA amyloidosis is a potential complication of chronic diseases in which there is ongoing or recurring inflammation that results in sustained high-level production of serum amyloid A protein, an acute phase reactant, which can form amyloid deposits,
such as rheumatoid arthritis, spondyloarthritis, or inflammatory bowel disease; chronic infections; and heredofamilial periodic fever syndromes (eg, familial Mediterranean fever)

● Other types of amyloidosis – Additional forms of amyloid seen clinically include dialysis-related amyloidosis , heritable amyloidoses, organ-specific amyloid, leukocyte cell-derived chemotaxin-2 (LECT2) amyloid , insulin amyloid, and others.

Question 18

Therapies for individual amyloid types

Answer 18

● AL amyloidosis – In AL amyloidosis, treatment is directed primarily at suppressing the underlying plasma cell dyscrasia.

● AA amyloidosis – In AA amyloidosis, therapy is aimed primarily at suppressing the underlying infectious or inflammatory disorder, some biologic agents (eg, tumor necrosis factor [TNF], interleukin [IL] 6, and IL-1 inhibitors) have shown particular benefit.

● Dialysis-related amyloidosis – In patients with dialysis-related amyloidosis, treatment is directed at either altering the mode of dialysis or considering renal transplantation.

● Transthyretin amyloidosis – Several approaches have become available for the treatment of hereditary TTR amyloidosis (ATTR).
These include the use of ribonucleic acid (RNA)-targeted therapies that interfere with hepatic TTR synthesis and other agents that reduce formation of TTR amyloid through stabilization of the tetramer configuration, preventing release of amyloidogenic monomers.

Liver transplantation has also been used for the treatment of hereditary (variant or mutant) ATTR (ATTRv) as a form of “surgical gene therapy.”
Liver transplantation is not applicable to wild-type ATTR (ATTRwt), and in most cases, access to heart transplantation is limited by the advanced age of the patient.

Question 19

hATTR amyloid polyneuropathy pattern of inheritance

Answer 19

Autosomal dominant

Question 20

Διάγνωση hATTR

Answer 20

Σε ασθενείς με γνωστό οικογενειακό ιστορικό: αρκεί ο γονιδιακός έλεγχος
Σε σποραδικές μορφές: πρέπει να αποδειχθεί η παρουσία αμυλοειδούς. Ο λόγος είναι ότι κάποιες από τις μεταλλάξεις δεν έχουν πλήρη διεισδυτικότητα (μπορεί να φέρεις μιά μεταλλαγή και να μη νοσείς). Πρέπει αρχικά να αποκλεισθεί η AL αμυλοείδωση. Ακολούθως τεκμηριώνεται η παρουσία αμυλοειδούς με σπινθηρογράφημα.

ENE Ιανουάριος 22’

Question 21

targeted therapies for hereditary ATTR amyloidosis-related cardiomyopathy and neuropathy

Answer 21

++ RNA-targeted therapies – RNA-targeted therapies for ATTR amyloidosis-related cardiomyopathy and neuropathy have become available that interfere with hepatic TTR synthesis and the resultant availability of misfolded monomers to aggregate and form amyloid deposits; these include patisiran, vutrisiran, inotersen, and eplontersen

Patisiran
δίκλωνο μικτό παρεμβαλλόμενο ριβονουκλεϊκό οξύ (siRNA) που στοχεύει ειδικά μια γενετικά διατηρημένη αλληλουχία στην 3’ μη μεταφραζόμενη περιοχή του συνόλου του μεταλλαγμένου και μη-μεταλλαγμένου (φυσιολογικού) γονιδίου mRNA της TTR.
Το patisiran διαμορφώνεται ως νανοσωματίδια λιπιδίων για τη μεταφορά του siRNA στα ηπατοκύτταρα, την πρωταρχική πηγή πρωτεΐνης TTR στην κυκλοφορία.
Μέσω μιας φυσικής διεργασίας που ονομάζεται παρεμβολή RNA (RNAi), το patisiran προκαλεί την καταλυτική αποικοδόμηση του mRNA της TTR στο ήπαρ, με αποτέλεσμα τη μείωση της πρωτεΐνης TTR.
Patisiran is administered every three weeks by intravenous infusion.

Vutrisiran
σταθεροποιημένο δίκλωνο μικρό παρεμβαλλόμενο ριβονουκλεϊκό οξύ (siRNA) που στοχεύει ειδικά το παραλλαγμένο και μη μεταλλαγμένο αγγελιοφόρο RNA (mRNA) της τρανσθυρετίνης (TTR)
Μέσω μιας φυσικής διεργασίας που ονομάζεται παρεμβολή RNA (RNAi), το vutrisiran προκαλεί την καταλυτική αποικοδόμηση του mRNA της TTR στο ήπαρ, με αποτέλεσμα τη μείωση των επιπέδων παραλλαγμένης και μη μεταλλαγμένης πρωτεΐνης TTR στον ορό
every-three-month subcutaneous injection
Benefits have also been shown in patients with amyloid cardiomyopathy due to ATTR.

Inotersen
Inotersen is an antisense oligonucleotide (ASO) construct that inhibits hepatic production of TTR, resulting in reduced levels of TTR in both healthy controls and in patients with hereditary ATTR with polyneuropathy.
Moderate to severe thrombocytopenia and bleeding complications have been reported with this agent.
Benefits have also been shown for amyloid cardiomyopathy due to ATTR.
Inotersen is administered once weekly by subcutaneous injection.

Eplontersen
Eplontersen is a ligand-conjugated ASO given by subcutaneous injection once monthly

++ Stabilization of transthyretin tetramers –
Tafamidis and diflunisal each can reduce formation of TTR amyloid through stabilization of the TTR tetramer configuration, preventing release of amyloidogenic monomers.
Tafamidis is a transthyretin (TTR) stabilizer that selectively binds to TTR at the thyroxine binding sites and stabilizes the tetramer of the TTR transport protein, slowing dissociation into monomers
Oral 60 or 80mg once daily

Question 22

Common medications that affect autonomic functions

Answer 22

cisplatin, vincristine, paclitaxel, docetaxel, amiodarone.

Question 23

Collagen vascular disorders associated with autonomic dysfunction

Answer 23

• Sjogren syndrome
• Systemic lupus erythematosus
• Mixed connective tissure disease
• Rheumatoid arthritis
• Inflammatory bowel disease

Question 24

Hereditary autonomic neuropathies

Answer 24

Most common:
* HSAN
* Porphyria
* Fabry disease
* Dopamine β-hydroxylase deficiency

Question 25

Small fiber neuropathy common etiologies, clinical findings and diagnosis

Answer 25

Common etiologies include
* diabetes mellitus
* autoimmune/ paraneoplastic
* vitamin deficiencies/toxicities
* toxic exposure to alcohol
* heavy metals
* medications
* Amyloidosis

Small fiber neuropathies typically present as a progressive burning pain, commonly seen first in the feet.
Lancinating pain, numbness, and paresthesias along with symptoms of autonomic dysfunction are commonly seen.
Examination demonstrates abnormalities of pinprick and temperature sensation in most patients.
Reflexes commonly are normal.

Conventional electrodiagnostic studies are normal, as they only access large fiber nerves.
* Since sweat glands are innervated by small fiber nerves, quantitative sudomotor axon reflex test (QSART) exams are highly specific and sensitive.
* Skin biopsies are an effective and safe method for diagnosing SFN.

Question 26

Postural orthostatic tachycardia syndrome: definition, clinical findings

Answer 26

Orthostatic intolerance describes an abnormal autonomic response causing symptoms that develop while sustaining an upright posture.
The clinical syndrome of POTS includes intermittent symptoms of orthostatic intolerance accompanied by excessive tachycardia without arterial hypotension.

Clinical features

Orthostatic intolerance – Symptoms of orthostatic intolerance in patients with POTS are brought on by standing and are relieved by sitting down.
They typically include lightheadedness, palpitations, fading of vision, presyncope, and headache.

Nonorthostatic symptoms –
Many patients with POTS also report symptoms that are unrelated to postural changes. Symptoms may be intermittent or constant and include anxiety, fatigue, resting or nocturnal paroxysmal tachycardia, and acrocyanosis.
Anxiety is common in POTS but appears phenomenologically distinct from symptoms of generalized anxiety disorder or panic disorder

Question 27

Postural orthostatic tachycardia syndrome: diagnosis and management

Answer 27

Diagnosis –
The diagnosis of POTS is made by

• History of symptoms of orthostatic intolerance with or without systemic symptoms
• Correlation of symptoms with a sustained increase in upright heart rate by at least 30 beats/minute (40 beats/minute for patients under the age of 20 years) within 10 minutes of standing or head-up tilt, without orthostatic hypotension
• Autonomic testing to correlate symptoms with heart rate changes, confirm the diagnosis, and assess the degree of objective signs of orthostatic intolerance
• Other diagnostic testing as needed to exclude alternative diagnoses or confounding concomitant conditions

Initial conservative management –
The therapeutic strategy for POTS relies on symptom management. For most patients with POTS, we suggest conservative interventions such as increasing fluid and salt intake, a regular exercise regimen, and targeted lifestyle modifications

Adjunctive treatments –
In patients with severe symptoms and those whose symptoms persist in spite of initial treatment strategies, we add compressive garments and medications to the management regimen. Individual options among choices is guided by patient preferences and concomitant medical comorbidities.

There is no specific pharmacologic algorithm that applies to all patients. We commonly use beta blockers, midodrine, fludrocortisone, or pyridostigmine and reserve the other medications listed above in select severe or refractory cases.

Question 28

Causes of hyperhidrosis

Answer 28

Essential hyperhidrosis

pheochromocytoma, thyrotoxicosis, pituitary and hypothalamic dysfunction, anxiety disorders, menopause, carcinoid syndrome, and drug withdrawal.