A Middle Aged Woman With Nausea Weight Loss and Orthostatic Hypotension

7/28/2019 A Middle Aged Woman With Nausea Weight Loss and Orthostatic Hypotension

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A middle-aged woman with nausea, weightloss, and orthostatic hypotension

W. Singer, MD

I.O. Yung, MD

R. Wollmann, MD,

PhD

T. Kelly, MD

B.M. Keegan, MD,

FRCP(C)

CASE PRESENTATION A 54-year-old, right-

handed, Caucasian woman presented with intermit-

tent nausea, vomiting, and orthostatic hypotension

of 1 year duration. Following every meal, she would

belch and vomit nonbloody undigested food. She re-

ported constipation and fatigue and felt lightheaded

and occasionally lost consciousness on standing. She

denied visual changes, dysphagia, dysarthria, weak-

ness, involuntary movement, or loss of urinary or fe-

cal continence. She denied fever, chill, dysuria,

diarrhea, or coughing. At one point, she was hospi-

talized for rehydration every 2 weeks. She had lostnearly 80 pounds over the prior year.

She had a history of osteoarthritis with bilateral

knee replacements. Her current medications were

lansoprazole, midodrine hydrochloride, fludrocorti-

sone acetate, and metoclopramide without signifi-

cant relief. Her family history was remarkable for

cancer and a brother had Down syndrome. She pre-

viously worked as a draftsman. She did not use to-

bacco or recreational drugs and rarely drank alcohol.

NEUROLOGIC EXAMINATION General examina-

tion was significant for orthostasis. Supine blood pres-sure was 143/89 mm Hg with heart rate of 88 beats per

minute. Upon standing, her blood pressure dropped to

63/44 mm Hg with heart rate increasing to 102 beats

per minute. Mental status, language, and cranial nerve

examination were normal. Sensation to vibration and

pinprick was decreased distally in the lower extremities

bilaterally. Light touch and temperature sensation were

normal. Romberg sign was negative. Muscle strength

and tone was normal in all extremities. Deep tendon

reflexes were intact in biceps, triceps, brachioradialis,

and patellar but absent at the Achilles. Plantar responses

were flexor. Limb coordination was normal. She could

stand without assistance for only under 1 minute before

becoming lightheaded, requiring sitting.

INVESTIGATIONS Extensive gastrointestinal

workup at different hospitals including mesenteric

lymph node biopsy led to the diagnosis of sclerosing

mesenteritis. Treatment with prednisone provided

only transient relief. Her endocrine evaluation did not

reveal a cause for the orthostasis. Transthoracic echocar-

diogram showed mild left ventricular hypertrophy with

diastolic dysfunction. EKG recorded a prolonged cor-

rected QT interval of 0.495 seconds (reference range:

0.44 seconds or less). CT chest, abdomen, and pelvis

with contrast showed increased density in the left lower

quadrant mesentery compatible with sclerosing mesen-

teritis with soft tissue thickening encasing the celiac axis

raising the question of lymphoma, pancreatic cancer, or

vasculitis. FDG-PET demonstrated mildly increasedFDG activity in the left lower quadrant mesentery likely

related to sclerosing mesenteritis.

She was anemic with a hemoglobin of 10.3 g/dL

(reference range 11.515.5 g/dL) and MCV 90.3 fL.

Comprehensive metabolic panel was normal. Hemo-

globin A1c was normal. Serum vitamin B12 was 276

pg/mL (reference range 240900 pg/mL), total ho-

mocysteine was elevated at 22.8 mol/L (reference

range 4.513 mol/L), but methylmalonic acid level

and parietal cell antibody titer were normal and in-

trinsic factor blocking antibody was positive. Para-neoplastic autoantibody panel was negative. Serum

protein electrophoresis (SPEP) with immunofixation

showed a monoclonal immunoglobulin A spike.

Angiotensin converting enzyme (ACE) and thyroid

stimulating hormone (TSH) were normal. Syphilis

screen was nonreactive. SSA and SSB antibodies were

negative. HIV-RNA level was undetectable.

Brain MRI with and without contrast displayed

normal sella and parasellar regions, craniocervical

junction, seventh and eighth nerve complexes. CSF

was clear with normal cell count (3 white blood cells;0 red blood cells), normal glucose (49 mg/dL; 0.64

CSF-to-serum glucose ratio), and elevated protein at

52 mg/dL (reference range 1545 mg/dL), without

unique CSF oligoclonal bands, or malignant cells.

CSF herpes simplex virus, acid fast bacilli, and fungal

cultures were negative.

CME

Scan this code with yoursmartphone to access thisfeature

Address correspondence and

reprint requests to Dr. B. Mark

Keegan, Department of

Neurology, Mayo Clinic Collegeof Medicine, 200 First St. SW,

Rochester, MN 55905

[email protected]

From the Department of Neurology (W.S., B.M.K.), Mayo Clinic, Rochester, MN; and Departments of Neurology (I.O.Y., T.K.) and Pathology

(R.W.), University of Chicago, Chicago, IL.

Disclosure: Author disclosures are provided at the end of the article.

NEUROLOGY

CLINICAL

PATHOLOGICAL

CONFERENCE

Section Editors

Joseph E. Parisi, MD

B. Mark Keegan, MD

Copyright 2011 by AAN Enterprises, Inc. 489


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Nerve conduction study and EMG (NCS/EMG)

evaluations were as follows: sural sensory responses

were unobtainable bilaterally, the right radial sensory

response was normal. Left peroneal motor amplitude

was reduced with mild slowing of conduction veloc-

ity. The right tibial motor amplitude was mildly re-

duced; the distal latency and conduction velocity

were normal. The left peroneal F wave was unobtain-

able. The right tibial F wave latency was minimallyprolonged. The right ulnar motor response and F

wave latency were normal. Needle examination of

the right lower extremity musculature showed mild

spontaneous activity in the medial gastrocnemius.

These findings were consistent with a length-

dependent, axonal, sensorimotor polyneuropathy.

A single 5-day trial of IV immunoglobulin (IVIg)

did not result in substantial improvement.

E XP ER T D IS CU SS IO N: D R. W OL FG AN G

SINGER A middle-aged woman presented with a1-year history of upper and lower gastrointestinal

symptoms, orthostatic hypotension (OH), fatigue,

and considerable weight loss. Physical examination

confirmed the presence of OH, detected hypesthesia

in a stocking distribution affecting small and large

fiber modalities, and absent Achilles tendon reflexes.

Comprehensive workup is remarkable for several

findings: 1) EMG evidence of a length-dependent

axonal-predominant sensorimotor peripheral neu-

ropathy, 2) mild left ventricular hypertrophy with

diastolic dysfunction and QT prolongation, 3) in-creased CT density and FDG-PET activity in the left

lower quadrant mesentery, compatible with a diag-

nosis of sclerosing mesenteritis as also suggested by

mesenteric lymph node biopsy, but also soft tissue

thickening encasing the celiac axis, 4) monoclonal

gammopathy (IgA ), and 5) normocytic anemia

with positive intrinsic factor blocking antibody but

without evidence of overt vitamin B12 deficiency.

Notably negative were CSF studies apart from a

mildly elevated protein, MRI of the brain, paraneo-

plastic panel, and ACE. A transient positive response

to prednisone and no response to 5 days of IVIg areof interest.

A major aspect of this patients presentation is

that of severe OH. Neurogenic and non-neurogenic

etiologies of OH exist, but a severe orthostatic blood

pressure drop as documented along with only mild,

inadequate cardioacceleration and negative endocri-

nologic workup would argue for a neurogenic cause.

Formal autonomic testing would have been helpful

to further document this with abnormal blood pres-

sure responses to autonomic reflex maneuvers, such

as the Valsalva maneuver. Formal autonomic testing

would have also been helpful to document severity

and distribution of autonomic failure which can re-

veal important diagnostic clues. Neurogenic OH has

a broad differential diagnosis that includes peripheral

and central etiologies, including autonomic neuropa-

thies, pure autonomic failure, myelopathy, multiple

system atrophy, Parkinson disease, and several other

parkinsonian syndromes. Clinical presentation and ex-

amination findings argue against multiple system atro-

phy, a parkinsonian syndrome, or myelopathy. While

constipation is common in pure autonomic failure, up-

per gastrointestinal symptoms, particularly of the degree

reported in this patient, would be highly unusual for

that condition.1,2 The presentation would be most con-

sistent with an autonomic neuropathy.

Apart from neurogenic OH, this patient presents

with persistent postprandial belching, nausea, vomit-

ing, and weight loss. The patient carries a diagnosis

of sclerosing mesenteritis based on mesenteric lymph

node biopsy. This condition is characterized by such

upper gastrointestinal symptoms, and has been asso-ciated with mechanical small bowel obstruction and

chronic intestinal pseudo-obstruction.3,4 Conversely,

gastroparesis as seen in autonomic neuropathies pres-

ents with similar symptoms and may be more likely

to be the underlying etiology here considering the

consistent postprandial occurrence of symptoms,

vomiting of undigested food, apparent lack of signif-

icant pain, and association with constipation and

neurogenic OH. Yet another consideration could be

a gastrointestinal infiltrative process such as gastroin-

testinal amyloidosis.5,6

Apart from the patients symptoms and examina-

tion findings, we are provided with additional clues

to the diagnosis. The patient was documented to

have clinical and EMG findings suggestive of a

length-dependent peripheral neuropathy with elec-

trophysiologic characteristics suggestive of a predom-

inantly axonal process. Considering that the patient

was apparently asymptomatic in regards to a somatic

peripheral neuropathy, there is a possibility that this

is an incidental, unrelated finding, but nonetheless,

this finding is intriguing and would lend further sup-

port to our suspicion of a peripheral neuropathicprocess underlying this patients presentation.

The differential diagnosis for peripheral neuropa-

thies with autonomic involvement is broad. Dispro-

portionate involvement of autonomic fibers in a

peripheral neuropathic process is helpful in that the

differential diagnosis can be significantly narrowed.

Further narrowing of the differential can usually be

achieved by considering the onset of symptoms

(acute/subacute vs insidious/chronic) and differential

involvement of sympathetic and parasympathetic

function through a comprehensive autonomic review

490 Neurology 77 August 2, 2011


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of systems and standardized autonomic testing. A

broad differential in this case would include amyloid

neuropathy, autoimmune/paraneoplastic etiologies

such as autoimmune autonomic ganglionopathy or

connective tissue disorders, genetic etiologies includ-

ing Fabry disease and hereditary sensory and auto-

nomic neuropathies (HSAN), metabolic etiologies

such as diabetes mellitus, toxic etiologies, and several

infectious etiologies.

The patient does not have a history of diabetes

mellitus with a normal comprehensive metabolic

panel. Vitamin B12 deficiency, even though autoim-

mune gastric disease appears to be present, should

not account for the majority of symptoms and find-

ings described. The patient does not have clinical or

electrophysiologic characteristics of Guillain-Barre

syndrome, botulism, or porphyria. There is no his-

tory of exposure to chemotherapy or other med-

ications and toxins associated with autonomic

neuropathies. Connective tissue disorders associated

with peripheral neuropathies can have various auto-nomic involvement but the laboratory testing pro-

vided would argue at least against more common

entities in that category such as Sjogren syndrome.

Although the possibility of a vasculitic process was

raised based on imaging, the clinical picture does not

seem consistent with a vasculitic neuropathy. Lack of

family history, clinical presentation, and age at onset

argue against inherited autonomic neuropathies in

the different categories of HSAN. OH and gastroin-

testinal symptoms have been reported in female car-

riers of Fabry disease, but the patients age, lack of

family history, EMG findings, lack of neuropathic

pain, lack of reported cutaneous or ocular findings,

inability to account for the monoclonal gammopa-

thy, and described CT/PET findings make that diag-

nosis highly unlikely.7,8 Leprosy, AIDS, diphtheria,

Lyme disease, and celiac disease can all affect auto-

nomic fibers but the clinical presentation is inconsis-

tent with these diagnoses.

Autoimmune autonomic ganglionopathy cer-

tainly would be a consideration. Many cases of idio-

pathic autonomic neuropathy (AAG) have long been

assumed to be of autoimmune etiology, but it wasnot until the recent discovery of specific antibodies

targeted against ganglionic nicotinic acetylcholine re-

ceptors (nAChR) that this concept could be proven.

Patients with this disorder are typically previously

healthy young or middle-aged individuals who de-

velop severe panautonomic failure over the course of

a few days to weeks with subsequent slow spontane-

ous recovery, which is often incomplete.911An ante-

cedent respiratory or gastrointestinal viral syndrome

is reported in many cases while an association with

preceding immunization or minor surgical proce-

dures has been made in other cases. Subacute auto-

nomic failure indistinguishable from AAG with a

paraneoplastic etiology has also been described.12,13

The typical patient with AAG has diffuse autonomic

dysfunction. Sympathetic failure results in OH and

widespread anhidrosis; parasympathetic failure pres-

ents as dry mouth, dry eyes, sexual dysfunction, uri-

nary retention, impaired pupillary responses, and

abnormal heart rate variation. Problems with the en-

teric autonomic nervous system present as gastroin-

testinal dysmotility with anorexia, early satiety,

postprandial abdominal pain, vomiting, diarrhea,

constipation, and intestinal pseudo-obstruction. Pa-

tients present with different combinations of these

signs and symptoms, with the most common pre-

senting symptoms being OH and gastrointestinal

dysmotility, each occurring in 70% to 80% of pa-

tients.9,14 Patients typically have normal strength and

reflexes. About 25% of patients describe minor sen-

sory symptoms, but objective sensory loss is usually

not present. EMG and nerve conduction studies aretypically normal. Laboratory autonomic testing re-

veals evidence of diffuse autonomic failure, with

characteristically severe adrenergic failure resulting in

OH, but also cardiovagal and baroreflex failure, as

well as widespread anhidrosis.9 The most frequent

pattern of sweat loss seen on thermoregulatory sweat

testing is a ganglionopathy pattern rather than a

length-dependent pattern.15 AAG is associated with

antibodies specifically binding to the ganglionic nico-

tinic acetylcholine receptor (AChR) in approximately

50% of cases.13,14 Although subacute symptom onset,

sicca complex, pupillary abnormalities, and lower gas-

trointestinal tract symptoms are more common in the

antibody-positive group, the clinical presentation is

overall similar in seropositive and seronegative cases.16

The concept of an antibody-mediated disorder has been

thoroughly studied and confirmed using animal models

of experimental AAG, passive transfer studies, and stud-

ies on in vitro effects of antibodies on ganglionic

AChRs.14,1719 In addition to the classic presentation of

subacute pandysautonomia, several other clinical phe-

notypes of AAG have been described, including chronic

diffuse autonomic failure similar to pure autonomicfailure, and limited forms of autonomic dysfunction

such as isolated gastrointestinal dysmotility, isolated

cholinergic autonomic failure, and cases of postural

tachycardia syndrome.9,13,14 There are a number of

reports on immunomodulatory and immunosup-

pressive therapy of AAG with promising results, al-

though no controlled trials have been conducted to

date.2022 Lack of response to an IVIg treatment trial

does not rule out the diagnosis, as not all patients

may respond to immunomodulatory therapy and

some patients have been reported to respond to

Neurology 77 August 2, 2011 491


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plasma exchange or immunosuppressant agents afternot responding to IVIg.21,22

The fact that a paraneoplastic panel in this case

was negative does not rule out the possibility of an

autoimmune or paraneoplastic autonomic neuropathy,

particularly not an autonomic neuropathy associated

with lymphoma. In fact, the presence of a monoclonal

gammopathy could argue for that. Also arguing for that

diagnosis would be the lymph node biopsy findings felt

to be consistent with sclerosing mesenteritis, along with

CT/PET mesentery findings and soft tissue thickening

encasing the celiac axis. Lymphoma has been reported

to be associated with sclerosing mesenteritis or has beenmistaken for that condition.2325 Lymphoma has also

been described in association with autoimmune auto-

nomic ganglionopathy.12

Not explained by a paraneoplastic autonomic

neuropathy associated with lymphoma, however,

would be the cardiac findings of mild left ventricular

hypertrophy, diastolic dysfunction, and QT prolon-

gation. That last piece of the puzzle could however

be explained by a condition associated with mono-

clonal gammopathy, lymphoma, and peripheral neu-

ropathy with prominent autonomic features, namely

AL amyloidosis. The described cardiac findings are

somewhat nonspecific but have all been reported as

features of amyloid cardiomyopathy.26,27 While the

elevated homocysteine level may relate to vitamin de-

ficiencies (including B6, folate, and less likely B12

based on available data) in the setting of significant

weight loss, an alternative but purely speculative ex-

planation could be the presence of subclinical amy-

loid nephropathy, considering the known influence

of renal function on homocysteine levels.28

Among the different types of amyloidosis, only

some have been associated with amyloid neuropathy.

Among those, the most common type represents pri-mary (AL) amyloidosis. The fibrils in AL amyloid

consist of monoclonal or light chains. Rarely,

monoclonal heavy chains are found. Familial (AF)

amyloidosis represents another, less common cause

of amyloid neuropathy with precursor proteins most

commonly variants of the transthyretin (TTR) mole-

cule. While the clinical presentation of TTR amyloid

neuropathy can be similar to that of primary amy-

loidosis, it would not account for the monoclonal

gammopathy and CT/PET findings.

Amyloid neuropathy is typically associated with

fatigue and weight loss. The neuropathy is frequently

a sensorimotor peripheral neuropathy or polyradicu-

loneuropathy with loss of pain and temperature sen-

sation, paresthesias, neuropathic pain, weakness, and

characteristically prominent autonomic dysfunc-

tion.29 EMG findings are characteristically those of

an axonal neuropathy.30 On nerve biopsy, axonal de-

generation, sometimes with predominant involve-

ment of small myelinated and unmyelinated fibers, is

seen.29 Deposits of a homogenous, amorphous sub-

stance are found infiltrating epineurial and endo-

neurial connective tissue and blood vessel walls,which stain pink with hematoxylin & eosin (H&E),

metachromatically with methyl violet, and produce

apple-green birefringence when stained with Congo

red and viewed under polarized light.29,31 Immunos-

tains are available to help distinguish the different

types of amyloid in pathologic specimens, and most

recently, laser microdissection along with mass

spectrometry based proteomic analysis of amyloid de-

position has been introduced with promising results.32

A recent manuscript describes patterns of neurop-

athy and autonomic failure in patients with amyloid-

Figure1 Hematoxylin & eosinstained section of sural nerve biopsy

demonstrating hyaline deposits in wallsof endoneurial

blood vessels

Figure2 Toluidine bluestained epoxy section of nerve showing amorphous

material (amyloid)surrounding endoneurial vessels (arrows)



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osis.33A total of 62% of patients were found to have

generalized autonomic failure and polyneuropathywith pain, 17% had generalized autonomic failure

and polyneuropathy without pain, and 11% had iso-

lated autonomic failure. Only 6% of patients had

peripheral neuropathy without autonomic failure,

and 5% had autonomic failure and somatic small-

fiber neuropathy. The most common autonomic

symptoms associated with amyloid neuropathy were

orthostatic intolerance (74%) and gastrointestinal

(71%) symptoms. Autonomic function testing

showed moderately severe to severe autonomic fail-

ure in all domains (sudomotor, cardiovagal, cardio-

vascular adrenergic), with cardiovagal function most

severely affected.

While no somatic neuropathic symptoms, including

neuropathic pain, were reported for the patient dis-

cussed here, there were unequivocal physical and elec-

trophysiologic findings of a somatic neuropathic

process. The electrophysiologic findings showed pre-

dominant axonal features as typically seen in amyloid

neuropathy. Autonomic failure as evidenced by neuro-

genic OH would also be characteristic for that condi-

tion. The gastrointestinal symptoms could be explained

by a combination of autonomic neuropathy, gastroin-

testinal amyloidosis, and the described sclerosing mes-

enteritis. The cardiac findings could indicate early

amyloid cardiomyopathy. This diagnosis would fur-

thermore account for the reported monoclonal gam-

mopathy. In the vast majority of cases, AL amyloidosis

relates to a monoclonal gammopathy with or without

multiple myeloma. Although rare, both focal and sys-

temic forms of amyloidosis have been reported in lym-

phoma.34,35 Alternatively, the imaging findings could

relate to amyloid deposition rather than lymphoma, al-

though a correlation between amyloid and sclerosing

mesenteritis has not been reported.

Therefore, the diagnosis that would seem to bestfit the whole clinical picture would be primary (AL)

amyloidosis with amyloid neuropathy, possibly in

the setting of underlying lymphoma. Still to be consid-

ered, however, would have to be the possibility of a

paraneoplastic autonomic neuropathy in the setting of

lymphoma. I have to again emphasize that formal auto-

nomic testing, including tests to assess cardiovascular

adrenergic, cardiovagal, and sudomotor function,

would likely have provided a higher degree of diagnostic

certainty, as the pattern of autonomic dysfunction can

give important diagnostic clues. Specifically, a length-

dependent pattern of sweat loss and severe cardiovagalfailure would have further supported the diagnosis of

amyloid neuropathy, while a ganglionopathy pattern of

sweat loss and moderate cardiovagal impairment would

have made a stronger case for an autoimmune/paraneo-

plastic autonomic ganglionopathy.

Regardless, at this point, a comprehensive search

for amyloid deposition is clearly indicated, perhaps

starting with a search in tissue obtained previously

(mesenteric lymph node biopsy) and fat aspirate, and

consideration for a peripheral nerve (sural) biopsy,

bone marrow biopsy, rectal biopsy, or rebiopsy of thedescribed CT/PET abnormality if negative. If de-

tected, hematologic treatment approaches, including

peripheral stem cell transplantation, will have to be

considered, which have shown benefit in the treat-

ment of AL amyloidosis.36,37

Clinical diagnosis. Primary (AL) amyloidosis with

amyloid neuropathy.

NEUROPATHOLOGIC FINDINGS Based on her

NCS/EMG abnormalities, the patient underwent bi-

opsy of the left sural nerve. The H&E stain demon-

Figure3 Congo redstained section demonstrating amyloid deposits within

nervefascicle

Figure4 Congored stain, higher magnification,demonstratingamyloid deposits

in a perivascular distribution around endoneurial vessels



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strated pale hyaline deposits within nerve fascicles,

most of which were centered on blood vessels (figure

1). There were no inflammatory cell infiltrates. The

trichrome stain showed a mild diffuse loss of myelin-

ated axons from all fascicles at all levels. The trans-

verse semithin Epon sections also demonstrated

hyaline thickening of endoneurial vessels with a

mild diffuse loss of large myelinated axons (fig-

ure 2). A rare acutely degenerating axon was seen

in a few fascicles.

A diagnostic stain was employed. The Congo red

stain highlighted amyloid deposits in the walls of

most endoneurial vessels and also in a rare epineurial

vessel (figures 3 and 4). The amyloid was not immu-

noreactive with the amyloid A antibody. Despite a

monoclonal IgA spike in SPEP, immunohisto-

chemical staining did not specifically demonstrate

or immunoglobulin (Ig) light chain likely related

to the background Ig in paraffin embedded periph-

eral nerve, a common technical problem in nerve bi-

opsies. Mass spectrometrybased proteomic analysisof microdissected amyloid deposits can provide a de-

finitive diagnosis of the amyloid subtype. Further

analysis was not pursued as the result was unlikely to

affect the overall treatment plan.

Final pathologic diagnosis. Amyloid neuropathy.

COMMENTS Based on her predominantly auto-

nomic and neurologic symptoms and nerve biopsy

result, we referred the patient to hematology to eval-

uate for amyloidosis. Our hematologist suspected

primary amyloidosis. Given the severity of her symp-toms and the involvement of multiple organs, fur-

ther d iagnostic s tudy was not p ur sued to

distinguish among primary, secondary, or familial

amyloidosis as the distinction was unlikely to

change the overall poor prognosis or treatment de-

cision. After a cycle of melphalan and dexametha-

sone, the patient and her family requested

palliative care in a local hospice.

Amyloidosis is a multisystem disorder resulting

from excessive monoclonal plasma cell expansion or

mutation in the transthyretin gene. The tissue depo-sition of insoluble amyloid fibrils leads to organ dys-

function. The clinical presentation depends on the

organs affected. Typical clinical findings include pro-

teinuria, restrictive cardiomyopathy, hepatospleno-

megaly, and polyneuropathy. Tissue biopsy is needed

to confirm the diagnosis. While amyloidosis has a

poor prognosis, chemotherapy and hematopoietic

cell transplantation may prolong survival. To avoid

delayed diagnosis and treatment, amyloidosis should

be considered in patients with unexplained auto-

nomic and neurologic dysfunction.

AUTHOR CONTRIBUTIONS

Dr. Singer contributed the expert discussion format. Dr. Yung drafted and

revised the manuscript. Dr. Wollmann revised the manuscript. Dr. Kelly

revised the manuscript. Dr. Keegan accepted the final revised manuscript.

DISCLOSURE

Dr. Singer is a consultant for Pfizer Inc. Dr. Yung reports no disclosures.

Dr. Wollmann examines neuromuscular biopsies at the Department of

Pathology at the University of Chicago (about 50% effort). Dr. Kelly

reports no disclosures. Dr. Keegan serves as Clinical Pathological Confer-

ence Section Co-Editor for Neurologyand NeurologyPodcast panel and

Chief Editor for eMedicine; and has served as a consultant for Novartis.

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