NEUROLOGY CLINICAL PATHOLOGICAL CONFERENCE Section Editors Joseph E. Parisi, MD B.

Mark Keegan, MD

A middle-aged woman with nausea, weight loss, 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

Address correspondence and reprint requests to Dr. B. Mark Keegan, Department of Neurology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905 keegan.bmark@mayo.edu

A 54-year-old, righthanded, Caucasian woman presented with intermittent nausea, vomiting, and orthostatic hypotension of 1 year duration. Following every meal, she would belch and vomit nonbloody undigested food. She reported constipation and fatigue and felt lightheaded and occasionally lost consciousness on standing. She denied visual changes, dysphagia, dysarthria, weakness, involuntary movement, or loss of urinary or fecal continence. She denied fever, chill, dysuria, diarrhea, or coughing. At one point, she was hospitalized for rehydration every 2 weeks. She had lost nearly 80 pounds over the prior year. She had a history of osteoarthritis with bilateral knee replacements. Her current medications were lansoprazole, midodrine hydrochloride, fludrocortisone acetate, and metoclopramide without significant relief. Her family history was remarkable for cancer and a brother had Down syndrome. She previously worked as a draftsman. She did not use tobacco or recreational drugs and rarely drank alcohol.

NEUROLOGIC EXAMINATION

General examination was significant for orthostasis. Supine blood pressure 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
CME

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 echocardiogram showed mild left ventricular hypertrophy with diastolic dysfunction. EKG recorded a prolonged corrected 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 mesenteritis with soft tissue thickening encasing the celiac axis raising the question of lymphoma, pancreatic cancer, or vasculitis. FDG-PET demonstrated mildly increased FDG 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. Hemoglobin A1c was normal. Serum vitamin B12 was 276 pg/mL (reference range 240 900 pg/mL), total homocysteine 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 intrinsic factor blocking antibody was positive. Paraneoplastic 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 15 45 mg/dL), without unique CSF oligoclonal bands, or malignant cells. CSF herpes simplex virus, acid fast bacilli, and fungal cultures were negative.

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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. Copyright 2011 by AAN Enterprises, Inc. 489

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 velocity. The right tibial motor amplitude was mildly reduced; the distal latency and conduction velocity were normal. The left peroneal F wave was unobtainable. The right tibial F wave latency was minimally prolonged. 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 lengthdependent, axonal, sensorimotor polyneuropathy. A single 5-day trial of IV immunoglobulin (IVIg) did not result in substantial improvement.
EXPERT SINGER DISCUSSION: DR. WOLFGANG

A middle-aged woman presented with a 1-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 neuropathy, 2) mild left ventricular hypertrophy with diastolic dysfunction and QT prolongation, 3) increased CT density and FDG-PET activity in the left lower quadrant mesentery, compatible with a diagnosis 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, paraneoplastic panel, and ACE. A transient positive response to prednisone and no response to 5 days of IVIg are of 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 endocrinologic workup would argue for a neurogenic cause. Formal autonomic testing would have been helpful to further document this with abnormal blood pressure responses to autonomic reflex maneuvers, such as the Valsalva maneuver. Formal autonomic testing
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would have also been helpful to document severity and distribution of autonomic failure which can reveal important diagnostic clues. Neurogenic OH has a broad differential diagnosis that includes peripheral and central etiologies, including autonomic neuropathies, pure autonomic failure, myelopathy, multiple system atrophy, Parkinson disease, and several other parkinsonian syndromes. Clinical presentation and examination findings argue against multiple system atrophy, a parkinsonian syndrome, or myelopathy. While constipation is common in pure autonomic failure, upper gastrointestinal symptoms, particularly of the degree reported in this patient, would be highly unusual for that condition.1,2 The presentation would be most consistent with an autonomic neuropathy. Apart from neurogenic OH, this patient presents with persistent postprandial belching, nausea, vomiting, 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 associated with mechanical small bowel obstruction and chronic intestinal pseudo-obstruction.3,4 Conversely, gastroparesis as seen in autonomic neuropathies presents 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 significant pain, and association with constipation and neurogenic OH. Yet another consideration could be a gastrointestinal infiltrative process such as gastrointestinal amyloidosis.5,6 Apart from the patients symptoms and examination 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 electrophysiologic characteristics suggestive of a predominantly 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 support to our suspicion of a peripheral neuropathic process underlying this patients presentation. The differential diagnosis for peripheral neuropathies with autonomic involvement is broad. Disproportionate 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

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 including Fabry disease and hereditary sensory and autonomic 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 autoimmune gastric disease appears to be present, should not account for the majority of symptoms and findings described. The patient does not have clinical or electrophysiologic characteristics of Guillain-Barre syndrome, botulism, or porphyria. There is no history of exposure to chemotherapy or other medications and toxins associated with autonomic neuropathies. Connective tissue disorders associated with peripheral neuropathies can have various autonomic involvement but the laboratory testing provided would argue at least against more common entities in that category such as Sjo gren 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 gastrointestinal symptoms have been reported in female carriers 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 gammopathy, and described CT/PET findings make that diagnosis highly unlikely.7,8 Leprosy, AIDS, diphtheria, Lyme disease, and celiac disease can all affect autonomic fibers but the clinical presentation is inconsistent with these diagnoses. Autoimmune autonomic ganglionopathy certainly would be a consideration. Many cases of idiopathic autonomic neuropathy (AAG) have long been assumed to be of autoimmune etiology, but it was not until the recent discovery of specific antibodies targeted against ganglionic nicotinic acetylcholine receptors (nAChR) that this concept could be proven. Patients with this disorder are typically previously healthy young or middle-aged individuals who develop severe panautonomic failure over the course of a few days to weeks with subsequent slow spontaneous recovery, which is often incomplete.9 11 An antecedent 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 autonomic 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 presents as dry mouth, dry eyes, sexual dysfunction, urinary retention, impaired pupillary responses, and abnormal heart rate variation. Problems with the enteric autonomic nervous system present as gastrointestinal dysmotility with anorexia, early satiety, postprandial abdominal pain, vomiting, diarrhea, constipation, and intestinal pseudo-obstruction. Patients present with different combinations of these signs and symptoms, with the most common presenting symptoms being OH and gastrointestinal dysmotility, each occurring in 70% to 80% of patients.9,14 Patients typically have normal strength and reflexes. About 25% of patients describe minor sensory symptoms, but objective sensory loss is usually not present. EMG and nerve conduction studies are typically normal. Laboratory autonomic testing reveals 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 nicotinic acetylcholine receptor (AChR) in approximately 50% of cases.13,14 Although subacute symptom onset, sicca complex, pupillary abnormalities, and lower gastrointestinal 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 studies on in vitro effects of antibodies on ganglionic AChRs.14,1719 In addition to the classic presentation of subacute pandysautonomia, several other clinical phenotypes of AAG have been described, including chronic diffuse autonomic failure similar to pure autonomic failure, 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 immunosuppressive therapy of AAG with promising results, although no controlled trials have been conducted to date.20 22 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
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Figure 1

Hematoxylin & eosinstained section of sural nerve biopsy demonstrating hyaline deposits in walls of endoneurial blood vessels

plasma exchange or immunosuppressant agents after not 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 been mistaken for that condition.2325 Lymphoma has also been described in association with autoimmune autonomic ganglionopathy.12
Figure 2 Toluidine bluestained epoxy section of nerve showing amorphous material (amyloid) surrounding endoneurial vessels (arrows)

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 prolongation. That last piece of the puzzle could however be explained by a condition associated with monoclonal gammopathy, lymphoma, and peripheral neuropathy 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 deficiencies (including B6, folate, and less likely B12 based on available data) in the setting of significant weight loss, an alternative but purely speculative explanation could be the presence of subclinical amyloid 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 primary (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) molecule. While the clinical presentation of TTR amyloid neuropathy can be similar to that of primary amyloidosis, 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 polyradiculoneuropathy with loss of pain and temperature sensation, paresthesias, neuropathic pain, weakness, and characteristically prominent autonomic dysfunction.29 EMG findings are characteristically those of an axonal neuropathy.30 On nerve biopsy, axonal degeneration, sometimes with predominant involvement of small myelinated and unmyelinated fibers, is seen.29 Deposits of a homogenous, amorphous substance are found infiltrating epineurial and endoneurial 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 Immunostains 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 deposition has been introduced with promising results.32 A recent manuscript describes patterns of neuropathy and autonomic failure in patients with amyloid-

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Figure 3

Congo redstained section demonstrating amyloid deposits within nerve fascicle

osis.33 A total of 62% of patients were found to have generalized autonomic failure and polyneuropathy with pain, 17% had generalized autonomic failure and polyneuropathy without pain, and 11% had isolated autonomic failure. Only 6% of patients had peripheral neuropathy without autonomic failure, and 5% had autonomic failure and somatic smallfiber 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 failure in all domains (sudomotor, cardiovagal, cardiovascular adrenergic), with cardiovagal function most severely affected. While no somatic neuropathic symptoms, including neuropathic pain, were reported for the patient disFigure 4 Congo red stain, higher magnification, demonstrating amyloid deposits in a perivascular distribution around endoneurial vessels

cussed here, there were unequivocal physical and electrophysiologic findings of a somatic neuropathic process. The electrophysiologic findings showed predominant axonal features as typically seen in amyloid neuropathy. Autonomic failure as evidenced by neurogenic OH would also be characteristic for that condition. The gastrointestinal symptoms could be explained by a combination of autonomic neuropathy, gastrointestinal amyloidosis, and the described sclerosing mesenteritis. The cardiac findings could indicate early amyloid cardiomyopathy. This diagnosis would furthermore account for the reported monoclonal gammopathy. In the vast majority of cases, AL amyloidosis relates to a monoclonal gammopathy with or without multiple myeloma. Although rare, both focal and systemic forms of amyloidosis have been reported in lymphoma.34,35 Alternatively, the imaging findings could relate to amyloid deposition rather than lymphoma, although a correlation between amyloid and sclerosing mesenteritis has not been reported. Therefore, the diagnosis that would seem to best fit the whole clinical picture would be primary (AL) amyloidosis with amyloid neuropathy, possibly in the setting of underlying lymphoma. Still to be considered, however, would have to be the possibility of a paraneoplastic autonomic neuropathy in the setting of lymphoma. I have to again emphasize that formal autonomic 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 lengthdependent pattern of sweat loss and severe cardiovagal failure 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/paraneoplastic 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 the described CT/PET abnormality if negative. If detected, hematologic treatment approaches, including peripheral stem cell transplantation, will have to be considered, which have shown benefit in the treatment of AL amyloidosis.36,37
Clinical diagnosis. Primary (AL) amyloidosis with

amyloid neuropathy.
NEUROPATHOLOGIC FINDINGS Based on her NCS/EMG abnormalities, the patient underwent biopsy of the left sural nerve. The H&E stain demonNeurology 77 August 2, 2011 493

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 myelinated axons from all fascicles at all levels. The transverse semithin Epon sections also demonstrated hyaline thickening of endoneurial vessels with a mild diffuse loss of large myelinated axons (figure 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 immunoreactive with the amyloid A antibody. Despite a monoclonal IgA spike in SPEP, immunohistochemical staining did not specifically demonstrate or immunoglobulin (Ig) light chain likely related to the background Ig in paraffin embedded peripheral nerve, a common technical problem in nerve biopsies. Mass spectrometry based proteomic analysis of microdissected amyloid deposits can provide a definitive 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

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 Conference Section Co-Editor for Neurology and Neurology Podcast panel and Chief Editor for eMedicine; and has served as a consultant for Novartis.

Based on her predominantly autonomic and neurologic symptoms and nerve biopsy result, we referred the patient to hematology to evaluate for amyloidosis. Our hematologist suspected primary amyloidosis. Given the severity of her symptoms and the involvement of multiple organs, further diagnostic study was not pursued to distinguish among primary, secondary, or familial amyloidosis as the distinction was unlikely to change the overall poor prognosis or treatment decision. After a cycle of melphalan and dexamethasone, 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 deposition of insoluble amyloid fibrils leads to organ dysfunction. The clinical presentation depends on the organs affected. Typical clinical findings include proteinuria, restrictive cardiomyopathy, hepatosplenomegaly, 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 autonomic and neurologic dysfunction.
August 2, 2011

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