Painful Small Fiber Neuropathy in Sarcoidosis: A Report
of Two Patients
David
S Younger, Kenneth B Hymes, Kurenai Tanji, Cynthia Liu, Jennifer Zeng, Roy A
Raad, Kyra F Doumlele, Seth Younger
David S Younger, Kyra F Doumlele, Department of Neurology, New York
University Langone Medical Center, New York University School of Medicine, and
the Global Institute of Public Health, New York University, New York, the
United States
Kenneth B Hymes, Department of Medicine, Division of
Hematology, New York University School of Medicine, New York, the United States
Kurenai Tanji, Department of Pathology and Cell Biology, Neuromuscular
Laboratory2, College of Physicians and Surgeons, Columbia University, New York,
the United States
Cynthia Liu, Department of Pathology/Hematopathology, New York
University School of Medicine, and the Global Institute of Public Health, New
York University, New York, the United States
Jennifer Zeng, Department of Pathology, New York University School of
Medicine, and the Global Institute of Public Health, New York University, New
York, the United States
Roy A Raad, Department of Radiology, New York University School of
Medicine, and the Global Institute of Public Health, New York University, New
York, the United States
Seth Younger, Horace Mann School, Bronx, New York, the United States
Correspondence to: David S Younger,
MD, MPH, Department of Neurology, New York
University Langone Medical Center, New York University School of Medicine, and
the Global Institute of Public Health, New York University, New York, the
United States
Email: david.younger@nyumc.org
Telephone: +1-212-213-3778
Fax:
+1-212-213-3779
Received: November 30,
2014 Revised: December 26, 2014
Accepted: January 2, 2015
Published online: February 2, 2015
ABSTRACT
Two patients with
histologically-proven sarcoidosis are reported, both with initial presentation
of painful small fiber neuropathy. Positron emission tomography fused with
computed tomography revealed the first evidence of sarcoidosis in both
patients, and provided a useful guide for bone marrow and bronchoscopic lymph
node and lung tissue biopsy.
© 2015 ACT. All
rights reserved.
Key words: Epidermal nerve fiber; Sarcoidosis; Skin biopsy
Younger DS, Hymes KB, Tanji K, Liu C,
Zeng J, Raad RA, Doumlele KF, Younger S. Painful Small Fiber Neuropathy in
Sarcoidosis: A Report of Two Patients. International
Journal of Neurology Research 2015; 1(1): 14-17 Available from: URL:
http://www.ghrnet.org/index.php/ijnr/article/view/930
INTRODUCTION
Sarcoidosis is a multiorgan autoimmune granulomatous disorder with
worldwide prevalence of less than 1 to 64 per 100,000, and predilection for
adults, particularly women less than 40 years of age[1]. The lymph
nodes, lung, skin, liver and spleen are the commonest sites of granuloma
formation and deposition. Stern and colleagues[2] found neurological
involvement in 33 (5.1%) of 649 patients with pathologically-confirmed
sarcoidosis, 16 (49%) of whom presented neurologically including 1 (6%) with
biopsy-proven peripheral nerve involvement and another with clinically
suspected disease. Sarcoid involvement of small unmyelinated C-, and thinly
myelinated A-d intraepidermal
nerve fibers (IENF) encoding thermal and nociceptive sensation, was noted in up
to 40% of patients after detailed neurophysiological and histopathologic
studies[3]. Such patients were categorized by the World Association
of Sarcoidosis and Other Granulomatous Disorders (WASOG) Sarcoidosis Organ
Assessment Instrument Investigators as “paraneurosarcoid”[4].
CASE REPORT
Patient 1: A 47-year-old
woman noted dysesthesia along the left leg and lateral chest with radiation
across the midline under the breasts in May 2013, later associated with
concentration difficulty, palpitation, lightheadedness, constipation, decreased
libido, and extreme fatigue. Past medical history was remarkable for migraine
headaches, endometriosis, polycystic ovarian disease (PCOD) and
anti-phospholipid antibody (APA) syndrome. There were five miscarriages
followed by successful in vitro fertilization while receiving intravenous
immune globulin (IVIg) with two term gestations. She took venlafaxine
hydrochloride for hot flashes, spironolactone for PCOD, aspirin for APA,
gabapentin for pain, zolpidem for sleep, topiramate for headaches, and diazepam
for anxiety. Neurological
examination in May 2014 showed sensory loss to cold temperature in the hands
and feet, with a positive Romberg sign, and normal strength, reflexes,
cognition and cranial nerve function. Electromyography (EMG) and nerve
conduction studies (NCS) were normal. Autonomic neurophysiological studies (WR
Electronics, MN) showed 20 beat per minute acceleration in heart rate from
baseline to the erect posture during tilting insufficient for the diagnosis of
postural orthostatic tachycardia syndrome; deep breathing, and Valsalva
maneuver (VM) were normal. IENF studies (Figure 1) of the left calf and thigh
showed thin, short axons with frequent complex branching patterns and focal
swellings near the dermoepidermal junction with normal IENF densities. Blood studies
showed normal chemistries, complete blood count (CBC), angiotensin converting
enzyme (ACE), antinuclear antibody (ANA) titers, erythrocyte sedimentation rate
(ESR), C reactive protein (CRP), lymphocyte flow cytometry, B12, hemoglobin
(Hg)A1c, and thyroid function tests (TFT). Magnetic resonance imaging (MRI) of
the brain and spine were normal. Whole body positron emission tomography (PET)
fused with computed tomography (CT) after injection of 18flurodeoxyglucose
(FDG) showed extensive FDG avid adenopathy above and below the diaphragm, lytic
and sclerotic bone lesions through the axial and appendicular skeleton, and
bilateral ill-defined lung air space opacities (Figure 2). Pulmonary function
tests were normal. Posterior iliac crest bone marrow aspiration biopsy (Figure
3) and transbronchial biopsy of the left upper lobe and left lower lobe biopsy
(Figure 4) showed multiple non-caseating granulomas composed of epithelioid
cells and occasional multi-nucleated giant cells with mild central necrosis. Stains
for acid fast bacilli (AFB) and Gömöri methenamine silver stain (GMS) for
fungal organisms were negative. Subcarinal transbronchial and lymph node
biopsies showed benign bronchial tissue. Cerebrospinal fluid (CSF) showed 0
nucleated cells, 3 red blood cells, protein 27 mg/dL, and glucose 58 mg/dL,
with normal or negative IgG, oligoclonal bands, and bacterial, fungal, and acid
fast cultures, and deoxynucleic and ribonucleic acid viral titers by real-time
polymerase chain reaction. She was
treated with 1.6 grams per kilogram of IVIg per month administered over 4 days
without significant improvement in neuropathic pain when last seen in November
2014.
Patient 2: A previously
published 32-year-old woman[5] developed pain along the left face
and neck later followed by pins and needles sensation of the left hand in 2002.
Past medical history was remarkable for hypergonadotropic hypogonadism and
premature ovarian failure with elevated titers of anti-ovarian and APA for
which she received eight months of intravenous corticosteroids and IVIg in
2005. She took no other medications. Examination in 2006 showed hyperesthesia
of the left side of the face with mild distal weakness of the left wrist and
foot in extension, and flexion, with a positive Romberg sign, tandem imbalance,
and otherwise normal strength, sensation, tendon reflexes, cognition and
cranial nerve function. EMG and NCS were normal. Autonomic neurophysiological
studies showed increased sweating volume in the proximal left thigh with an
absent phase IV blood pressure overshoot on VM. There was heat-pain
hypersensitivity in the left hand and foot on quantitative sensory testing
(QST) employing computer assisted sensory testing (CASE IV) (WR Electronics,
MN). Blood studies showed normal chemistries, CBC, ACE, ANA, ESR, CRP,
lymphocyte flow cytometry, B12, HgA1c, and TFT. Non-contrast brain and spinal
cord MRI were normal. Whole body FDG-PET/CT showed extensive mediastinal and
bilateral hilar adenopathy without abnormal radiotracer in the lungs (Figure 5).
Pulmonary function tests were normal. IENF studies showed significantly low
density of the left thigh (7.2/mm, 5th% reference value 8/mm), and low normal
density in the left calf (6.2/mm, 5th percentile reference value
5/mm) without histological abnormalities. Left sural nerve and soleus muscle
biopsy showed no significant pathology. Posterior iliac bone marrow aspiration
and biopsy showed mildly hypocellularity without evidence of granulomas or
lymphoid aggregates. Right paratracheal lymph node biopsy showed extensive
non-caseating granuloma composed of epithelioid cells and occasional
multi-nucleated giant cells with mild central necrosis (Figure 6).
Immunohistochemical stains performed on formalin-fixed, paraffin-embedded
tissue sections for CD3 and CD20 highlighted the presence of scattered T-cells
and B-cells at the peripheral of the granulomas. Immunotyping analysis by flow
cytometry revealed polyclonal B-cells and a normal CD4/CD8 ratio; AFB and GMS
stains were negative. There was no improvement after three months of 2 grams
per kilogram of IVIg administered over 5 days per month. However, treatment
with infliximab followed by methotrexate for one year led to sustained
neurological improvement. She was normal at followup examination in August 2014
and repeat chest-CT showed no evidence of sarcoidosis.
DISCUSSION
Although similar in presentation of painful small fiber neuropathy,
dysautonomia, and APA, our two patients differed in the extent of sarcoid
involvement as detected by whole body FDG-PET/CT and the findings of IENF
analysis. Extensive lytic bone lesions were noted in the first patient with
qualitative IENF changes and normal density measures, whereas the second
patient had less extensive lesions with low nerve fiber density.
It is unclear
whether IENF measures accurately predict the prognosis of sarcoidosis or
associated dysautonomia. The concurrence of APA syndrome and sarcoidosis was
uniquely described in two patients[6], both of whom had concomitant
systemic lupus erythematosus, neither of whom had painful small fiber
neuropathy or dysautonomia. The presence of APA in both of our patients
suggested a possible common predisposing common autoimmune etiopathogenesis in
additional to sarcoidosis. While useful in the treatment of concomitant APA,
IVIg did not show clear benefit in sarcoidosis-associated painful small fiber
neuropathy or dysautonomia.
A Joint Task
Force of the European Federation of Neurological Societies and the Peripheral
Nerve Society[7] found that IENF analysis was a reliable technique
to ascertain small fiber neuropathy but questionably useful in screening for
peripheral autonomic neuropathy.
Further studies of IENF studies in small fiber neuropathy and
dysautonomia are needed before integrating them into clinical practice,
especially as a useful outcome measure in patients with sarcoidosis, painful
small fiber neuropathy or dysautonomia.
CONFLICT OF INTERESTS
The Author has no conflicts of interest to declare.
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Peer
reviewer: Janny Sun, Emeritus Professor, Hong Kong, Editor-In-Chief
of International Journal of Neurology Research, ACT Publishing Group Limited
Company.
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