- Email: [email protected]
Erythromelalgia-like presentation of chronic acquired demyelinating polyneuropathy in a setting of past alcohol abuse
Accepted Manuscript Title: Erythromelalgia-like presentation of chronic acquired demyelinating polyneuropathy in a setting of past alcohol abuse Author: Miguel Chuquilin, Upinder K. Dhand PII: DOI: Reference:
S0960-8966(15)00795-6 http://dx.doi.org/doi: 10.1016/j.nmd.2015.11.007 NMD 3123
To appear in:
Neuromuscular Disorders
Received date: Revised date: Accepted date:
6-6-2015 22-9-2015 16-11-2015
Please cite this article as: Miguel Chuquilin, Upinder K. Dhand, Erythromelalgia-like presentation of chronic acquired demyelinating polyneuropathy in a setting of past alcohol abuse, Neuromuscular Disorders (2015), http://dx.doi.org/doi: 10.1016/j.nmd.2015.11.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
ERYTHROMELALGIA-LIKE PRESENTATION OF CHRONIC ACQUIRED DEMYELINATING POLYNEUROPATHY IN A SETTING OF PAST ALCOHOL ABUSE
Miguel Chuquilin MD Upinder K. Dhand MD*
Department of Neurology, University of Missouri 5 Hospital Drive #CE57, Columbia MO 65212
*Present Address: University of Tennessee Graduate School of Medicine 1924 Alcoa Highway #U114, Knoxville TN 37920
Address Correspondence to Upinder K. Dhand MD Professor of Medicine, Division of Neurology University of Tennessee Graduate School of Medicine 1924 Alcoa Highway #U114 Knoxville TN 37920 Phone: (865) 305-3940 Fax: (865) 305-9144 Email: [email protected]
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Highlights
A patient with erythromelalgia and acquired demyelinating neuropathy is presented.
Erythromelalgia in acquired demyelinating neuropathy is previously not reported.
Extremely slow motor nerve conduction and distal conduction blocks were noted.
Unusual clinical and electrodiagnostic features suggest a novel immune neuropathy.
Past exposure to neurotoxic effect of alcohol may have predisposed to axonal damage.
ABSTRACT Erythromelalgia may be primary or secondary to an underlying medical condition. Association with small fiber neuropathy and axonal large fiber peripheral neuropathy has been described. Erythromelalgia in the setting of acquired demyelinating neuropathy has not been reported. We report a 52-year-old woman with severe erythromelalgia, pain and burning, progressive weakness, hyporeflexia and distal pan-sensory deficits. Cerebrospinal fluid protein was 219 mg/dL. Nerve conduction study revealed extreme (ten-fold) prolongation of distal motor latencies, markedly slow motor nerve conduction, reduced terminal latency index, reduced distal compound muscle action potential (CMAP) amplitude, possible conduction blocks, and distal denervation. Treatment with intravenous immunoglobulin, prednisone and azathioprine resulted in marked clinical and electrophysiological improvement. Our patient fulfills the diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP); however, the unique electrodiagnostic features and presentation with erythromelalgia may represent a CIDP variant or a novel dysimmune neuropathy, or may partly be related to neurotoxic effects of prior alcohol abuse.
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Key Words: Alcohol-related neuropathy Chronic Inflammatory Demyelinating Polyradiculoneuropathy Conduction Block Distal Acquired Demyelinating Symmetric Neuropathy Erythromelalgia Immune-mediated neuropathy Terminal Latency Index
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1. INTRODUCTION: Erythromelalgia (EM) is a rare clinical syndrome of intermittent or constant erythema, warmth, edema and intense burning pain affecting the distal extremities [1,2]. The symptoms are aggravated by heat and relieved by cooling. The disorder is classified into primary EM which includes familial or sporadic cases of Nav.1 sodium channel mutation [3], and secondary EM related to medical conditions such as myeloproliferative disorders, connective tissue diseases, HIV, or occurring in association with peripheral neuropathy [1,2,4]. The relationship of peripheral nerve involvement with EM appears to be multifold. First, the Nav.1 mutation in autosomal dominant primary EM involves the sodium channel subunit of the sensory and sympathetic neurons [3]. Secondly, there is considerable evidence for subclinical small nerve fiber dysfunction in patients with primary EM, including quantitative sensory testing, QSART, autonomic reflexes and decreased intraepidermal nerve fiber density [5-7]. It is postulated that both vasculopathy and small fiber neuropathy may underlie the pathogenic mechanism for EM [5]. Finally, EM as the presenting symptom has been reported in patients with clinical peripheral neuropathy especially small fiber axonopathy, and occasionally in large fiber axonal neuropathy [8-10]. EM as the presenting feature of demyelinating neuropathy has not been reported. We present a patient with chronic acquired demyelinating neuropathy who presented with erythromelalgia and severe painful polyneuropathy at onset. She also exhibited unique electrodiagnostic features of extreme slowing of motor nerve conduction, disproportionate distal slowing and distal conduction blocks, and showed excellent clinical and electrophysiological recovery with immune treatment.
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2. CASE REPORT 52-year-old woman presented with 5 months of progressive severe burning pain, heat sensation, redness and swelling of hands and feet. Symptoms were partially relieved by using icepacks. Gradually, the pain became so intense that she could not stand without assistance, and had difficulty using hands even to feed herself, leading to weight loss. She also became aware of inability to feel the floor and difficulty lifting feet when attempting to stand or walk. There was history of hypertension, left nephrectomy and alcohol abuse in the past. Clinical examination revealed erythema and swelling of distal extremities, dark discoloration of her toes and fingers (Figure 1.1), and bilateral mild claw-hand posturing. Muscle strength was MRC (Medical Research Council) 4 in proximal muscles, being weaker in lower extremities, 2 in hand muscles, minimal movement at ankles and toes (Table 1), and generalized hypo/areflexia. Grip and distal testing was limited due to severe pain. She had marked allodynia and impairment of pain, touch and temperature sensation in glove and stocking distribution up to knees and elbows. Joint position sensation was absent at toes, vibration sensation was absent at toes and ankles and impaired at fingers.
Work up showed normal or negative blood counts, chemistry, thyroid function, antinuclear antibody, B12, B1, B6, folate, HIV, immunofixation electrophoresis, heavy metals, paraneoplastic profile, myelin associated glycoprotein (MAG) and sulfated glucuronyl paragloboside (SGPG) antibody. Cerebrospinal fluid was acellular with protein of 219 mg/dL. Electrodiagnostic evaluation showed extremely prolonged distal motor latencies (41.4 ms, 35.6 ms, 28.6 ms) for the median, ulnar and peroneal (recording site tibialis anterior) nerves
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respectively, very slow motor nerve conduction velocity with markedly reduced CMAP amplitudes, and probable conduction block in the median nerve (Table 2, Figure 1.2). Terminal latency index (TLI) for the median nerve was 0.20 (normal >0.33). Ulnar motor response was unobtainable at elbow therefore TLI could not be calculated, however using forearm conduction velocity of median nerve as approximate representation for ulnar motor forearm conduction velocity, the TLI for ulnar nerve was 0.23. Peroneal (extensor digitorum brevis) and tibial (abductor hallucis) motor responses, and sensory nerve action potentials (SNAP) of the median, ulnar and sural nerves were absent. Needle electromyography showed severe active denervation in distal muscles with no voluntary motor unit potential recorded in lower extremity and discrete/ single motor unit potential pattern recorded in the upper extremity muscles. She received intravenous immunoglobulin (IVIG) as 2g/kg over 5 days, followed by prednisone 60 mg every other day for 2 weeks and then 40 mg every other day.
On follow up at 6 weeks, pain, erythromelalgia and swelling had markedly improved, some discoloration and trophic changes persisted (Figure 1.1). Muscle strength was 4+ in proximal muscles, 4 in hand muscles, 3/5 in ankle dorsiflexion and 4/5 in plantar-flexion (Table 1). She ambulated without assistance with steppage gait. Prednisone was tapered down to 10 mg daily in the following months and she was started on azathioprine 50 mg twice a day. Follow up 1 year later, showed no recurrence of pain or erythromelalgia, improved muscle strength (Table 1), and hyporeflexia only in lower extremities. Steppage gait had resolved. A repeat nerve conduction study at 1 year showed markedly improved CMAP amplitude, distal motor latencies and conduction velocity for median, ulnar and peroneal (tibialis anterior) nerves, no conduction block or temporal dispersion. Sensory responses of the median and ulnar nerves were well elicited but
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with moderately reduced SNAP amplitude and slow conduction. (Table 2, figure 1.2). Distal peroneal and tibial motor responses and sural sensory responses were still unrecordable. Needle EMG showed reduction of active denervation in the distal muscles and partial reinnervation. At last follow up she continued to be independent in walking and daily activities.
3. DISCUSSION
Our patient had typical features of erythromelalgia along with symptoms of small fiber neuropathy at the onset of her illness; however, progressed to generalized weakness and pansensory involvement within a few months, and showed elevated CSF protein with albumincytologic dissociation as well as pronounced demyelination findings on nerve conduction study consistent with chronic acquired demyelinating polyneuropathy. To our knowledge there are no published cases of chronic acquired demyelinating neuropathy presenting with erythromelalgialike symptoms. A few patients with small fiber neuropathy [8,9] and one patient with axonal large fiber neuropathy [10] have been reported with acute erythromelalgia. These patients had responded to treatment with corticosteroids, and immune basis of neuropathy was proposed. Our patient also had marked improvement with immune treatment, and in fact fulfills the diagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) [11,12], except the unusual presentation with erythromelalgia and prominent small fiber involvement. CIDP is the most common form of chronic acquired demyelinating polyneuropathy. The classic phenotype is characterized by symmetric proximal and distal weakness, hypo/areflexia and predominantly large fiber sensory deficits [13]. Several clinical variants have been defined, including distal acquired demyelinating symmetric (DADS) neuropathy, multifocal
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demyelinating sensory and motor (MADSAM) neuropathy or Lewis-Sumner syndrome, multifocal motor neuropathy, and pure sensory CIDP [12,14]. Neuropathic pain may be a prominent or presenting symptom in some patients with CIDP, usually in the form of radicular pains or paresthesias. Occasionally dysesthesia and allodynia are described, [15,16]; however, occurrence of erythromelalgia was not reported in these patients.
Additionally, the electrodiagnostic findings in our patient were remarkable for extremely slow motor nerve conduction with more severe distal involvement (reduced TLI), and markedly reduced distal CMAP with full recovery in amplitude on follow up suggestive of distal conduction block. Disproportionate distal slowing is reminiscent of anti-MAG neuropathy. Our patient however, did not have clinical phenotype of DADS, IgM gammopathy or anti-MAG antibodies, and showed excellent response to immune therapy unlike anti-MAG neuropathy [14,17,18]. Mechanism of erythromelalgia with these findings of demyelinating neuropathy is uncertain. . Reduced CMAP amplitude and denervation on EMG were also observed in our patient along with pronounced demyelination and may reflect secondary axonal involvement which is not uncommon in patients with CIDP [13].
It seems concomitant axonal damage and
small fiber involvement, as indicated clinically by severe burning pain, allodynia, and distal pain and temperature sensory impairment may underlie the erythromelalgia-like presentation in our patient. Evaluation for small fiber neuropathy with skin biopsy or autonomic testing; or SCN9A genetic testing for hereditary cause of erythromelalgia were not performed.
The role of our patient’s past history of alcohol abuse in her clinical presentation and electrodiagnostic findings needs to be discussed. Alcohol-related peripheral neuropathy,
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considered to be due to direct neurotoxic effects of ethanol and/or associated nutritional deficiencies, is characterized by chronic distal axonopathy [19]. In EMG and nerve conduction study, findings are usually of an axonal neuropathy with normal or mildly slow conduction with reduced SNAP and CMAP amplitudes. Pure form of alcohol neuropathy is small-fiberpredominant, and painful symptoms are common [20]; however, we are not aware of any published cases of alcohol-related erythromelalgia. There are also reports of patients developing rapidly progressive neuropathy mimicking axonal Guillain-Barre syndrome [23] with normal CSF findings. The clinical phenotype, markedly slow nerve conduction, elevated CSF protein, and significant response to immune therapy make alcohol-related neuropathy unlikely in our patient. However, past alcohol abuse may have led to a background neuropathy with predisposition of peripheral nerves to increased autoimmune injury, or susceptibility to small axon damage. The residual axonal loss seen after her clinical recovery and persisting trophic changes may also suggest an underlying neuropathy and/or secondary axonal damage due to severe CIDP [13].
In summary, the clinical presentation of chronic acquired demyelinating polyneuropathy with erythromelalgia, and electrophysiological findings of distal predominant extreme slowing of nerve conduction and reversible distal conduction blocks, may represent a unique subtype of CIDP or a novel immune-mediated neuropathy. A background neuropathy or increased vulnerability of peripheral nerves due to past exposure to the neurotoxic effects of alcohol or its metabolites in this patient may have contributed to the unusual clinical presentation.
ACKNOWLEDGEMENTS
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Authors wish to thank Mr. S.K. Campbell for assistance with the preparation of illustrations.
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References:
[1] Kalgaard OM, Seem E, Kvernebo K. Erythromelalgia: a clinical study of 87 cases. J Intern Med. 1997;242:191-7. [2] Layzer RB. Hot feet: erythromelalgia and related disorders. J Child Neurol.2001;16:199202. [3] Waxman SG, Dib-Hajj S. Erythermalgia: molecular basis for an inherited pain syndrome. Trends Mol Med. 2005;11:555-62. [4] Herskovitz S, Loh F, Berger AR, Kucherov M. Erythromelalgia: association with hereditary sensory neuropathy and response to amitriptyline. Neurology. 1993;43:621-2. [5] Davis MD, Sandroni P, Rooke TW, Low PA. Erythromelalgia: vasculopathy, neuropathy, or both? A prospective study of vascular and neurophysiologic studies in erythromelalgia. Arch Dermatol. 2003;139:1337-43. [6] Davis MD, Weenig RH, Genebriera J, Wendelschafer-Crabb G, Kennedy WR, Sandroni P. Histopathologic findings in primary erythromelalgia are nonspecific: special studies show a decrease in small nerve fiber density. J Am Acad Dermatol. 2006;55:519-22. [7] Genebriera J, Michaels JD, Sandroni P, Davis MD. Results of computer-assisted sensory evaluation in 41 patients with erythromelalgia. Clin Exp Dermatol. 2012;37:350-4. [8] Dabby R, Gilad R, Sadeh M, Lampl Y, Watemberg N. Acute steroid responsive smallfiber sensory neuropathy: a new entity? J Peripher Nerv Syst. 2006;11:47-52. [9] Paticoff J, Valovska A, Nedeljkovic SS, Oaklander AL. Defining a treatable cause of erythromelalgia: acute adolescent autoimmune small-fiber axonopathy. Anesth Analg. 2007;104:438-41.
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[10] Pfund Z, Stankovics J, Decsi T, Illes Z. Childhood steroid-responsive acute erythromelalgia with axonal neuropathy of large myelinated fibers: a dysimmune neuropathy? Neuromuscul Disord. 2009;19:49-52 [11] Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Report from an Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Neurology. 1991;41:617-8. [12] Saperstein DS, Katz JS, Amato AA, Barohn RJ. Clinical spectrum of chronic acquired demyelinating polyneuropathies. Muscle Nerve. 2001;24:311-24. [13] Barohn RJ, Kissel JT, Warmolts JR, Mendell JR. Chronic inflammatory demyelinating polyradiculoneuropathy. Clinical characteristics, course, and recommendations for diagnostic criteria. Arch Neurol. 1989;46:878-84 [14] Nobile-Orazio E. Chronic inflammatory demyelinating polyradiculoneuropathy and variants: where we are and where we should go. J Peripher Nerv Syst. 2014;19:2-13. [15] Boukhris S, Magy L, Khalil M, Sindou P, Vallat JM. Pain as the presenting symptom of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). J Neurol Sci. 2007;254:33-8. [16] Pazzaglia C, Briani C, Nobile-Orazio E et al. Occurrence and characterization of Pain in immune-mediated neuropathies: a multicentre prospective study. Eur J Neurol. 2011;18:177-83. [17] Latov N. Diagnosis and treatment of chronic acquired demyelinating polyneuropathies. Nat Rev Neurol. 2014;10:435-46. [18] Dalakas MC. Pathogenesis and Treatment of Anti-MAG Neuropathy. Curr Treat Options Neurol. 2010;12:71-83.
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[19] Koike H, Sobue G. Alcoholic neuropathy. Curr Opin Neurol 2006;19:481-86. [20] Koike H, Mori K, Misu K, et al. Painful alcoholic polyneuropathy with predominant small-fiber loss and normal thiamine status. Neurology 2001; 56:1727-32. [21] Whorle JC, Spengos K, Steinke W, et al. Alcohol-related acute axonal polyneuropathy. A differential diagnosis of Guillain-Barre syndrome. Arch Neurol 1998; 55:1329-34.
Figure Captions Figure 1.1. A) Erythema, swelling and discoloration of hands and feet on initial examination. Trophic changes seen on toes and lower legs. B) Improvement in edema and redness on follow up. Some trophic changes persisting. (Note: different hue of discoloration partly related to changed lighting and camera). Figure 1.2. Nerve conduction study: Initial study at 5 months after symptom onset and Follow up study one year after treatment. Sensory responses for median (A) and ulnar (B) absent initially were recordable on follow up. Extremely prolonged distal motor latencies, marked slow conduction and severely reduced compound muscle action potential (CMAP) amplitude for median (C), ulnar (D) and Peroneal (E) nerves initially, and normal CMAP amplitude, improved conduction velocity and latencies on follow up. Initial median motor study (C) also shows probable conduction block with recovery on follow up.
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Table 1. Summary of serial muscle motor examination (MRC scale) at initial visit and follow up Muscle Deltoid Biceps Triceps Wrist extensors Grip First dorsal interosseous Abductor pollicis brevis Iliopsoas Quadriceps Hamstring Tibialis anterior Gastrocnemius Extensor hallucis longus
Initial 4 4+ 5 4 2 2 2 444 1 1 0
6 weeks 4+ 5 5 4 4 4 4 4 4 4 3 4 0
1 year 5 5 5 5 5 4 4 5 5 5 4 4 3
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Table 2 Summary of nerve conduction study: A) Initial, and B) Follow up at 1 year after treatment. Study
A
Nerve
Median W
SNC
SNAP
DML
MNC
CMAP
F Wave
m/s
uV
ms
m/s
mV
ms
NR
NR
41.4 (<4.2)
E Ulnar
W
71.6 NR
NR
E Peroneal BFH*
Median W
NA
NA
W
35.6 (<3.6)
37.4 (>48)
9.9 (>15)
4.9 (>10)
9.3 (>42)
3.95 (<3.6)
8.0 (>5)
11.6
28.6 (>48)
7.8
AE
14.5
34.5
6.5
Knee
NA
NA
5.35 (<6.6) 9.10
4.0 (>4) 26.7 (>42)
37.5 (<32)
5.9
BE
Peroneal BFH*
ND
0.1 6.7 (>5)
32.6 (>48)
NR
-0.2 (>4)
5.30 (<4.2) 12.3
29.8 (>48)
--
NR
0.2 0.4 (>5)
28.6 (<6.6) 37.2
E Ulnar
8.4 (>48)
NR
Knee B
0.9 (>5)
40.7 (<32)
ND
4.0
BE: below elbow; BFH: below fibular head; CMAP: compound muscle action potential, DML: distal motor latency; E: elbow; MNC: motor nerve conduction, NA: not applicable; ND: not done; NR: no response; SNAP: sensory nerve action potential; SNC: sensory nerve conduction; W: wrist; * Recording site Tibialis Anterior; (Normal values)
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S0960-8966(15)00795-6 http://dx.doi.org/doi: 10.1016/j.nmd.2015.11.007 NMD 3123
To appear in:
Neuromuscular Disorders
Received date: Revised date: Accepted date:
6-6-2015 22-9-2015 16-11-2015
Please cite this article as: Miguel Chuquilin, Upinder K. Dhand, Erythromelalgia-like presentation of chronic acquired demyelinating polyneuropathy in a setting of past alcohol abuse, Neuromuscular Disorders (2015), http://dx.doi.org/doi: 10.1016/j.nmd.2015.11.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
ERYTHROMELALGIA-LIKE PRESENTATION OF CHRONIC ACQUIRED DEMYELINATING POLYNEUROPATHY IN A SETTING OF PAST ALCOHOL ABUSE
Miguel Chuquilin MD Upinder K. Dhand MD*
Department of Neurology, University of Missouri 5 Hospital Drive #CE57, Columbia MO 65212
*Present Address: University of Tennessee Graduate School of Medicine 1924 Alcoa Highway #U114, Knoxville TN 37920
Address Correspondence to Upinder K. Dhand MD Professor of Medicine, Division of Neurology University of Tennessee Graduate School of Medicine 1924 Alcoa Highway #U114 Knoxville TN 37920 Phone: (865) 305-3940 Fax: (865) 305-9144 Email: [email protected]
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Highlights
A patient with erythromelalgia and acquired demyelinating neuropathy is presented.
Erythromelalgia in acquired demyelinating neuropathy is previously not reported.
Extremely slow motor nerve conduction and distal conduction blocks were noted.
Unusual clinical and electrodiagnostic features suggest a novel immune neuropathy.
Past exposure to neurotoxic effect of alcohol may have predisposed to axonal damage.
ABSTRACT Erythromelalgia may be primary or secondary to an underlying medical condition. Association with small fiber neuropathy and axonal large fiber peripheral neuropathy has been described. Erythromelalgia in the setting of acquired demyelinating neuropathy has not been reported. We report a 52-year-old woman with severe erythromelalgia, pain and burning, progressive weakness, hyporeflexia and distal pan-sensory deficits. Cerebrospinal fluid protein was 219 mg/dL. Nerve conduction study revealed extreme (ten-fold) prolongation of distal motor latencies, markedly slow motor nerve conduction, reduced terminal latency index, reduced distal compound muscle action potential (CMAP) amplitude, possible conduction blocks, and distal denervation. Treatment with intravenous immunoglobulin, prednisone and azathioprine resulted in marked clinical and electrophysiological improvement. Our patient fulfills the diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP); however, the unique electrodiagnostic features and presentation with erythromelalgia may represent a CIDP variant or a novel dysimmune neuropathy, or may partly be related to neurotoxic effects of prior alcohol abuse.
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Key Words: Alcohol-related neuropathy Chronic Inflammatory Demyelinating Polyradiculoneuropathy Conduction Block Distal Acquired Demyelinating Symmetric Neuropathy Erythromelalgia Immune-mediated neuropathy Terminal Latency Index
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1. INTRODUCTION: Erythromelalgia (EM) is a rare clinical syndrome of intermittent or constant erythema, warmth, edema and intense burning pain affecting the distal extremities [1,2]. The symptoms are aggravated by heat and relieved by cooling. The disorder is classified into primary EM which includes familial or sporadic cases of Nav.1 sodium channel mutation [3], and secondary EM related to medical conditions such as myeloproliferative disorders, connective tissue diseases, HIV, or occurring in association with peripheral neuropathy [1,2,4]. The relationship of peripheral nerve involvement with EM appears to be multifold. First, the Nav.1 mutation in autosomal dominant primary EM involves the sodium channel subunit of the sensory and sympathetic neurons [3]. Secondly, there is considerable evidence for subclinical small nerve fiber dysfunction in patients with primary EM, including quantitative sensory testing, QSART, autonomic reflexes and decreased intraepidermal nerve fiber density [5-7]. It is postulated that both vasculopathy and small fiber neuropathy may underlie the pathogenic mechanism for EM [5]. Finally, EM as the presenting symptom has been reported in patients with clinical peripheral neuropathy especially small fiber axonopathy, and occasionally in large fiber axonal neuropathy [8-10]. EM as the presenting feature of demyelinating neuropathy has not been reported. We present a patient with chronic acquired demyelinating neuropathy who presented with erythromelalgia and severe painful polyneuropathy at onset. She also exhibited unique electrodiagnostic features of extreme slowing of motor nerve conduction, disproportionate distal slowing and distal conduction blocks, and showed excellent clinical and electrophysiological recovery with immune treatment.
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2. CASE REPORT 52-year-old woman presented with 5 months of progressive severe burning pain, heat sensation, redness and swelling of hands and feet. Symptoms were partially relieved by using icepacks. Gradually, the pain became so intense that she could not stand without assistance, and had difficulty using hands even to feed herself, leading to weight loss. She also became aware of inability to feel the floor and difficulty lifting feet when attempting to stand or walk. There was history of hypertension, left nephrectomy and alcohol abuse in the past. Clinical examination revealed erythema and swelling of distal extremities, dark discoloration of her toes and fingers (Figure 1.1), and bilateral mild claw-hand posturing. Muscle strength was MRC (Medical Research Council) 4 in proximal muscles, being weaker in lower extremities, 2 in hand muscles, minimal movement at ankles and toes (Table 1), and generalized hypo/areflexia. Grip and distal testing was limited due to severe pain. She had marked allodynia and impairment of pain, touch and temperature sensation in glove and stocking distribution up to knees and elbows. Joint position sensation was absent at toes, vibration sensation was absent at toes and ankles and impaired at fingers.
Work up showed normal or negative blood counts, chemistry, thyroid function, antinuclear antibody, B12, B1, B6, folate, HIV, immunofixation electrophoresis, heavy metals, paraneoplastic profile, myelin associated glycoprotein (MAG) and sulfated glucuronyl paragloboside (SGPG) antibody. Cerebrospinal fluid was acellular with protein of 219 mg/dL. Electrodiagnostic evaluation showed extremely prolonged distal motor latencies (41.4 ms, 35.6 ms, 28.6 ms) for the median, ulnar and peroneal (recording site tibialis anterior) nerves
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respectively, very slow motor nerve conduction velocity with markedly reduced CMAP amplitudes, and probable conduction block in the median nerve (Table 2, Figure 1.2). Terminal latency index (TLI) for the median nerve was 0.20 (normal >0.33). Ulnar motor response was unobtainable at elbow therefore TLI could not be calculated, however using forearm conduction velocity of median nerve as approximate representation for ulnar motor forearm conduction velocity, the TLI for ulnar nerve was 0.23. Peroneal (extensor digitorum brevis) and tibial (abductor hallucis) motor responses, and sensory nerve action potentials (SNAP) of the median, ulnar and sural nerves were absent. Needle electromyography showed severe active denervation in distal muscles with no voluntary motor unit potential recorded in lower extremity and discrete/ single motor unit potential pattern recorded in the upper extremity muscles. She received intravenous immunoglobulin (IVIG) as 2g/kg over 5 days, followed by prednisone 60 mg every other day for 2 weeks and then 40 mg every other day.
On follow up at 6 weeks, pain, erythromelalgia and swelling had markedly improved, some discoloration and trophic changes persisted (Figure 1.1). Muscle strength was 4+ in proximal muscles, 4 in hand muscles, 3/5 in ankle dorsiflexion and 4/5 in plantar-flexion (Table 1). She ambulated without assistance with steppage gait. Prednisone was tapered down to 10 mg daily in the following months and she was started on azathioprine 50 mg twice a day. Follow up 1 year later, showed no recurrence of pain or erythromelalgia, improved muscle strength (Table 1), and hyporeflexia only in lower extremities. Steppage gait had resolved. A repeat nerve conduction study at 1 year showed markedly improved CMAP amplitude, distal motor latencies and conduction velocity for median, ulnar and peroneal (tibialis anterior) nerves, no conduction block or temporal dispersion. Sensory responses of the median and ulnar nerves were well elicited but
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with moderately reduced SNAP amplitude and slow conduction. (Table 2, figure 1.2). Distal peroneal and tibial motor responses and sural sensory responses were still unrecordable. Needle EMG showed reduction of active denervation in the distal muscles and partial reinnervation. At last follow up she continued to be independent in walking and daily activities.
3. DISCUSSION
Our patient had typical features of erythromelalgia along with symptoms of small fiber neuropathy at the onset of her illness; however, progressed to generalized weakness and pansensory involvement within a few months, and showed elevated CSF protein with albumincytologic dissociation as well as pronounced demyelination findings on nerve conduction study consistent with chronic acquired demyelinating polyneuropathy. To our knowledge there are no published cases of chronic acquired demyelinating neuropathy presenting with erythromelalgialike symptoms. A few patients with small fiber neuropathy [8,9] and one patient with axonal large fiber neuropathy [10] have been reported with acute erythromelalgia. These patients had responded to treatment with corticosteroids, and immune basis of neuropathy was proposed. Our patient also had marked improvement with immune treatment, and in fact fulfills the diagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) [11,12], except the unusual presentation with erythromelalgia and prominent small fiber involvement. CIDP is the most common form of chronic acquired demyelinating polyneuropathy. The classic phenotype is characterized by symmetric proximal and distal weakness, hypo/areflexia and predominantly large fiber sensory deficits [13]. Several clinical variants have been defined, including distal acquired demyelinating symmetric (DADS) neuropathy, multifocal
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demyelinating sensory and motor (MADSAM) neuropathy or Lewis-Sumner syndrome, multifocal motor neuropathy, and pure sensory CIDP [12,14]. Neuropathic pain may be a prominent or presenting symptom in some patients with CIDP, usually in the form of radicular pains or paresthesias. Occasionally dysesthesia and allodynia are described, [15,16]; however, occurrence of erythromelalgia was not reported in these patients.
Additionally, the electrodiagnostic findings in our patient were remarkable for extremely slow motor nerve conduction with more severe distal involvement (reduced TLI), and markedly reduced distal CMAP with full recovery in amplitude on follow up suggestive of distal conduction block. Disproportionate distal slowing is reminiscent of anti-MAG neuropathy. Our patient however, did not have clinical phenotype of DADS, IgM gammopathy or anti-MAG antibodies, and showed excellent response to immune therapy unlike anti-MAG neuropathy [14,17,18]. Mechanism of erythromelalgia with these findings of demyelinating neuropathy is uncertain. . Reduced CMAP amplitude and denervation on EMG were also observed in our patient along with pronounced demyelination and may reflect secondary axonal involvement which is not uncommon in patients with CIDP [13].
It seems concomitant axonal damage and
small fiber involvement, as indicated clinically by severe burning pain, allodynia, and distal pain and temperature sensory impairment may underlie the erythromelalgia-like presentation in our patient. Evaluation for small fiber neuropathy with skin biopsy or autonomic testing; or SCN9A genetic testing for hereditary cause of erythromelalgia were not performed.
The role of our patient’s past history of alcohol abuse in her clinical presentation and electrodiagnostic findings needs to be discussed. Alcohol-related peripheral neuropathy,
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considered to be due to direct neurotoxic effects of ethanol and/or associated nutritional deficiencies, is characterized by chronic distal axonopathy [19]. In EMG and nerve conduction study, findings are usually of an axonal neuropathy with normal or mildly slow conduction with reduced SNAP and CMAP amplitudes. Pure form of alcohol neuropathy is small-fiberpredominant, and painful symptoms are common [20]; however, we are not aware of any published cases of alcohol-related erythromelalgia. There are also reports of patients developing rapidly progressive neuropathy mimicking axonal Guillain-Barre syndrome [23] with normal CSF findings. The clinical phenotype, markedly slow nerve conduction, elevated CSF protein, and significant response to immune therapy make alcohol-related neuropathy unlikely in our patient. However, past alcohol abuse may have led to a background neuropathy with predisposition of peripheral nerves to increased autoimmune injury, or susceptibility to small axon damage. The residual axonal loss seen after her clinical recovery and persisting trophic changes may also suggest an underlying neuropathy and/or secondary axonal damage due to severe CIDP [13].
In summary, the clinical presentation of chronic acquired demyelinating polyneuropathy with erythromelalgia, and electrophysiological findings of distal predominant extreme slowing of nerve conduction and reversible distal conduction blocks, may represent a unique subtype of CIDP or a novel immune-mediated neuropathy. A background neuropathy or increased vulnerability of peripheral nerves due to past exposure to the neurotoxic effects of alcohol or its metabolites in this patient may have contributed to the unusual clinical presentation.
ACKNOWLEDGEMENTS
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Authors wish to thank Mr. S.K. Campbell for assistance with the preparation of illustrations.
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References:
[1] Kalgaard OM, Seem E, Kvernebo K. Erythromelalgia: a clinical study of 87 cases. J Intern Med. 1997;242:191-7. [2] Layzer RB. Hot feet: erythromelalgia and related disorders. J Child Neurol.2001;16:199202. [3] Waxman SG, Dib-Hajj S. Erythermalgia: molecular basis for an inherited pain syndrome. Trends Mol Med. 2005;11:555-62. [4] Herskovitz S, Loh F, Berger AR, Kucherov M. Erythromelalgia: association with hereditary sensory neuropathy and response to amitriptyline. Neurology. 1993;43:621-2. [5] Davis MD, Sandroni P, Rooke TW, Low PA. Erythromelalgia: vasculopathy, neuropathy, or both? A prospective study of vascular and neurophysiologic studies in erythromelalgia. Arch Dermatol. 2003;139:1337-43. [6] Davis MD, Weenig RH, Genebriera J, Wendelschafer-Crabb G, Kennedy WR, Sandroni P. Histopathologic findings in primary erythromelalgia are nonspecific: special studies show a decrease in small nerve fiber density. J Am Acad Dermatol. 2006;55:519-22. [7] Genebriera J, Michaels JD, Sandroni P, Davis MD. Results of computer-assisted sensory evaluation in 41 patients with erythromelalgia. Clin Exp Dermatol. 2012;37:350-4. [8] Dabby R, Gilad R, Sadeh M, Lampl Y, Watemberg N. Acute steroid responsive smallfiber sensory neuropathy: a new entity? J Peripher Nerv Syst. 2006;11:47-52. [9] Paticoff J, Valovska A, Nedeljkovic SS, Oaklander AL. Defining a treatable cause of erythromelalgia: acute adolescent autoimmune small-fiber axonopathy. Anesth Analg. 2007;104:438-41.
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[10] Pfund Z, Stankovics J, Decsi T, Illes Z. Childhood steroid-responsive acute erythromelalgia with axonal neuropathy of large myelinated fibers: a dysimmune neuropathy? Neuromuscul Disord. 2009;19:49-52 [11] Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Report from an Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Neurology. 1991;41:617-8. [12] Saperstein DS, Katz JS, Amato AA, Barohn RJ. Clinical spectrum of chronic acquired demyelinating polyneuropathies. Muscle Nerve. 2001;24:311-24. [13] Barohn RJ, Kissel JT, Warmolts JR, Mendell JR. Chronic inflammatory demyelinating polyradiculoneuropathy. Clinical characteristics, course, and recommendations for diagnostic criteria. Arch Neurol. 1989;46:878-84 [14] Nobile-Orazio E. Chronic inflammatory demyelinating polyradiculoneuropathy and variants: where we are and where we should go. J Peripher Nerv Syst. 2014;19:2-13. [15] Boukhris S, Magy L, Khalil M, Sindou P, Vallat JM. Pain as the presenting symptom of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). J Neurol Sci. 2007;254:33-8. [16] Pazzaglia C, Briani C, Nobile-Orazio E et al. Occurrence and characterization of Pain in immune-mediated neuropathies: a multicentre prospective study. Eur J Neurol. 2011;18:177-83. [17] Latov N. Diagnosis and treatment of chronic acquired demyelinating polyneuropathies. Nat Rev Neurol. 2014;10:435-46. [18] Dalakas MC. Pathogenesis and Treatment of Anti-MAG Neuropathy. Curr Treat Options Neurol. 2010;12:71-83.
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[19] Koike H, Sobue G. Alcoholic neuropathy. Curr Opin Neurol 2006;19:481-86. [20] Koike H, Mori K, Misu K, et al. Painful alcoholic polyneuropathy with predominant small-fiber loss and normal thiamine status. Neurology 2001; 56:1727-32. [21] Whorle JC, Spengos K, Steinke W, et al. Alcohol-related acute axonal polyneuropathy. A differential diagnosis of Guillain-Barre syndrome. Arch Neurol 1998; 55:1329-34.
Figure Captions Figure 1.1. A) Erythema, swelling and discoloration of hands and feet on initial examination. Trophic changes seen on toes and lower legs. B) Improvement in edema and redness on follow up. Some trophic changes persisting. (Note: different hue of discoloration partly related to changed lighting and camera). Figure 1.2. Nerve conduction study: Initial study at 5 months after symptom onset and Follow up study one year after treatment. Sensory responses for median (A) and ulnar (B) absent initially were recordable on follow up. Extremely prolonged distal motor latencies, marked slow conduction and severely reduced compound muscle action potential (CMAP) amplitude for median (C), ulnar (D) and Peroneal (E) nerves initially, and normal CMAP amplitude, improved conduction velocity and latencies on follow up. Initial median motor study (C) also shows probable conduction block with recovery on follow up.
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Table 1. Summary of serial muscle motor examination (MRC scale) at initial visit and follow up Muscle Deltoid Biceps Triceps Wrist extensors Grip First dorsal interosseous Abductor pollicis brevis Iliopsoas Quadriceps Hamstring Tibialis anterior Gastrocnemius Extensor hallucis longus
Initial 4 4+ 5 4 2 2 2 444 1 1 0
6 weeks 4+ 5 5 4 4 4 4 4 4 4 3 4 0
1 year 5 5 5 5 5 4 4 5 5 5 4 4 3
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Table 2 Summary of nerve conduction study: A) Initial, and B) Follow up at 1 year after treatment. Study
A
Nerve
Median W
SNC
SNAP
DML
MNC
CMAP
F Wave
m/s
uV
ms
m/s
mV
ms
NR
NR
41.4 (<4.2)
E Ulnar
W
71.6 NR
NR
E Peroneal BFH*
Median W
NA
NA
W
35.6 (<3.6)
37.4 (>48)
9.9 (>15)
4.9 (>10)
9.3 (>42)
3.95 (<3.6)
8.0 (>5)
11.6
28.6 (>48)
7.8
AE
14.5
34.5
6.5
Knee
NA
NA
5.35 (<6.6) 9.10
4.0 (>4) 26.7 (>42)
37.5 (<32)
5.9
BE
Peroneal BFH*
ND
0.1 6.7 (>5)
32.6 (>48)
NR
-0.2 (>4)
5.30 (<4.2) 12.3
29.8 (>48)
--
NR
0.2 0.4 (>5)
28.6 (<6.6) 37.2
E Ulnar
8.4 (>48)
NR
Knee B
0.9 (>5)
40.7 (<32)
ND
4.0
BE: below elbow; BFH: below fibular head; CMAP: compound muscle action potential, DML: distal motor latency; E: elbow; MNC: motor nerve conduction, NA: not applicable; ND: not done; NR: no response; SNAP: sensory nerve action potential; SNC: sensory nerve conduction; W: wrist; * Recording site Tibialis Anterior; (Normal values)
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