RESIDENT & FELLOW SECTION Clinical Reasoning:

Section Editor Burning hands and feet Mitchell S.V. Elkind, MD, MS

Amanda C. Chan, MRCP SECTION 1 Medical Research Council 5/5 proximally and Einar Wilder-Smith, MD A 25-year-old banker, a nonsmoker and non- 4/5 distally, limited by pain. Reflexes were just drinker, presented with pain in the hands and feet elicitable (11); anal tone was intact. Cerebellar for 4 weeks that progressed to involve shoulders signs were absent. Gait was slow from bilateral sole Correspondence to and hips. Pain was associated with constipation, pain. No joint deformities or skin abnormalities Dr. Wilder-Smith: followed by diarrhea. He had no prior trauma, vac- [email protected] wereseen.Heoftenadoptedaposturewithboth cinations, or infectious symptoms. Medical history arms abducted and fingers extended, which allevi- was noncontributory; he was on no medication. ated pain. Sensory testing revealed hyperalgesia He had consulted numerous doctors for the pain, and brush allodynia over the hands and feet. who noted transient urinary hesitancy, tachycar- Temperature, vibration, and proprioception were dia, and hypertension that required short duration preserved. treatment with antihypertensives. All symptoms Questions for consideration: except the pain resolved spontaneously. On exam- ination, he was afebrile, alert, and oriented. Cra- 1. What differential diagnoses would you consider? nial nerves were intact; there was no ptosis, 2. What investigations would you perform to con- diplopia, or facial plegia. Four-limb power was firm the diagnosis?

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From National University Hospital, Singapore. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. e146 © 2015 American Academy of Neurology ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. SECTION 2 nociceptive small sensory fibers, sparing large sensory Hyporeflexia and glove stocking sensory disturbance fibers. strongly suggest a length-dependent polyneuropathy. Question for consideration: Allodynia and pain in the distal extremities in the absence of vibration, proprioception, and touch 1. What preliminary investigations would you involvement point toward involvement of the consider?

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Neurology 84 May 12, 2015 e147 ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. SECTION 3 common, chest X-ray is performed to look for hilar The most apparent abnormality in the blood tests was adenopathy or parenchymal changes consistent with hyponatremia. The syndrome of inappropriate antidi- pulmonary sarcoidosis, and serum angiotensin con- uretic hormone (SIADH) is diagnosed when urine verting enzyme levels checked. Chronic drinkers are osmolality and sodium are high in the presence of prone to developing thiamine deficiency, which may low serum osmolality and hyponatremia. In view of present as a small fiber neuropathy, necessitating the subacute onset of dysesthesia and pain, hypore- serum vitamin B1 level assessment. For patients of flexia, and SIADH, a sensory variant of Guillain- ethnicities where celiac disease is common (North Barré syndrome (GBS) should be considered. European and Australasian populations), antigliadin Workup for other causes of subacute polyneurop- antibodies should be worked up.

athy included normal values for vitamin B12, fasting Chest X-ray and CT of the thorax, abdomen, and glucose, and thyroid function, making nutritional pelvis were performed to exclude occult malignancies and metabolic disorders improbable. Normal eryth- as a cause of paraneoplastic neuropathy, which all had rocyte sedimentation rate (ESR), normal C-reactive normal results. Small-cell lung cancer is the common- protein, and absence of specific autoantibodies render est malignancy that can lead to sensory neuropathy, autoimmune causes from systemic lupus erythemato- mainly of the large fiber type. Other associated neo- sus or Sjögren syndrome unlikely. Thorough history plasias are multiple myeloma, monoclonal gammopa- and a normal toxicology screen excluded neurotoxins thies, and lymphomas. Normal ESR, lactate such as metronidazole and solvents, which can cause dehydrogenase, and hematologic profile exclude small fiber neuropathy. Infectious causes from HIV these. and hepatitis B and C were excluded with negative Contrasted MRI spine, brain, and brainstem to serum antibodies and negative hepatitis B surface look for inflammatory and demyelinating lesions antigen. Additionally, in parts of the world where had normal results. Enlarged nerve roots, such as Lyme disease is endemic, serologic testing for Borrelia can occur in chronic sensory ganglionopathies, were burgdorferi, an infectious cause of peripheral neurop- absent. athy, should be performed. A small proportion of Question for consideration: sarcoidosis patients have associated peripheral neuropathy, and in populations where sarcoidosis is 1. What further investigations would you consider?

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e148 Neurology 84 May 12, 2015 ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. SECTION 4 Antiganglioside antibodies (anti-GM1, anti-GQ1b, To define the type of polyneuropathy, nerve conduc- anti-GD1a, anti-GD1b, and anti-GT1a) were nega- tion studies (NCS) of all 4 limbs were ordered and tive, but the sensitivity and specificity of autoantibod- had normal results. ies in small fiber GBS is unknown. In the first days of Lumbar puncture showed normal opening pressure GBS, NCS may be normal. Initial changes include with a CSF leukocyte count of 5/mL, erythrocyte delayed, absent, or impersistent F and H reflexes, a count of 789/mL, glucose 3.3 mmol/L (reference range result of proximal nerve root demyelination. In the first [RR] 2.2–3.9 mmol/L), and protein of 2.3 g/L (RR to second week, sural sparing occurs with the demye- 0.1–0.4 g/L). Gram stain and cytology were normal, linating form. With subsequent segmental demyelina- further excluding infections. Despite a traumatic tap, tion, motor studies show prolonged distal latencies, the patient’s CSF studies showed albuminocytologic conduction block, and temporal dispersion.1 Half of dissociation, which often occurs in inflammatory the patients will have changes by 2 weeks, and most by neuropathies, malignancies, or leptomeningeal metas- 3 weeks. Our patient presented 4 weeks after the onset tases. The latter 2 are unlikely in view of normal imag- of symptoms, a time by which changes in NCS should ing and CSF cytology. be detectable. Repeated NCS throughout the illness Subacute glove and stocking sensory impairment had normal results. A limitation of NCS is that it can- with allodynia, hyporeflexia, and autonomic involve- not detect damage to small nerve fibers, which were ment in combination with normal NCS findings is predominantly affected in this patient. strongly suggestive of a small fiber neuropathy. The Question for consideration: presence of SIADH and albuminocytologic dissocia- tion makes GBS the likely cause. SIADH and albumi- 1. What further investigations can be done to help nocytologic dissociation occur in 50% and 80% of all confirm the diagnosis of small fiber/autonomic patients with GBS, respectively. involvement?

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Neurology 84 May 12, 2015 e149 ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. SECTION 5 Although unstable blood pressure and heart rate Skin biopsy was performed and stained for protein and enteric symptoms had resolved prior to admis- gene product 9.5, which showed absence of intraepi- sion, we attempted to further investigate for limb dermal nerve fibers, consistent with a small fiber sympathetic involvement. Stimulated skin wrinkling neuropathy. test with EMLA had normal results.

Figure Workup for the etiologic identification of small fiber neuropathy

ab 5 antibodies; ACEI 5 angiotensin-converting enzyme inhibitor; ANA 5 antinuclear antibodies; ANCA 5 antineutrophil cytoplasmic antibodies; CXR 5 chest X-ray; CRP 5 C-reactive protein; DM 5 diabetes mellitus; ENA 5 extractable nuclear antigens; ESR 5 erythrocyte sedimentation rate; FG 5 fasting glucose; GGT 5 gamma glutamyl transpeptidase; HBC 5 hepatitis B core; HBV 5 hepatitis B virus; HCV 5 hepatitis C virus; IENFD 5 intraepidermal nerve fiber density; IFG 5 impaired fasting glucose; LDH 5 lactate dehydrogenase; MCV 5 mean corpuscular volume; PGP 5 protein gene product; RF 5 rheumatoid factor; SLE 5 systemic lupus erythematosus; SPE 5 serum protein electrophoresis; TFT 5 thyroid function tests; UPE 5 urine protein electrophoresis. e150 Neurology 84 May 12, 2015 ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. The patient was treated with IV immunoglobulin Most diagnostic criteria for GBS emphasize the (IVIg) 2 G/kg over 5 days and symptomatically with motor nerves and criteria for sensory GBS are less gabapentin. At follow-up 6 weeks later, symptoms, as readily established.7 Small-fiber GBS, which is also assessed by the Visual Analogue Scale pain scale, had known as a form of sensory GBS,8 is a controversial improved by more than 80%. diagnosis, but needs consideration where weakness is minimal and nerve conduction tests are normal, DISCUSSION This case illustrates an approach to in the presence of monophasic signs and symptoms acute-onset small fiber neuropathy (figure). Small of small fiber involvement. fibers are unmyelinated C fibers, which are involved Saifudheen et al.9 found that 48% of patients with in thermal perception, nociception, and a number of GBS had associated SIADH, which was also found to autonomic and enteric functions. Hence in patients be a poor prognostic predictor. The pathogenesis of with small fiber neuropathies, in addition to SIADH in GBS has not been fully understood but presenting with burning dysesthesias or pain, which has been postulated to be due to osmotic resetting may be spontaneous or sensory induced, they may and enhanced renal tubular sensitivity to antidiuretic also present with autonomic and enteric features of hormone. constipation, diarrhea, urinary frequency, blood Treatment of small fiber GBS is the same as other pressure changes, and postural dizziness. forms of GBS, and includes immunomodulatory Multiple diagnostic tests are available to confirm therapy with IVIg or plasma exchange. Symptomatic the diagnosis of small fiber neuropathies. Skin treatment of neuropathic pain can be considered with biopsy with estimation of intraepidermal nerve GABA agonists, opioids, and nonsteroidal anti- fiber density is a commonly accepted gold standard inflammatory agents. in the diagnosis of small fiber neuropathies and has This case illustrates a patient with an acute small a high sensitivity (.80%).2 The skin wrinkling test fiber neuropathy and highlights the role of blood is simple with reasonable sensitivity (up to 80%).3 tests, neurophysiology, lumbar puncture, and skin However, it only tests the sympathetic portion of biopsy in its diagnosis. The most likely etiology is sen- small fiber neuropathy and in this case there were sory GBS. According to the proposed classification no clinical clues suggesting persistent sympathetic for sensory GBS, our patient has an acute sensory involvement. small fiber neuropathy-ganglionopathy.10 Other tests include quantitative sensory testing, which assesses psychophysical thresholds for cold AUTHOR CONTRIBUTIONS and warm sensations with a diagnostic efficiency of Amanda Chee Yun Chan: drafting/revising the manuscript, study con- around 50%. Sympathetic skin response is commonly cept or design, analysis or interpretation of data, accepts responsibility for conduct of research and final approval, acquisition of data, statisti- used to diagnose small fiber neuropathy but has vary- cal analysis. Einar P. Wilder-Smith: drafting/revising the manuscript, ing sensitivity and reproducibility due to complex study concept or design, analysis or interpretation of data, accepts central and peripheral pathways. Quantitative sudo- responsibility for conduct of research and final approval, study motor axon reflex test is an alternative diagnostic tool supervision. but test and pretest reliability have been found to be STUDY FUNDING 4 moderate. Finally, microneurography is an invasive No targeted funding reported. test, which by placing recording microelectrodes within nerve fascicles, enables multiple small fibers DISCLOSURE to be recorded simultaneously.5 A. Chan received a travel grant from Novartis Pharmaceuticals (Hong The diagnosis of the underlying cause of subacute Kong) to attend the World Congress of Neurology meeting. E. Wilder-Smith received a travel grant from GlaxoSmithKline French monophasic small fiber neuropathy depends on the to attend an American Epilepsy Society annual meeting, serves as an identification of likely underlying causes. When Associate Editor of Neurology Asia, and serves as a consultant to a diag- appropriate testing fails to identify the possible etiol- nostic laboratory that performs the investigations described in this article. ogies, an autoimmune cause similar to GBS can be Go to Neurology.org for full disclosures.

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e152 Neurology 84 May 12, 2015 ª 2015 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Clinical Reasoning: Burning hands and feet Amanda C. Chan and Einar Wilder-Smith Neurology 2015;84;e146-e152 DOI 10.1212/WNL.0000000000001559

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