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Acute Small Fiber Neuropathy Following Mycoplasma Infection: A Rare Variant of Guillain–Barre´ Syndrome Rohitha Makonahalli, FRACP,* Janaka Seneviratne, FRACP,* and Udaya Seneviratne, FRACP*†

Abstract Guillain–Barré syndrome (GBS) is a well-described condition involving the peripheral nervous system. The most well-known form of this disease is acute inflammatory demyelinating polyradiculoneuropathy. Among the different variants of GBS described in the literature, the sensory variant is scantily recognized. There has been a recent attempt to classify the sensory variants of the GBS and bring more objectivity to this diagnostic paradigm. We report a rare sensory variant of GBS presenting with isolated small nerve fiber involvement peripherally in the limbs and associated facial nerve palsy in a patient who had clinical and serological evidence of a preceding Mycoplasma pneumoniae infection. The symptoms resolved gradually with intravenous immunoglobulin therapy. This case adds to the growing literature of the rare form of acute small fiber neuropathy and GBS variants. Key Words: small fiber neuropathy, Guillain–Barré syndrome, mycoplasma infection, dysautonomia

( J Clin Neuromusc Dis 2014;15:147–151)

INTRODUCTION Since the original description of classic Guillain–Barré syndrome (GBS) by Guillain, Barré, and Strohl in 1916, several variants of this condition have been identified.1 Acute inflammatory demyelinating polyradiculoneuropathy is the commonest type. Ropper2 was the first to highlight groups of patients presenting with unusual clinical variants of GBS. Since then there have been other reports of similar presentations.3–5 Other variants include acute motor axonal neuropathy, acute motor sensory axonal neuropathy, Miller Fisher syndrome, pure dysautonomia

and sensory GBS.6,7 Acute small fiber neuropathy as a variant of GBS was reported more recently.8 Here we present the case of a young woman who presented with this rare disorder following an upper respiratory tract infection caused by Mycoplasma pneumoniae.

CASE REPORT A 33-year-old woman with no known medical problems presented with a history of dysesthesia in the form of burning sensation distally in all 4 limbs. This was associated with moderate postural lightheadedness. These symptoms had been progressive for 1 week. Three days from the onset of the sensory symptoms she noticed difficulty in closing her right eye and drooling of saliva from the right corner of her mouth. This whole symptom complex was preceded by an upper respiratory tract infection 2 weeks before, which was managed with a course of roxithromycin in the community. Severe discomfort because of burning sensation prompted her admission to the hospital. At the time of presentation, her upper respiratory symptoms had completely subsided, with no evidence of middle ear pathology. Neurologic examination confirmed right-sided lower motor neuron–type facial palsy and the rest of the cranial nerves were normal. Motor examination and cerebellar functions were completely normal. Sensory examination in the upper and lower limbs revealed diminished pinprick sensation in the glove and stocking distribution with

From the *Department of Neuroscience, Monash Medical Centre, Clayton, Victoria, Australia; and †Monash University, Melbourne, Victoria, Australia. The authors report no conflicts of interest. Reprints: Udaya Seneviratne, FRACP, Department of Neuroscience, Monash Medical Centre, Clayton Road, Clayton, Victoria 3168, Australia (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins

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preserved proprioception and vibration. Deep tendon reflexes were brisk but symmetrical in the extremities with down going plantars and normal gait. In addition, she had postural lightheadedness and was clinically confirmed to have postural systolic blood pressure drop. However, she had no other symptoms of dysautonomia, such as dry eyes, dry mouth, bladder or bowel dysfunction, nausea, and constipation. Blood tests, including serum biochemistry, vitamin B12, folate level, thyroid functions, C-reactive protein, antinuclear antibody, extractable nuclear antigen antibody panel, antineutrophil cytoplasmic antibodies, rheumatoid factor, and complement activity were normal. Mycoplasma IgM antibody titer was elevated consistent with a recent infection. Magnetic resonance imaging of the brain and spine were normal. Computerized tomography of the temporal bones did not show any evidence of mastoiditis or otitis media. The chest radiograph was unremarkable. The cerebrospinal fluid (CSF) analysis confirmed albumino-cytological dissociation with elevated protein of 0.76 g/L (reference range: 0.1–0.3 g/L) and no cells. Anti-ganglioside antibody titers were not tested. Nerve conduction and electromyographic studies were performed during the initial presentation and 2 months later. Motor nerve conduction studies included median, ulnar, tibial, peroneal and facial nerves. Blink reflex was not performed. Sensory studies involved median, ulnar, radial, medial plantar, lateral plantar, superficial peroneal, and sural nerves. Both studies did not reveal any electrophysiological evidence of demyelination, axonopathy, or denervation. Autonomic test battery included quantitative sudomotor axon reflex test, Valsalva maneuver, and 70-degree head-up tilt test. Quantitative sudomotor axon reflex test revealed normal sweat volumes but persistent sweat response in the leg proximally and distally (Fig. 1). The Valsalva maneuver evoked an excessive 40–50 mm Hg fall in mean blood pressure and collapse of pulse © 2014 Lippincott Williams & Wilkins

pressure in early phase II. The late phase II response and phase IV overshoot were absent (Fig. 2). The heart rate response revealed a normal Valsalva ratio of 1.79 (normal .1.5). Head-up tilt evoked oscillations in the blood pressure and heart rate traces with a mild drop in systolic blood pressure (13 mm Hg) as shown in Table 1. Overall, the autonomic tests were indicative of limited involvement of sympathetic vasomotor and possibly sudomotor fibers. Sural nerve biopsy was analyzed with paraffin-embedded sections, semi-thin plastic sections, electron microscopy, and teased fiber preparation. It was unremarkable with no evidence of significant demyelination, axonal loss, amyloidosis, vasculitis, or any other pathology. The patient was treated during the acute phase with a 5-day course of intravenous immunoglobulins (0.4 g/kg body weight per day 3 5 days). She improved following therapy, and almost total resolution of the sensory symptoms and complete resolution of facial palsy were noted on review 2 months later. The postural symptoms resulting from orthostatic intolerance were managed with a small dose of fludrocortisone to which she had a good response. When reviewed 6 months later, all symptoms had completely resolved, and fludrocortisone was successfully ceased.

DISCUSSION This case represents an acute presentation of sensory and autonomic symptoms suggestive of small fiber neuropathy, following an infection with M. pneumoniae. Normal routine nerve conduction studies of the extremities indicate absence of large nerve fiber involvement, which is supported by sural nerve biopsy findings, whereas abnormal autonomic tests are consistent with small nerve fiber dysfunction in the autonomic nervous system. The clinical presentation along with CSF findings would be consistent with features of GBS. Hence, it is reasonable to consider this a variant of GBS.

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FIGURE 1. Quantitative sudomotor axon reflex test showing persistent sweat response in the left leg proximally and distally.

A rare variant of acute, isolated, small fiber neuropathy with albumino-cytological dissociation was first reported in 2002. The researchers described a series of 6 patients and postulated the entity of “acute small fiber sensory variant of GBS.”8 Subsequent reports indicate that this entity does exist although rare.9–11 Recently, an attempt has been made to classify the sensory variants of GBS.12 The authors have proposed 3 types: acute sensory demyelinating neuropathy,

acute large fiber axonopathy and ganglionopathy, and acute small fiber neuropathy and ganglionopathy. Our patient would be classified as acute small fiber neuropathy and ganglionopathy according to the proposal of Uncini and Yuki.12 In this case, we report improvement following intravenous immunoglobulin therapy. However, this does not necessarily prove a therapeutic response as spontaneous improvement has been reported previously.8

FIGURE 2. Valsalva maneuver test showing excessive blood pressure drop in early phase II. Note: late phase II response and phase IV overshoot are absent. DBP, diastolic blood pressure; HR, heart rate; I, phase I; II(E), early phase II; II(L), late phase II; III, phase III; IV, phase IV; MBP, mean blood pressure; SBP, systolic blood pressure. www.jcnmd.com

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TABLE 1. Cardiovascular Response to 70-Degree Head-up Tilt for 10 Minutes Time (Min)

Systolic Blood Pressure (mm Hg)

Diastolic Blood Pressure (mm Hg)

Heart Rate (Beats Per Minute)

Baseline 1 5 10 1 (post-tilt) 3 (post-tilt)

118 105 120 118 110 122

78 72 78 84 70 80

57 84 81 83 58 62

Acute autonomic instability is a wellrecognized association with the common form of GBS, and isolated acute dysautonomia is considered a variant of GBS.6 As our patient clinically had features of small fiber dysfunction and orthostatic symptoms, we proceeded with autonomic tests, which indicated the involvement of sympathetic nervous system favoring our clinical diagnosis of small fiber neuropathy. Most patients with GBS are noted to have a preceding infection 1–2 weeks before the onset of neurologic symptoms. Gangliosides of the neuronal cell surface membrane have emerged as the potential target antigen in the pathogenesis, with an autoantibodymediated immunologic attack on the peripheral nervous system, resulting in demyelination or axonal loss.13 Mycoplasma infection is claimed to precede 5%–15% of GBS in various case series.14,15 Molecular mimicry between Mycoplasma and a major myelin glycolipid, Gal-C, has been reported.16 There are case reports of GBS with preceding Mycoplasma infection that have been noted to produce anti-GM1b IgG.17 Our patient had elevated IgM antibodies, suggesting a recent Mycoplasma infection, although we did not proceed with convalescent titers. Small fiber neuropathy is a distinct entity characterized by neuropathic pain, dysesthesia, loss of pain and temperature sensation, autonomic dysfunction, or a combination.18 Tendon reflexes, proprioception, and muscle power are classically spared. The routine nerve conduction studies yield normal findings as those evaluate only large © 2014 Lippincott Williams & Wilkins

myelinated nerve fibers. Common etiologies of small fiber neuropathy include diabetes mellitus, impaired glucose tolerance, Sjogren syndrome, alcohol, drugs, amyloidosis, and inherited conditions, such as Fabry disease and cancer (as a paraneoplastic manifestation).18,19 It is of interest to note that in a series of 150 cases with small fiber neuropathy, the etiology was found to be GBS in 2 patients.19 To our knowledge, acute small fiber neuropathy following Mycoplasma infection has not been reported before. Elevated CSF protein in GBS, as in our case, is considered to be because of a breakdown of the blood–CSF barrier.20 Whether this patient had subclinical and subtle proximal demyelination of peripheral nerves is debatable. She had normal facial nerve motor conduction studies, and in the context of definite right facial muscle weakness, proximal demyelination is a possibility. There are some drawbacks in the workup of our case. Anti-ganglioside antibody testing was not performed, which would have been useful in supporting the immunologic basis in the pathogenesis, although the test is positive in only small percentage of patients. Skin biopsy for morphometric analysis of dermal and epidermal nerves was not performed to confirm small nerve fiber involvement. Nicotinic ganglionic acetylcholine receptor autoantibody associated with autoimmune dysautonomia was not tested. Overall, this case demonstrates that patients presenting with predominantly acute onset paresthesia or dysesthesia, with no other motor manifestations or large fiber

Acute Small Fiber Neuropathy

sensory features like sensory ataxia, could be having a GBS variant with predominant affection of the small nerve fibers and associated autonomic nervous system involvement. In conclusion, this case highlights the fact that GBS may predominantly affect small nerve fibers in rare cases, clinically presenting in an atypical manner in comparison with the typical GBS and other well-established variants. Probably, this subset has a distinct, as yet undiscovered, autoantibody involved in the pathogenesis that needs further studies. Anti-ganglioside antibody testing and skin biopsy for morphometric analysis of dermal and epidermal nerve fibers are recommended in similar cases, in addition to routine investigations performed in GBS. Finally, we wish to emphasize the importance of prompt diagnosis and appropriate treatment of rare variants of GBS to ensure optimum recovery. REFERENCES 1. Seneviratne U. Guillain–Barré syndrome. Postgrad Med J. 2000;76:774–782. 2. Ropper AH. Unusual clinical variants and signs in Guillain–Barré syndrome. Arch Neurol. 1986;43: 1150–1152. 3. Hozumi A, Yuki N, Yamazaki K, et al. Facial diplegia with paraesthesias: facial nerve enhancement in three dimensional MRI. J Neurol Neurosurg Psychiatry. 1999;66:688. 4. Ropper AH. Further regional variants of acute immune polyneuropathy. Bifacial weakness or sixth nerve paresis with paresthesias, lumbar polyradiculopathy, and ataxia with pharyngeal-cervical-brachial weakness. Arch Neurol. 1994;51:671–675. 5. Susuki K, Atsumi M, Koga M, et al. Acute facial diplegia and hyperreflexia: a Guillain–Barré syndrome variant. Neurology. 2004;62:825–827. 6. Cortelli P, Contin M, Lugaresi A, et al. Severe dysautonomic onset of Guillain–Barré syndrome with good recovery. A clinical and autonomic follow-up study. Ital J Neurol Sci. 1990;11:159–162.

7. Dawson DM, Samuels MA, Morris J. Sensory form of acute polyneuritis. Neurology. 1988;38:1728–1731. 8. Seneviratne U, Gunasekera S. Acute small fibre sensory neuropathy: another variant of Guillain–Barré syndrome? J Neurol Neurosurg Psychiatry. 2002; 72:540–542. 9. Dabby R, Gilad R, Sadeh M, et al. Acute steroid responsive small-fiber sensory neuropathy: a new entity? J Peripher Nerv Syst. 2006;11:47–52. 10. Miyazaki Y, Koike H, Ito M, et al. Acute superficial sensory neuropathy with generalized anhidrosis, anosmia, and ageusia. Muscle Nerve. 2011;43:286– 288. 11. Souayah N, Ajroud-Driss S, Sander HW, et al. Small fiber neuropathy following vaccination for rabies, varicella or Lyme disease. Vaccine. 2009;27:7322– 7325. 12. Uncini A, Yuki N. Sensory Guillain–Barré syndrome and related disorders: an attempt at systematization. Muscle Nerve. 2012;45:464–470. 13. Schwerer B. Antibodies against gangliosides: a link between preceding infection and immunopathogenesis of Guillain–Barré syndrome. Microbes Infect. 2002;4:373–384. 14. Jacobs BC, Rothbarth PH, van der Meche FG, et al. The spectrum of antecedent infections in Guillain– Barré syndrome: a case-control study. Neurology. 1998;51:1110–1115. 15. Sinha S, Prasad KN, Jain D, et al. Preceding infections and anti-ganglioside antibodies in patients with Guillain–Barré syndrome: a single centre prospective case-control study. Clin Microbiol Infect. 2007;13: 334–337. 16. Kusunoki S, Shiina M, Kanazawa I. Anti-Gal-C antibodies in GBS subsequent to mycoplasma infection: evidence of molecular mimicry. Neurology. 2001;57: 736–738. 17. Kitazawa K, Tagawa Y, Honda A, et al. Guillain–Barré syndrome associated with IgG anti-GM1b antibody subsequent to Mycoplasma pneumoniae infection. J Neurol Sci. 1998;156:99–101. 18. Al-Shekhlee A, Chelimsky TC, Preston DC. Review: small-fiber neuropathy. Neurologist. 2002;8:237– 253. 19. Devigili G, Tugnoli V, Penza P, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain. 2008;131:1912–1925. 20. Schliep G, Felgenhauer K. Serum-CSF protein gradients, the blood-GSF barrier and the local immune response. J Neurol. 1978;218:77–96.

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Acute small fiber neuropathy following Mycoplasma infection: a rare variant of Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is a well-described condition involving the peripheral nervous system. The most well-known form of this disease is acute...
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