Recurrent miller fisher: a new case report and a literature review

e208 F. Barbato et al. Review Clin Ter 2017; 168 (3):e208-213. doi: 10.7417/T.2017.2008 Recurrent miller fisher: a new case report and a literature review F. Barbato 1, A. Di Paolantonio 1, M. Distefano 1, A. Mastrorosa 1, M. Sabatelli 1, S. Servidei 1*, M. Luigetti 1,2* 1 Institute of Neurology, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of Sacred Heart, Rome; 2 Fondazione Don Carlo Gnocchi, Milan, Italy These Authors contributed equally to this work. * These Authors shared senior Authorship. Abstract Miller Fisher syndrome (MFS) is considered to be an uncommon variant of Guillain-Barré Syndrome. The disease is clinically characterized by acute ataxia of limbs, areflexia and ophthalmoplegia, although the set of symptoms and signs can be quite heterogeneous, with a benign and monophasic course. We describe a case of recurrent MFS where there have been four clinical s occurred with complete remission after each relapse. Last recurrence was treated with oral steroids. The frequency of recurrent MFS in literature is variable as well as the best treatment in these cases. We add a new case treated with steroid and we perform a review of the literature. Clin Ter 2017; 168(3):e208-213. doi: 10.7417/CT.2017.2008 Key words: Recurrent, Miller-Fisher, autoimmune disease, anti- GQ1b antibodies Introduction In 1956 Fisher first described an unusual variant of acute idiopathic polyneuritis characterized by ophthalmoplegia, ataxia and areflexia. Additional signs and symptoms can accompany clinical condition such as sensory disturbances, bulbar palsy, limb weaknesses or even micturition disturbances (1). Most tested patients have a positivity to anti-gq1b antibodies, known since 1992 (2) are tested positive. Currently, treatment options are intravenous immunoglobulins () or plasmapheresis if therapy is indicated at all as many cases reveal a self-limiting course. However, randomized trials do not exist (3). Recurrences of MFS are extremely rare (1). We here describe a case of recurrent MSF with four clinical s in a sixteen years period and we provide a literature review. history In 1998 a 37-year-old healthy woman developed, after four days of flu-like syndrome, diplopia, paresthesias and gait instability. She presented ataxic gait, diffuse areflexia and external left ophthalmoplegia. Brain MRI, neurophysiological evaluation, including electromyography (EMG), nerve conduction studies (NCS) and low-rate repetitive nerve stimulation (LR-RNS), and orbits ultrasound proved normal. She was dismissed from the hospital with anxiety disorder, and she started therapy with Bromazepam 1 mg twice a day. In six months all symptoms remitted. In 2004 she newly experienced diplopia, left ptosis and gait instability. Considering previous diagnosis, she refused new neurological evaluations. Symptoms lasted 4 months and progressively improved. In 2010, six years later, the patient newly developed diplopia, ataxia and lower limb weakness, so she was admitted in hospital. Contrast-enhanced brain and spine MRI study was negative. A new neurophysiological evaluation proved normal, as well as serum dosage of AchR and Anti-MusK antibodies. Based on the hypothesis of an inflammatory origin of the symptomatology, the patient began therapy with prednisone 25 mg/day orally and B group vitamins i.m. with complete clinical remission after two months. The last, presenting with diplopia and generalized weakness, occurred on December 2014, two weeks after flu-like. Neurological examination showed bilateral external ophthalmoplegia, right peripheral facial palsy, dysarthria, rhinolalia, dysmetria, ataxic gait, worsened by eyes closure, and generalized areflexia with dysesthesias in four limbs. Admitted to our Neurology Department, considering clinical findings Miller-Fisher syndrome was diagnosed. Cerebro-spinal fluid (CSF) examination showed normal glucose and protein concentration, no malignant cells isolation, absence of Ig for common viruses and bacteria, including HIV-1 and HIV-2, and liquor IgG/albumin index of 34.1%. Neurophysiological examination further proved normal (Table 1). Serum anti-gq1b antibodies were negative. Patient received therapy with IVIg (2g/Kg). Considering previous clinical s, she also started chronic therapy with prednisone (50mg/die). After three weeks there was complete clinical remission. Neurophysiological follow-up showed mild reduction of sensory nerve action potentials (SNAPs) amplitude from lower limbs nerves and mild increase of mean F wave latency from upper and lower Correspondence: Dr. Francesco Barbato, Institute of Neurology, Largo F. Vito 1, 00168 Roma. Tel.: +39-06-30154435; Fax No.: +39-06-35501909. E-mail: francescobarbato.88@hotmail.it Copyright Società Editrice Universo (SEU) ISSN 1972-6007

Recurrent miller fisher: a new case report and a literature e209 Table 1. Serial electrophysiological studies of the patient. Nerve MCV First evaluation (admission) dl CMAP (mv) Second evaluation (one month) MCV dl CMAP (mv) MCV Third evaluation (six months) dl CMAP (mv) R Median E-W 56 8.0 54 7.8 55 8.0 W-APB 3.6 8.4 3.5 8.0 3.7 8.2 R Tibialis LM-AH 2.8 13.2 3.1 15.6 3.7 17.2 L Tibialis LM-AH 3.0 11.6 3.5 13.8 3.9 14.6 F wave ml R Median 25.5 27.8 25.4 ml ml R Tibialis 46.1 52.2 45.9 L Tibialis 45.7 51.4 46.1 Nerve SCV SNAP (μv) R Sural A-SURA 68 20.0 43 7.1 56 14.5 L Sural A-SURA 66 20.4 41 8.4 58 16.1 SCV SNAP (μv) SCV SNAP (μv) R. Peroneal Lat. Leg -Ret 66 22 44 14.1 55 20.2 Legend: MCV, motor conduction velocity; dl, distal latency; CMAP, compound muscle action potential; ml, median latency; SCV, sensory conduction velocity; SNAP, sensory nerve action potential; E, elbow; W, wrist; APB, abductor pollicis brevis; LM, lateral malleolus; AH, abductor hallucis; Lat, lateral; Ret, retinaculum; Follow-up time of examination is given in brackets. limbs (Table 1). Steroids was gradually tapered down after six months. Further neurophysiological evaluation showed normal results (Table 1). After two years clinical evaluation is still unremarkable. Discussion In Europe the incidence of MSF is between 0.04 and 0.18/100000 persons per year (4). MFS is associated in more than 85% of cases to the presence of antibodies against GQ1b, a ganglioside that has been isolated in the paranodal regions of third, fourth and sixth cranial nerves in humans (4). The presence of GT-1 GD-2 and GD1-b antibodies are much less frequently. Autoantibodies, identified in about 95% of cases, would induce neuro-muscular blockade responsible of a significant part of symptomatology (2). s and plasmapheresis, acting against auto-antibodies and the following inflammatory response, permit a more rapid resolution of symptoms and better outcomes in MFS (3). These therapeutic options, with the addition of steroid therapy in a few cases, have been successfully tested in recurrent MFS too (6). Recent data show that recurrent MFS is higher than expected (7). Anti-GQ1b in relapsing MFS are present in about 80% of patients, less commonly other antibodies (1). Nerve conduction studies demonstrated in most of relapses no specific alterations, probably because they were made early in the disease course (8). Indeed in our case considering normal laboratory findings and only mild alteration on neurophysiological follow-up examination, diagnosis was mainly made considering clinical findings (9). Up to now 34 cases of recurrent MFS were described (Table 2). Anti-GQ1b antibodies were found in 48% of cases; more than two relapses occurred in 19% of patients; 10 recurrent cases were treated with steroid with a good response in 88% of them (Table 2). IVIg or plasma exchange are used to treat MFS, and were successfully tested in recurrent MFS too (1, 6). Steroid use is limited, but single reports suggest an efficacy in recurrent cases (9, 10). In these, an overlap with CIDP with acute onset and relapsing-remitting course cannot be excluded (11). Further studies are necessary to confirm this hypothesis.

e210 F. Barbato et al. Supplementary table. Literature review of patients with recurrent Miller-Fisher syndrome. Case Burbaud et al. Recurrence of a Miller Fisher s syndrome. Rev Med Interne 1991;12:215-218 Gender of first Number of s Latency (years) of last Anti-GQ1b CSF Treatment Outcome M 56 2 9 65 Tested Negative Plasma (1 ) Grand Maison et al. Recurrent Guillain-Barre syndrome. and laboratory features. Brain. 1992;115:1093-1106 (first case) F 31 3 27-1 59 Tested Grand Maison et al. Recurrent Guillain-Barre syndrome. and laboratory features. Brain. 992;115:1093-1106. M 44 2 7 51 Tested (1 ) Plasma Grand Maison et al. Recurrent Guillain-Barre syndrome. and laboratory features. Brain. 1992;115:1093-1106 (third case) M 27 2 27 54 Tested Negative Plasma Dewarrat et al. Recurrent Miller Fisher syndrome: about signification of anti-gq1b antibodies. Schweizer Arch Neurol Psychiatr 1995;146:180-184 M 33 3 2-20 55 Positive (1 and 2 ) Specific Heckmann et al. Recurrent and laboratory features. Eur J Neurol. 2012;19:944-54. M 24 2 35 59 Positive Negative Heckmann et al. Recurrent and laboratory features. Eur J Neurol. 2012;19:944-54. F 19 2 44 63 Positive Negative (2 ) Battaglia F, Attane F, Robinson A, Martini L, Siboni J, Tannier C. Recurrent Miller Fisher syndrome. Rev Neurol (Paris) 2005;161:844-847. 2 19 C.R Tested Specific Kaplan JG et al. Relapsing ophthalmoparesis sensory neuropathy syndrome. Neurology 1985;35:595-596. (first case) F 42 3 4-1 47 Tested Tested Kaplan JG et al. Relapsing ophthalmoparesis sensory neuropathy syndrome. Neurology 1985;35:595-596. M 47 7 57 Tested Specific Schapira et al. A case of recurrent idiopathic ophthalmoplegic neuropathy (Miller Fisher syndrome). J Neurol Neurosurg Psychiatry 1986;49:463 464. M 33 2 1 34 Tested (1 and 2 ) Specific

Recurrent miller fisher: a new case report and a literature e211 Case Vincent FM et al. Relapsing Fisher s syndrome. J Neurol Neurosurg Psychiatry 1986;49:604-606. Sawyer CN et al. A case of recurrent Miller Fisher syndrome. Br J Hosp Med 1987;38:566. Vinals M et al. Recurrent Miller Fisher syndrome associated with brachial neuritis. Neurologia 1989;4:61-65. Kaiser-Smith B. Relapsing polyneuritis following classic Miller Fisher syndrome. J Neurol Neurosurg Psychiatry 1989;52:802-803. Gender of first Number of s Latency (years) of last Anti-GQ1b CSF Treatment Outcome F 52 2 6 58 Tested Negative Specific F 37 2 29 66 Tested Negative Specific M 18 2 6 24 Tested Specific F 21 2 8 weeks 21 Tested Partially Riche G, Caudie C, Vial C, Bourrat C. Recurrent Miller Fisher syndrome with anti-gq1b antibody. Rev Med Interne 1998;19:192-195. M 35 3 14-2 51 Positive Partially 1999;165:139-143. (first case) F 51 2 12 63 Positive 1999;165:139-143 M 28 2 2 30 Tested 1999;165:139-143 (third case) F 25 2 10 35 Tested Reported 1999;165:139-143 (fourth case) M 14 2 9 23 Positive Sitajayalakshmi S et al. Recurrent Miller Fisher syndrome: a case report. Neurol India 2002;50:365-367 Hamaguchi T. et al. Recurrent anti-gq1b Ig G antibody syndrome showing different phenotypes in different periods. J Neurol Neurosurg Psychiatry 2003; 74: 1348. M 35 2 4 39 Tested F 30 2 7 37 Tested Negative Specific Chan JW. Optic neuritis in anti- GQ1b positive recurrent Miller Fisher syndrome. Br J Ophthalmol 2003;87:1185-1186. F 23 2 6 months 23 Positive Plasma

e212 F. Barbato et al. Case Madhavan S. et al. Recurrent Miller Fisher syndrome. J Assoc Physicians India. 2004;52:582-584. Orr CF. et al. Recurrent Miller Fisher syndrome. J Clin Neurosci 2004;11:307-309. Gender of first Number of s Latency (years) of last Anti-GQ1b CSF Treatment Outcome M 31 2 2 33 Positive M 57 3 6-6 69 Positive Negative (1 and 2 ) Plasma (1 ) (2 and 3 ) Battaglia F. et al. Recurrent Miller Fisher syndrome. Rev Neurol (Paris) 2005;161:844-847. F 35 2 19 54 Positive (2 ) Negative Dorr J. et al. A case of recurrent Miller Fisher syndrome mimicking botulism. Neurol Sci 2006;27:424-425 Tomcik J. et al. Recurrent Miller Fisher syndrome with abnormal terminal axon dysfunction: a case report. Acta Neurol Belg 2007;107:112-114 M 19 2 22 41 Positive (2 ) M 16 2 14 30 Positive Negative and Pleyocitosis Plasma Toru S. et al. Successful steroid treatment for recurrent miller fisher syndrome. Muscle Nerve. 2012;45:763-764. F 22 2 32 54 Positive (2 ) Sci. 2016;364:59-64.(first case) F 21 2 10 31 Positive and Pleyocitosis (1 ) Specific Sci. 2016;364:59-64. (second case) F Positive Sci. 2016;364:59-64. (third case) M Positive Sci. 2016;364:59-64. (fourth case) Barbato et al. Recurrent miller fisher: a new case report and a literature review. M Positive M 37 4 6-6-4 53 Negative Negative Specific (1 and 2 ) (3 ) I.G (4 ) Abbrevations = Immunoglobuline e.v treatment

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