Corral, ÍC

Cánovas, AA

Estévez-Fraga, C

Martínez-Castrillo, JC

Natera-Villalba, E

Ruiz-Gómez, F

Sanz, BZ

Sánchez-Herrera, FA

UCL Discovery

Title page: 1  2 Title: Simultaneous acute presentation of generalized chorea and subacute combined degeneration secondary to vitamin b12 deficiency. 3  4 Authors.  5 Elena Natera Villalba, MDa,1 6 Carlos Estévez-Fraga, MD a,b,*,1 7 Fernando Acebrón Sánchez-Herrera, MDa  8 Fabio Ruiz-Gómez, MDc 9 Beatriz Zarza Sanz, MD, PhDa 10 Araceli Alonso Cánovas, MD, PhDa 11 Juan Carlos Martínez-Castrillo, MD, PhDa,d 12 Íñigo Corral Corral, MD, PhDa,d 13  14 a. Neurology Department. Ramón y Cajal University Hospital. Madrid. Spain. 15 b. Department of Neurodegenerative Diseases. UCL Institute of Neurology. London. UK. 16 c. Haematology Department. Ramón y Cajal University Hospital. Madrid. Spain. 17 d. IRYCIS. Ramón y Cajal University Hospital. Madrid. Spain. 18  19 1 Contributed equally to this work. 20  21 *Corresponding author: Carlos Estevez-Fraga 22 Email: c.fraga@ucl.ac.uk 23 Phone number: +442076795290 24 Postal Address: 25 2nd Floor Russell Square House.  26 10-12 Russell Square.  27 UCL Institute of Neurology.   28 WC1B 5EH. 29 London. UK.  30  31 Financial disclosures: 32 Carlos Estevez-Fraga has received educational grants from Zambon. 33 Juan Carlos Martínez-Castrillo has received honoraria for speaking at meetings sponsored by AbbVie, Allergan, Boehringer, GSK, Krka, Merz, Ipsen, 34 Italfarmaco, Medtronic, TEVA, UCB, Zambon. 35  36 Funding sources:  This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. 37  38 Word count: 857 39  40 Video:  The subject included in the video gave signed consent to be videoed for publication. 41  42  43  44  45  46 Main text 47 Subacute combined degeneration (SCD) of the spinal cord is the typical neurological presentation of vitamin B12 deficiency. Acute onset of movement 48 disorders (MD) associated with vitamin B12 deficiency are rare with only five cases reported in the literature and none discarding SCD clinically or with spine 49 MRI [1-5]. 50 We report an exceptional presentation of vitamin B12 deficiency with acute onset of choreic movements and myelopathy, followed by striking improvement 51 after treatment with parenteral cyanocobalamin. 52 An independent, cognitively normal eighty-year-old woman presented to the emergency room with confusion, involuntary generalized hyperkinetic 53 movements [video 1] and unstable gait. According to relatives, disease onset was 24 hours before arrival to our centre. She had a past medical history of 54 hypertension treated with angiotensin receptor antagonists and mild dyslipidemia without medical treatment. 55 On examination, the patient was disoriented in space and time and presented generalized severe uncontrolled choreic movements affecting her four limbs 56 without facial or tongue involvement. The abnormal movements did not change with visual fixation. Additionally, marked generalized proprioceptive 57 hypoesthesia with sensory ataxia in the four limbs as well as wide-based gait ataxia with inability to walk unassisted were noted. Muscle strength was normal, 58 reflexes were abolished and Romberg´s sign was present. 59 Laboratory tests showed severe pancytopenia: hemoglobin 7,4 g/dL with mean corpuscular volume 115 fl, leucocyte count 2,06x10^3/µl, platelets 60 114x10^3/µl. Serum folate was normal but vitamin B12 level was below detectable reference range (under 83 pg/mL). Methylmalonic acid and homocysteine 61 levels were not requested. Peripheral blood smear showed hypersegmented neutrophils suggestive of megaloblastic anemia. Thyroid function was normal and 62 no other clinical or analytical markers of autoimmune diseases were found. Cerebrospinal fluid was normal. Syphilis, HIV serologies, and ANAs were 63 negative. An upper gastrointestinal endoscopy disclosed atrophic pangastritic and antibodies against gastric parietal cells were positive at 1/160 suggesting a 64 diagnosis of pernicious anemia. 65 Cervical magnetic resonance imaging (MRI) showed bilateral and symmetric T2 hyperintensities of posterior columns from C2 to C6-C7 highly suggestive of 66 SCD (Figure 1). Cranial MRI did not disclose any acute lesions and body CT scan was normal. 67  68 The patient was transfused with two units of red blood cells. Treatment with intramuscular cyanocobalamin was started with 1000 mcg daily during 10 days 69 followed by 1000 mcg weekly during 6 weeks, and monthly thereafter, alongside folic acid 5 mg once daily. Progressive clinical and haematological 70 improvement were noted since the seventh day of treatment. Upon discharge, fifteen days after admission, only mild distal choreic movements affecting her 71 upper limbs were present [video 2] being able to walk with one support. The patient was asymptomatic at five months’ follow-up. 72 Vitamin B12 deficiency can lead to the development of haematological, neurological and psychiatric symptoms; however, SCD with peripheral neuropathy 73 and spinal cord involvement is the classical neurological syndrome1. On the other hand, MD such as chorea, dystonia, parkinsonism, blepharospasm, 74 orthostatic tremor or myoclonus have rarely been reported [see table 1] [1-11]. 75 In our patient, the dramatic response to vitamin B12 replacement in the context of pernicious anemia, the presence of lesions typical for SCD and the 76 exclusion of other reasonable causes of acute chorea suggest vitamin B12’s causative role in MD appearance. 77 Since Paccheti C. [2] reported the first case of chorea in the context of vitamin B12 deficiency, another five cases have been described [1-5]. On top of that, 78 cerebellar ataxia [3] has also been reported related to vitamin B12 deficiency but never with acute onset or associating myelopathy. 79 Pathophysiology of chorea induced by vitamin B12 deficiency is not completely understood. Low levels of vitamin B12 can lead to neurotoxic elevated levels 80 of methylmalonic acid, methyl-tetra-hydrofolate (MTHF) and homocysteine [1]. In addition methylmalonic acid produces abnormal myelination contributing 81 to the emergence of MD in a way similar to what happens in inborn metabolic disorders such as methylmalonic academia [1]. On the other hand, MTHF 82 accumulation can produce neuronal damage similar to the one seen in patients with Huntington´s disease [1]. Finally, hyperhomocysteinemia has a neurotoxic 83 N-methyl-D-aspartate (NMDA) agonist action leading to an excitatory activity in thalamocortical pathway that also results in the development of MD [1, 3]. 84 In our patient, a sensorial deafferentation cannot be definitely ruled out as a possible contributor to the development of abnormal movements. In fact, the term 85 “pseudoathetosis” has been coined for the slow, writhing movements due to loss of proprioception, which might be acute [12]. However, despite absence of 86 craniofacial involvement, the lack of change in patient’s movements with eye open and eye closed manoeuvres as well as its velocity support the appearance 87 of real chorea as a primary phenomenon in vitamin B12 deficiency instead of its emergence as secondary to the SCD or exclusively due to the sensory deficit. 88 This case report illustrates the importance of taking into consideration vitamin B12 deficiency in the differential diagnosis of acute-onset chorea, especially 89 when other typical signs as vibratory and positional sensation impairment, anemia and macrocytosis are present. The striking reversibility of neurological 90 symptoms with replacement therapy supports a causative role for vitamin B12 deficiency in the genesis of the movement disorder in our patient and advocates 91 the need for early diagnosis and supplementation, which may be essential to avoid permanent sequelae. 92  93 Acknowledgment: None 94  95  96  97  98  99  100  101  102  103  104  105  106  107  108  109  110 Legends 111 Figure 1. Sagittal T2 cervical magnetic resonance imaging showing bilateral and symmetric hyperintensities of posterior columns from C2 to C6-C7. 112 Video 1. Severe generalized choreoathetoid movements with greater involvement of upper limbs on patient admission.  113 Video 2. Mild distal choreothetoid movements 14 days after initiation of replacement therapy. 114 Table 1 Case reports of movement disorders associated with vitamin B12 deficiency in adults. 115  116  117  118  119  120  121  122  123  124  125  126  127  128  129  130  131 References: 132 [1] A. De Souza, M.W Moloi, Involuntary movements due to vitamin B12 deficiency. Neurol Res. 36 (2014) 1121-8. 133  134 [2] C. Pacchetti, S. Cristina, G. Nappi, Reversible chorea and focal dystonia in vitamin V12 deficiency. N Engl J Med. 347 (2002) 295. 135  136 [3] C. Shyambabu, S. Sinha, A.B. Taly, J. Vijayan, J.M. Kovo, Serum vitamin B12 deficiency and hyperhomocystinemia: a reversible cause of acute chorea, 137 cerebelar ataxia in an adult with cerebral ischemia. J Neurol Sci. 273 (2008) 152-4. 138 [4] B. Edvardsson, S. Persson, Chorea associated with vitamin B12 deficiency. Eur J Neurol. 18 (2011) e138-9. 139 [5] F. Gascón-Giménez, F. Coret-Ferrer, Reversible subacute chorea caused by vitamin B12 deficiency. Neurología. 32 (2017) 342-3. 140 [6] Santos AF, Rodrigues M, Abreu P, Ferreira C. Reversible parkinsonism and cognitive deficits due to vitamin B12deficiency. Neurol Sci. 141 36(6) (2015) 1031–2.  142 [7] Sharrief AZ, Raffel J, Zee DS. Vitamin B 12 deficiency with bilateral globus pallidus abnormalities. Arch Neurol 69(6) (2012) 769–72. 143 [8] Edvardsson B, Persson S. Blepharospasm and vitamin B12 deficiency. Neurol India 58(2) (2010) 320.  144 [9] Kumar S. Vitamin B12 deficiency presenting with an acute reversible extrapyramidal syndrome. Neurol India 52(4):2004 507–9.  145 [10] Çelik M, Barkut IK, Öncel Ç, Forta H. Involuntary movements associated with vitamin B12 deficiency. Park Relat Disord. 10 (1) (2003) 55–146 7.  147 [11] Benito-León J, Porta-Etessam J. Shaky-leg syndrome and vitamin B12 deficiency. N Engl J Med. 30;342(13) (2000) 981.  148 [12] F.R. Sharp, T.A. Rando, S.A. Greenberg, L. Brown, S.M. Sagar, Pseudochoreoathetosis movements associated with loss of 149 proprioception. Arch Neurol. 51 (11) (1994) 1103–1109.  150   151  152  153  154  155  156 Table 1. Reports of movement disorders associated with vitamin B12 deficiency in adults Author and year  Age Gender B12 vitamin levels (reference range) Homocysteine levels (reference range) MMA acid levels (reference range) Folic acid levels (reference range) Haematological disturbances  Movement disorder Subacute combined degeneration* Treatments administered (apart from IM cyanocobalamin) Improvement time after vitamin B12 Others Natera E 2018 (present case) 70 F < 82 pg/mL  (180-914) N/A N/A 17,50 ng/mL (3,90-20) + Generalized chorea + Folic acid 2 weeks Propioceptive dysfunction, Romberg´s sign present Positive anti-parietal cells antibodies Atrophic gastritis Gascón-Giménez F 2017 47 M 148 pg/mL (200-900) N/A N/A N/A + Choreoatetoid movements N/A Immunoglobulins IV Tiapride 1 week Migraine, moderate enolism Santos AF 2015 71 M 83 pg/mL (> 250) N/A N/A N/A - Parkinsonism N/A Levodopa 9 months Chronic gastritis De Souza A 2013 31 M 195 pg/mL (211-911) 16,75 µmol/L  (9-14) N/A N/A - Generalized chorea N/A Folic acid Haloperidol 3 months Marfabiud habitus Sharieff AZ 2012 43 M 254 pg/mL (200-900) 89,1 µmol/L  (4-15,2) 36000 nmol/L (87-318) Normal (N/A) + Delayed saccades, Parkinsonism + - 1 week Globus pallidus hyperintensities. Cognitive, piramidal and proprioceptive sensory alterations Romberg´s sign present Edvardsson B 2011 62 M 104 pmol/L (150-650) 25 µmol/L  (<15) 24 nmol/L  (7-40) 0,54 µmol/L (<42) - Chorea N/A - 3 months Positive anti-intrinsic factor antibodies Edvardsson B 2010 51 M 16 pmol/L (150-650) 43 µmol/L  (<15) N/A 24 nmol/L  (7-40) + Blepharospasm N/A - 9 months Positive anti-intrinsic factor antibodies. Decreased vibratory sensation. Shyambabu C  2008 40 M 62,96 pg/mL (243-894) 50 µmol/L  (5-15) N/A N/A + Chorea and cerebelar ataxia N/A - 2 months Limb ataxia Hyperpigmentation Parietal acute infarct Kumar S 2004 55 M 5 pg/mL N/A N/A 98 ng/mL (normal) + Parkinsonism  N/A - 1 week Positive anti-intrinsic factor antibodies Atrophic gastritis Çelik M 2003 55 M < 30 pg/mL (reference range N/A) N/A N/A N/A + Myoclonus N/A - 1 week Cognitive disturbances Sensory-motor demyelinating polyneuropathy Pacchetti C 2002 71 M 124 pg/mL (243-894) 40,1 µmol/L  (<15) N/A Normal (N/A) + Right hemichorea, blepharospam, postural tremor - Amantadine Tiapride Folic acid 1 year Sensory neuropathy Benito-León J 2000 68 M 132 ng/L (222-753) N/A N/A N/A - Orthostatic tremor N/A Clonazepam 1 year Positive Schilling test Sensory axonal polyneuropathy M: male; F: female; MMA = methylmalonic acid; IM: intramuscular; IV intravenous; +: present; - : absent; N/A: not available. Subacute combined degeneration was  considered when spinal MRI showed hyperintense lesions within the dorsal columns and discarded if spinal MRI did not have this findings. Figure 1 157  158  159 

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Simultaneous acute presentation of generalized chorea and subacute combined degeneration secondary to vitamin B12 deficiency

Simultaneous acute presentation of generalized chorea and subacute combined degeneration secondary to vitamin B12 deficiency

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