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Mystery Case: Anti-NMDAR encephalitis with overlapping demyelinating syndrome | Neurology

Pearls Anti-NMDA receptor encephalitis can coexist with an overlapping demyelinating syndrome. An atypical presentation of a single autoimmune disorder should prompt investigation for coexistent autoimmune disorders. Discovery of overlap syndromes is important because the management and prognosis may be different. Oysters In autoimmune encephalitis, shorter time from symptom onset to treatment initiation has been associated with better outcome.1 Treatment should not be delayed until the result of autoantibody testing is available. Case report A 31-year-old man developed a subacute onset of headache, left-sided numbness, and anterograde amnesia. In the following 2 weeks, he experienced personality changes, anxiety, paranoid thoughts, 7 kg weight loss, and worsening cognitive changes. He said that he felt as though he was trapped in a time loop, meaning that events seemed to be constantly recurring to him. He denied fever, night sweats, viral prodromal symptoms, or recent vaccinations. He was diagnosed with acute disseminated encephalomyelitis (ADEM) in 2007 from which he made a full recovery. On neurologic examination, he was inattentive and agitated. His word registration and short-term recall at 5 minutes were 0 of 5. He had verbal and motor perseveration with echolalia. He had decreased sensation to pinprick on his entire left side. He also had left pronator drift and bilateral athetosis of the upper limbs. The remainder of his examination was normal. His overall clinical examination finding was consistent with a multifocal process involving subcortical and cortical regions. On day 1, routine blood testing including complete blood cell count with differential, metabolic panel, liver function test, RPR, ESR, ANA, thyroid function tests, thiamine, B12, urinalysis, urine toxicology screen, heavy metal screening, and HIV were normal or negative. Brain MRI revealed multiple T2 hyperintensities within the right internal capsule, periventricular white matter, and bilateral mesial temporal lobes. There were contrast-enhancing lesions involving the right dorsal pons and right internal capsule and thalamus (figure, A–F). CSF analysis demonstrated 9 nucleated cells/µL with lymphocytic predominance. On day 2, CT of the chest, abdomen, and pelvis and testicular ultrasound were negative for malignancy. Cervical and thoracic spine MRI was performed to look for any past or active demyelinating lesions, especially in the setting of previous history of ADEM, and the result was normal. Video EEG did not demonstrate abnormal ictal or interictal epileptiform discharges. By this time, CSF Gram stain, cultures, and viral PCRs returned negative, and 8 CSF-specific oligoclonal bands were present. Serum and CSF NMDA-R IgG and serum MOG-IgG1 antibodies were sent to the laboratory. On hospital day 3, IV methylprednisolone 1000 mg was started and repeated daily for 5 total days. Left hemihypesthesia and pronator drift improved after treatment, and immediate follow-up brain MRI revealed resolution of contrast enhancement. However, his cognitive changes and neuropsychiatric symptoms persisted. His Montreal Cognitive Assessment (MOCA) score was 10 of 30 despite steroid treatment. Hence, on day 8, he was started on 5 rounds of plasmapheresis (PLEX). After PLEX, he became much calmer, his time loop ended, and his MOCA score improved to 19 of 30. His CSF NMDA-R IgG antibody and serum MOG-IgG1 returned positive. He was diagnosed with anti-NMDAR encephalitis with overlapping MOG-IgG–associated demyelinating syndrome (MOGAD). He was started on long-term maintenance therapy with rituximab. Figure Brain MRI findings in anti-NMDAR encephalitis with overlapping MOG-IgG–associated demyelinating syndrome (A) Axial T2-FLAIR brain MRI from September 2018 showing right greater than left T2 hyperintensities in the mesial temporal lobes, (B) in the right posterior limb of the internal capsule, and (C) in the right periventricular white matter tracts. (D) Axial T1 gadolinium-enhanced brain MRI showing right pontine crescent-shaped contrast enhancement and (E) punctate enhancement in the right pons and (F) in the right posterior limb of the internal capsule and thalamus. (G and H) Axial T2-FLAIR brain MRI from June 2007 showing T2 hyperintensities in the right subcortical region and periventricular white matter tracts. (I and J) Axial T2-FLAIR brain MRI from November 2007 showing largely resolved lesions. On 6-month follow-up, his MOCA score improved to 25 of 30 with resolution of neuropsychiatric symptoms and memory issues. He is planning to go back to work. Discussion We present a rare case of subacute autoimmune encephalitis with clinical features of both anti-NMDAR encephalitis and MOG-associated disorder (MOGAD), which was not fully encompassed by either entity alone. Anti-NMDAR encephalitis with overlapping demyelinating syndrome is rare, but has previously been described in the literature. In a large retrospective analysis of 691 patients with anti-NMDAR encephalitis,2 11 of 691 patients had anti-NMDAR encephalitis occurring simultaneously with additional clinical and MRI features inconsistent with anti-NMDAR encephalitis. Only 2 patients were seropositive for MOG-IgG1 antibodies with features that would be atypical for anti-NMDAR encephalitis alone, such as ataxia, unilateral hemiparesis, or infratentorial MRI abnormalities. Our patient presented with clinical features that are typical of anti-NMDAR encephalitis: headache, behavioral changes, abnormal movements (athetosis, chorea, and dystonia), memory loss, and speech disturbance. He did not develop other symptoms, such as autonomic dysregulation or severe encephalopathy requiring intensive care unit admission, which was perhaps related to the prompt recognition of the diagnosis and early treatment with immunotherapy.3 Brain MRI can be normal in as many as 50% of patients with anti-NMDAR encephalitis, although multiple abnormalities have been described in some patients including nonspecific T2 hyperintensities, most commonly in mesial temporal lobes, but also in the cerebellar or cerebral cortex, subcortical regions, or brainstem.4 In our patient, brain MRI demonstrated heterogeneous T2 hyperintensities in the bilateral mesial temporal lobes (figure, A). These lesions did not resemble demyelinating lesions, as there was an absence of confluent T2 hyperintensity or contrast enhancement. Our patient's presentation also included several features atypical of NMDAR encephalitis. His left hemihypesthesia and pronator drift are better explained by overlapping demyelinating syndrome because unilateral sensorimotor deficits are rarely seen in anti-NMDAR encephalitis. His sensorimotor symptoms were linked to MRI findings of demyelination including confluent T2 hyperintensity of the right thalamus, internal and external capsule, peripheral diffusion restriction, and rim enhancement along the leading edge of inflammation in T1 postgadolinium sequence5 (figure, C–F). These atypical features led to additional testing for MOG-IgG1 in serum. He did meet the criteria for the diagnosis of coexisting MOGAD with previous history of ADEM, MOG-IgG seropositivity, and MRI findings compatible with CNS demyelination.6 Our patient did not have other clinicoradiographic features of MOGAD, such as longitudinally extensive spinal cord lesions, conus medullaris lesions, or perioptic gadolinium enhancement of the optic nerves.7 MOGAD is generally highly responsive to corticoseroids,6 and his unilateral sensorimotor symptoms resolved rapidly on finishing 5 doses of IV methylprednisolone, whereas neuropsychiatric symptoms resulting from anti-NMDAR encephalitis took several weeks to resolve. The exact mechanism and frequency of overlapping anti-NMDAR and demyelination is uncertain. His previous presentation of encephalitis with diagnosis of ADEM occurred in 2007, a time when MOG-IgG antibody testing was not commercially available. A brain MRI obtained in 2007 at the time of his ADEM diagnosis revealed lesions in the right periventricular white matter tracts, which fully resolved months after the initial onset of symptoms (figure, G–J). Our patient's recurrent episode in 2018 affected these areas again (figure, B and C). Recurrence of disease in the same location has been described in patients with relapsing-remitting ADEM.8 Therefore, his case likely represents relapsing MOGAD, and it is quite possible that the patient was seropositive in 2007, as persistent seropositivity is associated with an increased risk of relapses.9 Although our patient has coexistent MOG and NMDAR antibodies, the initial treatment remains similar to that of a patient with either antibody alone. First-line immunotherapy consists of corticosteroids, IVIG, PLEX, or a combination of the 3. In patients with anti-NMDAR encephalitis associated with malignancy, tumor excision should also be performed. In patients whose symptoms are refractory to first-line therapy, additional second-line immunotherapy, such as rituximab or cyclophosphamide, is needed.3 If relapse occurs, a long-term maintenance immunotherapy after rescue treatment may reduce the likelihood of future relapses. Although initial treatment approach for anti-NMDAR encephalitis and demyelinating disorders is similar, subsequent management strategies for recurrence of symptoms, prognosis, and risk of recurrence could be different, which highlights the importance in diagnosing both conditions.2 Surveillance for relapse is more challenging because neurologist, patient, and family members need to monitor for relapses of both disorders, including not only typical neuropsychiatric symptoms of NMDAR encephalitis but also heterogeneous manifestations associated with MOGAD. Also, as in our case, subsequent treatment plan was more complex because his residual neuropsychiatric symptoms and executive dysfunction had to be managed with multidisciplinary approach including psychiatry and comprehensive rehabilitation. In summary, NMDAR encephalitis can occur simultaneously with MOGAD. If a patient presents with aforementioned demyelinating features that are atypical for NMDAR encephalitis alone, serum MOG-IgG1 should be tested. Likewise, clinicians should have a low threshold to test for other neural autoantibodies in patients who have a diagnosis of MOGAD who present with atypical features such as movement disorders or neuropsychiatric symptoms. Study funding No targeted funding reported. Disclosure The authors report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures. Mystery Case responses: A 31-year-old with left-sided numbness, amnesia, and personality changes The Mystery Case series was initiated by the Neurology® Resident & Fellow Section to develop the clinical reasoning skills of trainees. Residency programs, medical student preceptors, and individuals were invited to use this Mystery Case as an educational tool. Responses to multiple-choice questions formulated using this case were solicited through a group email sent to the American Academy of Neurology Consortium of Neurology Residents and Fellows and through social media. We received 580 responses. The majority of respondents (66%) had just been in practice for 1–4 years; 56% were residents or fellows, whereas 34% were faculty/board-certified physicians; the remainder were medical students or advanced practice providers. Seventy percent resided outside the United States. A wide range of practice settings was represented. When presented with this brief vignette and the brain MRI of a 31-year-old with left-sided numbness, amnesia, and personality changes and asked for the 2 most likely differential diagnoses, 58.3% correctly chose autoimmune encephalitis, and 37.6% correctly recognized demyelinating lesions. The most frequently selected incorrect options were CNS lymphoma (32.6%), tertiary syphilis (15.3%), and MELAS (14.3%), these are lower in the differential. After being given preliminary results, the participants were asked for the 3 most important next tests. Autoimmune encephalitis panel was correctly chosen by 70.7%. Because of the suspicion of demyelination, the other correct answers included whole-spine MRI with contrast (28.1%) and AQP4 and MOG antibodies (37.1%). The most commonly selected incorrect answers were CSF cytology and flow cytometry (46.4%), CSG HSV PCR (21.0%), and syphilis treponemal test (16.7%). Although these tests are reasonable, they are lower in priority for this patient. Finally, the participants were asked for the best empiric treatment while waiting for results. IV methylprednisolone was correctly selected by 55.9%. The most common incorrect answers were IV acyclovir (17.9%) and no therapeutic intervention (14.0%). This patient testing came back with a positive anti-NMDAR antibody and anti-MOG antibody. He was diagnosed with anti-NMDAR encephalitis with overlapping MOG-IgG–associated demyelinating syndrome. He received IV steroids, followed by PLEX with good response. This overlap syndrome has been previously described, and in a study, 5% of patients with anti-NMDAR encephalitis showed evidence of demyelinating disease.1 Antibodies against AQP4 and MOG have been reported in these cases.1,2 Although acute treatment is similar, recognition of these association is important to guide long-term treatment. Cincinnati Children's Hospital Medical Center Appendix Authors Footnotes Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. Survey and results: NPub.org/mc9417 © 2020 American Academy of Neurology References 1.↵Lancaster E. The diagnosis and treatment of autoimmune encephalitis. J Clin Neurol 2016;12:1–13.OpenUrlCrossRefPubMed 2.↵Titulaer MJ, Höftberger R, Iizuka T, et al. Overlapping demyelinating syndromes and anti–N-methyl-D-aspartate receptor encephalitis. Ann Neurol 2014;75:411–428.OpenUrlCrossRefPubMed 3.↵Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011;10:63–74.OpenUrlCrossRefPubMed 4.↵Dalmau J, Geis C, Graus F. Autoantibodies to synaptic receptors and neuronal cell surface proteins in autoimmune diseases of the central nervous system. Physiol Rev 2017;97:839–887.OpenUrlCrossRefPubMed 5.↵Tillema JM, Pirko I. Neuroradiological evaluation of demyelinating disease. Ther Adv Neurol Disord 2013;6:249–268.OpenUrlCrossRefPubMed 6.↵Jarius S, Paul F, Aktas O, et al. MOG encephalomyelitis: international recommendations on diagnosis and antibody testing. J Neuroinflammation 2018;15:134.OpenUrl 7.↵Jarius S, Ruprecht K, Kleiter I, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome. J Neuroinflammation 2016;13:280.OpenUrlCrossRefPubMed 8.↵Cohen O, Steiner-Birmanns B, Biran I, Abramsky O, Honigman S, Steiner I. Recurrence of acute disseminated encephalomyelitis at the previously affected brain site. Arch Neurol 2001;58:797–801.OpenUrlCrossRefPubMed 9.↵López-Chiriboga AS, Majed M, Fryer J, et al. Association of MOG-IgG serostatus with relapse after acute disseminated encephalomyelitis and proposed diagnostic criteria for MOG-IgG–associated disorders. JAMA Neurol 2018;75:1355–1363.OpenUrl References 1.Titulaer MJ, Hoftberger R, Iizuka T, et al. Overlapping demyelinating syndromes and anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol 2014;75:411–428.OpenUrlCrossRefPubMed 2.Hacohen Y, Absoud M, Hemingway C, et al. NMDA receptor antibodies associated with distinct white matter syndromes. Neurol Neuroimmunol Neuroinflamm 2014;1:e2.
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Autoimmune Encephalitis Misdiagnosis in Adults | Neurology | JAMA Neurology | JAMA Network

Autoimmune Encephalitis Misdiagnosis in Adults | Neurology | JAMA Neurology | JAMA Network | AntiNMDA | Scoop.it
This case series assesses the diseases misdiagnosed as autoimmune encephalitis and potential reasons for misdiagnosis.
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Diagnostic Value of 18F-FDG PET/CT Versus MRI in the Setting of Antibody-Specific Autoimmune Encephalitis

Diagnostic Value of 18F-FDG PET/CT Versus MRI in the Setting of Antibody-Specific Autoimmune Encephalitis | AntiNMDA | Scoop.it
Diagnosis of autoimmune encephalitis presents some challenges in the clinical setting because of varied clinical presentations and delay in obtaining antibody panel results.We examined the role of neuroimaging in the setting of autoimmune encephalitides, comparing the utility of <sup>18</sup>F-FDG...
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The Many Faces of Catatonia, An Under-Recognized Clinical Syndrome

The Many Faces of Catatonia, An Under-Recognized Clinical Syndrome | AntiNMDA | Scoop.it
Catatonia: learn more about how to best diagnose early.
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Why We Still Use “Organic Causes”: Results From a Survey of Psychiatrists and Residents

The diagnostic category of “organic disorders” was officially removed from the psychiatric nosology in DSM-IV, published in 1994. Despite this change, physicians continue to use the term “organic causes” to refer to medical and neurological causes of psychiatric symptoms, and it remains part of...
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Anti-NMDA receptor encephalitis and brain atrophy in children and adults: A quantitative study

Anti-NMDA receptor encephalitis and brain atrophy in children and adults: A quantitative study | AntiNMDA | Scoop.it
To determine whether brain atrophy was present in patients with anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) using qualitative and quantitative analyses of brain magnetic resonance imaging (MRI) and to explore clinical differences in patients with anti-NMDARE with or without brain...
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Eoin Flanagan, M.B., B.Ch., explains autoimmune encephalitis misdiagnosis in JAMA Neurology

Eoin Flanagan, M.B., B.Ch., explains autoimmune encephalitis misdiagnosis in JAMA Neurology | AntiNMDA | Scoop.it
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Characterization of cardiac bradyarrhythmia associated with LGI1-IgG autoimmune encephalitis

LGI1-IgG AE can be rarely associated with bradyarrhythmias. Although the disease course is mostly favorable, some cases may require pacemaker placement to avoid devastating outcomes.
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Event Announcement: Saturday, 21 January 2023, Paris, France

Event Announcement: Saturday, 21 January 2023, Paris, France | AntiNMDA | Scoop.it
Dear Subscriber, We are pleased to share with you details of an event that is being hosted by the newly established ENMDAR, a French anti-NMDA receptor encephalitis organisation. The event is free of charge and open to all. It will be in French.
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Autoimmune Encephalitis in Critical Care: Optimizing Immunosuppression

Autoimmune Encephalitis in Critical Care: Optimizing Immunosuppression | AntiNMDA | Scoop.it
Autoimmune diseases affecting the nervous systems are a common cause of admission to the intensive care unit (ICU).Although there exist several well-described clinical syndromes, patients more commonly present with progressive neurologic dysfunction and laboratory and radiographic evidence of centr...
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Diagnosis and Management of Autoimmune Encephalitis (Podcast) –

Diagnosis and Management of Autoimmune Encephalitis (Podcast) – | AntiNMDA | Scoop.it
The rarity and many mimics of autoimmune encephalitis make its diagnosis no easy task. An AE expert shares practical insights on how to promptly identify the condition to enable early treatment.
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Serum cystatin C and anti-N-methyl-D-aspartate receptor encephalitis

Serum cystatin C and anti-N-methyl-D-aspartate receptor encephalitis | AntiNMDA | Scoop.it
Our results show that the serum levels of CysC are associated with anti-NMDAR encephalitis and its clinical parameters and that the changes in CysC levels correlate with therapeutic effect.Therefore, our findings provide new insights into the association between serum CysC and anti-NMDAR encephalit...
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Molecular mimicry of NMDA receptors may contribute to neuropsychiatric symptoms in severe COVID-19 cases

Molecular mimicry of NMDA receptors may contribute to neuropsychiatric symptoms in severe COVID-19 cases | AntiNMDA | Scoop.it
Approximately 30% of individuals with severe SARS-CoV-2 infections also develop neurological and psychiatric complaints. In rare cases, the occurrence of autoimmune encephalitis has been reported after SARS-CoV-2 infection.
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The Increased Interleukin-6 Levels Can Be an Early Diagnostic Marker for New-Onset Refractory Status Epilepticus - PMC

The Increased Interleukin-6 Levels Can Be an Early Diagnostic Marker for New-Onset Refractory Status Epilepticus - PMC | AntiNMDA | Scoop.it
New-onset refractory status epilepticus (NORSE) is a condition defined as the occurrence of refractory status epilepticus in patients without active epilepsy and no other acute causes of seizure. Although there is evidence that immune-mediated pathogenesis ...
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Decreased occipital lobe metabolism by FDG-PET/CT: An anti-NMDA receptor encephalitis biomarker

Decreased occipital lobe metabolism by FDG-PET/CT: An anti-NMDA receptor encephalitis biomarker | AntiNMDA | Scoop.it
Marked medial occipital lobe hypometabolism by dedicated brain FDG-PET/CT may serve as an early biomarker for discriminating anti-NMDA receptor encephalitis from other AE.Resolution of lateral and medial occipital hypometabolism may correlate with improved neurologic status in anti-NMDA receptor ...
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Clinical Reasoning: A Young Adult Man With Cognitive Changes, Gait Difficulty, and Renal Insufficiency | Neurology

Clinical Reasoning: A Young Adult Man With Cognitive Changes, Gait Difficulty, and Renal Insufficiency | Neurology | AntiNMDA | Scoop.it
AbstractA 22-year-old right-handed man with recently diagnosed gout and renal insufficiency presented with 3 months of progressive gait instability and cognitive changes. He initially presented to an outside institution and underwent a broad workup, but an etiology for his symptoms was not found. On subsequent presentation to our institution, his examination revealed multidomain cognitive dysfunction, spasticity, hyperreflexia, and clonus. A broad workup was again pursued and was notable for an MRI of the brain, revealing cortical atrophy advanced for his age, bland CSF, and a weakly positive serum acetylcholine receptor ganglionic neuronal antibody of unclear significance. The history of gout and inadequately explained renal insufficiency led to a workup for inborn errors of metabolism, including urine amino acid analysis, which revealed a homocysteine peak. This finding prompted further evaluation, revealing markedly elevated serum homocysteine and methylmalonic acid and low methionine. He ultimately developed superficial venous thromboses, a segmental pulmonary embolism, and clinical and electrographic seizures. He was initiated on appropriate treatment, and his symptoms markedly improved. The case serves as a reminder to include late-onset inborn errors of metabolism in the differential for young adult patients with onset of neurologic, psychiatric, renal, and thromboembolic symptoms.Section 1A 22-year-old right-handed man with recently diagnosed gout and worsening renal function presented with 3 months of gait instability and cognitive changes. Approximately 5 months before presentation, he was diagnosed with gout, confirmed by uric acid crystals on synovial fluid. He was recommended to start a vegan diet then. He also developed worsening renal function. Until 3 months before presentation, he was a high-functioning student at his university. He then started struggling in classes, stopped interacting with family, stopped going to school, and became more introverted. He became clumsier, with difficulty going upstairs and downstairs. He initially presented to an outside hospital, where an extensive workup was performed, but no clear etiology was found, and he was discharged with a diagnosis of catatonia.Three months after onset of neurologic symptoms, the patient presented to our institution with worsened condition. He had recently become violent and started having abnormal movements of his extremities. Two weeks earlier, he had stopped walking and required assistance to move. He was urinating on himself and no longer told his parents when he needed to use the bathroom. There was no significant family history. On neurologic examination, mental status examination was notable for prominent inattention, perseveration, psychomotor slowing, and inappropriate laughter. He could not follow multistep commands and had reduced spontaneous speech with increased latency. Motor examination revealed mild spasticity in the lower greater than upper extremities. Detailed motor and sensory testing were limited by his mental status, but he had at least antigravity strength in the upper and lower extremities bilaterally. His tendon reflexes were 3 + throughout with crossed adductors, and he had bilateral ankle clonus for greater than 10 beats and a positive Hoffman reflex on the left.Questions for Consideration:What are the localization and broad categories to consider in the differential diagnosis?What diagnostic studies should be ordered initially?GO TO SECTION 2Section 2The multidomain cognitive dysfunction suggests diffuse bilateral cerebral hemispheric involvement, whereas the prominent spasticity, hyperreflexia, and clonus suggest upper motor neuron involvement, specifically within the corticospinal tracts. The bilateral pyramidal tract dysfunction could be localized intracranially, anywhere from the primary motor cortex to the internal capsule on down to the brainstem. Processes that could lead to such a diffuse bihemispheric process leading to cognitive symptoms and gait difficulties broadly include the following: vascular (e.g., CNS vasculitis); infectious and inflammatory (e.g., subacute to chronic meningoencephalitides); neoplastic or paraneoplastic; autoimmune (e.g., autoimmune encephalitis, demyelinating disease); toxic and metabolic (e.g., B12 deficiency leading to subacute combined degeneration)1; and inborn errors of metabolism, considered initially due to young age and gout history,2,3 as summarized in the Table.View inline View popup Table Broad Differential Diagnosis for Diffuse, Bihemispheric Processes Leading to Cognitive Symptoms and Gait DifficultiesBasic laboratory workup revealed SARS-CoV-2 positivity with lymphopenic leukopenia. B12 was 462 pg/mL and folate >20.0 ng/mL. Uric acid was 6.8 mg/dL (2.3–7.6, normal). An MRI of the brain with and without contrast revealed cortical atrophy (Figure 1) but no other acute findings, and an MRI of the cervical spine (not shown) was unremarkable. Continuous EEG (cEEG) monitoring for 48 hours revealed generalized continuous delta slow activity with superimposed faster frequencies. CSF studies revealed normal cell count, protein, glucose, IgG synthesis rate/index, and a negative meningitis panel. Encephalopathy, autoimmune, serum, and CSF panels were ordered. Given the patient's age and recent development of gout and renal dysfunction, urine amino acid analysis was sent.<img height="440" width="438" class="highwire-fragment fragment-image" src="https://n.neurology.org/content/neurology/100/4/206/F1.medium.gif"; alt="Figure 1">Download figure Open in new tab Download powerpoint Figure 1 Representative Neuroimaging From the CaseA) Sagittal T1-weighted MRI of the brain and B) axial T2/FLAIR MRI of the brain revealing cortical atrophy; C) continuous video EEG recording sample showing lateralized periodic discharges (black arrows) seen in the right fronto-central region consistent with an area of epileptogenic potential.Question for Consideration:Which entities on the differential are less likely, given this initial workup?GO TO SECTION 3Section 3Given the bland CSF and MRI brain without enhancement or FLAIR signal changes, meningoencephalitides, CNS vasculitis, demyelinating diseases, and CNS neoplastic processes are less likely. However, paraneoplastic or autoimmune encephalitis can present without MRI abnormalities.4 Furthermore, there was a weakly positive serum acetylcholine receptor ganglionic neuronal antibody from the previous institution. While this antibody is classically reported in the setting of autoimmune autonomic ganglionopathy,5 it has rarely been associated with predominantly neuropsychiatric presentations of autoimmune encephalitis.6 The patient was empirically initiated on IVIG for this possibility while awaiting other laboratory test results. In addition, inborn errors of metabolism remained high in the differential consideration, given the oddity of gout and inadequately explained renal insufficiency. Normal serum vitamin levels did not exclude the possibility of inborn errors of metabolism because they can classically be normal in these conditions.7The serum and CSF encephalopathy panels returned negative, and the serum NeoComplete Paraneoplastic Evaluation again revealed borderline anti-α 3AChR antibody. Notably, the urine amino acid analysis revealed a peak of homocysteine.Questions for Consideration:What is the significance of the homocysteine peak on urine amino acid analysis?What further studies should be ordered?GO TO SECTION 4Section 4Elevated urine homocysteine is classically found in the homocystinurias. This finding prompted a serum homocysteine level, which was >50.0 µmol/L (0–14.9, normal range), with the quantitative serum homocysteine measured at 283.3 µmol/L (6.1–10.8). Serum homocysteine is a key biochemical marker of disruption of the remethylation pathway. When elevated homocysteine is found, serum methionine and quantitative methylmalonic acid (MMA) levels in the serum should be ordered to isolate the defect in the biochemical pathway of cobalamin metabolism.7 Serum MMA was significantly elevated to 452,000 nmol/L (87–318). Serum methionine was 9 umol/L (16–34). This pattern is the biochemical hallmark of cobalamin C (CblC) deficiency.7 Genetic testing revealed 2 heterozygous pathogenic variants in the MMACHC gene: c.328_331del (p.Asn110Aspfs*13) and c.482G>A (p.Arg161Gln).DiscussionCobalamin C deficiency is the most common inherited disorder of intracellular cobalamin metabolism.8,9 It is most often due to pathogenic variants of the MMACHC gene. Because of defective gene product, methylcobalamin and adenosylcobalamin are not produced intracellularly. Methylcobalamin and adenosylcobalamin are critical cofactors for the remethylation of homocysteine to methionine and conversion of MMA to succinic acid, respectively (Figure 2). Thus, the deficiency of methylcobalamin and adenosylcobalamin leads to elevated serum homocysteine and MMA, low methionine levels, and normal serum B12 and folate.7<img src="https://n.neurology.org/content/neurology/100/4/206/F2.medium.gif"; height="251" class="highwire-fragment fragment-image" alt="Figure 2" width="440">Download figure Open in new tab Download powerpoint Figure 2 Schematic of Intracellular Cobalamin MetabolismCobalamin (Cbl) III is bound to transcobalamin (TC) in the blood. This complex is endocytosed into the cell. On entering the lysosome, Cbl III becomes unbound from TC. Cbl III then enters the cytosol and undergoes enzymatic reduction from Cbl III to Cbl II aided by MMACHC. Cbl II then undergoes adenosylation to form adenosylcobalamin (AdoCbl) in the mitochondrion and methylation to form methylcobalamin (MeCbl) in the cytosol, respectively. AdoCbl is a cofactor for methylmalonyl-CoA-mutase (MMUT), which catalyzes the conversion of L-Methylmalonyl-CoA (MMA-CoA) to succinyl-CoA. MeCbl is a cofactor in the conversion of homocysteine to methionine, mediated by the enzyme methionine synthase (MTR).7CblC disease is typically classified into 2 forms: early onset (typically within the first year of life)10 and late onset (which includes late-onset pediatric and adult cases).11 In the past couple of decades, there have been great advancements in newborn screening for cobalamin deficiencies, but many adults were born before such screening. The late-onset form was first reported in 197012 and the adult-onset (aged 18 years or older) form in 2001.13 As of 2022, only 45 cases of adult-onset CblC disease have been reported, but this is likely a vast underrepresentation. Whereas early-onset disease has a poor prognosis even with early diagnosis, the adult-onset form generally exhibits robust response to treatment. There is a genotype-phenotype correlation with adult-onset forms tending to have compound heterozygosity of missense variants, which leads to some residual protein function,7 as seen in our patient.In the adult-onset form, neuropathy or myelopathy are the most common clinical signs, followed by ataxia or dysarthria, cognitive decline, psychiatric symptoms, lower limb weakness, and seizures. Other features include thromboembolic disease and kidney failure often due to damage from thrombotic microangiopathy (TMA).7,14 Our patient did ultimately develop acute bilateral upper extremity cephalic vein thromboses and a right lower lobe segmental pulmonary embolism, for which he was initiated on therapeutic anticoagulation. He also had elevated creatinine (peak at 3.6–3.8 mg/dL), but the exact etiology of his renal disease was unclear, and he did not have the other accompanying signs of TMA (no hypertension, hematuria, or proteinuria). Kidney biopsy was deferred, given it was unlikely to change management and had elevated risks on therapeutic anticoagulation. In addition, his course was complicated by clinical seizures with left gaze deviation and generalized convulsions. He was reconnected to cEEG, which revealed right fronto-central lateralized periodic epileptiform discharges and seizures without definitive clinical correlation and was initiated on antiseizure medications. Finally, while gout is more commonly associated with inborn errors of metabolism dealing with purine metabolism, it has been reported in cases of methylmalonic acidemia and may be related to decreased renal clearance of uric acid.3The treatment for CblC disease is intramuscular or subcutaneous hydroxycobalamin, combined with oral betaine and folic acid.7 Of importance, oral cobalamin replacement approaches are ineffective because the patients require supplementation with the active form, which is not absorbed through the oral route; betaine facilitates the conversion of homocysteine to methionine; and folic acid can potentially augment remethylation.9 Our patient was initiated on this regimen soon after the biochemical markers confirmed the diagnosis. He improved significantly while still inpatient and was discharged to an inpatient acute rehabilitation facility. By approximately a month after discharge, he could hold an in-depth follow-up conversation over the phone, felt his cognition had significantly improved, and was able to stand and walk for 7–8 meters at a time. This case serves as a reminder to trust the neurologic examination, even if neuroimaging and other workup are unrevealing. In addition, in complicated cases, red herrings may arise,15 such as the AChR ganglionic antibody, not considered the pathogenic antibody in this case. Finally, the case reminds one to include the inborn errors of metabolism in the differential for young adult patients with onset of neurologic and psychiatric presentations, particularly when accompanied by other systemic findings.Study FundingThe authors report no targeted funding.DisclosureThe authors report no disclosures relevant to the manuscript. Go to Neurology.org/N for full disclosures.Appendix Authors<img class="highwire-fragment fragment-image" src="https://n.neurology.org/content/neurology/100/4/206/T2.medium.gif"; width="658" height="1273" alt="Table">Footnotes↵* These authors contributed equally to this work as senior authors.Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.Submitted and externally peer reviewed. The handling editor was Whitley Aamodt, MD, MPH.Received April 27, 2022.Accepted in final form September 16, 2022.© 2022 American Academy of NeurologyReferences1.↵Qudsiya Z, De Jesus O. Subacute combined degeneration of the spinal cord. In: StatPearls. StatPearls Publishing; 2021:1.2.↵Doucet BP, Jegatheesan D, Burke J. Late diagnosis of Lesch-Nyhan disease variant. BMJ Case Rep. 2013;2013:1-2. doi:10.1136/bcr-2013-201997OpenUrlCrossRef3.↵Charuvanij S, Pattaragarn A, Wisuthsarewong W, Vatanavicharn N. Juvenile gout in methylmalonic acidemia. Pediatr Int. 2016;58(6):501-503.OpenUrl4.↵Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12(2):157-165.OpenUrlCrossRefPubMed5.↵Vernino S. Autoimmune autonomic disorders. Continuum. 2020;26(1):44-57.OpenUrl6.↵McKeon A, Lennon VA, Lachance DH, Fealey RD, Pittock SJ. Ganglionic acetylcholine receptor autoantibody. Arch Neurol. 2009;66(6):735-741. doi:10.1001/archneurol.2009.78OpenUrlCrossRefPubMed7.↵Kalantari S, Brezzi B, Bracciamà V, et al. Adult-onset CblC deficiency: a challenging diagnosis involving different adult clinical specialists. Orphanet J Rare Dis. 2022;17(1):33.OpenUrl8.↵Mudd SH, Levy HL, Abeles RH. A derangement in B12 metabolism leading to homocystinemia, cystathioninemia and methylmalonic aciduria. Biochem Biophys Res Commun. 1969;35(1):121-126.OpenUrlCrossRefPubMed9.↵Adam MP, Ardinger HH, Pagon RA, et al.Sloan JL, Carrillo N, Adams D, Venditti CP. Disorders of intracellular cobalamin metabolism. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews®. University of Washington; 2008.10.↵Wang SJ, Yan CZ, Wen B, Zhao YY. Clinical feature and outcome of late-onset cobalamin C disease patients with neuropsychiatric presentations: a Chinese case series. Neuropsychiatr Dis Treat. 2019;15:549-555.OpenUrlCrossRefPubMed11.↵Huemer M, Scholl-Bürgi S, Hadaya K, et al. Three new cases of late-onset cblC defect and review of the literature illustrating when to consider inborn errors of metabolism beyond infancy. Orphanet J Rare Dis. 2014;9:161.OpenUrlCrossRefPubMed12.↵Goodman SI, Moe PG, Hammond KB, Mudd SH, Uhlendorf BW. Homocystinuria with methylmalonic aciduria: two cases in a sibship. Biochem Med. 1970;4(5):500-515.OpenUrlCrossRefPubMed13.↵Bodamer OA, Rosenblatt DS, Appel SH, Beaudet AL. Adult-onset combined methylmalonic aciduria and homocystinuria (cblC). Neurology. 2001;56(8):1113.OpenUrlFREE Full Text14.↵Lemoine M, François A, Grangé S, et al. Cobalamin C deficiency induces a typical histopathological pattern of renal arteriolar and glomerular thrombotic microangiopathy. Kidney Int Rep. 2018;3(5):1153-1162.OpenUrl15.↵Ebright MJ, Li SH, Reynolds E, et al. Unintended consequences of Mayo paraneoplastic evaluations. Neurology. 2018;91(22):e2057-e2066.OpenUrlAbstract/FREE Full Text
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