Survival and consciousness recovery are better in the minimally conscious state than in the vegetative state.

BACKGROUND: The prognosis value of early clinical diagnosis of consciousness impairment is documented by an extremely limited number of studies, whereas it may convey important information to guide medical decisions. OBJECTIVE: We aimed at determining if patients diagnosed at an early stage (<90 days after brain injury) as being in the minimally conscious state (MCS) have a better prognosis than patients in the vegetative state/Unresponsive Wakefulness syndrome (VS/UWS), independent of care limitations or withdrawal decisions. METHODS: Patients hospitalized in ICUs of the Pitié-Salpêtrière Hospital (Paris, France) from November 2008 to January 2011 were included and evaluated behaviourally with standardized assessment and with the Coma Recovery Scale-Revised as being either in the VS/UWS or in the MCS. They were then prospectively followed until 1July 2011 to evaluate their outcome with the GOSE. We compared survival function and outcomes of these two groups. RESULTS: Both survival function and outcomes, including consciousness recovery, were significantly better in the MCS group. This difference of outcome still holds when considering only patients still alive at the end of the study. CONCLUSIONS: Early accurate clinical diagnosis of VS/UWS or MCS conveys a strong prognostic value of survival and of consciousness recovery.

Regulatory T cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to intravenous immunoglobulin therapy.

BACKGROUND: Intravenous immunoglobulin (IVIG) is a polyspecific pooled immunoglobulin G preparation and one of the commonly used therapeutics for autoimmune diseases including those of neurological origin. A recent report in murine model proposed that IVIG expands regulatory T (Treg) cells via induction of interleukin 33 (IL-33). However, translational insight on these observations is lacking. METHODS: Ten newly diagnosed Guillain-Barré syndrome (GBS) patients were treated with IVIG at the rate of 0.4 g/kg for three to five consecutive days. Clinical evaluation for muscular weakness was performed by Medical Research Council (MRC) and modified Rankin scoring (MRS) system. Heparinized blood samples were collected before and 1, 2, and 4-5 weeks post-IVIG therapy. Peripheral blood mononuclear cells were stained for surface CD4 and intracellular Foxp3, IFN-γ, and tumor necrosis factor alpha (TNF-α) and were analyzed by flow cytometry. IL-33 and prostaglandin E2 in the plasma were measured by ELISA. RESULTS: The fold changes in plasma IL-33 at week 1 showed no correlation with the MRC and MRS scores at weeks 1, 2, and ≥4 post-IVIG therapy. Clinical recovery following IVIG therapy appears to be associated with Treg cell response. Contrary to murine study, there was no association between the fold changes in IL-33 at week 1 and Treg cell frequency at weeks 1, 2, and ≥4 post-IVIG therapy. Treg cell-mediated clinical response to IVIG therapy in GBS patients was associated with reciprocal regulation of effector T cells-expressing TNF-α. CONCLUSION: Treg cell expansion by IVIG in patients with autoimmune diseases lack correlation with IL-33. Treg cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to IVIG therapy.

Translation, cross-cultural adaptation, and validation of the french version of the 15-item Myasthenia Gravis Quality Of life scale.

INTRODUCTION: Evaluation of quality of life (QOL) has become essential in healthcare. Currently no MG-specific QOL measure exists in French. The aim of this study was to translate, culturally adapt, and evaluate the psychometric properties of the French version of the 15-Item Myasthenia Gravis Quality of Life Scale (MG-QOL15) scale for French myasthenia patients. METHODS: Translation and cross-cultural adaption of the MG-QOL15 was performed, followed by reliability and validity evaluations. RESULTS: One hundred and twenty-five patients were included. Internal consistency was excellent (Cronbach α = 0.92) as was test-retest reliability (ICC = 0.92, 95% CI 0.86-0.96). Concurrent validity was good for both clinical scores (myasthenic muscle score: ρ = -0.52, P < 0.001; Myasthenia Gravis-Activities of Daily Living scale score: ρ = 0.62, P < 0.001). Correlations were strongest for overall QOL (ρ = 0.62, P < 0.001) and physical health (ρ = 0.67, P < 0.001) on the World Health Organization Quality of Life short score (WHO-QOL BREF). CONCLUSION: The French version of the MG-QOL15 is valid and reliable and is now available for use with French-speaking patients. Muscle Nerve, 2016 Muscle Nerve 55: 639-645, 2017.

Guillain-Barré syndrome in France: a nationwide epidemiological analysis based on hospital discharge data (2008-2013).

Guillain-Barré syndrome (GBS) is potentially life threatening and typically occurs after an infection. No detailed information is available concerning the epidemiological characteristics of GBS in France. We estimated age- and sex-specific incidence rates (IRs) based on a French nationwide hospital discharge database. All patients hospitalized for GBS between 2008 and 2013 were identified by International Classification of Diseases-10 code G61.0 as principal diagnosis. Patients previously hospitalized for GBS in 2006 and 2007 were excluded. Sensitivity analyses were performed by considering alternative case definitions, based on more restrictive sets of codes. A total of 9,391 patients were identified, leading to an overall crude IR of 2.42 per 100,000 person-years (world standardized IR = 2.00). IRs increased with age, reaching a peak in the 70-79-year age group. IR was 46% higher in men than in women, and 44% higher in winter than in summer. In children, the highest IR was observed at the age of 2 years. These patterns were not modified by the use of alternative case definitions. This French nationwide study showed similar GBS epidemiological patterns in adults to those reported in other countries. We also report a childhood incidence peak around the age of 2 years, as previously observed in Latin American and Chinese populations.

Post-traumatic stress symptoms in Guillain-Barré syndrome patients after prolonged mechanical ventilation in ICU: a preliminary report.

Thirty percent of Guillain-Barré syndrome (GBS) patients require mechanical ventilation (MV) in intensive care unit (ICU). Post-traumatic stress disorder (PTSD) is found in ICU survivors, and the traumatic aspects of intubation and MV have been previously reported as risk factors for PTSD after ICU. Our objective was to determine long-term PTSD or post-traumatic stress symptoms (PTSS) in GBS patients after prolonged MV in ICU. We assessed GBS patients who had MV for more than 2 months. PTSD was assessed using Horowitz Impact of Event Scale (IES), IES-Revisited (IES-R), and the Post-traumatic CheckList Scale; functional outcome using Rankin and Barthel scales; quality of life (QoL) using Nottingham Health Profile (NHP) and 36-Item Short Form Health Survey (SF-36) and depression using Hospital Anxiety and Depression Scale (HAD) and Beck questionnaire. Thirteen patients could be identified and analyzed. They had only mild disability. They were neither anxious nor depressed with an anxiety HAD at 5 (4-11.5), a depression HAD at 1 (0-3.5) and a Beck at 1 (0-5). QoL was mildly decreased in our population with a NHP at 78.5 (12.8-178.8) and mild decreased SF-36. Compared with the French population, the SF-36 sub-categories were, however, not statistically different. Twenty-two percentage of our 13 patients had PTSD and PTSS with a Horowitz IES at 12 (2-29), and an IES-R at 16 (2-34.5). Although severe GBS patients requiring prolonged MV had good functional recovery and no difference in QoL, they had a high incidence of PTSS.

Comparison of juvenile and adult myasthenia gravis in a French cohort with focus on thymic histology.

Myasthenia gravis (MG) is an autoimmune disease characterized by muscle fatigability due to acetylcholine receptor (AChR) autoantibodies. To better characterize juvenile MG (JMG), we analyzed 85 pre- and 132 post-pubescent JMG (with a cutoff age of 13) compared to 721 adult MG patients under 40 years old using a French database. Clinical data, anti-AChR antibody titers, thymectomy, and thymic histology were analyzed. The proportion of females was higher in each subgroup. No significant difference in the anti-AChR titers was observed. Interestingly, the proportion of AChR+ MG patients was notably lower among adult MG patients aged between 30 and 40 years, at 69.7%, compared to over 82.4% in the other subgroups. Thymic histological data were examined in patients who underwent thymectomy during the year of MG onset. Notably, in pre-JMG, the percentage of thymectomized patients was significantly lower (32.9% compared to more than 42.5% in other subgroups), and the delay to thymectomy was twice as long. We found a positive correlation between anti-AChR antibodies and germinal center grade across patient categories. Additionally, only females, particularly post-JMG patients, exhibited the highest rates of lymphofollicular hyperplasia (95% of cases) and germinal center grade. These findings reveal distinct patterns in JMG patients, particularly regarding thymic follicular hyperplasia, which appears to be exacerbated in females after puberty.

A prehospital randomized trial in convulsive status epilepticus.

Therapeutic strategies for patients with generalized convulsive status epilepticus (GCSE) need to be improved. We present the design of an add-on, randomized, double-blind, placebo-controlled, phase III clinical trial, to compare the efficacy for GCSE of intravenous levetiracetam in association with clonazepam versus clonazepam alone. In the therapeutic arm, 1 mg clonazepam is injected together with 2500 mg levetiracetam over 5 min. In the control arm, 1 mg clonazepam is injected together with a placebo over 5 min. This ongoing study is managed by prehospital physicians within emergency mobile units (SAMU). Adult patients with GCSE lasting more than 5 minutes are included in the study. The primary outcome measure is the percentage of patients with cessation of convulsions within 15 minutes of the onset of initial injections. Emergency medical consent is obtained from family members. An informed consent for continued participation is also obtained from patients when they wake. The study is currently recruiting participants.

Not all patients with convulsive status epilepticus intubated in pre-hospital settings meet the criteria for refractory status epilepticus.

INTRODUCTION: Mechanically ventilated patients admitted to the intensive care unit (ICU) for generalized convulsive status epilepticus (GCSE) are a heterogeneous population. Our objective was to evaluate the number of patients who fulfilled the diagnostic criteria for refractory GCSE and describe their initial management and prognosis. METHODS: This multicenter retrospective study was conducted in four French ICUs in Pitié-Salpêtrière University Hospital in Paris and in the Hospital of Jossigny. Mechanically ventilated patients admitted to the ICU for GCSE between, January 1, 2014, and, December 31, 2016, were included. Patients with anoxia and traumatic brain injury were excluded. Their pre-hospital and ICU medical records were reviewed. The collected data included pre-hospital clinical status, pre-hospital antiepileptic treatment, reason for mechanical ventilation, duration of general anesthesia, and prognosis in the ICU. A retrospective initial diagnosis based on the findings of the analysis of the clinical records was attributed to each patient. RESULTS: Among the 98 patients included, 88.8% (n = 87/98) fulfilled the diagnostic criteria for GCSE; of these cases, 16.1% (n = 14/87) were refractory. Eleven percent of the patients did not fulfill the criteria for GCSE at the time of initial management (retrospective diagnosis of single convulsive seizure, repetitive convulsive seizures, or psychogenic non-epileptic seizures). Most patients were intubated for coma (58.9%, n = 56/95, missing data: n = 3). In the ICU, the median [Q1-Q3] duration of general anesthesia before weaning was 12.3 h (5.0-18.0 h); 7% of the patients had a relapse of status epilepticus, and 2% died in the ICU. CONCLUSION: Among the cases of confirmed GCSE in the mechanically ventilated patients admitted to the ICU, 16.1% were refractory, with an overall good prognosis. A significant proportion of patients did not fulfill the diagnostic criteria for refractory GCSE.

Acute disseminated encephalomyelitisin the intensive care unit:clinical features and outcome of 20 adults.

OBJECTIVE: Because acute disseminated encephalomyelitis (ADEM) is a rare disease in adults admitted to the intensive care unit (ICU), we describe its characteristics and patient outcomes. DESIGN AND SETTING: A retrospective (2000-2006), observational, multicenter study was conducted in seven medical ICUs. Clinical, biological and neuroimaging features of patients diagnosed with ADEM were evaluated. Functional prognosis was graded using the modified Rankin (mR) scale. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: At ICU admission, the 20 patients' median (25th-75th percentile) Glasgow coma score (GCS) was 7 (4-13), temperature 39 (38-39) degrees C. Six (30%) patients had seizures, 17 (85%) had a motor deficit and 14 (70%) required mechanical ventilation. Fifteen (75%) patients had cerebrospinal fluid pleocytocis. All patients had white-matter lesions on their magnetic resonance images. All patients received high-dose steroids. Five (25%) patients died. Fourteen (70%) patients were able to walk without assistance (mR3] had significantly lower GCS (4 (3-4) vs. 12 (7-13), p=0.002) and more frequent seizures [4 (67%) vs. 2 (14%), p=0.02] at admission. CONCLUSIONS: Unlike previous reports, our results showed that ADEM requiring ICU admission is a severe disease causing high mortality, and 35% of the patients had persistent functional sequelae. Intensivists should be aware of ADEM's clinical features to initiate appropriate immunomodulating therapy.

Surgery and risk of Guillain-Barré syndrome: A French nationwide epidemiologic study.

OBJECTIVE: To assess the association between Guillain-Barré syndrome (GBS) and recent surgery based on French nationwide data. METHODS: Data were extracted from the French health administrative databases (SNIIRAM/PMSI). All patients hospitalized for GBS between 2009 and 2014 were identified by ICD-10 code G61.0 as main diagnosis. Patients previously hospitalized for GBS in 2006, 2007, and 2008 were excluded. Surgical procedures were identified from the hospital database. Hospitalizations for surgery with no infection diagnosis code entered during the hospital stay were also identified. The association between GBS and a recent surgical procedure was estimated using a case-crossover design. Case and referent windows were defined as 1-60 days and 366-425 days before GBS hospitalization, respectively. Analyses were adjusted for previous episodes of gastroenteritis and respiratory tract infection, identified by drug dispensing data. RESULTS: Of the 8,364 GBS cases included, 175 and 257 patients had undergone a surgical procedure in the referent and case windows, respectively (adjusted odds ratio [OR] = 1.53, 95% confidence interval [CI]: 1.25-1.88). A slightly weaker association was observed for surgical procedures with no identified infection during the hospitalization (OR = 1.40, 95% CI: 1.12-1.73). Regarding the type of surgery, only surgical procedures on bones and digestive organs were significantly associated with GBS (OR and 95% CI = 2.78 [1.68-4.60] and 2.36 [1.32-4.21], respectively). CONCLUSION: In this large nationwide epidemiologic study, GBS was moderately associated with any type of recent surgery and was more strongly associated with bone and digestive organ surgery.

Regulatory B cells in myasthenia gravis are differentially affected by therapies.

We analyzed the number and functionality of regulatory B (Breg) cells in well-defined myasthenia gravis patients. We first showed a decreased number of circulating CD19+ CD24++ CD38++ Breg cells and an altered functionality of Breg cells in untreated myasthenia gravis patients. Next, we demonstrated that the proportion of circulating Breg cells was restored in myasthenia gravis patients after thymectomy, probably as Breg cells could be sequestered in the myasthenia gravis thymus. In contrast, corticosteroid treatments did not restore and decreased even more the proportion of Breg cells in myasthenia gravis patients. These results clearly demonstrated that two distinct immunomodulatory therapies affect differentially Breg cells.

Resistant myasthenia gravis and rituximab: A monocentric retrospective study of 28 patients.

This retrospective study evaluated the efficiency and tolerance of rituximab in the management of resistant myasthenia gravis (MG). All patients who received rituximab for the treatment of MG between 2004 and 2015 at Pitié-Salpétrière University Hospital (Paris, France) were included. The efficacy of rituximab was evaluated every 6 months by the myasthenic muscle score (MMS), the Myasthenia Gravis Foundation of America - Clinical Classification (MGFA-CC), the MGFA Therapy Status and the Postintervention Status (PIS). All rituximab-related side effects were noted. Twenty-eight patients were included: 21 with anti-acetylcholine receptor antibodies, 3 with anti-muscle-specific tyrosine kinase antibodies and 4 seronegatives. The mean age at day 1 of RTX was 50.6 ± 12.0 years. Patients previously received 1-4 immunosuppressants. The mean follow-up was 27.2 months (range: 6-60 months). The mean total dose of rituximab was 4.8 ± 2.5 g. The initial median MMS (58.8 points) improved significantly at M6 (74.5 ± 15.0 points; p < 0.0001) and remained stable thereafter: at M12: 75.9 ± 14.0 points (p = 0.00014), at M36: 72.5 ± 13.1 points (p = 0.0013). Among 16 patients with initial severe symptoms (MGFA-CC class IV), 14 improved. The PIS showed efficacy in about 50% of patients: at M6, 12/28 (43%) patients were considered improved. This benefit remained stable thereafter: at M12: 12/24, at M24: 7/17, at M36: 6/12. One patient developed a delayed progressive multifocal leukoencephalopathy. Based on the PIS, rituximab may be efficient in 50% of patients with MG resistant to immunosuppressants.

Persistence of CD16+/CD56-/2B4+ natural killer cells: a highly dysfunctional NK subset expanded in ocular myasthenia gravis.

We report a case of myasthenia gravis associated with marked expansion of an unusual CD16(+)CD56(-)2B4(+) NK subset. These atypical cells were characterized by poor cytotoxicity against CD48(+) target cells and high proliferation due to 2B4/CD48 interaction. IL18, IFN-gamma and TGF-beta levels were profoundly different in this patient than in healthy donors. Immunosuppressive treatment induced disease remission and decreased the CD16(+)CD56(-)2B4(+)NK cells count. Our data suggest that expansion of this NK subset in myasthenia gravis patients may account for the deleterious NK cell functioning that occurs in this autoimmune disease.

Prehospital treatment with levetiracetam plus clonazepam or placebo plus clonazepam in status epilepticus (SAMUKeppra): a randomised, double-blind, phase 3 trial.

BACKGROUND: Generalised convulsive status epilepticus (GCSE) should be treated quickly. Benzodiazepines are the only drug treatment available so far that is effective before admission to hospital. We assessed whether addition of the antiepileptic drug levetiracetam to the benzodiazepine clonazepam would improve prehospital treatment of GCSE. METHODS: We did a prehospital, randomised, double-blind, phase 3, placebo-controlled, superiority trial to determine the efficacy of adding intravenous levetiracetam (2.5 g) to clonazepam (1 mg) in treatment of GCSE in 13 emergency medical service centres and 26 hospital departments in France. Randomisation was done at the Paris Descartes Clinical Research Unit with a list of random numbers generated by computer. Adults with convulsions lasting longer than 5 min were randomly assigned (1:1) by prehospital physicians to receive levetiracetam or placebo in combination with clonazepam. All physicians and paramedics were masked to group assignments. If the status epilepticus lasted beyond 5 min after drug injection, a second dose of 1 mg clonazepam was given. The primary outcome was cessation of convulsions within 15 min of drug injection. We analysed the modified intention-to-treat population that had received at least one injection of clonazepam and levetiracetam or placebo, excluding patients without valid consent and those randomised more than once. The trial is registered at EudraCT, number 2007-005782-35. FINDINGS: Between July 20, 2009, and Dec 15, 2012, 107 patients were randomly assigned to receive placebo and 96 were assigned to receive levetiracetam. The trial was discontinued on Dec 15, 2012 when interim analysis showed no evidence of a treatment difference, and 68 patients in each group were included in the modified intention-to-treat analysis. Convulsions stopped at 15 min of drug injection in 57 of 68 patients (84%) receiving clonazepam and placebo and in 50 of 68 patients (74%) receiving clonazepam and levetiracetam (percentage difference -10.3%, 95% CI -24.0 to 3.4). Three deaths, 19 of 47 (40 %) serious adverse events, and 90 of 197 (46%) non-serious events were reported in the levetiracetam group, and four deaths, 28 of 47 (60%) serious events, and 107 of 197 (54%) non-serious events were reported in the placebo group. INTERPRETATION: The addition of levetiracetam to clonazepam treatment presented no advantage over clonazepam treatment alone in the control of GCSE before admission to hospital. Future prehospital trials could assess the efficacy of clonazepam alone as a first-line treatment in status epilepticus and the efficacy of a second injection of clonazepam with another antiepileptic drug as second-line treatment. FUNDING: UCB Pharma.

Multidrug-resistant bacteria transmitted through high-density EEG in ICU.

PURPOSE: Prevention of multidrug resistant (MDR) bacterial contamination remains a major challenge in ICUs. Many hospital outbreaks involving MDR transmitted through environmental contamination have been reported. Bedside high-density EEG allow for dynamic cognitive evaluation in brain-injured patients and is used more and more frequently in clinical practice to evaluate brain function and predict outcome in severely neurologically impaired patients. Unfortunately, the material used for this procedure is not entirely disposable. METHOD: We performed a systematic analysis of MDR bacterial contamination in patients contaminated in our ICU using specific bacteriological methods. RESULTS: We report a proven case of cross-contamination of an extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae strain, and a possible case of cross-contamination of a carbapenem-resistant Acinetobacter baumannii strain. CONCLUSION: Cross-contamination of MDR bacteria is possible through high-density EEG material. However, appropriate procedures can decrease this risk.

Treatment of myasthenia gravis exacerbation with intravenous immunoglobulin: a randomized double-blind clinical trial.

BACKGROUND: The optimal dose of intravenous immunoglobulin (IVIG) in acute exacerbation of myasthenia gravis remains unknown. Increasing the treatment duration might provide added efficacy. OBJECTIVE: To determine the optimal dose of IVIG for treating myasthenia gravis exacerbation. DESIGN: Randomized double-blind placebo-controlled multicenter trial designed to demonstrate superiority of the 2 g/kg dose over the 1 g/kg dose of IVIG, conducted between November 13, 1996, and October 26, 2002. PARTICIPANTS: One hundred seventy-three patients aged 15 to 85 years with acute exacerbation of myasthenia gravis. INTERVENTION: Participants were randomly assigned to receive 1 g/kg of IVIG on day 1 and placebo on day 2 (group 1) vs 1 g/kg of IVIG on 2 consecutive days (group 2). MAIN OUTCOME MEASURE: Improvement in the myasthenic muscular score after 2 weeks. RESULTS: The mean improvements in the myasthenic muscular scores after 2 weeks were 15.49 points (95% confidence interval, 12.09-18.90 points) in group 1 and 19.33 points (95% confidence interval, 15.82-22.85 points) in group 2. However, the difference between the 2 groups was not significant (effect size, 3.84 [95% confidence interval, -1.03 to 8.71]; P = .12). CONCLUSION: This trial found no significant superiority of 2 g/kg over 1 g/kg of IVIG in the treatment of myasthenia gravis exacerbation.

Macrophage migration inhibitory factor (MIF) seems crucially involved in Guillain-Barré syndrome and experimental allergic neuritis.

Macrophage migration inhibitory factor (MIF) is a proinflammatory type 1 cytokine that plays a pathogenic role in several inflammatory and autoimmune diseases. The role of this cytokine in peripheral nerve inflammatory disease has not been evaluated. Therefore, to evaluate the role of macrophage migration inhibitory factor (MIF) in Guillain-Barré syndrome (GBS) and experimental allergic neuritis (EAN), we determined MIF circulating levels in a series of patients with GBS and healthy subjects with ELISA and evaluated the effect of two specific inhibitors of MIF, a neutralizing monoclonal antibody or a chemical inhibitor ISO1 on the course of murine EAN. The data show increased MIF plasma levels in GBS patients as compared to healthy controls (p<0.0001) and a progressive increase of MIF circulating concentration with patient's disability (p<0.0001). Both anti-MIF mAb and ISO1 favorably influenced the course of EAN. Treated mice had a lower cumulative severity score (p=0.001) and reduced disease duration than the control mice (p<0.03). MIF may promote immune reaction in GBS. Therapeutic effects of both anti-MIF mAb and ISO1 in EAN suggest that MIF could be a promising therapeutic target in inflammatory demyelinating peripheral nerve disorders.

Neuropsychiatric disturbances in presumed late-onset cobalamin C disease.

BACKGROUND: Combined methylmalonic aciduria and homocystinuria cobalamin C type (cobalamin C disease) is an inborn metabolic disorder consisting of an impaired intracellular synthesis of the 2 active forms of vitamin B12 (cobalamin), namely, adenosylcobalamin and methylcobalamin, that results in increased levels of methylmalonic acid and homocysteine in the blood and urine. Most patients present in the first year of life with systemic, hematological, and neurological abnormalities. Late-onset forms are rare and had not been comprehensively characterized. They could be easily misdiagnosed. OBJECTIVE: To describe clinical and biochemical features of the disease in 2 siblings affected with presumed late-onset cobalamin C disease. DESIGN: Case report and review of the literature. SETTING: Neurological intensive care unit of a university hospital. OBSERVATION: We describe 2 patients with neurological deterioration due to presumed cobalamin C disease. A 16-year-old girl was initially seen with psychosis and severe progressive neuropathy requiring mechanical ventilatory support and her 24-year-old sister had a 2-year disease course of subacute combined degeneration of the spinal cord. A metabolic workup displayed increased methylmalonic acid levels, severe hyperhomocysteinemia, and low plasma methionine levels. The diagnosis was then confirmed by demonstration of impaired synthesis of adenosylcobalamin and methylcobalamin in cultured skin fibroblasts and Epstein-Barr virus-infected lymphocytes. Under specific treatment the younger sister's condition dramatically improved. CONCLUSIONS: Although complementation studies have not been conducted, it is most likely these patients had cobalamin C disease. This study emphasizes the possibility of late-onset disease with purely neurological manifestations. Left untreated, this treatable condition can lead to death or irreversible damage to the nervous system. Screening for intracellular vitamin B12 dysmetabolism should, therefore, be considered in the investigation of adults with unexplained neurological disease, particularly when they are initially seen with a clinical picture suggestive of vitamin B12 deficiency.