Vanda A. Lennon

NMO-IgG predicts the outcome of recurrent optic neuritis

Objective: To determine the prognostic value of neuromyelitis optica (NMO)–immunoglobulin G (IgG) in patients with recurrent optic neuritis (ON). The aquaporin-4-specific serum autoantibody, NMO-IgG, is a biomarker for NMO and relapsing transverse myelitis. Recurrent ON may herald multiple sclerosis (MS) or NMO, or it may occur as an isolated syndrome. The prognosis and response to therapy differs in each of these contexts. Methods: We evaluated 34 patients who were tested for NMO-IgG between 2000 and 2007 and who had two or more episodes of ON without satisfying a diagnosis of MS or NMO prior to serologic testing. Clinical data were available for 25 Mayo Clinic patients (5 NMO-IgG positive and 20 NMO-IgG negative) and for an additional 9 seropositive patients whose serum was referred to the Mayo Clinic Neuroimmunology laboratory for testing. Results: Twenty percent of the patients with recurrent ON seen at Mayo Clinic were seropositive. All NMO-IgG-positive patients (vs 65% NMO-IgG-negative patients) had at least one attack with visual acuity in the affected eye worse than 20/200 (p = 0.05). In seropositive patients for whom long-term follow-up was possible (median 8.9 years after the initial ON), 6 of 12 (50%) experienced an episode of myelitis and fulfilled criteria for NMO. In contrast, 1 of 15 seronegative patients (6.7%) fulfilled McDonald criteria for MS (p = 0.03). Seropositive patients had a final visual score which was worse than that of seronegative patients (p = 0.02). Conclusions: Neuromyelitis optica (NMO)–immunoglobulin G seropositivity predicts poor visual outcome and development of NMO. Seropositive recurrent optic neuritis is a limited form of NMO.

A secondary progressive clinical course is uncommon in neuromyelitis optica

We compared the clinical course of 96 patients with neuromyelitis optica (NMO) to multiple sclerosis (MS) natural history data. Based on the distribution of follow-up data (median 6.1 year), we estimated that 21 NMO patients would convert to a secondary progressive course, but we observed only two conversions (p = 0.00002; relative risk = 0.08). The disparate natural histories of MS and NMO suggest dissociation between relapses and clinical progression in CNS demyelinating diseases.

Posterior reversible encephalopathy syndrome in neuromyelitis optica spectrum disorders

Background: Posterior reversible encephalopathy syndrome (PRES) is characterized by vasogenic subcortical edema without infarction. It has been associated with hypertensive crises and with immunosuppressive medications but not with neuromyelitis optica (NMO). Methods: We reviewed the clinical and neuroimaging features of five NMO–immunoglobulin G (IgG) seropositive white women who experienced an episode of PRES and had a coexisting NMO spectrum disorder (NMOSD). We also tested for the aquaporin-4 (AQP4) water channel autoantibody (NMO-IgG) in 14 patients from an independently ascertained cohort of individuals with PRES. Results: All five patients developed abrupt confusion and depressed consciousness consistent with PRES. The encephalopathy resolved completely within 7 days. Comorbid conditions or interventions recognized to be associated with PRES included orthostatic hypotension with supine hypertension, plasma exchange, IV immunoglobulin treatment, and high-dose IV methylprednisolone. Brain MRI studies revealed bilateral T2-weighted (T2W) hyperintense signal abnormalities, primarily in frontal, parieto-occipital, and cerebellar regions. Three patients had highly symmetric lesions and three had gadolinium-enhancing lesions. Follow-up neuroimaging revealed partial or complete disappearance of T2W hyperintensity or gadolinium-enhancing lesions in all five patients. Patients with PRES without NMOSD were uniformly NMO-IgG seronegative. Conclusions: Brain lesions in some patients with neuromyelitis optica spectrum disorder (NMOSD) may be accompanied by vasogenic edema and manifest as posterior reversible encephalopathy syndrome (PRES). Water flux impairment due to aquaporin-4 autoimmunity may predispose to PRES in patients with NMOSD who experience blood pressure fluctuations or who are treated with therapies that can cause rapid fluid shifts. ADC = apparent diffusion coefficient; AQP4 = aquaporin-4; DWI = diffusion-weighted imaging; FLAIR = fluid-attenuated inversion recovery; Gd = gadolinium; IgG = immunoglobulin G; IVIg = IV immunoglobulin; IVMP = IV methylprednisolone; LETM = longitudinally extensive transverse myelitis; NMO = neuromyelitis optica; NMOSD = neuromyelitis optica spectrum disorder; ON = optic neuritis; PLEX = plasma exchange; PRES = posterior reversible encephalopathy syndrome; T2W = T2-weighted.

The spectrum of autoimmune autonomic neuropathies

We analyzed the clinical characteristics of 18 patients (13 female, 5 male) who had autoimmune autonomic neuropathy (AAN) and ganglionic acetylcholine receptor (AChR) autoantibodies. Mean age was 61.4 years (standard deviation, 12.0 years). Ten patients had subacute symptom onset, six with an antecedent event. Eight patients had chronic AAN, characterized by insidious symptom onset, without antecedent event, and gradual progression. A majority of patients with high antibody values (>1.00 nmol/L) had a combination of sicca complex (marked dry eyes and dry mouth), abnormal pupillary light response, upper gastrointestinal symptoms, and neurogenic bladder. Chronic AAN segregated into two subgroups. One subgroup (N = 4) had low antibody titer (0.09 ± 0.01 nmol/L) and a paucity of cholinergic symptoms. It was indistinguishable from pure autonomic failure. The other subgroup (N = 4) had high antibody titer (11.6 ± 2.08 nmol/L), sicca complex, abnormal pupils, and neurogenic bladder; three had severe upper gastrointestinal dysfunction. Higher antibody titers correlated with greater autonomic dysfunction and more frequent cholinergic dysautonomia. These observations expand the clinical spectrum of AAN to include chronic cases, some being indistinguishable from pure autonomic failure, and support the concept that ganglionic AChR antibodies are important diagnostically and pathophysiologically in acquired dysautonomia.Ann Neurol 2003;53:752–758

Paraneoplastic isolated myelopathy Clinical course and neuroimaging clues

Objective: To report the clinical phenotype and outcome of isolated paraneoplastic myelopathy. Methods: We systematically reviewed clinical, serologic, and MRI data for 31 patients (20 female) who presented with an isolated myelopathy and coexisting cancer: carcinoma (lung, 9; breast, 7; kidney, 2; thyroid, 2; ovary/endometrium, 2), melanoma (2), or other cancer (3), or a paraneoplastic autoantibody with strong cancer association (amphiphysin–immunoglobulin G [IgG], 9; collapsin response-mediator protein 5–IgG, 9; Purkinje-cell cytoplasmic autoantibody type 1, 2; antineuronal nuclear autoantibody [ANNA]–1, 1; ANNA-3, 1). Results: Of 31 patients who presented with a progressive myelopathy, symptom onset was subacute in 16 (52%). The median age was 62 years. CSF abnormalities included elevated protein (>45 mg/dL), 22; pleocytosis, 15; excess oligoclonal bands (normal <4), 7. MRI cord abnormalities identified in 20 patients were longitudinally extensive (>3 vertebral segments), 14; symmetric tract or gray matter–specific signal abnormality, 15 (enhancing in 13). Myelopathy preceded cancer diagnosis in 18 patients (median interval 12 months; range 2–44). After myelopathy onset, 26 patients underwent oncologic treatment, immunosuppressive treatment (median delay to commencing immunotherapy 9.5 months [range 1–54]), or both; only 8 improved (31%). At last neurologic evaluation (median interval after onset 17 months; range 1–165 months), 16 patients (52%) were wheelchair-dependent (median time from onset to wheelchair 9 months [range 1–21]). Ten patients died after a median of 38 months from symptom onset (range 7–152). Conclusion: Symmetric, longitudinally extensive tract or gray matter–specific changes on spinal MRI should raise suspicion for a paraneoplastic myelopathy. Resulting disability is often severe. Only a minority of patients improve with treatment.

Molecular Diversity of Neuronal-Type Calcium Channels Identified in Small Cell Lung Carcinoma

Using the polymerase chain reaction (PCR), we identified RNA transcripts for two distinct classes of neuronal-type voltage-gated Ca2+ channels (VGCC) in a prototypic small cell lung carcinoma (SCLC) cell line, SCC-9. Oligonucleotide primers were designed to encode amino acid sequences common to alpha 1-subunits of known neuronal VGCC classes. Sequencing of complementary DNA (cDNA) clones derived from two independent PCR products revealed that one corresponded to a brain class A VGCC fragment predicted to encode a P-type VGCC (insensitive to dihydropyridines and omega-conotoxin) characteristic of cerebellar Purkinje cells but not previously identified in humans. The second PCR product was identical (except for one conservative nucleotide difference) to a fragment of the class D VGCC of neurons and neuroendocrine cells, which encodes an L-type VGCC (sensitive to dihydropyridines). By Northern blot analyses, both cDNAs hybridized to messenger RNAs (mRNAs) obtained from SCC-9; class D hybridized additionally to human cerebral cortical mRNA, but neither hybridized to mRNA from the skeletal muscle cell line TE671. Although no cDNA corresponding to class B VGCC (N-type) was identified, SCLCs are known to express VGCC that are sensitive to omega-conotoxin and coprecipitate with 125I-labeled-omega-conotoxin when complexed with serum IgG from patients with the Lambert-Eaton myasthenic syndrome. The multiple classes of neuronal-type VGCC expressed in SCLC could conceivably have both unique and related antigenic determinants that may give rise to antineuronal autoimmune responses. This would account for a spectrum of paraneoplastic neurologic disorders including the Lambert-Eaton syndrome and subacute cerebellar degeneration.

Immunotherapy-responsive dementias and encephalopathies.

The diagnosis of an autoimmune dementia requires the detection of objective improvements in cognitive decline (usually subacute in onset with a fluctuating course) after a course of immunotherapy. Serum and CSF antibody markers of autoimmunity (particularly those with neural antigen specificity) as well as other CSF markers of inflammation increase the suspicion for an autoimmune cause. The detection of neural autoantibodies should raise concern for a paraneoplastic etiology and may inform a targeted oncologic evaluation (eg, NMDA receptor antibodies are associated with teratoma). MRI, EEG, functional imaging, and neuropsychological evaluations provide objective evidence of neurologic dysfunction by which the success of immunotherapy may be measured. Most treatment information emanates from retrospective case series and expert opinion. Nonetheless, early intervention allows reversal of deficits in many patients. Chronic treatment is often required to maintain remission.

Rare combination of myasthenia and motor neuronopathy, responsive to Msc-Ntf stem cell therapy

A 75-year-old man was referred to the Hadassah Medical Center with a 6-month history of progressive limb weakness, dysarthria, and cognitive deterioration. His past medical history included prostate hyperplasia, hypothyroidism, diabetes mellitus, cardiac arrhythmias controlled by pacemaker implantation (1997), and hypertension. Autoimmune myasthenia gravis (MG) had been diagnosed 2 years earlier, based on symptoms of fluctuating fatigue, dysarthric speech, eyelid ptosis, and seropositivity for muscle acetylcholine receptor (AChR) binding antibody. MRI did not reveal thymic enlargement, and malignancy markers (and whole-body computed tomography) were negative. Moderate improvement followed treatment, initially with intravenous immune globulin and later with low dose corticosteroids, pyridostigmine, and azathioprine. The patient was evaluated previously at the Mayo Clinic (Rochester, Minnesota) and had been diagnosed with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The diagnosis was based on the cognitive exam and clinical features of progressive diffuse upper and lower motor neuron dysfunction with electromyographic findings (low motor amplitudes, no focal slowing or conduction blocks, no postexercise facilitation, presence of diffuse fibrillation and fasciculation potentials, and large complex motor unit potentials in all limbs) fulfilling the El-Escorial criteria for ALS. MRI and positron emission tomography scans of the brain showed moderate atrophy predominantly affecting the frontal and temporal lobes. Spinal fluid was acellular with slightly elevated total protein (50 mg%). Autoimmune serology revealed antibodies specific for muscle (AChR binding 9.47 nmol/L [normal 0.00–0.02]; AChR modulating 100% loss [normal 0–20%]; striational 15,360 [normal <60]) and thyroglobulin, and antinuclear antibody. On admission, the patient had memory impairment and signs of frontotemporal functional deficits, typical of FTD. Dysarthria rendered speech totally incomprehensible. He had mild eyelid ptosis bilaterally (without extraocular muscle weakness or diplopia) and was markedly quadriparetic (confined to wheelchair) with bilateral foot drop. Distal hand and foot muscles were moderately atrophic, and fasciculations were prominent in all limbs. Deep tendon reflexes were brisk in arms and legs (except hypoactive Achilles reflexes), and an extensor plantar response was evoked bilaterally. Superficial sensation was normal, and vibration sense was reduced slightly distally in the legs. Due to the diagnosis of MG, the patient did not meet inclusion criteria for the Hadassah clinical trial in ALS with autologous enhanced mesenchymal stem cells (MSCNTF, BrainstormVR , Petach Tikva; NCT01051882). The Hadassah Ethics Committee issued a special license for treatment on a compassionate basis. MSC-NTF (prepared from the patient’s bone marrow) were injected intrathecally (1.5 3 10 per kilogram of body weight) and at 24 sites along the biceps and triceps muscles of the right arm (1.5 3 10 per site). The intrathecal and intramuscular administration of the cells were chosen based on previous animal and clinical studies from our groups, which showed good migration of the intrathecally injected cells to the CNS and amelioration of the “dying-back” phenomenon by intramuscularly injected MSC in early stages of ALS in the SOD mouse model (unpublished data and Dadon-Nachum et al.). For the next 2 days the patient had a low-grade fever, headache, and was more confused, but at discharge, these problems had completely subsided. Treatment with azathioprine (125 mg/day) was discontinued 1 month before the injection and readministered 30 days after the treatment. Pyridostigmine (60 mg 3 times daily) and low dose oral prednisolone (10 mg/day) were continued. At 1 month after transplantation, the patient and his family reported significant improvement in cognition, speech, and muscle power. He was able to walk at least 20 meters without any support. The dysarthria improved to the extent he was able to clearly deliver a speech to an audience. ALS Functional Score Scale-Revised (ALSFRS-R, performed at all time points by the same evaluator and confirmed by a second senior examiner) score rose from 36 to 44, and respiratory forced vital capacity (FVC) and cognitive function also improved significantly (Supplementary Table 1, which is available online, and Fig. 1). VC 2013 Wiley Periodicals, Inc.

NMDA Receptor Encephalitis: Late Treatment Also Effective

IGURE. Anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis is a severe form of encephalitis associated with antibodies against NR1-NR2 heteromers of the NMDA receptor.1 Although more common in woman with ovarian teratomas, cases have been reported in males and females without detectable neoplasm.1 Early treatment offers the best outcomes and often includes tumor resection and immunosuppression.2 We describe a tumor-negative, symptomatic girl who went undiagnosed for more than 2 years before immunotherapy was begun. Her symptoms improved despite this late treatment. A 9-year-old otherwise healthy African-American girl presented with headaches and new-onset seizures. She subsequently developed facial and extremity dyskinesias, encephalopathy with visual hallucinations, agitated behavior, and incomprehensible speech (Fig A). The patient continued to decline, ultimately developing autonomic instability with tachycardia and elevated blood pressure leading to respiratory failure and cardiac arrest requiring mechanical ventilation. Serial head magnetic resonance imaging, including fluid-attenuated inversion recovery and spectroscopy, were negative. Cerebrospinal fluid was inflammatory (leukocytes 41 per mm3, predominantly lymphocytes; glucose 69 mg/dL; protein 21 mg/dL) but without viral antigens. Electroencephalography showed bihemispheric slowing, maximal over the right temporal region. Extensive infectious, metabolic, and autoimmune evaluations were negative except for detection of glutamate decarboxylase 65 autoantibody in serum (0.07 nmol/L; normal range 0.00-0.02 nmol/L) but not in cerebrospinal fluid. Serum antiphospholipid antibodies were negative. Total body magnetic resonance imaging and metaiodobenzylguanidine scintigraphy for occult malignancy were negative. Suspicion of autoimmune encephalitis prompted a 5-day course of intravenous immunoglobulin therapy (0.4 g/kg/day) and methylprednisolone (40 mg/kg/ A) Pre-treatment; 9-year-old girl presents with facial and extremity dysinesias, acquired mutism, insomnia, and an inability to walk. (B) Postreatment; 13-year-old girl now 2 years post-treatment is ambulatory with inimal dyskinesias. Cognitive deficits remain. (Videos accompanying hese images may be viewed in the online version of the article at http:// * Communications should be addressed to: Dr. Hole; Stanford University School of Medicine; 108 Pope St.; Menlo Park, CA 94025. E-mail address: mhole@stanford.edu

Animal extremists' threats to neurologic research continue: Neuroreality IIAuthor Response

Editors’ Note: In WriteClick this week, the discussion centers on the Beversdorf et al. article, “Animal extremists’ threats to neurologic research continue: Neuroreality II,” and the controversies surrounding animal experimentation. Dr. Pistollato asks scientists to consider return on investment when beginning or continuing animal research, while Drs. Akhtar and Lopresti-Goodman both call for researchers to engage with critics and opponents in order to move science forward. The authors respond. Dr. Dees emphasizes that while there are many questions open to healthy debate, animal researchers should not be harassed. —Megan Alcauskas, MD, and Robert C. Griggs, MD