Paraneoplastic neurologic disorders (PND) are a heterogeneous group of immune-mediated neurological disorders associated with systemic cancers. When a PND is diagnosed prompt identification and treatment of the associated tumor is important as PND stabilization and in some cases improvement have been reported after tumor treatment. The cancer however, may be small and difficult to detect or the onset of the PND may precede the development of the cancer by months or years. In the latter cases patients often initially present to neurologists or internists who will need assistance from their oncology colleagues to uncover the cancer. It is therefore important to be aware of the associations of common cancers with specific PND syndromes and the significance in some PND of the presence in serum and/or cerebrospinal fluid (CSF) of specific anti-neuronal antibodies. Together, this information can focus the search for the tumor or support continued vigilance. Previously thought to be poorly responsive to therapies, it is now recognized that there is a subgroup of PND, mostly associated with antibodies to antigens on the neuronal cell surface that are highly treatment responsive. Treatments aimed at the PND are mostly immunosuppressive and include corticosteroids, plasma exchange and intravenous immunoglobulins (IVIg). Immunosuppressive chemotherapeutics and B-cell targeting drugs such as rituximab may also be useful. While cancer patients tolerate these therapies there is the risk of increased toxicity when combined with tumor-directed treatments and treatment plans should be coordinated between specialists.
paraneoplastic; neurologic; disorder; anti-neuronal; antibody; autoimmune; immune-mediated; immunosuppression; plasma exchange; intravenous immunoglobulins
Relapsing symptoms post herpes simplex virus 1 (HSV) encephalitis (HSVE) usually occur a few weeks after viral therapy and represent either 1) a true viral relapse of HSVE (CSF PCR positive for HSV, new necrotic lesions on brain MRI, and response to acyclovir therapy) or 2) a disorder postulated to be immune-mediated (CSF negative for HSV, no new necrotic lesions, and no response to acyclovir).1,2 It has been suggested that this immune-mediated disorder may be related to NMDA receptor (NMDAR) antibodies,3 and we recently reported a child in whom relapsing symptoms post HSVE were the presentation of anti-NMDAR encephalitis.4 We report an adult with this disorder, demonstrate that synthesis of NMDAR antibodies began after HSVE, and show that relapsing symptoms were due to steroid-responsive anti-NMDAR encephalitis.
To report the clinical features of 20 newly diagnosed patients with GABAB receptor (GABABR) antibodies and determine the frequency of associated tumors and concurrent neuronal autoantibodies.
Clinical data were retrospectively obtained and evaluated. Serum and CSF samples were examined for additional antibodies using methods previously reported.
Seventeen patients presented with seizures, memory loss, and confusion, compatible with limbic encephalitis (LE), one patient presented with ataxia, one patient presented with status epilepticus, and one patient presented with opsoclonus-myoclonus syndrome (OMS). Nineteen (95%) patients eventually developed LE during the course of the disease. Small-cell lung cancer (SCLC) was identified in 10 (50%) patients, all with LE. Treatment and outcome was available from 19 patients: 15 showed complete (n = 7) or partial (n = 8) neurologic improvement after steroids, IV immunoglobulins, or plasma exchange and oncologic treatment when indicated; 1 patient died of tumor progression shortly after the first cycle of immunotherapy, and 3 were not treated. Five patients with SCLC had additional onconeuronal antibodies (Ri, amphiphysin, or SOX1), and 2 without tumor had GAD65 and NMDAR antibodies, respectively. GABABR antibodies were not detected in serum of 116 patients with SCLC without neurologic symptoms.
Our study confirms GABABR as an autoantigen of paraneoplastic and nonparaneoplastic LE and expands the phenotype of GABABR antibodies to ataxia, OMS, and status epilepticus. The long-term prognosis is dictated by the presence of a tumor. Recognition of syndromes associated with GABABR antibodies is important because they usually respond to treatment.
To retrospectively determine the frequency of N-Methyl-D-Aspartate (NMDA) receptor (NMDAR) autoantibodies in patients with different forms of dementia.
Clinical characterization of 660 patients with dementia, neurodegenerative disease without dementia, other neurological disorders and age-matched healthy controls combined with retrospective analysis of serum or cerebrospinal fluid (CSF) for the presence of NMDAR antibodies. Antibody binding to receptor mutants and the effect of immunotherapy were determined in a subgroup of patients.
Serum NMDAR antibodies of IgM, IgA, or IgG subtypes were detected in 16.1% of 286 dementia patients (9.5% IgM, 4.9% IgA, and 1.7% IgG) and in 2.8% of 217 cognitively healthy controls (1.9% IgM and 0.9% IgA). Antibodies were rarely found in CSF. The highest prevalence of serum antibodies was detected in patients with “unclassified dementia” followed by progressive supranuclear palsy, corticobasal syndrome, Parkinson’s disease-related dementia, and primary progressive aphasia. Among the unclassified dementia group, 60% of 20 patients had NMDAR antibodies, accompanied by higher frequency of CSF abnormalities, and subacute or fluctuating disease progression. Immunotherapy in selected prospective cases resulted in clinical stabilization, loss of antibodies, and improvement of functional imaging parameters. Epitope mapping showed varied determinants in patients with NMDAR IgA-associated cognitive decline.
Serum IgA/IgM NMDAR antibodies occur in a significant number of patients with dementia. Whether these antibodies result from or contribute to the neurodegenerative disorder remains unknown, but our findings reveal a subgroup of patients with high antibody levels who can potentially benefit from immunotherapy.
Acquired neuromyotonia is increasingly recognized as an autoimmune disorder, frequently associated with antibodies against voltage-gated potassium channel complex proteins. We present a case of acquired neuromyotonia as the heralding symptom of recurrent thymoma in a patient with myasthenia gravis.
A report of a single case of a 53-year-old man with myasthenia gravis and a prior thymectomy presenting with 2 months of diffuse, involuntary muscle twitching in the absence of myasthenic symptoms, electrophysiologically confirmed to be neuromyotonia. Further evaluation revealed the recurrence of malignant thymoma, accompanied by refractory arrhythmia. Serologic and cerebrospinal fluid testing confirmed the presence of antibodies directed against 2 voltage-gated potassium channel–associated proteins: LGI1 and Caspr2.
CONCLUSIONS AND RELEVANCE
This case highlights the overlap of myasthenia, neuromyotonia, and thymoma, emphasizing the importance of appropriate tumor screening in the presence of either of the former 2 conditions.
To describe the clinical features and outcome of anti–NMDA receptor (NMDAR) encephalitis in patients ≥45 years old.
Observational cohort study.
In a cohort of 661 patients with anti-NMDAR encephalitis, we identified 31 patients ≥45 years old. Compared with younger adults (18–44 years), older patients were more often male (45% vs 12%, p < 0.0001), had lower frequency of tumors (23% vs 51%, p = 0.002; rarely teratomas), had longer median time to diagnosis (8 vs 4 weeks, p = 0.009) and treatment (7 vs 4 weeks, p = 0.039), and had less favorable outcome (modified Rankin Scale score 0–2 at 2 years, 60% vs 80%, p < 0.026). In multivariable analysis, younger age (odds ratio [OR] 0.15, confidence interval [CI] 0.05–0.39, p = 0.0001), early treatment (OR 0.60, CI 0.47–0.78, p < 0.0001), no need for intensive care (OR 0.09, CI 0.04–0.22, p < 0.0001), and longer follow-up (p < 0.0001) were associated with good outcome. Rituximab and cyclophosphamide were effective when first-line immunotherapies failed (OR 2.93, CI 1.10–7.76, p = 0.031). Overall, 60% of patients older than 45 years had full or substantial recovery at 24 months follow-up.
Anti-NMDAR encephalitis is less severe in patients ≥45 years old than in young adults, but the outcome is poorer in older patients. In this age group, delays in diagnosis and treatment are more frequent than in younger patients. The frequency of underlying tumors is low, but if present they are usually carcinomas instead of teratomas in younger patients. Early and aggressive immunotherapy will likely improve the clinical outcome.
The recent discovery of a category of autoimmune encephalitis associated with antibodies against neuronal cell-surface and synaptic proteins has renewed interest for autoimmune causes of epilepsy. The identification of autoimmune encephalitis has changed paradigms in the diagnosis and management of several novel and treatable syndromes that occur with seizures and status epilepticus previously attributed to viral or idiopathic etiologies. This review focuses on the novel group of autoimmune encephalitis and also discusses some classical paraneoplastic syndromes that constitute another group of autoimmune disorders that may result in seizures.
autoimmune; encephalitis; epilepsy; seizures; status epilepticus
N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis is an autoimmune encephalitis that can be paraneoplastic and usually responds to treatment. It is quickly becoming the most common paraneoplastic encephalitis.
We present a case of a woman in her late 30s who developed psychiatric symptoms that progressed to encephalopathy, seizures, autonomic instability, and hyperkinetic movements. The patient was found to have an ovarian teratoma and serum and cerebrospinal fluid NMDAR antibodies. Despite resection of the teratoma and treatment with immunosuppressive therapy, the patient progressed to a minimally conscious state. She was supported medically in our institution for 25 months. During her hospitalization, she was treated with multiple immunosuppressive agents. With each treatment, we analyzed the serum and cerebrospinal fluid for NMDAR antibodies. While there was some initial reduction in the serum antibodies, the spinal fluid antibodies remained persistently elevated. The patient did not have any clinical improvement and eventually died after the family decided to withdraw care.
CONCLUSIONS AND RELEVANCE
As far as we know, this case represents the longest active treatment without improvement of a patient with anti-NMDAR encephalitis. The patient had persistently high cerebrospinal fluid and serum antibody titers, which may be of prognostic significance.
Anti-NMDA receptor encephalitis is an autoimmune disorder in which antibodies attack NMDA (N-methyl-D-aspartate)-type glutamate receptors at central neuronal synapses. Symptoms include a highly characteristic set of neurologic deficits, but also prominent psychiatric manifestations that often bring mental health professionals into the course of care. Distinct phases of illness have become increasingly appreciated, and include a range of psychotic symptoms early in the course of the disease followed by more severe fluctuations in consciousness with neurologic involvement, and ultimately protracted cognitive and behavioral deficits. Young women are most commonly impacted and an ovarian teratoma is sometimes associated with the syndrome. Patients respond well to immunotherapy, but psychiatric symptoms can be challenging to manage. We provide an up to date review of this disorder and highlight the role of psychiatry in diagnosis, symptomatology, and treatment.
NMDA receptor; autoimmune; synapse; paraneoplastic; schizophrenia
A 35-year-old man developed progressive memory problems and personality changes over the course of 6 months. This amnesia culminated in overt functional impairment as he began getting lost in familiar places and paid his rent multiple times in one day. He then displayed increased aggression and was admitted to hospital after assaulting a family member.
To report the clinical features of 20 pediatric patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.
Review of clinical data, long-term follow-up, and immunological studies performed in a single center in Spain in the last 4 years.
The median age of the patients was 13 years (range, 8 months-18 years), 70% were female. In 12 patients (60%) the initial symptoms were neurologic, usually dyskinesias or seizures, and in the other 40% psychiatric. One month into the disease, all patients had involuntary movements and alterations of behavior and speech. All patients received steroids, intravenous immunoglobulin (IVIG) or plasma exchange, and 7 rituximab or cyclophosphamide. With a median follow up of 17.5 months, 85% had substantial recovery, 10% moderate or severe deficits, and 1 died. Three patients had previous episodes compatible with anti-NMDAR encephalitis, 2 of them with additional relapses after the diagnosis of the disorder. Ovarian teratoma was identified in two patients, one at onset of encephalitis and the other one year later. Two novel observations (one patient each) include, the identification of an electroencephalographic pattern (“extreme delta brush”) considered characteristic of this disorder, and the development of anti-NMDAR encephalitis after herpes simplex encephalitis (HSE).
The initial symptoms of pediatric anti-NMDAR encephalitis vary from those of the adults (more neurologic and less psychiatric in children), the development of a mono-symptomatic illness is extremely rare (except in relapses), and most patients respond to treatment. Our study suggests a link between post-HSE choreoathetosis and anti-NMDAR encephalitis.
Autoimmune encephalitis; Choreoathetosis; Herpes simplex encephalitis; Child; Extreme delta brush
Patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis often develop prominent psychiatric manifestations. The frequency and type of isolated psychiatric episodes (pure psychiatric symptoms without neurological involvement) either as initial presentation of the disease or as relapse are unknown.
To determine the frequency, symptoms, and outcome of isolated psychiatric episodes in a cohort of patients with anti-NMDAR encephalitis.
Observational cohort of patients diagnosed over a 5 year period (median follow-up 2 years).
Patients and setting
571 patients with IgG antibodies against the NR1 subunit of the NMDAR were included in the study. Antibody studies were performed at the Universities of Pennsylvania and Barcelona, and clinical information was obtained by the authors or referring physicians.
Main Outcome Measures
Frequency, type of symptoms, and outcome of patients with anti-NMDAR encephalitis and isolated psychiatric manifestations.
23/571 patients (4%) developed isolated psychiatric episodes, 5 at disease onset and 18 during relapses. For all 23 patients, age (median 20 years), gender (91% female), and tumor association (43%, ovarian teratoma) were similar to the population at large. Predominant symptoms included, delusional thinking (74%), mood disturbances (70%, usually manic), and aggression (57%). Brain MRI was abnormal in 10/22 (45%) and CSF showed pleocytosis in 17/22 (77%). Eighty three percent of the patients had full/substantial recovery after immunotherapy and tumor resection when appropriate. After relapse, 17/18 (94%) patients returned to a similar or better pre-relapse functional level.
Isolated psychiatric episodes are rare but can occur as initial onset or relapse of anti-NMDAR encephalitis. Recognition of these episodes is important because they respond to immunotherapy. In patients with new onset psychosis, history of encephalitis, subtle neurological symptoms, and/or abnormal ancillary tests should prompt screening for NMDAR antibodies.
Anti-AMPAR encephalitis is a recently discovered disorder characterized by the presence of antibodies in serum or cerebrospinal fluid against the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. Here, we examine the antigenic specificity of anti-AMPAR antibodies, screen for new patients, and evaluate functional effects of antibody treatment of neurons.
We developed a fusion protein (FP)-based western blotting test for anti-AMPAR encephalitis antibodies. Antibody specificity was also evaluated using immunocytochemistry of HEK293 cells expressing deletion mutants of AMPAR subunits. Purified patient immunoglobulin G (IgG) or AMPAR antibody-depleted IgG was applied to live neuronal cultures; amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs) were measured to evaluate functional effects of antibodies.
Using both immunocytochemistry and FP western blots, we defined an antigenic region of the receptor in the bottom lobe of the amino terminal domain. Additionally, we used FPs to screen 70 individuals with neurologic symptoms of unknown cause and 44 patients with no neurologic symptoms or symptoms of known neuroimmunological origin for anti-AMPAR antibodies. Fifteen of the 70 individuals had anti-AMPAR antibodies, with broader antigenic reactivity patterns. Using purified IgG from an individual of the original cohort of anti-AMPAR encephalitis patients and a newly discovered patient, we found that application of IgG from either patient cohort caused an AMPAR antibody-dependent decrease in the amplitude and frequency of mEPSCs in cultured neurons.
These results indicate that anti-AMPAR antibodies are widespread and functionally relevant; given the robust response of patients to immunomodulation, this represents a significant treatable patient population.
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder in which the use of immunotherapy and the long-term outcome have not been defined.
In this multi-institutional observational study (2007-2012), all patients with GluN1 antibodies were assessed at symptom onset and 4, 8, 12, 18, and 24 months using the modified Rankin Scale (mRS). Treatment included first-line immunotherapy (steroids, intravenous immunoglobulin, plasmapheresis), second-line immunotherapy (rituximab, cyclophosphamide), and tumor removal. Predictors of outcome were determined at the Universities of Pennsylvania and Barcelona using generalized linear mixed models with binary distribution.
577 patients (1-85 years, median 21) were studied, 212 were children (<18 years). Treatment effects and outcome were assessable in 501 (median follow-up 24 months): 472 (94%) underwent first-line immunotherapy or tumor removal, resulting in improvement within four weeks in 251 (53%). Of 221 patients who failed first-line therapy, 125 (57%) received second-line immunotherapy resulting in better outcome than those who did not (OR 2·69, CI 1·24-5·80, p=0·012). During the first 24 months, 394/501 reached good outcome (mRS 0-2; median 6 months), and 30 died. At 24 month follow-up 204/252 (81%) had good outcome. Outcomes continued to improve for up to 18 months after symptom onset. Predictors of good outcome were early treatment (OR 0·62, CI 0·50-0·76, p<0·0001) and lack of ICU admission (OR 0.12, CI 0·06-0·22,p<0·0001). 45 patients had one or multiple relapses (representing a 12% risk within 2 years); 46/69 (67%) relapses were milder than previous episodes (p<0·0001). In 177 children, predictors of good outcome and the magnitude of effect of second-line immunotherapy were comparable to those of the entire cohort.
Patients with anti-NMDAR encephalitis respond to immunotherapy. Second-line immunotherapy is usually effective when first-line therapies fail. Recovery can take more than 18 months.
anti-NMDA-receptor antibodies; encephalitis; paraneoplastic; teratoma; behavior; seizures; treatment; outcome
To report a novel cell-surface autoantigen of encephalitis that is a critical regulatory subunit of the Kv4.2 potassium channels.
Four patients with encephalitis of unclear etiology and antibodies with a similar pattern of neuropil brain immunostaining were selected for autoantigen characterization. Techniques included immunoprecipitation, mass spectrometry, cell-base experiments with Kv4.2 and several dipeptidyl-peptidase-like protein-6 (DPPX) plasmid constructs, and comparative brain immunostaining of wild-type and DPPX-null mice.
Immunoprecipitation studies identified DPPX as the target autoantigen. A cell based assay confirmed that all 4 patients, but not 210 controls, had DPPX antibodies. Symptoms included agitation, confusion, myoclonus, tremor, and seizures (one case with prominent startle response). All patients had pleocytosis, and three had severe prodromal diarrhea of unknown etiology. Given that DPPX “tunes up” the Kv4.2 potassium channels (involved in somatodendritic signal integration and attenuation of dendritic backpropagation of action potentials), we determined the epitope distribution in DPPX, DPP10 (a protein homologous to DPPX) and Kv4.2. Patients’ antibodies were found specific for DPPX, without reacting with DPP10 or Kv4.2. The unexplained diarrhea led to demonstrate a robust expression of DPPX in the myenteric plexus, which strongly reacted with patients’ antibodies. The course of neuropsychiatric symptoms was prolonged and often associated with relapses while decreasing immunotherapy. Long-term follow-up showed substantial improvement in 3 patients (1 is lost to follow-up).
Antibodies to DPPX associate with a protracted encephalitis characterized by CNS hyperexcitability (agitation, myoclonus, tremor, seizures), pleocytosis, and frequent diarrhea at symptom onset. The disorder is potentially treatable with immunotherapy.
Antibodies; encephalitis; autoimmune; DPP6; DPPX; potassium channels
Cell-based assays (CBA) have increased the sensitivity of the neuromyelitis optica (NMO)-IgG/aquaporin-4-antibody detection compared to classical tissue-based indirect assays. We describe the sensitivity of an optimized immunohistochemistry (IHC-o) to detect NMO-IgG/aquaporin-4-antibody in comparison with that of two CBA: an in-house (CBA-ih) and a commercial (CBA-c) assay (Euroimmun, Germany). Coded serum from 103 patients with definite NMO and 122 inflammatory controls were studied by IHC-o, CBA-ih, and CBA-c. IHC-o used the same protocol described to detect antibodies against cell surface antigens. CBA-ih used live cells transfected with the aquaporin-4-M23-isoform. The sensitivity of the IHC-o was 74.8% (95% confidence interval [CI] 65-83) and was similar to that of the CBA-ih 75.7% (95% CI 66-84) and the CBA-c 73.8% (95% CI 64-82). The specificity of the three assays was 100% (95% CI 97-100). Interassay concordance was high, 100 of 103 samples were coincident in all techniques. The optimized immunohistochemistry proves to be as sensitive and specific as the cell-based assays. This assay extends the available tools for NMO-IgG/aquaporin-4-antibody detection.
The causes of encephalitis are numerous, and extensive investigations for infectious agents and other etiologies are often negative. The discovery that many of these encephalitis are immune mediated has changed the approach to the diagnosis and treatment of these disorders. Moreover, the broad spectrum of symptoms including, psychosis, catatonia, alterations of behavior and memory, seizures, abnormal movements, and autonomic dysregulation usually requires a multidisciplinary treatment approach. This review focuses in several forms of encephalitis that occur in children, and for which an autoimmune etiology has been demonstrated (eg, anti-N-methyl-D-aspartate receptor encephalitis) or is strongly suspected (eg, Rasmussen encephalitis, limbic encephalitis, opsoclonus-myoclonus). The authors also review several disorders that may be immune mediated, such as the rapid onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) syndrome and some encephalopathies with fever and status epilepticus. Recognition of novel immune-mediated encephalitis is important because some of these disorders are highly responsive to immunotherapy.
autoimmune; encephalitis; limbic; anti-NMDA receptor; NMDA
Homer proteins are a family of scaffolding proteins of the postsynaptic density. Homer-3 colocalizes and modulates the activity of group I metabotropic glutamate receptors (mGluR1 and mGluR5). Cerebellitis has been reported in association with antibodies to mGluR1. We describe the second patient with cerebellitis and Homer-3 antibodies and report a novel, highly specific immunoblot assay.
A 38-year-old man had acute onset of headache, nausea, vomiting, and confusion. He developed a pancerebellar syndrome during the ensuing week. Extensive studies did not reveal any tumor. Cerebrospinal fluid analysis showed a white blood cell count of 60/µL (to convert to ×109 per liter, multiply by 0.001). Brain magnetic resonance imaging findings were normal. For 2 years, the patient was treated with intravenous immunoglobulins and steroids, with partial improvement of the cerebellar ataxia. The patient was negative for onconeural (Hu, Yo, Ri, CV2, Tr, amphiphysin, and Ma2), glutamic acid decarboxylase, and mGluR1 antibodies. Immunohistochemistry on rat brain revealed immunostaining of the cerebellar molecular layer. Homer-3 antibodies were demonstrated by immunoblot of recombinant Homer-3. The clinical features of this patient and a previously described patient with Homer-3 antibodies are similar to those of patients with mGluR1 antibodies.
Conclusions and Relevance
We report the second case of autoimmune cerebellar ataxia associated with Homer-3 antibodies. The presence of Homer-3 autoantibodies should be considered in the differential diagnosis of patients with subacute cerebellar ataxia of unknown cause.
To determine continuous EEG (cEEG) patterns that may be unique to anti-NMDA receptor (NMDAR) encephalitis in a series of adult patients with this disorder.
We evaluated the clinical and EEG data of 23 hospitalized adult patients with anti-NMDAR encephalitis who underwent cEEG monitoring between January 2005 and February 2011 at 2 large academic medical centers.
Twenty-three patients with anti-NMDAR encephalitis underwent a median of 7 (range 1−123) days of cEEG monitoring. The median length of hospitalization was 44 (range 2−200) days. Personality or behavioral changes (100%), movement disorders (82.6%), and seizures (78.3%) were the most common symptoms. Seven of 23 patients (30.4%) had a unique electrographic pattern, which we named “extreme delta brush” because of its resemblance to waveforms seen in premature infants. The presence of extreme delta brush was associated with a more prolonged hospitalization (mean 128.3 ± 47.5 vs 43.2 ± 39.0 days, p = 0.008) and increased days of cEEG monitoring (mean 27.6 ± 42.3 vs 6.2 ± 5.6 days, p = 0.012). The modified Rankin Scale score showed a trend toward worse scores in patients with the extreme delta brush pattern (mean 4.0 ± 0.8 vs 3.1 ± 1.1, p = 0.089).
Extreme delta brush is a novel EEG finding seen in many patients with anti-NMDAR encephalitis. The presence of this pattern is associated with a more prolonged illness. Although the specificity of this pattern is unclear, its presence should raise consideration of this syndrome.
Immune-mediated paraneoplastic neurologic disorders (PND) may affect any part of the nervous system, and can mimic many non-cancer associated disorders. The availability of diagnostic tests based on the presence of specific anti-neuronal antibodies facilitates diagnosis and can suggest treatment strategies. Once thought to be poorly responsive to therapies, it is now recognized that there is a subgroup of PND, mostly associated with antibodies to antigens on the neuronal cell surface that are highly treatment responsive. For all PND, identification and treatment of the underlying tumor is the most effective step in the potential control or stabilization of the neurological disorder.
paraneoplastic; neurologic; autoimmunity; antibodies
We review novel findings in paraneoplastic syndromes including the Lambert-Eaton myasthenic syndrome, and then focus on the novel disorders associated with antibodies against cell surface antigens, discussing the importance and caveats of antibody testing, and providing an algorithm for interpretation of results. In anti-NMDAR encephalitis 2 novel findings include the recognition of a characteristic EEG pattern (“extreme delta brush”) in 30% of patients and the demonstration of a fronto-temporo-occipital gradient of glucose metabolism that correlates with disease activity. In limbic encephalitis, antibodies to GABA(B) receptor are the most frequently detected in patients with small-cell lung cancer who are anti-Hu negative, and antibodies to mGluR5 distinctively associate with Hodgkin lymphoma (Ophelia syndrome). We also address the syndromes associated with “VGKC-complex antibodies,” a problematic term that groups well-characterized immune-mediated disorders (LGI1, Caspr2) with others that lack syndrome specificity, are less responsive to treatment, and for which the target antigens are unknown.
Tumor resection is recommended in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, however it is often difficult during an early stage of the disease. We report here the efficacy of early tumor removal in a patient with anti-NMDAR encephalitis. This 21-year-old woman was admitted to another hospital with rapidly progressive psychiatric symptoms, a decreased level of consciousness, and seizures. Abdominal CT showed a pelvic mass. On day 1 of admission to our center, she developed hypoventilation requiring mechanical support. She had orofacial dyskinesias with well-coordinated, pseudo-piano playing involuntary finger movements. Based on these clinical features, she was immediately scheduled for tumor resection on day 3. While awaiting surgery, she began to receive high-dose intravenous methylprednisolone. After tumor removal, she received plasma exchange, followed by intravenous immunoglobulin and additional high-dose methylprednisolone. Two weeks after tumor removal, she started following simple commands and progressive improvement, although she remained on mechanical ventilation for 10 weeks due to nocturnal central hypoventilation. Anti-NMDAR antibodies in serum/CSF were detected. Pathological examination showed immature teratoma with foci of infiltrates of B- and T-cells. Early tumor resection with immunotherapy facilitates recovery from this disease, but central hypoventilation may require long mechanical support. Non-jerky elaborate finger movements suggest antibody-mediated disinhibition of the cortico-striatal systems.
paraneoplastic; encephalitis; ovarian tumor; NMDA receptor; early treatment