Prediction of small cell lung cancer in the Lambert-Eaton myasthenic syndrome

The Lambert-Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder in which patients have muscle weakness and autonomic dysfunction. Half of the patients have small cell lung cancer (SCLC). SCLC is a very aggressive lung tumour with a median survival of only 9 months. Quick discovery and treatment is of uttermost importance for both patient and physician to improve the chance of cure. SCLC-LEMS is related to smoking, a higher age at onset and weight loss. The clinical symptoms develop more quickly and more severely if the LEMS is related to SCLC. The discovery of SOX antibodies is described specific for SCLC-LEMS. Based on simple epidemiological and clinical parameters, we created the DELTA-P score and validated it in an independent second cohort. The DELTA-P score predicts already shortly after onset of symptoms with 95% accuracy who has or will have an SCLC. The reliability of imaging to detect SCLC is analyzed in 100 patients, creating a new screening protocol. For other paraneoplastic syndromes, screening guidelines are updated. SOX and Hu antibodies are also found in 43% of SCLC patients (without LEMS). Combination of different antibodies might lead to reliable screening strategies in high-risk patients.The studies described in this dissertation were supported in part by a European Neurological Society fellowship, the Leiden University Medical Center, the European Union research project “PNSEuronetwork”, contract number LSSM-CT 2005-518174, another grant from the European Union (QLG1-CT-2002-01756), PI030028 Fondo de Investigaciones Sanitarias, Spain and by the Prinses Beatrix Fonds, the Netherlands. Printing of this thesis was supported financially by the Stichting het Remmert Adriaan Laan Fonds.UBL - phd migration 201

From VGKC to LGI1 and Caspr2 encephalitis: The evolution of a disease entity over time

AbstractA wide variety of clinical syndromes has been associated with antibodies to voltage-gated potassium channels (VGKCs). Six years ago, it was discovered that patients do not truly have antibodies to potassium channels, but to associated proteins. This enabled the distinction of three VGKC-positive subgroups: anti-LGI1 patients, anti-Caspr2 patients and VGKC-positive patients lacking both antibodies. Patients with LGI1-antibodies have a limbic encephalitis, often with hyponatremia, and about half of the patients have typical faciobrachial dystonic seizures. Caspr2-antibodies cause a more variable syndrome of peripheral or central nervous system symptoms, almost exclusively affecting older males. Immunotherapy seems to be beneficial in patients with antibodies to LGI1 or Caspr2, stressing the need for early diagnosis. Half of the VGKC-positive patients lack antibodies to both LGI1 and Caspr2. This is a heterogeneous group of patients with a wide variety of clinical syndromes, raising the question whether VGKC-positivity is truly a marker of disease in these patients. Data regarding this issue are limited, but a recent study did not show any clinical relevance of VGKC-positivity in the absence of antibodies to LGI1 and Caspr2. The three VGKC-positive subgroups are essentially different, therefore, the lumping term ‘VGKC-complex antibodies’ should be abolished

Lowering the cutoff value for increment increases the sensitivity for the diagnosis of Lambert-Eaton myasthenic syndrome

Background: Increment of compound muscle action potential amplitude is a diagnostic hallmark of Lambert-Eaton myasthenic syndrome (LEMS). Making a diagnosis can be challenging, therefore, a proper cutoff for abnormal increment is highly relevant for improved recognition

From VGKC to LGI1 and Caspr2 encephalitis: The evolution of a disease entity over time

A wide variety of clinical syndromes has been associated with antibodies to voltage-gated potassium channels (VGKCs). Six years ago, it was discovered that patients do not truly have antibodies to potassium channels, but to associated proteins. This enabled the distinction of three VGKC-positive subgroups: anti-LGI1 patients, anti-Caspr2 patients and VGKC-positive patients lacking both antibodies. Patients with LGI1-antibodies have a limbic encephalitis, often with hyponatremia, and about half of the patients have typical faciobrachial dystonic seizures. Caspr2-antibodies cause a more variable syndrome of peripheral or central nervous system symptoms, almost exclusively affecting older males. Immunotherapy seems to be beneficial in patients with antibodies to LGI1 or Caspr2, stressing the need for early diagnosis. Half of the VGKC-positive patients lack antibodies to both LGI1 and Caspr2. This is a heterogeneous group of patients with a wide variety of clinical syndromes, raising the question whether VGKC-positivity is truly a marker of disease in these patients. Data regarding this issue are limited, but a recent study did not show any clinical relevance of VGKC-positivity in the absence of antibodies to LGI1 and Caspr2. The three VGKC-positive subgroups are essentially different, therefore, the lumping term ‘VGKC-complex antibodies’ should be abolished

Innate and adaptive immunity in human epilepsies

Inflammatory mechanisms have been increasingly implicated in the origin of seizures and epilepsy. These mechanisms are involved in the genesis of encephalitides in which seizures are a common complaint. Experimental and clinical evidence suggests different inflammatory responses in the brains of patients with epilepsy depending on the etiology. In general, activation of both innate and adaptive immunity plays a role in refractory forms of epilepsy. Epilepsies in which seizures develop after infiltration of cells of the adaptive immune system in the central nervous system (CNS) include a broad range of epileptic disorders with different (known or unknown) etiologies. Infiltration of lymphocytes is observed in autoimmune epilepsies, especially the classical paraneoplastic encephalitides with antibodies against intracellular tumor antigens. The presence of lymphocytes in the CNS also has been found in focal cerebral dysplasia type 2 and in cortical tubers. Various autoantibodies have been shown to be associated with temporal lobe epilepsy (TLE) and hippocampal sclerosis of unknown etiology, which may be due to the presence of viral DNA. During the last decade, an increasing number of antineuronal autoantibodies directed against membranous epitopes have been discovered and are associated with various neurologic syndromes, including limbic encephalitis. A major challenge in epilepsy is to define biomarkers, which would allow the recognition of patient populations who might benefit from immune-modulatory therapies. Some peripheral inflammatory markers appear to be differentially expressed in patients with medically controlled and medic

Prevalence of intrathecal acyclovir resistant virus in herpes simplex encephalitis patients

Herpes simplex encephalitis (HSE) is a life-threatening complication of herpes simplex virus (HSV) infection. Acyclovir (ACV) is the antiviral treatment of choice, but may lead to emergence of ACV-resistant (ACVR) HSV due to mutations in the viral UL23 gene encoding for the ACV-targeted thymidine kinase (TK) protein. Here, we determined the prevalence of intrathecal ACVR-associated HSV TK mutations in HSE patients and compared TK genotypes of sequential HSV isolates in paired cerebrospinal fluid (CSF) and blister fluid of mucosal HSV lesions. Clinical samples were obtained from 12 HSE patients, encompassing 4 HSV type 1 (HSV-1) and 8 HSV-2 encephalitis patients. HSV DNA load was determined by real-time PCR and complete HSV TK gene sequences were obtained by nested PCR followed by Sanger sequencing. All HSV-1 HSE patients contained viral TK mutations encompassing 30 unique nucleotide and 13 distinct amino acid mutations. By contrast, a total of 5 unique nucleotide and 4 distinct amino acid changes were detected in 7 of 8 HSV-2 patients. Detected mutations were identified as natural polymorphisms located in non-conserved HSV TK gene regions. ACV therapy did not induce the emergence of ACVR-associated HSV TK mutations in consecutive CSF and mucocutaneous samples of 5 individual patients. Phenotypic susceptibility analysis of these mucocutaneous HSV isolates demonstrated ACV-sensitive virus in 2 HSV-1 HSE patients, whereas in two HSV-2 HSE patients ACVR virus was detected in the absence of known ACVR-associated TK mutations. In conclusion, we did not detect intrathecal ACVR-associated TK mutations in HSV isolates obtained from 12 HSE patients

Intracranial actinomycosis of odontogenic origin masquerading as auto-immune orbital myositis: a fatal case and review of the literature

Background: Actinomycetes can rarely cause intracranial infection and may cause a variety of complications. We describe a fatal case of intracranial and intra-orbital actinomycosis of odontogenic origin with a unique presentation and route of dissemination. Also, we provide a review of the current literature. Case presentation: A 58-year-old man presented with diplopia and progressive pain behind his left eye. Six weeks earlier he had undergone a dental extraction, followed by clindamycin treatment for a presumed maxillary infection. The diplopia responded to steroids but recurred after cessation. The diplopia was thought to result from myositis of the left medial rectus muscle, possibly related to a defect in the lamina papyracea. During exploration there was no abnormal tissue for biopsy. The medial wall was reconstructed and the myositis responded again to steroids. Within weeks a myositis on the right side occurred, with CT evidence of muscle swelling. Several months later he presented with right hemiparesis and dysarthria. Despite treatment the patient deteriorated, developed extensive intracranial hemorrhage, and died. Autopsy showed bacterial aggregates suggestive of actinomycotic meningoencephalitis with septic thromboembolism. Retrospectively, imaging studies showed abnormalities in the left infratemporal fossa and skull base and bilateral cavernous sinus. Conclusions: In conclusion, intracranial actinomycosis is difficult to diagnose, with potentially fatal outcome. An accurate diagnosis can often only be established by means of histology and biopsy should be performed whenever feasible. This is the first report of actinomycotic orbital involvement of odontogenic origin, presenting initially as bilateral orbital myositis rather than as orbital abscess. Infection from the upper left jaw extended to the left infratemporal fossa, skull base and meninges and subsequently to the cavernous sinus and the orbits

Antibodies to TRIM46 are associated with paraneoplastic neurological syndromes.

Paraneoplastic neurological syndromes (PNS) are often characterized by the presence of antineuronal antibodies in patient serum or cerebrospinal fluid. The detection of antineuronal antibodies has proven to be a useful tool in PNS diagnosis and the search for an underlying tumor. Here, we describe three patients with autoantibodies to several epitopes of the axon initial segment protein tripartite motif 46 (TRIM46). We show that anti-TRIM46 antibodies are easy to detect in routine immunohistochemistry screening and can be confirmed by western blotting and cell-based assay. Anti-TRIM46 antibodies can occur in patients with diverse neurological syndromes and are associated with small-cell lung carcinoma

Pathologically confirmed autoimmune encephalitis in suspected Creutzfeldt-Jakob disease

Objective: To determine the clinical features and presence in CSF of antineuronal antibodies in patients with pathologically proven autoimmune encephalitis derived from a cohort of patients with suspected Creutzfeldt-Jakob disease (CJD). Methods: The Dutch Surveillance Centre for Prion Diseases performed 384 autopsies on patients with suspected CJD over a 14-year period (1998-2011). Clinical information was collected from treating physicians. Antineuronal antibodies were tested in CSF obtained postmortem by immunohistochemistry on fresh frozen rat brain sections, by Luminex assay for the presence of wellcharacterized onconeural antibodies, and by cell-based assays for antibodies against NMDAR, GABABR1/2, GABAAR GLUR1/2, LGI1, Caspr2, and DPPX. Results: In 203 patients, a diagnosis of definite CJD was made, while in 181 a variety of other conditions were diagnosed, mainly neurodegenerative. In 22 of these 181, the neuropathologist diagnosed autoimmune encephalitis. One patient was excluded because of lack of clinical information. Inflammator

Pediatric autoimmune encephalitis: Recognition and diagnosis

OBJECTIVE: The aims of this study were (1) to describe the incidence of autoimmune encephalitis (AIE) and acute dissemi