Jean-Christophe Antoine

Paraneoplastic neurological syndromes

Paraneoplastic neurological syndromes (PNS) can be defined as remote effects of cancer that are not caused by the tumor and its metastasis, or by infection, ischemia or metabolic disruptions. PNS are rare, affecting less than 1/10,000 patients with cancer. Only the Lambert-Eaton myasthenic syndrome is relatively frequent, occurring in about 1% of patients with small cell lung cancer. PNS can affect any part of the central and peripheral nervous system, the neuromuscular junction, and muscle. They can be isolated or occur in association. In most patients, the neurological disorder develops before the cancer becomes clinically overt and the patient is referred to the neurologist who has the charge of identifying a neurological disorder as paraneoplastic. PNS are usually severely disabling. The most common PNS are Lambert-Eaton myasthenic syndrome (LEMS), subacute cerebellar ataxia, limbic encephalitis (LE), opsoclonus-myoclonus (OM), retinopathies (cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR), Stiff-Person syndrome (SPS), chronic gastrointestinal pseudoobstruction (CGP), sensory neuronopathy (SSN), encephalomyelitis (EM) and dermatomyositis. PNS are caused by autoimmune processes triggered by the cancer and directed against antigens common to both the cancer and the nervous system, designated as onconeural antigens. Due to their high specificity (> 90%), the best way to diagnose a neurological disorder as paraneoplastic is to identify one of the well-characterized anti-onconeural protein antibodies in the patients serum. In addition, as these antibodies are associated with a restricted range of cancers, they can guide the search for the underlying tumor at a stage when it is frequently not clinically overt. This is a critical point as, to date, the best way to stabilize PNS is to treat the cancer as soon as possible. Unfortunately, about one-third of patients do not have detectable antibodies and 5% to 10% have an atypical antibody that is not well-characterized. As PNS are believed to be immune-mediated, suppression of the immune response represents another treatment approach.

Antibodies to a subpopulation of glial cells and a 66 kDa developmental protein in patients with paraneoplastic neurological syndromes.

BACKGROUND: Paraneoplastic neurological syndromes (PNS) are inflammatory disorders that probably depend on autoimmune processes. Several autoantibodies (anti-Hu, anti-Ri, and anti-Yo) have been characterised in PNS and proved to be helpful in the diagnosis. However, these do not account for all the cases and the possibility that other types of antibodies could be detected was investigated. METHODS AND RESULTS: Of 45 patients with PNS whose serum was probed on paraformaldehyde fixed rat brain sections, 11 patients were identified whose serum samples recognised a cytoplasmic antigen in a subpopulation of glial cells in the white matter of adult rat brainstem, cerebellum, and spinal cord that were double labelled with a monoclonal antibody specific for oligodendrocytes. All serum samples reacted with a 66 kDa protein of newborn rat brain on western blot analysis. These antibodies were designated as anti-CV2 antibodies. Only one of the 11 patients had one of the well characterised autoantibodies (anti-Hu). Five patients had cerebellar degeneration, three had limbic encephalitis, two had encephalomyelitis, and one had Lambert-Eaton myasthenic syndrome. The tumours were small cell lung cancer or undifferentiated mediastinal cancer in seven patients, uterine sarcoma in two, and malignant thymoma in two. Among 1061 control serum samples, only two patients had anti-CV2 antibodies. One had small cell lung cancer and the other malignant thymoma. CONCLUSIONS: The detection of anti-CV2 antibodies in patients with neurological disorders should be considered as an indication of the presence of an occult cancer.

Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies

Objective: Anti-Hu antibodies (Hu-Ab) and anti-CV2/CRMP5 antibodies (CV2/CRMP5-Ab) have been identified in association with paraneoplastic neurological disorders. However, it is not clear whether these antibodies are associated with specific neurological symptoms or are only markers of anti-cancer immune reaction. Methods: To address this question, 37 patients with CV2/CRMP5-Ab and 324 patients with Hu-Ab were compared. Results: Whereas the age and sex ratio were the same between the two groups, the distribution of neurological symptoms was not. Patients with CV2/CRMP5-Ab presented more frequently cerebellar ataxia, chorea, uveo/retinal symptoms and myasthenic syndrome (Lambert–Eaton myasthenic syndrome LEMS or myasthenia gravis). They also had a better Rankin score. In contrast, dysautonomia, brainstem encephalitis and peripheral neuropathy were more frequent in patients with Hu-Ab. Limbic encephalitis occurred similarly in both groups. Small-cell lung cancer was the most frequently associated tumour in both groups of patients, while malignant thymoma was observed only in patients with CV2/CRMP5-Ab. In particular, patients with CV2/CRMP5-Ab and thymoma developed myasthenic syndrome more frequently, while patients with SCLC developed neuropathies more frequently. Chorea and myasthenic syndrome were only seen in patients with CV2/CRMP5-Ab. The median survival time was significantly longer in patients with CV2/CRMP5-Ab, and this effect was not dependent on the type of tumour. Interpretation: The data demonstrate that in patients with paraneoplastic neurological syndromes, the neurological symptoms and survival vary with both the type of associated onco-neural antibody and the type of tumour.

Paraneoplastic anti-CV2 antibodies react with peripheral nerve and are associated with a mixed axonal and demyelinating peripheral neuropathy.

Subacute sensory neuronopathy with anti‐Hu antibodies is the best‐characterized paraneoplastic peripheral neuropathy associated with carcinoma. Anti‐CV2 antibodies, another group of paraneoplastic antibodies, react with a 66‐kd brain protein belonging to the family of Ulip/CRMP proteins. The manifestations associated with anti‐CV2 antibodies include cerebellar degeneration, uveitis, and peripheral neuropathy. Some of these patients also have anti‐Hu antibodies. We have compared the clinical, electrophysiological, and pathological characteristics of the peripheral neuropathy in 9 patients with anti‐CV2 antibodies (3 of whom also had anti‐Hu antibodies) and 12 patients with only anti‐Hu antibodies. Data for patients with anti‐Hu antibodies alone indicated subacute sensory neuronopathy. Patients with anti‐CV2 antibodies had a mixed axonal and demyelinating sensory motor neuropathy that was sometimes superimposed on subacute sensory neuronopathy when both anti‐CV2 and anti‐Hu antibodies were present. Unlike anti‐Hu antibodies, anti‐CV2 antibodies reacted with peripheral nerve antigens, as shown by their ability to bind to a 66‐kd protein in human and rat nerve on Western blot analysis and to immunolabel peripheral nerve axons and sensory neurons on immunohistochemical study. Ann Neurol 2001;49:214–221

Carcinoma associated paraneoplastic peripheral neuropathies in patients with and without anti-onconeural antibodies

OBJECTIVE When to suspect a paraneoplastic disorder is a puzzling problem that has not recently been studied in a large series of patients referred for peripheral neuropathy. METHODS From 422 consecutive patients with peripheral neuropathy, 26 were analysed who concomitantly had carcinoma but no tumorous infiltration, drug toxicity, or cachexia. Their clinical, pathological, and electrophysiological data were analysed according to the presence of anti-onconeural antibodies, the latency between presentation and cancer diagnosis, and the incidence of carcinoma in the corresponding types of neuropathy of the population of 422 patients. RESULTS Seven patients (group I) had anti-onconeural antibodies (six anti-Hu, one anti-CV2) and 19 did not (groups IIA and B). In group I, subacute sensory neuropathy (SSN) was the most frequent but other neuropathies including demyelinating neuropathies were present. Patients in group II A had a short latency (mean 7.88 months), and a rapidly and usually severe neuropathy which corresponded in 11/14 to an established inflammatory disorder including neuropathy with encephalomyelitis, mononeuritis multiplex, and acute or chronic inflammatory demyelinating polyneuropathy (CIDP). Patients in group IIB had a long latency (mean 8.4 years) and a very chronic disorder corresponding in four of five to an axonal non-inflammatory polyneuropathy. In this population, the incidence of carcinoma occurring with a short latency was 47% in sensory neuronopathy, 1.7% in Guillain-Barré syndrome, 10% in mononeuritis multiplex and CIDP, and 4.5% in axonal polyneuropathy. CONCLUSIONS Paraneoplastic neuropathies associated with carcinoma are heterogeneous disorders. Neuropathies occurring with a long latency with tumours probably resulted from a coincidental association. Neuropathies which occurred within a few years of the tumour evolved rapidly and corresponded mostly to inflammatory disorders. As dysimmune neuropathies are probably paraneoplastic in a limited number of cases, patients with these disorders should probably not be investigated systematically for carcinoma in the absence of anti-onconeural antibodies, except when the neuropathy is associated with encephalomyelitis and probably with vasculitis. Questions remain concerning CIDP.

The pattern and diagnostic criteria of sensory neuronopathy: a case–control study

Acquired sensory neuronopathies encompass a group of paraneoplastic, dysimmune, toxic or idiopathic disorders characterized by degeneration of peripheral sensory neurons in dorsal root ganglia. As dorsal root ganglia cannot easily be explored, the clinical diagnosis of these disorders may be difficult. The question as to whether there exists a common clinical pattern of sensory neuronopathies, allowing the establishment of validated and easy-to-use diagnostic criteria, has not yet been addressed. In this study, logistic regression was used to construct diagnostic criteria on a retrospective study population of 78 patients with sensory neuronopathies and 56 with other sensory neuropathies. For this, sensory neuronopathy was provisionally considered as unambiguous in 44 patients with paraneoplastic disorder or cisplatin treatment and likely in 34 with a dysimmune or idiopathic setting who may theoretically have another form of neuropathy. To test the homogeneity of the sensory neuronopathy population, likely candidates were compared with unambiguous cases and then the whole population was compared with the other sensory neuropathies population. Criteria accuracy was checked on 37 prospective patients referred for diagnosis of sensory neuropathy. In the study population, sensory neuronopathy showed a common clinical and electrophysiological pattern that was independent of the underlying cause, including unusual forms with only patchy sensory loss, mild electrical motor nerve abnormalities and predominant small fibre or isolated lower limb involvement. Logistic regression allowed the construction of a set of criteria that gave fair results with the following combination: ataxia in the lower or upper limbs + asymmetrical distribution + sensory loss not restricted to the lower limbs + at least one sensory action potential absent or three sensory action potentials <30% of the lower limit of normal in the upper limbs + less than two nerves with abnormal motor nerve conduction study in the lower limbs.

Peripheral nervous system involvement in patients with cancer

Involvement of the peripheral nervous system (PNS) is common in patients with cancer and any part, including motor neurons, sensory ganglia, nerve roots, plexuses, cranial and peripheral nerves, and neuromuscular junctions, can be affected. Different mechanisms can initiate damage associated with cancer-related PNS disorders. These include tumour infiltration, toxicity of treatments, metabolic and nutritional perturbations, cachexia, virus infections, and paraneoplastic neurological syndromes. The type of cancer, lymphoma, or solid tumour is a further determinant of a PNS disorder. In this Review we discuss the different causes and mechanisms of disorders of the PNS in patients with cancer and we will focus on their assessment and diagnosis.

Clinical specificities of adult male patients with NMDA receptor antibodies encephalitis

Objective: The aim of this study was to describe the clinical features and specificities of adult male patients with NMDA receptor antibodies (NMDAr-Abs) encephalitis. Methods: Observational study of 13 adult male patients who were diagnosed with NMDAr-Abs encephalitis at the French Paraneoplastic Neurological Syndrome Reference Center. Results: Adult male patients frequently presented initially with a seizure (8/13, 61.5%). Seizures were partial in 5/8 patients and were followed only a few days later (median 12 days; range 2–17 days) by psychiatric or cognitive symptoms. Conversely, adult female patients rarely presented with a seizure initially (8/58, 14%, p < 0.001), and most of their seizures were generalized and were rapidly followed (median 2 days; range 1–7 days) by behavioral and psychiatric features. Additionally, in male patients the disease was rarely associated with a tumor (1/13 or 8%, a perineal schwannoma); in contrast, 41% of female patients had an associated tumor (95% of which were ovarian teratomas; p = 0.02 male vs female association with tumor). The incidences of abnormalities in ancillary tests, treatment modalities, clinical evolution, and outcome were equal for both subgroups. Conclusion: Adult male patients who have partial seizures, normal MRI results, and no clear etiology should be tested for NMDAr-Abs to avoid any delays in treatment initiation. Adult female patients who had a seizure as the first symptom are infrequent when NMDAr-Abs encephalitis is diagnosed; additionally, their clinical pattern is different from male patients, with more generalized seizures and rapid development of behavioral and psychiatric symptoms. The differences in hormonal influence could contribute to this difference in clinical pattern.

Brain immunohistopathological study in a patient with anti-NMDAR encephalitis.

Background and purpose:  Anti‐N‐methyl‐d‐asparate (NMDA) receptor encephalitis is thought to be antibody‐mediated. To perform an immunohistopathological study of the inflammatory reaction in a brain biopsy performed before immunomodulatory treatments in a patient with anti‐NMDA receptor encephalitis.

Limbic encephalitis and immunological perturbations in two patients with thymoma.

Two patients with clinical and radiological evidence of limbic encephalitis associated with an invasive lymphoepithelial thymoma who improved after thymectomy and radiotherapy are reported. The serum of both patients and the CSF of one of them contained different types of antibodies that immunoreacted with human and rat brain and newborn rat thymus. After treatment of the tumour, the antibody titres decreased. Similar antibodies were not found in various controls. Two out of 16 patients with thymoma, myasthenia gravis, and no CNS involvement had low titres of antibodies reacting with the brain. It is suggested that in some patients with thymoma, an autoimmune reaction involving antigens common to the brain and thymus is possibly misdirected against the CNS.