Immunohistochemical analysis of the immune reaction in the nervous system in paraneoplastic encephalomyelitis

We examined frozen sections of frontal cortex, medulla, and dorsal root ganglia from a patient with small-cell lung cancer and paraneoplastic encephalomyelitis, involving the medulla and dorsal root ganglia, with a panel of antibodies reactive for IgG, IgM, C3, B cells, T cells, T cell subsets, macrophages, and class I and II (HLA-DR) major histocompatibility complex (MHC) antigens. We detected an antineuronal antibody (anti-Hu) in the serum and CSF of the patient and found deposits of IgG in the periphery of some neurons in dorsal root ganglia. The infiltrates were almost exclusively T cells with a predominance of CD8-positive cells. Neurons did not express class I or II MHC antigens. Satellite cells in the dorsal root ganglia from the patient and controls were HLA-DR-positive. These data indicate that CD8-positive T cells predominate in the inflammatory infiltrates of paraneoplastic encephalomyelitis. IgG deposits may be relevant in the damage of the sensory neurons.     

Anti-Hu antibody neuropathy: a clinical, electrophysiological, and pathological study.

OBJECTIVE: The objective is to report the clinical, electrophysiological, and histopathological features of 16 patients with anti-Hu antibody neuropathy. METHODS: Clinical and electrophysiological data in 16 patients (11 females and 5 males) with positive anti-Hu antibody and nerve biopsy data in 9 cases were analyzed. RESULTS: Cancer was detected in 11 patients, including 9 with small-cell lung cancer. Classical paraneoplastic subacute sensory neuronopathy (SSN) and/or encephalomyelitis (EM) was observed in 7 patients (44%), including 5 with SSN. The most common clinical feature was sensory-motor neuropathy (SMN), accounting for 50% of cases. Though sensory nerve conduction abnormality was the prominent feature in 14 (88%) cases, sensory and motor nerve conduction was abnormal in all cases. Motor nerve conduction findings were typical of axonal degeneration. The most common nerve conduction pattern was that of SMN, with a sensory neuronopathy pattern being observed in only 3 cases. Sural nerve biopsy in 9 patients showed axonal degeneration in all cases and inflammatory cells in 4 cases. CONCLUSIONS: Classical sensory neuronopathy is rarer than expected, both clinically and electrophysiologically. Motor involvement is not uncommon and motor nerve conduction abnormality is frequently seen. A diverse clinical and electrophysiological, and histopathological spectrum was observed in this neuropathy. SIGNIFICANCE: New guidelines for the selection of patients for anti-Hu antibody test are recommended.     

Phenotypic and neuropathologic heterogeneity of anti-Hu antibody-related paraneoplastic syndrome presenting with progressive dysautonomia: report of two cases

The anti-Hu antibody (HuAb) is directed against RNA-associated neuronal proteins and is known to cause paraneoplastic encephalomyelitis/sensory neuronopathy syndrome mostly when associated with small cell lung cancer (SCLC). Paraneoplastic encephalomyelitis/sensory neuronopathy syndrome with concurrent autonomic neuropathy has been reported to occur in paraneoplastic syndromes, although its occurrence concomitant with acute pandysautonomia is less frequent. The authors describe the clinical, neuropathologic, and serologic features of two cases with an anti-Hu-related paraneoplastic syndrome presenting with progressive autonomic neuropathy. Both patients showed features of dysautonomia, including postural dizziness, abdominal pain, and diarrhea, and symptoms of sensory neuropathy. Investigations disclosed severe sensory and autonomic neuropathy and positive HuAb titers. The disease of patient 1 had a very rapid progression, and the patient died of cardiac arrest within 2 months of the onset of symptoms. The autopsy revealed SCLC. In contrast, the disease of patient 2 had a less aggressive course. An extensive tumor search disclosed SCLC only 28 months after onset of symptoms, and the patient died 1 month later of cardiorespiratory arrest. Autopsies in both cases showed inflammation involving the intermediolateral columns and the dorsal root ganglia. These two cases illustrate the association of early dysautonomia with HuAb-related paraneoplastic syndrome and the variations of clinical, neuropathologic, and serologic findings in these types of cases.     

Anti-Hu associated paraneoplastic sensory neuronopathy with upper motor neurone involvement

Paraneoplastic neurological syndrome is characterised by neuronal degeneration with lymphocytic infiltration in various regions of the central and peripheral nervous systems. Motor neurone symptoms may occur as a remote effect of malignancy, and have been considered because of the involvement of lower motor neurones. A case is reported of an 80 year old woman suffering from paraneoplastic sensory neuronopathy with anti-Hu antibody. Postmortem examination showed adenocarcinoma of the gall bladder and small cell carcinoma of the duodenum. Neuronal loss with lymphocytic infiltration was found in the dorsal root ganglia, brain stem, and cerebellum. Despite the absence of upper motor neurone signs, there was severe loss of Betz cells and degeneration of the bilateral pyramidal tracts. To our knowledge, this is the first demonstration of upper motor neurone involvement in anti-Hu associated paraneoplatic syndrome.     

Peripheral neuropathies associated with antibodies directed to intracellular neural antigens

Antibodies directed to intracellular neural antigens have been mainly described in paraneoplastic peripheral neuropathies and mostly includes anti-Hu and anti-CV2/CRMP5 antibodies. These antibodies occur with different patterns of neuropathy. With anti-Hu antibody, the most frequent manifestation is sensory neuronopathy with frequent autonomic involvement. With anti-CV2/CRMP5 the neuropathy is more frequently sensory and motor with an axonal or mixed demyelinating and axonal electrophysiological pattern. The clinical pattern of these neuropathies is in keeping with the cellular distribution of HuD and CRMP5 in the peripheral nervous system. Although present in high titer, these antibodies are probably not directly responsible for the neuropathy. Pathological and experimental studies indicate that cytotoxic T-cells are probably the main effectors of the immune response. These disorders contrast with those in which antibodies recognize a cell surface antigen and are probably responsible for the disease. The neuronal cell death and axonal degeneration which result from T-cell mediated immunity explains why treating these disorders remains challenging.     

Paraneoplastic peripheral neuropathies

Paraneoplastic peripheral neuropathies constitute a heterogeneous group of conditions. A link between the tumor and the neuropathy has been demonstrated in a subgroup only. Definite paraneoplastic neuropathies correspond to neuropathies associated with antibodies reacting with antigens common to the peripheral nervous system and the cancer. Neuropathies associated with anti-Hu antibodies are the most frequent and consist mainly in subacute sensory neuronopathy. Sensory or sensory-motor neuropathies with anti-CV2 antibodies are less frequent. The link between the cancer and the neuropathy is less clear in the other forms. The frequency of cancer in this group varies from 1 to 18 p.cent.These neuropathies include inflammatory demyelinating neuropathies, neuropathy and vasculitis, lower motor neurone diseases, and autonomic neuropathies. Occasionally, the neuropathy improves with treatment of the tumor. Recent data suggest that gangliosides may be the target of the immune process in neuropathies associated with melanoma.     

The dorsal root ganglion under attack: the acquired sensory ganglionopathies

Acquired sensory ganglionopathies--or sensory neuronopathies--are a rare type of peripheral neuropathy characterised by damage to the sensory nerve cell bodies in the dorsal root ganglia. Subacute or chronic in onset, sensory ganglionopathies typically present with a non-length dependent pattern of large fibre sensory loss. The causes of this distinct clinical picture include paraneoplastic syndromes, immune mediated diseases, infections, as well as drug, toxin and excess vitamin exposure. Here we discuss the clinical and pathological features of acquired sensory ganglionopathies and focus on a practical approach to their diagnosis and management.     

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.     

Paraneoplastic syndromes of the peripheral nerves

PURPOSE OF REVIEW: To describe the paraneoplastic disorders of the motor and sensory nerves and neurons, and their immunologic associations. RECENT FINDINGS: Recently proposed diagnostic criteria for paraneoplastic disorders may assist in determining the likelihood a given neuropathy or neuronopathy is related to an underlying malignancy. Of this group of disorders, paraneoplastic sensory neuronopathies are the most frequent; many of these patients have anti-Hu antibodies and small-cell lung cancer. There is often motor, autonomic, or central nervous system involvement, and electrophysiological studies may demonstrate not only sensory changes, but also motor abnormalities. While cancer has been found more frequently than expected in patients with Guillain-Barré syndrome, this association is extremely rare. A limited number of reports have described chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy with conduction block, vasculitic neuropathies, and motor neuron disease as paraneoplastic disorders. Anti-CV2 antibodies are frequently associated with a paraneoplastic sensorimotor axonal neuropathy and small-cell lung cancer. Peripheral nerve hyperexcitability may occur with or without a cancer association, and in both instances patients often have antibodies to voltage-gated potassium channels; thymoma and small-cell lung cancer are the most common underlying tumors. Plasma cell proliferative disorders are frequently associated with neuropathies, particularly demyelinating ones. SUMMARY: There is increasing recognition of an extensive variety of paraneoplastic disorders of the peripheral nerves. In many of these disorders onconeuronal antibodies are absent. Whole body fluorodeoxyglucose positron emission tomography scanning helps uncover the associated tumor, and recently proposed criteria may assist in the diagnosis. In many instances, prompt treatment of the tumor and immunotherapy result in symptom stabilization or neurologic improvement.     

Detection of the anti-Hu antibody in the serum of patients with small cell lung cancer--a quantitative western blot analysis

We looked for the presence of the anti-Hu antibody in the sera from 50 normal subjects; 44 patients with small cell lung cancer, not associated with paraneoplastic disease; and 25 patients with small cell lung cancer associated with paraneoplastic sensory neuropathy, encephalomyelitis, or both. Using the avidin-biotin immunoperoxidase method and a highly sensitive quantitative Western blot analysis, the anti-Hu antibody was not detected in the 50 normal human sera. Seven of the 44 patients with small cell lung cancer but no paraneoplastic syndrome had detectable levels (average titer, 76 U/ml) of anti-Hu antibody on Western blot. These levels are significantly lower than the average titer of the 25 patients who had small cell lung cancer and paraneoplastic sensory neuropathy or encephalomyelitis (average titer, 4,592 U/ml). In the group with nonparaneoplastic small cell lung cancer (low anti-Hu titer) there was a predominance of women (5 women: 2 men), and all patients had "limited" disease when diagnosed. In the antibody-negative group the sex ratio was 16 women to 21 men and 51% of the patients had "extensive" disease. None of the 7 patients with a low-titer anti-Hu antibody developed a paraneoplastic syndrome by the time of writing. The anti-Hu antibody appears, when present, to be a good marker for small cell lung cancer and, when present at high titer, for small cell lung cancer associated with a paraneoplastic syndrome.     

Spontaneous neurological improvement in anti-Hu associated encephalomyelitis.

Symptoms of anti-Hu associated paraneoplastic encephalomyelitis (PEM) and sensory neuropathy (PSN) are usually severe and irreversible. Two patients are reported whose symptoms improved spontaneously, and in one of them they resolved after resection of an inflammatory lesion of the lung. Spontaneous neurological improvement, although rare, should be considered in the evaluation of therapies for PEM/PSN.     

Clinical and immunohistochemical comparison of in vivo injected anti-Hu and control IgG in the nervous system of the mouse

Anti-Hu antibodies are usually present in patients with paraneoplastic encephalomyelitis/sensory neuropathy (PEM/SN), and anti-Hu IgG is found in the nucleus of neurons in the autopsy of these patients. To investigate the clinical effect and distribution of anti-Hu IgG in the nervous system in an experimental animal model, we injected intraperitoneally anti-Hu IgG from five patients with PEM/SN to mice daily for 1 or 2 weeks. The IgG distribution in the nervous system was analyzed by an avidin-biotin immunoperoxidase technique in animals sacrificed 24 h after the last injection. In one group of mice the nervous system was fixed by perfusion and in another (autopsy group) by immersion after keeping the dead animal 16 h at 4°C. None of the mice showed clinical or pathological abnormalities. IgG immunoreactivity was similar in the nervous system of mice injected with anti-Hu or control IgG. In the perfusion-fixed mice, IgG was present in leptomeninges, choroid plexus and extracellular space of Gasserian and dorsal root ganglia (DRG). In the autopsy group, there was IgG immunoreactivity in the cytoplasm of neurons of many areas of the brain and in more than 90% of neurons of DRG. Neuronal nuclear IgG deposits were only rarely observed. We conclude that anti-Hu antibodies alone probably are not responsible for the PEM/SN syndrome. IgG diffusion into the cytoplasm of neurons is a post-mortem artifact, but this model did not reproduce the predominant nuclear IgG staining observed in autopsies from PEM/SN patients.     

Is there involvement of the central nervous system in hereditary sensory radicular neuropathy?

There is pathological evidence that hereditary sensory radicular neuropathy (HSN type I) is a disorder related to multi-system atrophy with marked cell loss in the cerebral cortex, thalamus, brain stem and cerebellum. We report here a clinical study of a case of HSN-I including audiometric testing, autonomic functions, electromyography, transcranial magnetic stimulation and magnetic resonance imaging of the brain. There were no signs of central nervous system involvement. It is stated that HSN-I remains a disorder of dorsal root ganglia and sensory nerves, leading to painless perforating ulceration and mutilation, within the course of the disease peripheral motor nerve involvement, but without involvement of central motor pathways.     

Acute motor and sensory neuronopathy associated with small‐cell lung cancer: A clinicopathological study

A 48‐year‐old Chinese woman developed ascending motor paralysis while visiting Japan, leading to tetraplegia and respiratory failure over 2 weeks. The patient’s course was complicated by anoxic encephalopathy. Nerve conduction studies revealed a severely decreased amplitude of compound muscle action potentials and a sural nerve biopsy specimen showed findings consistent with axonal‐form Guillain–Barré syndrome. An autopsy, excluding the brain, demonstrated small‐cell lung cancer that was not detected clinically, axonal‐dominant degeneration in the nerve roots and distal peripheral nerves, and the loss of both myelin and axons in the dorsal spinal column. The spinal anterior horn cells were severely decreased and were accompanied by astrocytic reaction in all spinal segments with lymphocytic infiltration. A limited examination of the dorsal root ganglia did not show Nageotte nodules, but the infiltration of T cells was observed. Although the clinical course mimicked axonal‐form Guillain–Barré syndrome, the autopsy demonstrated both sensory and motor neuronal involvement, as well as small‐cell lung cancer. Although anti‐Hu and antiganglioside antibodies were negative in the patient’s serum, the paraneoplastic mechanism might have damaged the anterior horn and dorsal root ganglia cells, which subsequently led to secondary axonal degeneration. There has been a report on a case of paraneoplastic subacute motor neuronopathy, but the acute course described here has not been reported before.     

Inflammation near the nerve cell body enhances axonal regeneration

Although crushed axons in a dorsal spinal root normally regenerate more slowly than peripheral axons, their regeneration can be accelerated by a conditioning lesion to the corresponding peripheral nerve. These and other observations indicate that injury to peripheral sensory axons triggers changes in their nerve cell bodies that contribute to axonal regeneration. To investigate mechanisms of activating nerve cell bodies, an inflammatory reaction was provoked in rat dorsal root ganglia (DRG) through injection of Corynebacterium parvum. This inflammation enhanced regeneration in the associated dorsal root, increasing 4-fold the number of regenerating fibers 17 d after crushing; peripheral nerve regeneration was not accelerated. A milder stimulation of dorsal root regeneration was detected after direct injection of isogenous macrophages into the ganglion. It is concluded that changes favorable to axonal regeneration can be induced by products of inflammatory cells acting in the vicinity of the nerve cell body. Satellite glial cells and other unidentified cells in lumbar DRG were shown by thymidine radioautography to proliferate after sciatic nerve transection or injection of C. parvum into the ganglia. Intrathecal infusion of mitomycin C suppressed axotomy-induced mitosis of satellite glial cells but did not impede axonal regeneration in the dorsal root or the peripheral nerve. Nevertheless, the similarity in reactions of satellite glial cells during 2 processes that activate neurons adds indirect support to the idea that non-neuronal cells in the DRG might influence regenerative responses of primary sensory neurons.     

Is early diabetic neuropathy a disorder of the dorsal root ganglion? A hypothesis and critique of some current ideas on the etiology of diabetic neuropathy

Investigations into the etiology of diabetic polyneuropathy have largely concentrated on the mixed peripheral nerve trunk. Although a number of workers have suggested that reductions in mixed nerve blood flow account for early diabetic polyneuropathy, experimental results remain controversial and are not fully sustained by human studies. Later disease is unquestionably associated with microangiopathy. Patients with diabetic neuropathy may have exclusive and severe sensory and autonomic involvement without obvious motor disease. The prominent sensory involvement in early diabetic polyneuropathy may suggest that the disease particularly targets dorsal root ganglia. Dorsal root ganglia (DRG) have features that might suggest they would be vulnerable to changes known to occur in diabetes, i.e. microangiopathy, excessive polyol flux and protein glycosylation. Autonomic ganglia may also be targeted early in the disease. The interest in using growth factors to treat diabetic neuropathy is at least partly based on the hypothesis that these agents might provide important trophic support for DRG neurons.     

Inflammatory sensory polyganglionopathies.

The inflammatory sensory polyganglionopathies are a group of uncommon neurologic disorders primarily affecting dorsal root ganglion cells and their processes. Subdivided into malignant and nonmalignant inflammatory sensory polyganglionopathy, these conditions are important in the differential diagnosis of sensory neuropathy. The clinical significance of malignant inflammatory sensory polyganglionopathy, a paraneoplastic syndrome, rests in the discovery of subclinical cancer, which may produce antineuronal nuclear antibodies directed against the dorsal root ganglion cell and other neurons resulting in characteristic neurologic deficits. Prompt recognition of these distinctive signs and symptoms may result in early diagnosis and improved patient survival and lead to a better understanding of immune-mediated neurologic disease.     

Retinal ganglion cell axons regenerate in the presence of intact sensory fibres

A novel allograft paradigm was used to test whether adult mammalian central axons regenerate within a peripheral nerve environment containing intact sensory axons. Retinal ganglion cell axon regeneration was compared following anastomosis of dorsal root ganglia grafts or conventional peripheral nerve grafts to the adult rat optic nerve. Dorsal root ganglia grafts comprised intact sensory and degenerate motor axons, whereas conventional grafts comprised both degenerating sensory and motor axons. Retinal ganglion cell axons were traced after 2 months. Dorsal root ganglia survived with their axons persisting throughout the graft. Comparable numbers of retinal ganglion cells regenerated axons into both dorsal root ganglia (1053+/-223) and conventional grafts (1323+/-881; P>0.05). The results indicate that an intact sensory environment supports central axon regeneration.