Immune checkpoint inhibitor refractory colitis leading to total colectomy in a melanoma patient.

Immunotherapy is becoming more and more relevant in the treatment of advanced melanoma. Proper management of its side effects can prevent severe complications. We describe the case of a 73-year-old patient with severe refractory colitis secondary to immunotherapy. The patient has been treated for 6 months with Nivolumab, an anti-PD-1, as adjuvant therapy for locally advanced melanoma. He was admitted to the hospital with a deteriorating general condition associated with severe diarrhea and rectal bleeding for 3 weeks. Despite three lines of treatment (high dose corticosteroids, infliximab, mycophenolate mofetil), the patient still presented clinical and endoscopic colitis, with additional infectious complications. The patient required surgical management for total colectomy. In this article we present one of the rare cases of autoimmune colitis that did not respond to various immunosuppressive treatments and required surgery.

An unusual recurrent ileocolonic injury.

Potassium binders (Kayexalate® and Sorbisterit®) are commonly used to treat hyperkaliemia. They are made of sodium or calcium polystyrene sulfonate. Their use is associated with multiple adverse effects including ileocolonic (or more rarely upper digestive tract) injuries which can lead to necrosis or perforations. This side effect is mostly seen in patients with chronic kidney disease or constipation. It presents with abdominal pain, diarrhea or hematochezia. The diagnosis is made when the histo-logical analysis of samples from the erythematous or ulcerated digestive wall finds polystyrene sulfonate crystals embedded in the mucosa. This diagnosis can be suspected by taking a careful initial drug inventory, if the clinician is aware of this rare but serious adverse effect. The lack of specificity of clinical symptoms and endoscopic lesions makes this inventory even more essential. Treatment is mainly supportive and requires cessation of the drug, while surgery is inevitable in the most severe cases.

Neuroleptic binding to sigma receptors: possible involvement in neuroleptic-induced acute dystonia.

Several antipsychotic drugs, belonging to various chemical classes, were compared for their affinity for the sigma, dopamine-D2, and muscarinic receptors. Many neuroleptic drugs were found to bind with high affinity to sigma 2 receptors, and the binding affinity was clearly different from that observed for dopamine-D2 receptors. The dopaminergic and muscarinic theories for the physiopathology of acute dystonia are not completely satisfactory. Since the sigma receptors were reported to play a role in the control of movement, the high affinity of some neuroleptics for these sites suggests their possible involvement in some side effects, such as drug-induced dystonia. There was a correlation between the clinical incidence of neuroleptic-induced acute dystonia and binding affinity of drugs for the sigma receptor, except for some drugs, with a lower incidence, displaying significant affinity for the cholinergic muscarinic receptor. Therefore, we conclude that the affinity for the sigma receptor might be involved in neuroleptic-induced acute dystonia, but this might be partially corrected by the intrinsic anticholinergic properties of the drug.

Oligoclonal free kappa and lambda bands in the cerebrospinal fluid of patients with multiple sclerosis and other neurological diseases. An immunoaffinity-mediated capillary blot study.

We describe an affinity-mediated capillary blotting technique for the detection of free kappa or lambda light chains in native cerebrospinal fluid (CSF) after isoelectric focusing in agarose gel. Interferences by light chains bound to immunoglobulins were carefully excluded. An absolute amount of 20-50 ng of free kappa or lambda Bence-Jones proteins were detectable by this method, under the form of several discrete bands with isoelectric points between 5 and 8.5. No free light chains were observed in CSF and sera from patients without neurological disorders (n = 26). Such bands were present in most CSF samples in the case of central nervous system (CNS) infections, except in aseptic meningitis. In a group of 48 multiple sclerosis (MS) patients, 44 (92%) displayed oligoclonal free kappa bands restricted to the CSF; oligoclonal IgG bands were observed in 40 cases, and oligoclonal free lambda bands in 33. In this group, the presence of CSF free light chain bands was highly correlated with their absolute levels (p less than 0.001). In other neurological diseases (n = 44), oligoclonal free kappa and free lambda bands were detected much more rarely, in seven (16%) and four (9%) cases respectively. Surprisingly, the CSF from three unrelated patients with Huntington's disease (out of five tested) contained both oligoclonal IgG and free kappa bands.

The intrathecal synthesis of virus-specific oligoclonal IgG in multiple sclerosis.

A highly sensitive antigen-mediated capillary blot technique was developed for the detection of virus-specific oligoclonal IgG in paired CSF and serum samples from patients with various neurological diseases. In multiple sclerosis, intrathecal synthesis of oligoclonal antibodies was present against measles (70%), rubella (60%), varicella zoster (40%) and mumps (30%); in most cases (75%), such synthesis involved two or more viruses. In contrast, antibodies against a non-neurotropic virus (cytomegalovirus) were rarely produced in CSF from MS patients (5%). However, this 'polyspecific' reaction was not restricted to MS samples but was also observed in neurolupus and in the late phase of infectious diseases of the central nervous system. These anti-viral antibodies could be produced without de novo replication of the corresponding viral genome and are likely mere bystanders of an ongoing immune response.

Polyclonal and oligoclonal IgA synthesis in the cerebrospinal fluid of neurological patients: an immunoaffinity-mediated capillary blot study.

An intrathecal synthesis of IgA has been reported in various neurological disorders. However, the frequency of its occurrence and the electrophoretic characteristics of the locally produced IgA remained a matter of controversy. We developed a sensitive immunoaffinity-mediated capillary blot technique for the detection of polyclonal and oligoclonal IgA in the CSF of 115 patients with various neurological disorders. Paired CSF and serum samples containing 50 ng IgA after appropriate dilutions were submitted to isoelectric focusing in agarose gels; IgA was then blotted onto a polyvinylidene difluoride sheet coated by an anti-IgA antiserum or by infectious antigens. The immunoblots were revealed by an alkaline phosphatase-conjugated anti-IgA antiserum. Only five samples displayed CSF-restricted oligoclonal IgA bands, including two out of 33 from MS patients. In herpetic encephalitis (n = 5) and varicella-zoster meningitis (n = 2), a strong intrathecal production of virus-specific IgA antibodies was detectable. In such cases, faint oligoclonal IgA antibodies were superimposed on a polyclonal background. A weak local production of anti-Borrelia burgdorferi IgA antibodies was present in two out of four cases of neuroborreliosis.

Study of IgA in the cerebrospinal fluid of neurological patients with special reference to size, subclass and local production.

IgA was assayed by particle counting immunoassay in cerebrospinal fluid (CSF) from non-neurological and neurological patients. Reference values had a logarithmic normal distribution with a mean of 1.54 mg/l and an upper limit of 5 mg/l. To estimate the possible intra-blood-brain barrier (BBB) production of IgA we have calculated an IgA index: CSF-IgA/serum-IgA: CSF-albumin/serum-albumin. Values higher than the upper reference limit of 0.41 were found in 12 out of 67 patients with multiple sclerosis (18%), in 5 out of 11 with aseptic meningitis, in 7 out of 8 with herpetic encephalitis, in 1 out of 8 with Guillain-Barré syndrome and in 2 cases of tuberculous meningitis. However, this index does not take into account the relative proportions of monomeric and polymeric IgA in CSF and serum. We therefore ultracentrifuged 17 paired CSF and serum samples and determined the relative proportions of monomeric and dimeric IgA and calculated the indices for monomeric and dimeric IgA. In controls the proportion of dimeric IgA in CSF was below 5% of total IgA whereas this proportion was increased up to 53.9% in the case of intra-BBB production of IgA, which is thus characterized by a very high dimeric IgA index. In all cases IgA1 remained the predominant subclass. These results had to be compared with those observed in cultures of peripheral blood lymphocytes, which secrete about equal proportions of monomeric and polymeric IgA pertaining to the IgA1 subclass.

Immune complexes in cerebrospinal fluid and serum of neurological patients. Possible intrathecal formation in bacterial meningitis and herpetic encephalitis.

We assayed immune complexes (IC) by Particle Counting ImmunoAssay in the serum and cerebrospinal fluid (CSF) of patients with various neurological disorders. In pyogenic meningitis, the levels of IC sharply increased 4-8 days after onset with a fall before the 10th day of the disease. In herpetic encephalitis the IC and antibody levels started to increase about 12 days after onset. The IC persisted at high values for 3-4 weeks, whereas the high antibody titers persisted for several months during the follow-up. In these 2 groups of patients IC were probably locally produced as indicated by the lack of correlation with the IC levels in the serum. We did not detect any significant increase of IC in the serum and CSF of patients with multiple sclerosis (N = 48) or with acute idiopathic polyradiculoneuritis (N = 11). Using another technique based on the determination of IgG and C4 in polyethylene glycol precipitates we also failed to detect any significant increase of IC in multiple sclerosis sera.

IgE in the cerebrospinal fluid.

The level of IgE in the cerebrospinal fluid (CSF) was determined by particle counting immunoassay. With a limit of sensitivity of 0.2 IU/ml, this immunoglobulin was detected neither in CSF of non-neurological patients (n = 27) nor of patients with sciatica (n = 13). IgE was present in samples from some patients with either multiple sclerosis (MS) or various infections of the central nervous system. In these cases, an IgE index [CSF IgE/serum IgE: CSF albumin/serum albumin] was calculated as 0.29 (SD 0.12). This value is not abnormal as the mean IgG and monomeric IgA indices are 0.45 and 0.34, respectively. Therefore, the IgE detected in most of the CSF samples was not locally produced. However, most patients with tuberculous meningitis had clearly an increased IgE index suggesting a local biosynthesis, but we failed to detect any IgE antibody activity against purified protein derivatives.

Physostigmine results in an increased decrement in brain glucose consumption in Alzheimer's disease.

The responsibility of cerebral cholinergic lesions for the weak clinical response to cholinergic neurotransmission enhancement of Alzheimer's disease (AD) was studied by measuring the effects of physostigmine on glucose consumption and neuropsychological tests. Ten AD and ten aged normals (AN) were examined twice, under placebo and under maximal tolerated dose of physostigmine, in randomized order and blind fashion. Under physostigmine, both groups showed better performances in tests measuring attention (P < 0.05-0.001) but not long-term memory, and cerebral glucose consumption was regionally modified (P < 0.0001). We observed a regional decrease in AD and in AN which was larger in AD, where each patient exhibited a mean metabolic decrease. With normalized values, AD and AN showed a similar decrease in the metabolic values of prefrontal cortex and striatum (P = 0.0003). These findings suggest that cholinergic neurotransmission enhancement depresses glucose consumption and increases selective attention in similar ways in both groups, but to a larger extent in AD. This suggests that brain metabolism in AD over-responds to enhancement of cholinergic neurotransmission. The observed weak response of clinical symptomatology to anticholinesterase agents does not appear to be due to the failure to enhance the activity of the cholinergic system in AD.

Identification of different ? amyloid cDNAs cloned from the brain of a patient with sporadic alzheimer's disease.

Neurofibrillary tangles and senile plaques, two neuropathological markers of Alzheimer's disease, may both contain peptide fragments derived from the ? amyloid protein. Human ? amyloid peptide precursor cDNAs have been isolated from normal foetal and adult brain libraries. In peripheral tissue and cultured cells, a novel precursor containing a protease inhibitor domain has been cloned. A cDNA library from the cerebral cortex of a patient with sporadic Alzheimer's disease was constructed and several clones coding for the ? amyloid peptide precursor were isolated cDNAs containing two types of insertion coding for a serine protease inhibitor domain were identified. The use of another polyadenylation site available in the 3?-untranslated region of the mRNA was observed. These results indicate that, in one patient with Alzheimer's disease, different RNA species coding for the ? amyloid peptide precursor arise by alternative splicing of a single transcriptional unit, and use different polyadenylation sites.

Sulfonylurea binding sites in normal human brain and in Parkinson's disease, progressive supranuclear palsy and Huntington's disease.

In human brain, [3H]glibenclamide binds with high affinity (KD about 3.5 nM) to sulfonylurea binding sites which are associated with ATP-sensitive potassium (KATP) channels. Regarding to the important neuromodulatory action of KATP channels in some neuronal populations, sulfonylurea binding sites were measured in several cortical areas (frontal and temporal cortex, hippocampus) and striatum (caudate nucleus and putamen) in controls and patients with Parkinson's disease or progressive supranuclear palsy. There was no modification of [3H]glibenclamide specific binding in the cerebral regions studied in both pathologies. These results indicate that KATP channels do not seem to be involved in the pathophysiology of these degenerative processes. Brain samples from five patients with Huntington's disease were studied. A small decrease in sulfonylurea binding sites was measured in the frontal cortex, caudate nucleus and putamen which could be due to the loss of either neurons or nerve endings. This low decrease contrasts with the dramatic diminution of many other markers associated with the profound striatal degeneration occurring in Huntington's disease.

[3H]MK-801 binding to NMDA glutamatergic receptors in Parkinson's disease and progressive supranuclear palsy.

The interactions existing between glutamatergic and dopaminergic systems, notably in the basal ganglia, suggest that glutamatergic antagonists may have therapeutic interest in extrapyramidal disorders characterized by impaired dopaminergic transmission. The binding of [3H]dizocilpine maleate (MK-801) to glutamate receptors of the N-methyl-D-aspartate (NMDA)-subtype was characterized in temporal and frontal cortex, in hippocampus and in subcortical areas (caudate nucleus and putamen) from controls and patients with Parkinson's disease or progressive supranuclear palsy. The binding affinity (KD) and the maximal specific binding capacity (Bmax) of [3H]MK-801 were unchanged in all the cerebral regions studied in both diseases. This indicates the existence of preserved NMDA glutamate receptors, which is required for potential therapeutic efficacy of specific antagonists.

Benzodiazepine receptors in normal human brain, in Parkinson's disease and in progressive supranuclear palsy.

Benzodiazepine receptors have been characterized in human brain. They have been localized mainly in the cerebral cortex and a synaptosomal enrichment was observed after brain fractionation by differential centrifugation. Benzodiazepine receptors were studied in Parkinson's disease and in progressive supranuclear palsy (PSP). In both diseases, the [3H]flunitrazepam specific binding was unchanged when compared to control groups (Bmax and KD values) except in the caudate nucleus of parkinsonian patients where an increase of the specific binding was observed. The subcellular distribution profile of benzodiazepine receptors in Parkinson's disease was similar to that of controls. gamma-Aminobutyric acid (GABA) still enhanced the [3H]flunitrazepam-specific binding (increase of binding affinity), indicating that the functional link between GABA and benzodiazepine receptors remained intact in Parkinson's disease. The present results suggest that benzodiazepine receptors in human striatum are localized on neuronal elements which do not degenerate in Parkinson's disease and PSP.

Subacute sensory neuronopathy associated with Sjögren's sicca syndrome.

Sensory subacute neuropathies associated with sicca syndrome without any systemic involvement have been reported rarely. A sixth case is described with what appears to be the first report of muscle and nerve biopsy findings. The histological studies revealed axonal degeneration without vasculitis in the sural nerve, and a slight denervation process and a discrete myositis in the gastrocnemius muscle, reflecting a subtle systemic disorder. The clinical course of a long-standing subacute sensory neuropathy, the biopsy-documented axonal degeneration, and the neurophysiological findings suggest involvement of the dorsal root ganglia.

Spinal arachnoiditis due to aspergillus meningitis in a previously healthy patient.

A 30-year-old, previously healthy, non-addicted man presented with a chronic spinal meningitis complicated by arachnoiditis and spinal cord compression. Biopsy showed a chronic granulomatous leptomeningitis, in which some cells contained branching septate organisms that were immunostained with an antiserum to Aspergillus fumigatus. Precipitins to A. fumigatus were detected in cerebrospinal fluid (CSF), but not in blood, and aspergillus infection was apparently restricted to the leptomeninges. Clinically successful treatment led to the disappearance of CSF precipitins and oligoclonal bands.

Functional dihydropyridine binding site associated with slow calcium channel in rat cultured neurones.

There is a high affinity binding of [3H]PN 200-110 (Kd = 0.21 nM) to slow calcium channels in cultured neurones. Several calcium antagonists, which recognize the [3H]PN 200-110 binding site, did not affect the K+-induced calcium uptake. The calcium channel activator BAY K 8644 increased the calcium uptake in depolarizing conditions and this effect was antagonized by pharmacological concentrations of calcium entry blockers. We conclude that the dihydropyridine binding site is involved in the modulation of calcium entry through the voltage-sensitive channel in depolarized cultured neurones.

Occurrence of oligoclonal IgM bands in the cerebrospinal fluid of neurological patients: an immunoaffinity-mediated capillary blot study.

We developed a highly sensitive and specific immunoaffinity-mediated capillary blot technique for the detection of oligoclonal IgM bands in CSF and sera from patients with various neurological disorders. Pre-treatment of the samples by dithiothreitol was necessary to obtain a migration of the IgM molecule into the gel of isoelectric focusing. IgM was then transferred by immunoaffinity onto a polyvinylidene difluoride sheet previously coated with anti-IgM antiserum. The limit of detection was found to be 6 ng in 15-microliters samples. The presence of CSF-restricted IgM bands was considered the result of an intrathecal synthesis and was observed in 13 out of 46 (28%) patients with MS, more frequently in acute relapses (9 out of 21, 43%), including 6 cases out of 13 presenting the first bout of the disease. Similar IgM bands were also detected in 15 out of 46 (38%) patients with CNS infections, especially in cases of neurosyphilis and neuroborreliosis. The presence of CSF oligoclonal IgM bands was linked to an increase of the IgM index in the MS group, but not in the group of infectious diseases as a whole. The occurrence of CSF-restricted oligoclonal IgM bands seems to be the most specific indicator of an intrathecal synthesis of this isotype.

C-reactive protein in serum and cerebrospinal fluid in various neurological disorders. Apparent local consumption during bacterial meningitis.

The level of C-reactive protein (CRP) was determined in the cerebrospinal fluid (CSF) by particle counting immunoassay. In non-neurological patients (N = 24), CRP was detectable only in 10 samples at concentrations ranging from 1.5 to 37 micrograms/l. The multiple sclerosis group did not differ from the controls. The highest CRP levels were found in viral and bacterial, including tuberculous, infections of the nervous system, with overlapping results for the various types of infections. However, in serum, the levels of CRP were much higher in pyogenic than in viral meningitis. We compared the CSF CRP/serum CRP ratio to the same ratio for albumin and found a significant correlation between the two ratios in viral, but not in bacterial, infections. These results suggest a local consumption of CRP during bacterial meningitis.

The concentration of IgM in the cerebrospinal fluid of neurological patients.

The level of IgM was determined by Particle Counting Immunoassay in the cerebrospinal fluid. In non-neurological patients (N = 20) the mean was 97.5 micrograms/l with the upper reference limit at 380 micrograms/l. The mean IgM index was 0.021 with the upper reference limit at 0.071. Of 21 patients with stroke, 5 had an IgM index exceeding the reference limit. High levels and indices of IgM were observed in most patients (N = 27) with infectious meningo-encephalitis. In this group, the IgM index was abnormal in about 30% of cases with a normal total protein content, and was more often increased than the IgG index. In multiple sclerosis patients (N = 80), the IgM index was increased in 32%. In this disease very high values of IgM index (greater than 0.13) were never associated with very high values of IgG index (greater than 1.8). A significantly higher proportion of males was found in the group of patients with very high values of IgM index (N = 11). No significant influence of the age of onset, the interval between onset and sampling and clinical state was observed. However, of 10 patients with a multiple sclerosis history exceeding 15 years none had an IgM index exceeding the upper reference limit. Four patients with multiple sclerosis had a high IgM index without either an increase of the IgG index or the presence of oligoclonal bands.