Progressive encephalomyelitis with rigidity and myoclonus: the first pediatric case with glycine receptor antibodies.

IMPORTANCE: Progressive encephalomyelitis with rigidity and myoclonus is characterized by rigidity, painful muscle spasms, hyperekplexia, and brainstem signs. Recently, glycine receptor alpha 1 antibodies have been described in adult patients with progressive encephalomyelitis with rigidity and myoclonus. We describe a pediatric case. OBSERVATIONS: A 14-month-old child developed startle-induced episodes of generalized rigidity and myoclonus, axial hyperextension, and trismus, without impairment of consciousness. Episodes occurred during wakefulness and sleep, lasted seconds, and were accompanied by moaning, tachypnea, and oxygen desaturation. Imaging, cerebrospinal fluid, endocrine, metabolic, and genetic screening findings were normal or negative. She was treated with intravenous steroids and immunoglobulins with resolution of symptoms, but she relapsed weeks later. At this time, episodes were more severe. Glycine receptor alpha 1 antibodies were found in serum (titer of 1:200, later 1:320) and cerebrospinal fluid (titer of 1:2). Treatment was restarted with intravenous steroids and immunoglobulins, with major improvement, and she began treatment with oral steroids. She had 4 milder relapses, with improvement after treatment adjustments. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first pediatric case of progressive encephalomyelitis with rigidity and myoclonus associated with glycine receptor alpha 1 antibodies, a potentially severe but treatable antibody-mediated neurological disorder.

Cerebrospinal fluid nitric oxide levels in subacute sclerosing panencephalitis.

Oxidative damage plays a role in neurodegenerative diseases. Levels of cerebrospinal fluid nitrite and nitrate levels (oxidation products that provide an indirect estimation of nitric oxide) were investigated in relation to clinical and laboratory features in subacute sclerosing panencephalitis (n = 47) and age-matched control (n = 43) groups. Significantly decreased levels of nitrite (median, 4.91 micromol/L) and nitrate (median, 6.14 micromol/L) were found in the patients. Nitrite and nitrate levels did not correlate with clinical or laboratory findings, except for presence of myoclonus. Cerebrospinal fluid nitrite levels of subacute sclerosing panencephalitis patients without myoclonic jerks were significantly higher than in those with myoclonus (median, 15.63 vs 4.34 micromol/L, respectively). The higher levels of nitrite in these patients can be explained by short disease duration and early stages of disease. Nitrate levels in subacute sclerosing panencephalitis patients with myoclonus (median, 9.26 micromol/L) were higher than in those without myoclonus (median, 4.25 micromol/L). Microbleeding resulting in conversion of nitrite to nitrate and increased production of superoxide can be suggested as possible mechanisms underlying these findings.

Progressive myoclonic ataxia with intrathecal immune activation in six patients.

In six patients with slowly progressive sporadic cerebellar ataxia and cortical multifocal action myoclonus, cerebrospinal fluid (CSF) IgG index was persistently very high (1.2-6.7) and numerous oligoclonal bands were detected. Progressive cognitive impairment and MRI cerebellar and cerebral atrophy were observed. No serum antibodies were found. Various degenerative, metabolic, inflammatory and systemic diseases were excluded. The cerebellum may be the main target of a degenerative or immune process and releases antigens that, enhancing a compartmentalised (auto)immune response, as suggested by the persistent intrathecal activation, could lead to further cerebellar damage. As the frequency of CSF oligoclonal banding in myoclonic ataxia is unknown, our patients' disease might represent a hitherto unreported entity or a subset of progressive myoclonic ataxia.

Detection of herpesvirus-6A in a case of subacute cerebellitis and myoclonic dystonia.

This is a case study of a child who developed roseola infantum first, then varicella, and was later affected by acute cerebellar syndrome, severe truncal ataxia, and myoclonic dystonia. Human herpesvirus 6 (HHV-6) A and B were detected in the cerebrospinal fluid (CSF) and peripheral blood, respectively, upon ataxia onset. The intricacy of this case suggests multifaceted conclusions ranging from the need for a multidirectional approach to neurological diseases, to confirmation of a more pronounced neurotropism of HHV-6A and a possible role of viruses in myoclonic dystonia syndrome, although this last hypothesis should be confirmed by larger studies.

Opsoclonus-myoclonus-dysequilibrium syndrome: cytological and immunological dynamics in the serial cerebrospinal fluid in two patients.

A peculiar clinical presentation characterized by the triad of opsoclonus,myoclonus and ataxia, mainly in a form of dysequilibrium, is usually associated with infectious or paraneoplastic processes. Serial cerebrospinal fluid (CSF) analysis in two patients with opsoclonus-myoclonus-dysequilibrium syndrome suggestive of viral encephalitis were performed from disease onset for up to 8 months. A cell count, cytology, total protein and glucose concentrations in CSF, the blood-CSF barrier function, intrathecal synthesis of immunoglobulins (Ig) in class M, G and A expressed as IgM, IgG and IgA indices and oligoclonal IgG bands were monitored. Cellular and humoral alterations in both patients were slight at the onset becoming more pronounced a month later. The kinetics of the CSF changes mirrored the subacute clinical deterioration and subsequent recovery. The delayed response in the CSF measures and the gradual clinical deterioration suggest the development of subacute brain inflammation. A mononuclear pleocytosis, including macrophages and plasma cells, increased within the first month and then normalized during the following weeks. Intrathecally synthesized IgM occurred only transiently after one month of illness, whereas intrathecal IgG production increased during the first month and persisted for at least eight months. An increasing number of oligoclonal IgG bands during the course, indicative of expanding local intrathecal synthesis, was noted. The dynamics of these CSF changes supports the hypothesis that opsoclonus-myoclonus syndrome is a post-infectious immune- mediated condition.

[Paraneoplastic opsoclonus-myoclonus syndrome revealing T-cell lymphoma]. / Syndrome opsoclonus-myoclonus paranéoplasique révélateur d'un lymphome T.

BACKGROUND: Nonrhythmic involuntary ocular oscillations and axial and segmentary myoclonia are associated in the opsoclonus-myoclonus syndrome. In adults, a paraneoplastic origin is generally found. We report the first of opsoclonus-myoclonus associated with non-Hodgkin's lymphoma. CASE REPORT: A 66-year-old woman rapidly developed a typical opsoclonus-myoclonus syndrome within a few hours, presenting vertigo, cerebellous ataxia, multidirectional involuntary ocular movements and non-rhythmic axial and segmentary myoclonia. Brain computed tomography and magnetic resonance imaging demonstrated discrete diffuse anomalies of the white substance predominating in the pons. The cerebrospinal fluid showed discrete lymphocytosis. Antineuron antibodies were negative. No cause could be identified until the development 11 months later of pleomorphic T-cell mediastino-cervical lymphoma. The patient responded moderately to a CHOP regimen which had no effect on the opsoclonus-myoclonus syndrome. Death occurred after a 16-month course due to pulmonary complications. DISCUSSION: Neuroblastoma and infectious causes predominate in opsoclonus-myoclonus syndromes observed in children; in adults, the predominant cause is cancer. Antineuron, anti-Ri and anti-Hu antibodies can be evidenced in some cases, arguing in favor of a paraneoplastic mechanism. Recent reports have evidenced MRI anomalies in the pons and the cerebellum, anatomically well correlated with the opsoclonus-myoclonus syndrome. Besides small-cell bronchogenic anaplastic cancer, the possibility of cancer of the breast and uterus, and both non-Hodgkin and Hodgkin lymphoma should be explored, knowing the cancer develops several month after the opsoclonus-myoclonus syndrome.

Monoaminergic effects of high-dose corticotropin in corticotropin-responsive pediatric opsoclonus-myoclonus.

Children with the opsoclonus-myoclonus syndrome (OMS) usually respond to corticotropin (adrenocorticotrophic hormone, ACTH) treatment but the mechanism of benefit is unknown. We previously showed that both cerebrospinal fluid (CSF) homovanillic acid (HVA) and 5-hydroxyindole-acetic acid (5-HIAA) concentrations are low in pediatric OMS. In this study, we measured levels of CSF Dopa, catecholamines, deaminated metabolites of catecholamines, as well as HVA and 5-HIAA in eight patients before and during treatment with ACTH. All the children were ACTH-responsive with 50-70% improvement in multiple clinical features of OMS. ACTH treatment reduced the HVA concentration in every child by a mean of 21% (p < 0.001). Treatment with ACTH was associated with significant correlations between dopaminergic markers such as HVA, dihydroxyphenylacetic acid (DOPAC), and Dopa. There were no significant changes in the CSF concentrations of the noradrenergic markers norepinephrine (NE) and dihydroxyphenylglycol (DHPG), or the serotonergic marker 5-HIAA. The only child with a marked inflammatory pattern in CSF, which was reversed by ACTH, was atypical for a large increase in NE and decrease in 5-HIAA during ACTH treatment. Beneficial effects of ACTH in OMS are not associated with normalization of HVA or 5-HIAA levels. The pattern of decreased HVA and unchanged DOPAC levels could reflect decreased extraneuronal uptake of catecholamines (which steroids inhibit) or decreased 0-methylation of catecholamines in nonneuronal cells.

A novel substance associated with gallamine-induced myoclonus.

If gallamine or d-tubocurarine gains access to the central nervous system it produces a myoclonus, a synchronized jerking of many skeletal muscles. Each jerk is accompanied by a slow wave in the inferior olive. The jerking continues for 24 h or more after the gallamine or d-tubocurarine can no longer be detected in the CSF. We report here that a novel substance appears in the CSF and persists for a long period of time, possibly as long as the twitching. This substance is not corticotrophin-releasing factor (CRF) nor does CRF or harmaline (a substance causing a tremor by an action on the inferior olive) lead to the appearance of the novel substance. At present the nature of this substance is not known.

Neonatal segmental myoclonus associated with hyperglycorrhachia.

Segmental or spinal myoclonus is an uncommon involuntary movement in infancy which has been attributed to sepsis, degenerative and developmental diseases of the spinal cord, birth trauma, and sclerosing panencephalitis. A premature infant presenting with segmental myoclonus associated with extreme hyperglycorrhachia secondary to the administration of parenteral nutrition through a femoral percutaneous indwelling central catheter that had inadvertently migrated into a paravertebral vein is reported. We recommend a lateral abdominal radiograph in addition to the usual anteroposterior view to confirm the correct placement of femoral catheters.

Cerebrospinal fluid 5-hydroxyindoleacetic acid and homovanillic acid in the pediatric opsoclonus-myoclonus syndrome.

To study the purported role of central monoamine disturbances in the pathophysiology of the opsoclonus-myoclonus syndrome, the serotonin metabolite 5-hydroxyindoleacetic acid and the dopamine metabolite homovanillic acid were measured in cerebrospinal fluid samples from 27 affected children and 47 age- and gender-matched control subjects by high-pressure liquid chromatography with electrochemical detection. 5-Hydroxyindoleacetic acid and homovanillic acid concentrations in the cerebrospinal fluid were approximately 30 to 40% lower in opsoclonus-myoclonus patients compared to control subjects, and the normal inverse correlation between age and monoamine metabolite concentrations in the cerebrospinal fluid of control subjects was not found in opsoclonus-myoclonus patients. Patients with the lowest values were less than 4 years old, and a subgroup had extremely low levels, but differences in older children were not significant. Cerebrospinal fluid levels of 5-hydroxyindoleacetic acid and homovanillic acid were more positively correlated in control subjects than in opsoclonus-myoclonus patients. None of the patients exhibited high levels of monoamine metabolites. Homovanillic acid levels were slightly lower in the cerebrospinal fluid of patients receiving corticotropin or steroids at the time of lumbar puncture. Clinical variables that could be excluded were paraneoplastic etiology, anesthetic for lumbar puncture, syndrome duration, age at onset, gender, response to steroids, length of time until initiation of corticotropin or steroids, presence of seizures, opsoclonus, and functional impairment. These data suggest a disturbance and possible altered ontogeny of serotonin or dopamine neurotransmission in a subpopulation of children with opsoclonus-myoclonus with low cerebrospinal fluid levels of 5-hydroxyindoleacetic acid and homovanillic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebrospinal fluid neurochemistry in the myoclonic subtype of Alzheimer's disease.

Monoamine metabolites, biopterin, acetylcholinesterase (AChE) activity, and somatostatin-like immunoreactivity (SLI) were determined in the lumbar cerebrospinal fluid (CSF) of 24 patients with dementia of the Alzheimer type (DAT) without myoclonus or extrapyramidal signs, in 8 patients with DAT and myoclonus, and in 14 age-matched healthy control subjects. In patients with DAT with myoclonus as compared with both DAT patients without myoclonus and control subjects, the concentrations of homovanillic acid and biopterin were significantly decreased. 5-Hydroxyindoleacetic acid was significantly lower in patients with myoclonic DAT as compared to patients with nonmyoclonic DAT, but not significantly lower than in control subjects. CSF AChE and SLI were significantly reduced in patients with DAT with or without myoclonus, as compared with control subjects, but AChE and SLI were not significantly different between dementia groups. These results suggest that DAT patients with myoclonus represent a distinct clinical and neurochemical DAT subtype.

Clinical, biochemical, and pharmacological observation in a patient with postasphyxic myoclonus: association to serotonin hyperactivity.

Posthypoxic action myoclonus is usually associated with impaired serotonin (5-HT) neurotransmission but in some patients 5-HT precursors aggravate and 5-HT blockers improve action myoclonus. We studied a 65-year-old man who presented with action myoclonus following a prolonged episode of moderate hypoxia and severe hypercarbia. The myoclonus increased with 5-hydroxytryptophan (5-HTP) 1,200 mg/day plus carbidopa 300 mg/day and sodium salt of valproic acid (SVA) 800 mg/day, and improved with 1 mg of clonazepam (CNZ) in an intravenous bolus. Biochemical analysis of the cerebrospinal fluid (CSF) prior to any drug therapy did not reveal abnormalities in the levels of homovanillic acid (HVA) and methoxyhydroxyphenylglycol (MHPG) but 5-hydroxyindoleacetic acid (5-HIAA) levels were elevated in comparison with controls (33 versus 21 ng/ml). SVA therapy produced a moderate increase and 5-HTP plus carbidopa a threefold elevation of 5-HIAA in CSF and marked aggravation of action myoclonus. Methysergide (3 mg/day) totally suppressed myoclonus and decreased CSF 5-HIAA to undetectable levels. Methysergide also reduced CSF tryptophan to 40% of baseline levels. Discontinuation of methysergide and substitution by placebo was followed by reappearance of myoclonus. A partial and incomplete spontaneous remission of symptoms took place 7 months after the asphyxic episode. Action myoclonus and enhanced 5-HT neurotransmission may be present in patients in which acidosis reverses the effects of hypoxia on 5-HT neurotransmission.

Intrathecal immune activation in a case of progressive action myoclonus.

The case of a patient affected by progressive multifocal myoclonus associated with inflammatory reaction in the cerebrospinal fluid is reported. A multiple sclerosis diagnosis is suggested, even if typical disease course and features are lacking.

Oligoclonal IgG bands in the CSF of a patient with progressive familial myoclonus.

An oligoclonal IgG pattern was found in the CSF of a patient who is known to suffer from progressive familial myoclonus. In view of this finding the possibility arises that immunological mechanisms participate in the etiopathogenesis of this disease.

Syndrome of opsoclonus-myoclonus caused by Coxsackie B3 infection.

Coxsackie B3 was cultured from 2 children who presented within two weeks of each other from the Cape Cod, Massachusetts, area showing opsoclonus and myoclonus. The organism was recovered from the cerebrospinal fluid of 1 patient and from the stools of both. Both children had cerebrospinal fluid pleocytosis and gradual, spontaneous resolution of their symptoms.

Opsoclonus in Hemophilus influenzae meningitis.

We studied a 3-month-old boy who had opsoclonus in association with acute bacterial meningitis. The CSF IgG and IgM were elevated acutely, gradually returning to normal with clinical improvement. Correspondingly, CSF cytomorphology showed excessive plasmocytosis and a higher proportion of reactive lymphocytes than expected in an acute bacterial meningitis. These abnormalities in CSF cytology are effects of an abnormal immune response in the CNS, and provide evidence to support an immunopathic basis to opsoclonus.

[Palatal myoclonus associated with a decrease in 5-hydroxy-indole acetic acid in cerebrospinal fluid and responding to clonazepam]. / Myoclonies du voile associées à une diminution de l'acide 5-hydroxy-indole-acétique céphalo-rachidien et répondant au clonazépam.

A patient representing with palatal myoclonus was diagnosed as suffering from possible multiple sclerosis. A reduction of cerebrospinal 5-hydroxy-indole-acetic acid suggested a decreased central serotonergic turnover. A therapeutic trial with clonazepam, a serotonergic agonist, improved the myoclonus symptomatically. The possible involvement of serotonergic inhibitory systems in the expression of palatal myoclonus is discussed.

Postanoxic myoclonus. Treatment of a case with 5-hydroxytryptophane and a decarboxylase inhibitor.

Postanoxic myoclonus was first accepted as being related to a dysfunction of the ventrolateral thalamic nucleus. Several stereotaxic studies have invalidated this hypothesis. The neurochemical approach, in particular the measure of 5-hydroxyindolacetic acid in the cerebrospinal fluid, has opened new theoretical and therapeutic possibilities involving serotoninergic pathways. A typical case is presented who improved markedly under a combined therapy with 5-hydroxytryptophan and a decarboxylase inhibitor. A review of the pathogenesis and therapeutic approach to postanoxic myoclonus is presented.

Clinical, biochemical, and physiological features distinguishing myoclonus responsive to 5-hydroxytryptophan, tryptophan with a monoamine oxidase inhibitor, and clonazepam.

Fifteen patients with a variety of myoclonic syndromes were studied clinically, pharmacologically, and physiologically. CSF tryptophan, 5HIAA, and HVA were also measured. Of these patients, 8 were improved to varying degrees by therapy with 5HTP, tryptophan in combination with MAOI (but not tryptophan alone), and clonazepam. This group included 6 cases of post-anoxic myoclonus, one case of post-traumatic myoclonus and one undiagnosed case of non-progressive focal myoclonus and epilepsy. In this group low levels of CSF 5HIAA were found compared to non-responsive cases and controls. Two cases of dysynergia cerebellaris myoclonica, 2 cases of undiagnosed aetiology, 2 cases of essential myoclonus, and one case of palatal myoclonus failed to respond to drug therapy. However, even amongst the responsive group the improvement varied. The most dramatic responses were seen in those patients in whom physiological study suggested that myoclonus was mediated by brain-stem structures. Less dramatic responses were seen in patients in whom the myoclonus appeared to originate from cortical structures. The neurochemical basis of myoclonus responding to 5HT precursors and clonazepam is discussed. It is suggested that such myoclonus arises from a relative hypoactivity of the 5HT neuronal system which results in a release of abnormal responses to sensory stimuli which characterize this type of myoclonus.