Association of autonomic symptoms with cerebrospinal fluid biomarkers in Parkinson disease and scans without evidence of dopaminergic deficit.

ABSTRACT: Dysautonomia is common in patients with Parkinson disease (PD) since disease early phase. Scales for Outcomes in Parkinson's disease - Autonomic (SCOPA-AUT) is a well-designed scale assessing the autonomic dysfunctions of PD patients. Our objectives were to examine the autonomic dysfunction in PD and scan without evidence of dopaminergic deficit (SWEDD) patients and to assess the correlation of autonomic dysfunctions with cerebrospinal fluid (CSF) biomarkers.An analysis of the Parkinson's Progression Markers Initiative (PPMI) data including 414 PD patients, 60 SWEDD patients, and 170 healthy controls (HCs) with baseline CSF biomarker measurements and SCOPA-AUT assessments was presented. Autonomic symptoms including gastrointestinal, urinary, cardiovascular, pupillomotor, thermoregulatory and sexual dysfunctions were assessed by SCOPA-AUT scales. Spearman correlation test was used to examine the correlations between CSF measurements and each section of SCOPA-AUT scales in HCs and subjects with PD or SWEDD.More severe autonomic dysfunctions were observed in patients with SWEDD than those with PD (P < .001). Specifically, patients with PD have lower scores on the urinary scale [4 (0-17) vs 5 (1-18)], pupillomotor scale [0 (0-3) vs 0 (0-3)], thermoregulatory scale [0 (0-4) vs 1.5 (0-10)] and sexual scale [1 (0-6) vs 2 (0-6)] compared with SWEDD patients. Thermoregulatory dysfunction scores were found correlated with CSF α-syn levels in SWEDD group, and gastrointestinal dysfunction scores were correlated with CSF Abeta1-42 in PD group. Additionally, urinary dysfunction scores were correlated with CSF total tau and tau phosphorylated at threonine 181(p-tau181) levels in both HCs and PD patients.

Anti-Hypothalamus and Anti-Pituitary Auto-antibodies in ROHHAD Syndrome: Additional Evidence Supporting an Autoimmune Etiopathogenesis.

BACKGROUND: Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD) is a very rare and complex pediatric syndrome characterized by altered hypothalamic thermal regulation, pain threshold, and respiratory control, hyperphagia with rapid weight gain and, often, hypothalamic-pituitary dysfunction. Its etiopathogenesis remains undetermined. We investigated the presence of alterations to target genes and hypothalamic-pituitary autoimmunity in a patient with -ROHHAD syndrome. METHODS: A 3-year-old girl presenting with obesity after rapid weight gain was diagnosed with ROHHAD syndrome based on clinical features and abnormal biochemical and functional testing results. Because of worsening of rapid symptoms and demonstration of oligoclonal bands on cerebrospinal fluid (CSF) analysis, she was treated with plasmapheresis, methylprednisolone, anti-CD20 monoclonal antibodies, and azathioprine. Despite initial partial clinical improvement, the patient soon died of cardiorespiratory arrest. Post-mortem, whole exome sequencing, high-resolution comparative genomic hybridization array, and optimized indirect immunofluorescence (IIF) analysis were performed on blood and CSF. RESULTS: No putative causative genomic variants compatible with dominant or recessive inheritance nor clinically significant structural rearrangement were detected. IIF on serum and CSF demonstrated the presence of anti-pituitary and anti-hypothalamus autoantibodies. CONCLUSIONS: These findings support the involvement of autoimmunity in ROHHAD syndrome. However, response to immunosuppressive treatment was only transient and the patient died. Further cases are required to define the complex disease pathogenesis.

Post-ganglionic autonomic neuropathy associated with anti-glutamic acid decarboxylase antibodies.

PURPOSE: Antibodies to glutamic acid decarboxylase (GAD-Abs) have been associated with several conditions, rarely involving the autonomic nervous system. Here, we describe two patients complaining of autonomic symptoms in whom a post-ganglionic autonomic neuropathy has been demonstrated in association with significantly elevated serum and CSF GAD-Abs levels. METHODS: Patients underwent nerve conduction studies, sympathetic skin response testing, evaluation of autonomic control of the cardiovascular system and skin biopsy. Also, serum screening to exclude predisposing causes of peripheral neuropathy was performed. Anti-GAD65 antibodies were evaluated in serum and CSF. RESULTS: GAD-Abs titer was increased in both serum and CSF in both patients. Sympathetic skin response was absent and skin biopsy revealed a non-length-dependent small-fiber neuropathy with sympathetic cholinergic and adrenergic post-ganglionic damage in both patients. Nerve conduction studies and evaluation of autonomic control of the cardiovascular system were normal in both patients. Both patients were treated with steroids with good, but partial, (patient 2) recovery of the autonomic dysfunctions. CONCLUSIONS: Although the pathophysiological mechanisms involved are not fully defined, GAD-abs positivity in serum and CSF should be searched in patients with autonomic neuropathy when no other acquired causes are evident. This positivity may help to clarify autoimmune etiology and, subsequently, to consider immunomodulatory treatment.

Intrathecal synthesis of oligoclonal bands in rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome: new evidence supporting immunological pathogenesis.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation syndrome (ROHHADS) is a rare, but potentially lethal, pediatric disorder. To date, nearly 80 patients have been reported in the literature; however, the etiopathogenesis is still unclear and debated. Both genetic and paraneoplastic or immune-mediated causes have been supposed to be involved in this syndrome. Nonetheless, at this time, a diagnostic biomarker is not available and diagnosis is based exclusively on clinical criteria. Aiming to establish the immune-mediated pathogenesis, we report 2 children with a clinical picture consistent with ROHHADS and whose cerebrospinal fluid analysis disclosed an intrathecal synthesis of oligoclonal bands. Even if many aspects remain to be explained, this finding suggests that ROHHADS could share similar pathogenetic mechanisms with other immune-mediated central nervous system disorders, and even more important, it might pave the way to a therapeutic chance for these patients by means of immunotherapy.

Encephalitis and acute autonomic neuropathy.

We present a case of acute autonomic sensory and motor neuropathy complicating encephalitis. To our knowledge, this is only the second report of acute autonomic neuropathy with sensory and motor dysfunction associated with central nervous system dysfunction.Our patient also had a false positive cerebrospinal fluid 14-3-3.

Successful treatment for sympathetic storms in a patient with neuro-Behçet's disease.

Sympathetic storms (SyS) are characterized by hyperactivity of autonomic functions, resulting in episodes of hyperthermia, hypertension, tachycardia, and hyperhidrosis. We show here a patient with neuro-Behçet's disease (NBD) complicated by SyS. Although SyS is well known to occur with brain tumors, trauma, and hydrocephalus, this is the first report to show that SyS is a manifestation of central nervous system involvement in a patient with NBD. High concentrations of norepinephrine (NE) and IL-8 in cerebrospinal fluid reflected the activity of SyS. The patient's symptoms showed almost complete improvement after treatment with corticosteroids and intravenous cyclophosphamide. Also, the concentrations of NE and IL-8 were decreased to normal levels. An awareness of the potential for SyS and adequate immunosuppressant therapy are of importance when dealing with patients with NBD.

Prevalence of anti-locus coeruleus immunoreactivity in CSF of patients with autonomic failure.

In this study we evaluated by indirect immunohistochemistry the prevalence of cerebrospinal fluid (CSF) antibodies reacting with structures of rat pons/medulla in patients with multiple system atrophy (MSA) (n = 29), Parkinson disease with neurogenic orthostatic hypotension (n = 13), or pure autonomic failure (n = 11) and in control subjects without autonomic failure (n = 33). About 10-20% of CSF samples had positive immunoreactivity to rat locus coeruleus (LC), regardless of clinical diagnosis. The results failed to confirm the previously reported high prevalence of immune binding to rat LC in CSF from patients with MSA.

Cerebrospinal fluid levels of catechols in patients with neurogenic orthostatic hypotension.

In multiple system atrophy (MSA) and pure autonomic failure (PAF), orthostatic hypotension (OH) results from deficient noradrenaline release from sympathetic nerves during standing. Post-mortem findings have indicated loss of central noradrenergic cells in both diseases. The present study sought in vivo neurochemical evidence for central noradrenergic deficiency in patients with OH due to MSA or PAF. A total of 28 patients with OH (18 with MSA; 10 with PAF) had cerebrospinal fluid and blood sampled for levels of noradrenaline and its neuronal metabolite dihydroxyphenylglycol. A control group of 44 subjects included 10 elderly normal volunteers, 10 patients with Alzheimer's disease, 18 patients with dysautonomia (postural tachycardia syndrome or neurocardiogenic syncope) and six patients with MSA in the absence of OH. Patients with OH had lower cerebrospinal fluid concentrations of noradrenaline (0.53+/-0.07 nmol/l) and dihydroxyphenylglycol (6.52+/-0.46 nmol/l) than did control subjects (0.90+/-0.09 and 9.64+/-0.46 nmol/l respectively; P =0.0001). The MSA+OH group had higher plasma levels of both catechols (noradrenaline, 1.31+/-0.16 nmol/l; dihydroxyphenylglycol, 5.08+/-0.43 nmol/l) than did the PAF group (noradrenaline, 0.38+/-0.08 nmol/l; dihydroxyphenylglycol, 2.53+/-0.30 nmol/l; P <0.001), despite similarly low cerebrospinal fluid levels. Among MSA patients, those with OH had lower cerebrospinal fluid levels of noradrenaline and dihydroxyphenylglycol than those without OH (noradrenaline, 1.71+/-0.64 nmol/l; dihydroxyphenylglycol, 10.41+/-1.77 nmol/l respectively; P =0.006). The findings are consistent with central noradrenergic deficiency in both MSA+OH and PAF. In MSA, central noradrenergic deficiency seems to relate specifically to OH.

Relapsing-remitting autoimmune agrypnia.

A woman affected by multiple cranial nerve palsy developed several episodes of total insomnia and respiratory crises resulting from central breathing depression associated with dysautonomic symptoms. Oligoclonal IgG bands were present in her cerebrospinal fluid, and immunohistochemistry showed increased binding of serum and cerebrospinal fluid on gamma-aminobutyric acid-ergic, synapse-rich neuronal cells. Immunosuppressive treatment and plasma exchange were followed by clinical improvement, with restoration of sleep architecture and disappearance of respiratory crises, suggesting autoimmune pathogenesis of the syndrome.

Epstein-Barr virus--associated acute autonomic neuropathy.

A 44-year-old man developed blurry vision, photosensitivity, orthostasis, constipation, and acrodysesthesias after a febrile illness. The neurologic examination and ancillary studies were consistent with a dysautonomic small fiber neuropathy. The cerebrospinal fluid (CSF) contained both Epstein-Barr virus (EBV) DNA and antibody to EBV. This is the first report of an acute autonomic neuropathy with documented EBV infection in CSF.

Autoimmune autonomic failure in a patient with myeloma-associated Shy-Drager syndrome.

We report here the case of a patient with the Shy-Drager syndrome and multiple myeloma who had evidence consistent with a central neural autoimmune basis for sympathetic autonomic failure. Autonomic function testing showed no recordable peroneal skeletal muscle sympathoneural traffic, normal arterial norepinephrine (NE) spillover during supine rest and no increment in NE spillover during exposure to lower body negative pressure. The patient's cerebrospinal fluid and serum contained an immunoglobulin G that bound to rat locus ceruleus (LC) in an in vitro test system. The myeloma protein was of the lambda subtype and bound in the rat LC, without binding in the substantia nigra, as demonstrated with anti-lambda antiserum. Since in this case the monoclonal antibody produced by the myeloma bound specifically to LC cells, the results are consistent with the hypothesis that in this patient the Shy-Drager syndrome may have had an immune-mediated basis.

[Repeated closed craniocerebral trauma]. / Povtornaia zakrytaia cherepno-mozgovaia trama.

As many as 446 patients with repeated craniocerebral injury and 386 patients with primary injury, analogous in respect of severity, were subjected to clinical and physiological examinations. On comparison of the results of examining the above two patients' groups it has been revealed that repeated brain injury may be characterized by its own features and runs a graver course as compared to primary injury. This manifests by more pronounced and persistent general cerebral and focal symptoms, disorders of the dynamics of the CSF toward hypotension, vegetative disorders in the form of lability and asymmetry of arterial pressure, thermal asymmetry, prolongation of the time of the thermoregulation vascular reflex and resolution of the blister according to the McClure-Aldrich test, and so forth. According to the therapeutic indications, 204 patients with repeated injury underwent pneumoencephalography. Manifest alterations in CSF-containing spaces, the intensity of which depended on the number of injuries, were revealed in 90.2% of them early after the injury. A special complex of pathogenetic therapy provided to 212 patients with repeated injury allowed attaining more favourable results as compared to 234 analogous patients who received routine treatment.

Aluminum-induced acute cholinergic neurotoxicity in rat.

In the present study the acute effect of intravenous aluminum chloride (1 mg/kg) on choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities of rats was investigated. Aluminum was found to cross the blood-brain barrier (BBB) as indicated by the detection of aluminum in the cerebrospinal fluid (CSF) 30 min after femoral vein injection. Two hours following aluminum injection, ChAT activity in the basal forebrain and hippocampus was significantly reduced by 30% and 22%, respectively, whereas no change was observed in the caudate nuclei. On the other hand, AChE activity was significantly increased by 45% in the caudate nuclei, whereas little change was observed in other brain areas. This report demonstrates that rapid transport of Al across the BBB, and the acute nature of Al neurotoxicity in rats.

Antibody in the CSF of patients with multiple system atrophy reacts specifically with rat locus ceruleus.

Idiopathic chronic autonomic dysfunction may occur as pure autonomic failure (PAF) or in association with multiple system atrophy (MSA). CSF immunoreactivity to rat locus ceruleus occurred in a significantly greater number of samples from MSA patients compared to control subjects or patients with PAF. Other brain regions infrequently showed immunoreactivity. These findings suggest that degeneration in MSA may release antigen(s) that induce antibodies against locus ceruleus neurons. Further studies are required to determine whether immune abnormalities play a pathogenetic role in MSA. Lack of CSF immunoreactivity in PAF is consistent with primarily peripheral involvement.

CSF acetylcholinesterase levels are reduced in multiple system atrophy with autonomic failure.

Diminished CSF levels of acetylcholinesterase in patients with multiple system atrophy attended by autonomic failure suggest that CNS cholinergic involvement may occur in this disorder. The lack of correlation between the low enzyme levels and low CSF levels of monoamine metabolites in these patients indicates that the acetylcholinesterase reduction is not directly related to disruption in these neurotransmitter systems. Normal CSF acetylcholinesterase levels in those patients with pure autonomic failure are consistent with functional integrity of central cholinergic pathways and support a pathophysiologic involvement limited to the peripheral nervous system.

Low lumbar CSF levels of homovanillic acid and 5-hydroxyindoleacetic acid in multiple system atrophy with autonomic failure.

Low lumbar CSF concentrations of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in patients with multiple system atrophy attended by autonomic failure (MSA) reflect decreased activity in central dopaminergic and serotonergic pathways. These neurochemical changes are consistent with the neuropathological involvement in MSA and distinguish such patients from those with pure autonomic failure who have normal CSF metabolite levels.

Ventricular somatostatin-like immunoreactivity in patients with basal ganglia disease.

The concentrations of somatostatin-like immunoreactivity (SLI) in lateral ventricular fluid of patients with extrapyramidal motor disease were determined by specific radio-immunoassay. Mean SLI levels were significantly lower in patients with Parkinson's disease (mean +/- SEM); 42.9 +/- 2.9 fmol/ml) and in patients with dystonic syndromes (39.4 +/- 3.2) than in patients with benign essential tremor (65.3 +/- 9.7). The lowest levels were found in patients with athetosis (34.7 +/- 5.4). In parkinsonian patients somatostatin levels correlated with the degree of akinesia, rigidity and autonomic disturbances.

Chronic autonomic failure: CSF and plasma 3-methoxy-4-hydroxyphenylglycol.

We measured CSF and plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG) in patients with orthostatic hypotension. Total CSF MHPG levels were significantly lower than normal in patients with either multiple system atrophy (MSA) or idiopathic orthostatic hypotension (IOH). Only IOH patients had low plasma levels of MHPG. Correction of CSF MHPG levels for the contribution from plasma free MHPG provides an index of central norepinephrine metabolism. In MSA, abnormal function of central noradrenergic pathways seems to cause the low CSF MHPG levels. In IOH, the decreased CSF MHPG results from the diminished plasma MHPG levels.

Substance P in human cerebrospinal fluid: reductions in peripheral neuropathy and autonomic dysfunction.

Substance P (SP), a putative peptide neurotransmitter, was measured in human lumbar cerebrospinal fluid (CSF) by radioimmunoassay. Substance P-like immunoreactivity (SPLI) was present in the CSF of 18 neurologically normal adults in concentrations ranging from 2.9 to 11.1 fmol per milliliter, with a mean of 7.0 /+- 0.6 fmol per milliliter (mean /+- SE). Slightly more than half of the CSF-SPLI cochromatographed with synthetic SP on Sephadex G-25. There was no apparent gradient in CSF-SPLI concentration over the first 30 ml of CSF removed by lumbar puncture. Mean concentrations CSF-SPLI in patients with Huntington disease, parkinsonism, miscellaneous dyskinesias, progressive supranuclear palsy, myopathy, and amyotrophic lateral sclerosis did not differ significantly from normal. Patients with neuropathy or multiple-system atrophy (Shy-Drager syndrome) had significantly reduced mean CSF-SPLI concentrations. These observations suggest that lumbar CSF-SPLI arises largely from spinal cord, nerve roots, or dorsal root ganglia, and that pathologic processes affecting these structures may be reflected by reduced levels of CSF-SPLI.