Radiological remission and recovery of thirst appreciation after infliximab therapy in adipsic diabetes insipidus secondary to neurosarcoidosis.

BACKGROUND: Neurosarcoidosis is a rare and aggressive variant of systemic sarcoidosis which may result in hypothalamic-pituitary dysfunction. We report a case of hypothalamic hypopituitarism secondary to neurosarcoidosis complicated by adipsic diabetes insipidus (ADI). Initiation of anti-tumour necrosis factor-α (TNF-α) therapy resulted in both radiological disease remission and recovery of osmoregulated thirst appreciation after 3 months. CASE SUMMARY: A 22-year-old man was referred to the endocrinology service with profound weight gain, polyuria and lethargy. Biochemical testing confirmed anterior hypopituitarism while posterior pituitary failure was confirmed by hypotonic polyuria responding to desmopressin. Magnetic resonance imaging (MRI) demonstrated extensive hypothalamic infiltration; neurosarcoidosis was confirmed histologically after excisional cervical lymph node biopsy. Osmoregulated thirst appreciation was normal early in the disease course despite severe hypotonic polyuria. However, subsequent subjective loss of thirst appreciation and development of severe hypernatraemia in the setting of normal cognitive function indicated onset of ADI. MANAGEMENT: Clinical management involved daily weighing, regular plasma sodium measurement, fixed daily fluid intake and oral desmopressin. We initiated immunosuppressive therapy with pulsed intravenous anti-TNF-α therapy (infliximab) after multidisciplinary team consultation. OUTCOME: Infliximab therapy resulted in successful radiological disease remission and complete recovery of osmoregulated thirst appreciation. This was confirmed by subjective return of thirst response and maintenance of plasma sodium in the normal range in the absence of close biochemical monitoring.

Does long-term partial sodium channel blockade alter disease progression in MS? Evidence from a retrospective study.

BACKGROUND: There is accumulating evidence that long-term disability and disease progression in multiple sclerosis (MS) are due to prolonged sodium channel opening along demyelinated axons. Despite good evidence in animal models of MS that partial voltage-gated sodium channel (VGSC) blockade reduces disease progression, little is known about its effects in patients, despite widespread use of such agents in the symptomatic management of MS. OBJECTIVE: To determine if long-term exposure to the VGSC-blocking drug carbamazepine (CBZ) alters disease progression in MS. METHODS: Using a retrospective chart review of patients diagnosed with MS, we compared progression of disability between patients exposed the VGSC blocker CBZ with those who were not exposed to the drug. Both whole-group and matched case-control analyses were performed after correcting for the influence of age, gender, MS subtype, expanded disability status score at diagnosis, use of disease-modifying therapy, and year of initial therapy. The multiple sclerosis severity scale (MSSS) was used as a measure of disease severity. The primary outcome measure was MSSS score difference between groups. RESULTS: Four hundred patients were included; 51 received CBZ symptomatic therapy (average duration of therapy 27 months). There was no significant difference in mean MSSS between the two groups in either the whole group comparison (p = 0.63) or the matched analysis (p = 0.12). CONCLUSION: Despite preclinical evidence suggesting a neuroprotective role of VGSC blockers in animal models of MS, this retrospective study suggests that long-term exposure to the VGSC-blocking drug CBZ fails to alter long-term disability and disease progression in MS patients.

The clinical spectrum of Lyme neuroborreliosis.

Lyme disease is a multisystem infectious disease, endemic in parts of Europe, including the West of Ireland. Neurological manifestions (neuroborreliosis) are variable. Presenting neurological syndromes include meningitis, cranial neuropathies, myeloradiculitis and mononeuritis multiplex. A lack of specificity in serological diagnosis may add to diagnostic confusion. We reviewed thirty cases of acute Lyme disease in the West of Ireland and found neurological syndromes in 15 (50%), with painful radiculopathy (12 patients; 80%) and cranial neuropathy (7 patients; 46%) occurring frequently. Neuroborreliosis needs to be considered in the differential diagnosis of these neurological syndromes in the appropriate clinical context.

Acute aseptic meningitis and diffuse myelitis as the presenting features of neurological Behcet disease.

We report an explosive presentation of neurological Behcet disease, in an Irish male patient. We present the clinical and radiological findings in our patient and discuss a novel and effective therapeutic approach. We review other treatment modalities of patients with neurological involvement.

When a stroke is not a stroke; posterior leukoencephalopathy syndrome mimicking posterior circulation stroke.

Posterior leukoencephalopathy syndrome (PLS) is a potentially reversible syndrome that may mimic the clinical and radiological features of posterior circulation cerebral infarction. Three cases of PLS are presented which were erroneously diagnosed as strokes and treated in accordance with recent evidence based guidelines; none of the cases fulfilled the current criteria requiring treatment for hypertension in the acute stroke setting. Once the diagnosis of PLS was made, and the patients blood pressure treated aggressively, all patients had rapid and full clinical resolution of their symptoms. Given the important differences in management and prognosis, rapid and accurate diagnosis is essential. Posterior leukoencephalopathy syndrome needs to be considered in patients presenting with clinical and/or radiological findings that predominantly affect the occipital lobes.

Outcomes following staged bilateral pallidotomy in advanced Parkinson's disease.

The authors assessed clinical outcome for up to one year after staged bilateral pallidotomy in 14 patients with advanced PD. One year after surgery, dyskinesias were virtually abolished and there were significant reductions in "off" time (67%) and activities of daily living "off" scores (24%), as well as nonsignificant reduction in "off" motor score (39%); "on" scores were unchanged. One patient developed a visual field deficit; two had transient confusion. Staged bilateral pallidotomy improves motor function in selected patients with advanced PD.

Stereotactic pallidotomy performed without using microelectrode guidance in patients with Parkinson's disease: surgical technique and 2-year results.

OBJECT: Pallidotomy for the treatment of medically refractory Parkinson's disease (PD) has enjoyed renewed popularity. However, the optimal surgical technique, lesion location, and long-term effectiveness of pallidotomy remain subjects of debate. In this article the authors describe their surgical technique for performing pallidotomy without using microelectrode guidance, and the clinical and radiological results of this procedure. METHODS: Patients were evaluated preoperatively by using a battery of validated clinical rating scales and magnetic resonance (MR) imaging of the brain. Individuals with severe treatment-refractory idiopathic PD who were believed to be good candidates for surgery underwent computerized tomography scanning- and MR imaging-guided stereotactic pallidotomy. Intraoperative macrostimulation was used to optimize lesion placement and to avoid injury to nearby structures. Lesion location and size were calculated from MR imaging sequences of the brain obtained within the first 24 hours after surgery and again 3 months later. Clinical examinations were conducted at 1.5, 3, 6, 12, and 24 months after surgery. Seventy-five patients (mean age 61 years, range 38-79 years) underwent unilateral pallidotomy. Significant improvements were observed in the "off' period scores for the activities of daily living portion of the Unified Parkinson's Disease Rating Scale (UPDRS), the UPDRS motor scores, total "on" time, levodopa-induced dyskinesias, and contralateral tremor. These improvements were maintained 24 months postoperatively. The mean lesion volume measured on the immediate postoperative MR image was 73 +/- 5.4 mm3. Radiological analysis suggests that initial lesion volume does not predict outcome. The only permanent major complication was a single visual field defect. CONCLUSIONS: Pallidotomy performed without using microelectrode guidance is a safe and effective treatment for selected patients with medically refractory PD.

Regional dopamine transporter gene expression in the substantia nigra from control and Parkinson's disease brains.

OBJECTIVE: To test the hypothesis that differential regional dopamine transporter (DAT) gene expression may underlie the selective vulnerability of certain nigral dopaminergic neurons in Parkinson's disease, DAT mRNA expression was examined in neuronal subpopulations of human postmortem ventral mesencephalon from patients with Parkinson's disease and controls. METHODS: Radioactive in situ hybridisation histochemistry using a polymerase chain reaction derived ribonucleotide probe for DAT was performed on sections of ventral mesencephalon from the brains of five donors with no history of neurological illness and from five patients with pathologically established Parkinson's disease. The number of silver grains overlying melanised neurons from the paranigral nucleus, dorsal and ventral tier, and pars lateralis of the substantia nigra pars compacta were compared with each other and to background labelling by using a one way factorial analysis of variance (ANOVA) with a significance level of 5%. RESULTS: In control brains, there was intense DAT mRNA expression in the ventral midbrain with no significant difference in mRNA concentrations among the four regions studied. In the Parkinson's disease brains, there was an overall decrease in the intensity of DAT mRNA expression in the surviving dopaminergic neurons. There were no significant differences in signal between regions in either the control or parkinsonian brains. CONCLUSION: Taken together, these findings do not support the hypothesis that differential regional DAT gene expression underlies the selective vulnerability of certain nigral dopaminergic neurons in Parkinson's disease, as the vulnerable neurons of the substantia nigra pars compacta do not express more DAT mRNA than the resistant paranigral neurons.

Expression of N-methyl-D-aspartate receptor subunit mRNAs in the human brain: striatum and globus pallidus.

N-methyl-D-aspartate receptors (NRs) play an important role in basal ganglia function. By using in situ hybridization with ribonucleotide probes, we investigated the regional and cellular distribution of NR subunit mRNA expression in the human basal ganglia: caudate nucleus, putamen, lateral globus pallidus (LGP), and medial globus pallidus (MGP). Analysis of both film autoradiograms and emulsion-dipped slides revealed distinct distribution patterns for each subunit. On film autoradiograms, the signal for NR1, NR2B, and NR2C in the striatum (STR) was higher than in globus pallidus (GP). The NR2D probe gave a stronger signal in GP than in STR. For NR2A we found a signal in all regions. Analysis of emulsion-dipped sections demonstrated that in striatal neurons, the NR2B signal was higher than in GP neurons. In GP neurons, NR2D was more abundant than in striatal neurons. Despite the relatively low signal on film for NR2C in GP, we found a slightly higher signal in GP per neuron than in STR since in the pallidal areas neurons were sparse but intensely labeled. NR1 and NR2A were more evenly distributed over neurons of STR and GP Between the different parts of STR and GP, we observed only minor differences in the expression of NRs. In MGP a subpopulation of neurons exhibiting low NR2D signals could be separated from the majority of neurons showing an intense NR2D signal. Since the physiological properties of NRs are dependent on subunit composition, these data suggest a high degree of regional specialization of NR properties in the human basal ganglia.

Expression of N-methyl-D-aspartate receptor subunit mRNAs in the human brain: hippocampus and cortex.

N-methyl-D-aspartate receptor (NR) activation in the hippocampus and neocortex plays a central role in memory and cognitive function. We analyzed the cellular expression of the five NR subunit (NR1 and NR2A-D) mRNAs in these regions with in situ hybridization and human ribonucleotide probes. Film autoradiograms demonstrated a distinct pattern of hybridization signal in the hippocampal complex and the neocortex with probes for NR1, NR2A, and NR2B mRNA. NR2C and NR2D probes yielded scattered signals without a distinct organization. At the emulsion level, the NR1 probe produced high-density hybridization signals across the hippocampal complex. NR2A mRNA was higher in dentate granule cells and pyramidal cells in CA1 and subiculum compared to hilus neurons. NR2B mRNA expression was moderate throughout, with higher expression in dentate granule cells, CA1 and CA3 pyramidal cells than in hilus neurons. In the hippocampal complex, the NR2C probe signal was not different from background in any region, whereas the NR2D probe signal resulted in low to moderate grain densities. We analyzed NR subunit mRNA expression in the prefrontal, parietal, primary visual, and motor cortices. All areas displayed strong NR1 hybridization signals. NR2A and NR2B mRNAs were expressed in cortical areas and layers. NR2C mRNA was expressed at low levels in distinct layers that differed by region and the NR2D signal was equally moderate throughout all regions. Pyramidal cells in both hippocampus and neocortex express NR1, NR2A, NR2B, and, to a lesser extent, NR2D mRNA. Interneurons or granular layer neurons and some glial cells express NR2C mRNA.

Expression of N-methyl-D-aspartate receptor subunit mRNA in the human brain: mesencephalic dopaminergic neurons.

Evidence is accumulating that glutamate-mediated excitotoxicity plays an important role in neuronal degeneration in Parkinson's disease (PD). In addition, alterations in excitatory amino acid neurotransmission in the basal ganglia contribute to the clinical manifestations of motor dysfunction. However, detailed knowledge of the anatomical distribution and subtype specificity of glutamate receptors in the dopamine neurons of human substantia nigra (SN) has been lacking. In order to test the hypothesis that selective expression of particular N-methyl-D-aspartate receptor (NR) subunit mRNA contributes to the differential vulnerability of specific neuronal populations to excitotoxic injury in PD, we have used a quantitative dual label, in situ hybridization technique with ribonucleotide probes to examine the cellular distribution of NR subunit mRNA in postmortem human mesencephalic dopaminergic neurons from subjects with no known neurological disorder. Analysis of both film autoradiograms and emulsion-dipped sections demonstrated significant labeling of nigral neurons for each NR subunit. Neuronal labeling was most intense for the NR1 and NR2D subunits, with low level labeling for the remaining subunits. In addition, we examined four subregions of the ventral mesencephalon for differential expression of NR subunit mRNA. For all NR subunits, the pars lateralis (PL) exhibited the most intense signal, while neurons of the ventral tier substantia nigra pars compacta (SNpc) failed to demonstrate a preponderance of a particular subunit. These results demonstrate that NRs are expressed to a significant degree in dopaminergic neurons of the SN and that their distribution does not correlate with the characteristic pattern of neuronal degeneration in PD.