Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA.

Neurodegeneration with brain iron accumulation (NBIA) is a group of genetic disorders characterized by abnormal iron deposition in the basal ganglia. We report that de novo mutations in WDR45, a gene located at Xp11.23 and encoding a beta-propeller scaffold protein with a putative role in autophagy, cause a distinctive NBIA phenotype. The clinical features include early-onset global developmental delay and further neurological deterioration (parkinsonism, dystonia, and dementia developing by early adulthood). Brain MRI revealed evidence of iron deposition in the substantia nigra and globus pallidus. Males and females are phenotypically similar, an observation that might be explained by somatic mosaicism in surviving males and germline or somatic mutations in females, as well as skewing of X chromosome inactivation. This clinically recognizable disorder is among the more common forms of NBIA, and we suggest that it be named accordingly as beta-propeller protein-associated neurodegeneration.

ß-Propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation.

Neurodegenerative disorders with high iron in the basal ganglia encompass an expanding collection of single gene disorders collectively known as neurodegeneration with brain iron accumulation. These disorders can largely be distinguished from one another by their associated clinical and neuroimaging features. The aim of this study was to define the phenotype that is associated with mutations in WDR45, a new causative gene for neurodegeneration with brain iron accumulation located on the X chromosome. The study subjects consisted of WDR45 mutation-positive individuals identified after screening a large international cohort of patients with idiopathic neurodegeneration with brain iron accumulation. Their records were reviewed, including longitudinal clinical, laboratory and imaging data. Twenty-three mutation-positive subjects were identified (20 females). The natural history of their disease was remarkably uniform: global developmental delay in childhood and further regression in early adulthood with progressive dystonia, parkinsonism and dementia. Common early comorbidities included seizures, spasticity and disordered sleep. The symptoms of parkinsonism improved with l-DOPA; however, nearly all patients experienced early motor fluctuations that quickly progressed to disabling dyskinesias, warranting discontinuation of l-DOPA. Brain magnetic resonance imaging showed iron in the substantia nigra and globus pallidus, with a 'halo' of T1 hyperintense signal in the substantia nigra. All patients harboured de novo mutations in WDR45, encoding a beta-propeller protein postulated to play a role in autophagy. Beta-propeller protein-associated neurodegeneration, the only X-linked disorder of neurodegeneration with brain iron accumulation, is associated with de novo mutations in WDR45 and is recognizable by a unique combination of clinical, natural history and neuroimaging features.

Peripheral nervous system pathology in fragile X tremor/ataxia syndrome (FXTAS).

Fragile X tremor/ataxia syndrome (FXTAS) occurs in individuals with moderate CGG expansion of the fragile X mental retardation 1 (FMR1) gene and is associated with intranuclear inclusions in neurons and astrocytes. Although the neuropathologic findings in the brain and spinal cord were described, pathological features in the peripheral nervous system were not reported. Here, we report on novel neuropathological findings in the peripheral nervous system and especially in autonomic ganglia at autopsy in a man with FXTAS. In addition to the characteristic brain and spinal cord findings, typical intranuclear inclusions were identified in the ganglion cells of adrenal medulla, dorsal root ganglia, paraspinal sympathetic ganglia, myenteric ganglia of the stomach and subepicardial autonomic ganglion of the heart. Our findings indicate that FXTAS diffusely involves the central and peripheral nervous systems, which explains the protean neurological symptoms ranging from dementia to dysautonomia.

Episodic nausea and abdominal sensations as sole manifestations of simple partial seizures.

In adults, seizures manifesting with abdominal complaints are usually associated with complex partial or secondary generalized seizures. Also, seizure periodicity is not expected in postmenopausal women. We encountered a 72-year-old woman with episodic nausea and abdominal pain that usually occurred with predictable regularity. When symptoms persisted after extensive gastrointestinal investigations and cholecystectomy, she was referred to us and the diagnosis of simple partial seizures was suspected. Both EEG and brain MRI were normal. The diagnosis was established by video/EEG monitoring, which recorded several typical clinical events associated with right temporal ictal discharges. Because treatment with several antiepileptic medications caused intolerable side effects, the patient is now maintained on a low dose of Lamotrigine, which reduced seizure frequency and severity. This patient demonstrates that `abdominal` complaints, although rare, may be the sole manifestation of simple partial seizures. Unless considered in the differential diagnosis, the patient may undergo unnecessary and potentially harmful procedures.

Tiagabine-induced non-convulsive status epilepticus in a patient without history of epilepsy.

Cases of non-convulsive status epilepticus (NCSE) induced by tiagabine (TGB) were occasionally reported. Almost all had a prior history of epilepsy. We describe here, the clinical and EEG findings in a patient, without history of seizures, who after the start of TGB developed NCSE. A 53-year-old man with history of paranoid schizophrenia, presented with "alteration of his mental state." Three weeks early, TGB was added to his psychiatric regimen. On the second day of admission, he became unresponsive with a blank stare. Concomitant EEG showed abundant sharp and slow wave complexes. The episode lasted for 4 hours and was aborted by the intravenous administration of lorazepam. The TGB was discontinued without recurrence of subsequent seizure activity. This case supports the contention that TGB can induce NCSE in subjects not previously known to have seizures.

Post t-PA transfer to hub improves outcome of moderate to severe ischemic stroke patients.

BACKGROUND AND PURPOSE: Telemedicine offers rural hospitals the ability to treat acute ischemic stroke on site with intravenous tissue plasminogen activator (t-PA). Most patients are subsequently transferred to a hub hospital with a primary stroke center for post t-PA care. There is little evidence that such transfer is beneficial. The purpose of our study is to determine whether the transfer of patients to hub hospitals is beneficial. METHODS: We retrospectively analyzed data from our prospectively collected cohort in the AR SAVES (Stroke Assistance through Virtual Emergency Support) telestroke network from November 2008 till January 2012. We compared the outcome of patients who were transferred to a "hub" with those who remained at the "spoke" hospital where thrombolysis took place. We stratified patients according to stroke severity using admission NIHSS scores into two groups: patients with mild stroke (NIHSS <8) and those with moderate to severe stroke (NIHSS ≥8). We defined good outcome as a modified Rankin Scale (mRS) score ≤2. Statistical analysis was performed using Fisher's exact test, two-tailed, and significance was considered at p < 0.05. RESULTS: Out of 894 telestroke consultations, 206 patients received thrombolytic therapy; 134 patients had moderate to severe strokes and 160 patients (78%) were transferred to the hub after thrombolytic therapy. The percentage of patients with good outcome at 3 months was similar between patients transferred to hub and those who stayed at the spoke (61% vs. 55%, p = NS). However, when only patients with moderate to severe strokes were analyzed, patients transferred to the hub were more likely to have good outcomes at three months post t-PA (50% versus 24%, p = 0.026). CONCLUSIONS: Patients with moderate to severe ischemic strokes who were treated with t-PA in a telestroke network may potentially benefit from expert care at a primary stroke center.

Acute bilateral inferior cerebellar infarction in a patient with neurosyphilis.

BACKGROUND: Bilateral simultaneous infarction in the territories of the posterior inferior cerebellar arteries (PICAs) is rare but was recently reported with increasing frequency, probably because of the wider availability of magnetic resonance imaging. The cause of these infarcts is believed to be atherosclerotic or embolic occlusion of a dominant PICA, which perfused the territories of the medial branches of both PICAs. RESULTS: We encountered a patient with simultaneous infarction in the territories of the medial branches of both PICAs. The clinical course, imaging results, and laboratory findings are presented. The patient was diagnosed with neurosyphilis based on a history of chancre, positive serum and cerebrospinal serologies, cerebrospinal pleocytosis, and increased intrathecal immunoglobulin synthesis. We believe that meningovascular syphilis caused the bilateral cerebellar infarct via presumed thromboangiitis of a dominant PICA perfusing both cerebellar hemispheres. The patient was treated with intravenous high doses of penicillin. CONCLUSIONS: This case reminds us that meningovascular syphilis should be considered in younger patients with stroke. Patients with bilateral cerebellar infarction may solely have symptoms of vertigo and ataxia but can develop life-threatening complications because of edema of the infarcted tissue with resultant hydrocephalus and pressure on the brainstem.

Multiple myeloma invasion of the central nervous system.

BACKGROUND: Although neurologic manifestations often complicate the course of patients with multiple myeloma (MM), direct central nervous system invasion is rare. OBJECTIVE: To describe the neurologic symptoms and signs, imaging, cerebrospinal fluid findings, and the clinical course of patients with central nervous system myeloma invasion, all of whom had leptomeningeal myelomatosis. DESIGN AND PARTICIPANTS: Review of 23 patients with MM and leptomeningeal myelomatosis proven by malignant plasma cells in their cerebrospinal fluid. SETTING: Tertiary-care university medical center. RESULTS: Twenty-one patients had advanced-stage MM. Leptomeningeal myelomatosis was diagnosed up to 29 months (median, 13 months) after diagnosis of MM. Symptoms precipitating neurologic evaluation included manifestations of diffuse cerebral dysfunction, cranial nerve palsies, and spinal radiculopathies. Cerebrospinal fluid was abnormal in all patients, usually exhibiting pleocytosis and elevated protein content, plus positive cytologic findings. Specific magnetic resonance imaging findings suggestive of central nervous system invasion were found in 70% of the patients. These included leptomeningeal contrast enhancement and evidence of meningeal-based lesions sometimes masquerading as intraparenchymal lesions. Despite aggressive systemic and local treatment, the outcome was poor, reflecting the aggressiveness of the underlying MM. CONCLUSION: Leptomeningeal myelomatosis, although rare, should be considered in patients with MM and symptoms suggestive of widespread nervous system involvement.

Myeloma of the central nervous system: strong association with unfavorable chromosomal abnormalities and other high-risk disease features.

Involvement of the central nervous system (CNS) by multiple myeloma, defined by the detection of malignant plasma cells in the cerebrospinal fluid in the presence of suggestive symptoms, is considered extremely rare. We present the characteristics of 25 such patients (18 previously reported) intended to receive high-dose treatment at the University of Arkansas over the last 12 years; an extensive review of the published literature since 1968, including 71 patients, is also presented. In both patient groups, high tumor burden was overwhelmingly present while circulating plasma cells were detected in a significant proportion of cases. We also observed a strong association of CNS involvement with unfavorable cytogenetic abnormalities (especially translocations and deletion of the chromosome 13), plasmablastic morphology and additional extramedullary myeloma manifestations. The presence of these features should alert clinicians to the possibility of CNS involvement. The prognosis of such patients is poor despite aggressive systemic and local treatment and reflects the underlying disease biology. Application of allogeneic transplantation and administration of prophylactic CNS treatment are also discussed. Further elucidation of the factors predisposing patients with high-risk disease features to CNS myeloma involvement is needed.

Albuterol improves response to levodopa and increases skeletal muscle mass in patients with fluctuating Parkinson disease.

Animal studies indicate that beta(2)-adrenergic receptor agonists enhance transport of levodopa across the blood-brain barrier. Preliminary studies showed improved response to levodopa in patients with Parkinson disease (PD) who were given albuterol as adjunctive therapy. Beta(2)-adrenergic agonists may offer additional benefits to PD patients via their skeletal muscle anabolic effects, particularly those who experience decreased muscle strength and weight loss. Nondemented, fluctuating PD patients receiving levodopa but not experiencing severe dyskinesias underwent the following tests at baseline and 14 weeks after treatment with albuterol sulfate (4 mg four times a day, orally): Unified Parkinson's Disease Rating Scale motor, tapping, and stand-walk-sit tests every 30 minutes between 8 am and 5 pm; body composition analyses using whole-body plethysmography and computed tomography of the thigh; muscle strength tests; and the Parkinson's Disease Questionnaire (PDQ-39). Results were analyzed using paired t-tests (2 tailed), repeated-measures analysis of variance, and the Wilcoxon signed-rank test. Seven of 8 enrolled patients completed the study; 1 patient withdrew because of headache and anxiety. The area under the curve for all-day UPDRS motor scores improved by 9.8 +/- 9.1% (mean +/- standard deviation; P < 0.05) and tapping improved by 7.6 +/- 8.1% (P < 0.05). The effect was more pronounced when only the response to the first levodopa dose (area under the curve, 8-11 am) was analyzed: 13.0 +/- 9.8% and 9.8 +/- 9.6% respectively. Thigh muscle cross-sectional area increased significantly as measured by computed tomography (5.3 +/- 3.2%, P < 0.01), as did fat-free mass by whole-body plethysmography combined with total-body water determination (9.5 +/- 2.9%, P < 0.05). There was no significant improvement in the stand-walk-sit test, muscle strength tests, other UPDRS sections, daily OFF time, or PDQ-39. Four patients were rated as having a mild global improvement (+1 point) on a -3 to +3-point scale, and 3 of them chose to continue albuterol beyond the termination of the study. The mean heart rate increased from 78.3 +/- 9.3 beats/minute to 85.6 +/- 8.7 beats/minute (P < 0.05). No laboratory abnormalities or electrocardiographic changes were induced by albuterol in any subject. This open-label pilot study suggests that albuterol increases muscle mass and improves the therapeutic response to levodopa in patients with fluctuating PD. A double-blind, placebo-controlled study is needed to confirm the effects and safety profile of beta(2)-agonists in PD.

Hemiparkinsonism after unilateral traumatic midbrain hemorrhage in a young woman.

The relationship between head trauma and parkinsonism has been debated since James Parkinson's first description of the shaking palsy in the late 19th century. We observed in our outpatient clinic a young woman in whom hemiparkinsonism developed within 3 weeks of sustaining closed head trauma with loss of consciousness. The patient had a discrete unilateral midbrain hemorrhage on head MRI which involved the contralateral substantia nigra. The condition responded well to carbidopa/levodopa. This patient is a convincing example of posttraumatic midbrain hemorrhage causing parkinsonism.

Fragile X premutation in a woman with cognitive impairment, tremor, and history of premature ovarian failure.

Few women with Fragile X tremor ataxia syndrome (FXTAS) have been reported. They have milder manifestations at a later age than men. This gender difference may be related to the X inactivation pattern in women. We describe a woman who presented to her geriatrician with poor memory and was found to have ataxia and tremor. Additional queries yielded history of premature ovarian failure. Genetic testing showed heterozygous fragile X mental retardation gene premutation with 103 CGG repeats in the abnormal allele and 31 CGG repeats in the normal allele. Also, the X inactivation pattern was skewed with the active X chromosome predominantly having the premutation allele. We believe that FXTAS is more common in women than is generally thought and that many such patients masquerade as dementia of old age. Action tremor and ataxia associated with a history suggestive of premature ovarian failure should raise suspicions for FXTAS.

Neurologic complications of gastric bypass surgery for morbid obesity.

BACKGROUND: The number of bariatric procedures is rapidly growing as the prevalence of obesity in the USA is increasing. Such procedures are not without complications, and those affecting the nervous system are often disabling and irreversible. We now describe our experience with these complications and review the pertinent literature. METHODS: We describe 26 patients with major neurologic conditions that seemed causally related to bariatric surgery encountered in the neurology service of a tertiary referral university medical center over a decade. RESULTS: The neurologic complications affected most regions of the nervous system: encephalopathy, optic neuropathy, myelopathy, polyradiculoneuropathy, and polyneuropathy. Myelopathy was the most frequent and disabling problem; symptoms began about a decade after surgery. Encephalopathy and polyradiculoneuropathy were acute and early complications. Except for vitamin B(12) and copper deficiencies in patients with myelopathy, we could not correlate specific nutritional deficiencies to the neurologic complications. All patients had multiple nutritional deficiencies, but their correction did not often yield dramatic results. The best result was achieved in one patient after surgical revision to reduce the bypassed jejunum. CONCLUSIONS: A wide spectrum of serious neurologic conditions may follow bariatric surgery. These complications may occur acutely or decades later.

ß-Adrenergics enhance brain extraction of levodopa.

We sought to determine whether beta-adrenergic agonists enhance the brain extraction of L-dopa and L-leucine. Systemic administration of beta-adrenergic agonists increase brain concentrations of L-dopa and other large neutral amino acids (LNAA) in rats and monkeys and may improve symptoms and reduce daily L-dopa requirement in patients with Parkinson's disease. Cerebral blood flow (CBF) using [3H]nicotine and the extraction fraction of 14C-labeled L-dopa or L-leucine were measured simultaneously in various brain regions of conscious rats using the dual-isotope indicator fractionation technique after intraperitoneal administration of isoproterenol (a peripheral nonselective beta-adrenergic agonist), or clenbuterol (a beta2-adrenergic agonist that crosses the blood-brain barrier), or beta-adrenergic agonist preceded by nadolol (a peripheral nonselective beta-adrenergic antagonist), or saline vehicle. Both beta-adrenergic agonists increased regional brain extraction fraction of L-dopa and L-leucine tracers by 35-45%, without altering regional CBF. These changes were accompanied by about a 30% decrease in plasma branched chain LNAA concentrations. Nadolol blocked all these effects. beta-Adrenergic agonists increase the brain extraction of L-dopa and leucine, mainly by peripheral mechanisms that reduce the levels of other competing plasma LNAAs for transport. Thus, beta-adrenergic agonists might be useful in the treatment of patients with Parkinson's disease by enhancing delivery of L-dopa to the brain.

Myeloma of the central nervous system: association with high-risk chromosomal abnormalities, plasmablastic morphology and extramedullary manifestations.

Involvement of the central nervous system (CNS) by multiple myeloma, as defined by the detection of malignant plasma cells in the cerebrospinal fluid in the presence of suggestive symptoms, is considered extremely rare. We report on the characteristics of 18 such patients diagnosed and treated at the University of Arkansas over the last 10 years for an overall incidence of approximately 1%. Their evaluation revealed association of CNS involvement with unfavourable cytogenetic abnormalities (especially translocations and deletion of the chromosome 13), high tumour mass, plasmablastic morphology, additional extramedullary myeloma manifestations and circulating plasma cells. The presence of these features should alert clinicians to the possibility of CNS involvement. The outcome of these patients was extremely poor despite the use of aggressive local and systemic treatment including autologous stem cell transplants. Given this universally poor prognosis, the application of allogeneic transplants should be studied in this clinical setting.