Brain Clears Toxins During Sleep.

Scientists have long wondered why sleep is restorative and why lack of sleep impairs brain function.

Now, new animal research suggests how the sleep state may help clear the body of potentially toxic central nervous system (CNS) metabolites.

Proteins linked to neurodegenerative diseases, including β-amyloid (), are present in the interstitial space surrounding cells in the brain. In a series of experiments, researchers tested the hypothesis that Aβ clearance is increased during sleep and that the sleep-wake cycle regulates the glial cell–dependent glymphatic system, which is responsible for clearing waste from the brain and spinal cord.

“Basically, we found a new function of sleep,” said study lead author Lulu Xie, PhD, Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester Medical Center, New York.

“When mice are awake, the brain cells continuously produce toxic waste. This waste can build up in the spaces between the brain cells and damage them. However, during sleep, the spaces between brain cells increase, which may help the brain flush out the toxic waste. Therefore, a good sleep can clear the brain.”

“Sleep changes the cellular structure of the brain. It appears to be a completely different state,” Maiken Nedergaard, MD, DMSc, codirector of the Center for Translational Neuromedicine at the University of Rochester Medical Center, who is a leader of the study, said in a statement from the National Institute of Neurological Disorders and Stroke, which supported the study.

The new research was published October 18 in Science.

Sleeping vs Awake Brain

The researchers infused fluorescent dye into the cerebrospinal fluid (CSF) of mice and observed it flow through the brain. At the same time, they monitored electrical brain activity and wakefulness with electrocorticography (EcoG) and electromyography (EMG)..

“In the sleeping brain, we found the CSF flushed into the brain very quickly and broadly,” said Dr. Xie. “After half an hour, we woke the mice up by gently touching their tails, and injected another color of dye. But what we saw is that CSF barely flowed when the same mice were awake.”

These results suggest that the awake brain may have more resistance to CSF influx, which leads to the assumption that the path of CSF flow into the brain is smaller in the awake brain, said Dr. Xie.

Next, the scientists inserted electrodes into the brain to directly measure the space between brain cells, and found that it increased by around 60% when the mice were asleep.

“Theoretically, big spaces lead to easier fluid influx,” said Dr. Xie. “So we presumed that the clearance of the toxic protein between cells will become more efficient.”

To test this assumption, they infused radio-labeled Aβ into the brain and measured how long it stayed in both the sleeping brain and the awake brain.

We found Aβ disappeared 2-fold faster in the sleeping mice brains as compared with awake mice,” noted Dr. Xie. “Based on this experiment, we can see that the sleeping brain is more capable of clearing out the toxic protein.”

Technically, it might be relatively easy to study these processes in humans, possibly using magnetic resonance imaging. However, Dr. Xie said she does not know when human trials, which involve “a lot more concerns” than animal experiments, might come about.

“These results may have broad implications for multiple neurological disorders,” said Jim Koenig, PhD, a program director at the National Institute of Neurological Disorders and Stroke (NINDS), which funded the study, in a statement. “This means the cells regulating the glymphatic system may be new targets for treating a range of disorders.”

Antibody Index Test May Aid PML Diagnosis on Natalizumab.

A new test that compares JC virus (JCV) antibody levels in cerebrospinal fluid (CSF) with those in serum might be a useful complementary tool in the diagnostic workup for progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) treated with natalizumab (Tysabri, Biogen Idec), a new study suggests.

The study was presented by Clemens Warnke, MD, Heinrich Heine University, Düsseldorf, Germany, at the recent 29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). 

Dr. Warnke explained that PML caused by JCV can be difficult to diagnose because early symptoms can be mistaken for a relapse in MS.

“At present, JCV-DNA detection by polymerase chain reaction (PCR) in cerebrospinal fluid is used for diagnosis of PML. However, false-negatives often occur, leading to delayed diagnosis and poor patient outcome in some cases,” he said. “So we need more tests to allow earlier diagnosis.”

“Our main findings are when you have clinical suspicion of PML — changes in behavior, personality, and motor function untypical for MS in patients treated with natalizumab, we might suspect it to be PML,” he told Medscape Medical News.

He and his colleagues have proposed using the anti-JCV antibody specificity index (ASI-JCV) as an additional test for JCV DNA detection. This involves measuring the JCV antibody level in both serum and CSF and calculating the proportion of antibodies in CSF compared with serum.

In this study, Dr. Warnke and colleagues calculated the anti-JCV antibody specificity index in 25 patients who had developed PML while receiving natalizumab and in 47 patients also taking natalizumab who had not developed PML. Results showed that none of the control patients had JCV antibodies in CSF, whereas CSF antibodies were detected in more than 60% of the patients with PML.

And while all patients with natalizumab-associated PML exhibited an ASI-JCV of 0.47 or higher, this was seen in none of the 47 patients with MS treated with natalizumab who did not develop PML (P < .0001).

Dr. Warnke stressed that this test would not replace the PCR test for JCV DNA. “But levels of JCV DNA detection and the antibody index tests do not exactly correlate, so here is an argument for using the antibody index alongside the DNA test for additional diagnostic value,” he suggested.

“If we assume an estimate of 70% to 80% for the early diagnosis of PML using PCR, maybe we can increase this up to 85% using this antibody index test as well,” he added.

The antibody index test is not yet commercially available.

“We have developed our own test and now use it at our hospital,” he noted. “But it is not an established procedure yet. It is still a clinical research tool which needs further validation.”


Angiostrongylus meningoencephalitis: survival from minimally conscious state to rehabilitation.

The nematode Angiostrongylus cantonensis has spread down the eastern coast of Australia over recent decades. A healthy 21-year-old man developed life-threatening eosinophilic meningoencephalitis following ingestion of a slug in Sydney. We describe the first case of this severity in which the patient survived.

Clinical record

A 21-year-old man presented with a 3-day history of insomnia and paraesthesia affecting his lower limbs bilaterally. He had no associated headache, meningism or fever. He was previously well with no significant medical history.

On admission, he had begun to develop progressive weakness of his lower limbs associated with pain and dysaesthesia. A full blood count showed a total white cell count of 10.6 × 109/L (reference interval [RI], 4.0–11.0 × 109/L) with mild eosinophilia (0.5 × 109/L [RI, < 0.4 × 109/L]). Magnetic resonance imaging (MRI) scans of his brain and spine showed no abnormality. His cerebrospinal fluid (CSF) was acellular, with normal glucose and protein levels.

A provisional diagnosis of Guillain–Barré syndrome was made and the patient was treated with a 5-day course of intravenous immunoglobulin. Over 1 week he developed evidence of autonomic instability with urinary retention, fluctuating sinus tachycardia and hypertension, and a paralytic ileus. By the second week of hospitalisation he had developed hallucinations and a fluctuating level of consciousness.

A repeat CSF sample revealed a raised protein level of 1.20 g/L (RI, 0.15–0.45 g/L), a low glucose level of 2.3 mmol/L (RI, 2.5–5.6 mmol/L), with 2 × 109/L red cells (RI, < 5 × 109/L), 406 × 109/L mononuclear cells (RI, < 5 × 109/L), and 30 × 109/L polymorphs (RI, nil). The opening pressure was elevated at 31 cm H2O (RI, 6–20 cm H2O). He was commenced on empirical antibiotic and antiviral treatment, with intravenous hydrocortisone (100 mg four times daily) to cover the possibility of a steroid-responsive encephalopathy. An electroencephalogram was consistent with generalised encephalopathy without focal epileptiform activity. CSF bacterial cultures, cryptococcal antigen testing and polymerase chain reaction testing for herpes simplex virus and enterovirus were negative. HIV serological testing was negative. The patient’s condition continued to deteriorate, with a declining level of consciousness, progressive quadriparesis and respiratory failure necessitating endotracheal intubation and mechanical ventilation on Day 12 after admission.

Progress computed tomography (CT) brain imaging results remained normal. His peripheral eosinophil count had risen, later peaking at 1.9 × 109/L on Day 24. A third lumbar puncture was performed. His CSF protein remained elevated at 0.71g/L, CSF red cell count was 216 × 109/L and CSF white cell count was 504 × 109/L. Specific staining for eosinophils was performed, showing 37% of the leukocytes to be eosinophils (RI, < 10%,Box 1).

By this stage it had emerged that the patient had eaten a slug from a Sydney garden, as a dare, 7 days before presentation. An enzyme immunoassay for Angiostrongylus IgG performed on the CSF was positive. A progress MRI scan, performed on Day 26 after admission, revealed multiple foci of hyperintensity in the cerebral hemispheres, brainstem and cerebellum as well as within the spinal cord (Box 2). Several of the lesions showed restricted diffusion and some showed contrast enhancement. Pial enhancement was seen within the posterior fossa and over the spinal cord.

Treatment with high-dose corticosteroids was continued but the patient’s condition continued to decline. An unresponsive state developed, with flaccid tone in all four limbs and the loss of brainstem reflexes. Given the severity of the patient’s condition, a trial of albendazole 400 mg twice daily was given, with continued corticosteroid cover (dexamethasone 4 mg intravenously four times daily) and he remained on this treatment for 1 month. There was no change in his condition and he remained supported by mechanical ventilation via a tracheostomy in a minimally conscious state for 8 months.

During this time, there was much discussion between the patient’s family and treating doctors about his prognosis and probable outcome. Treatment was continued on the basis of his age and the uncertainty of the natural history of this rare disease. His clinical course was complicated by hydrocephalus requiring a ventriculoperitoneal shunt, recurrent episodes of ventilator-associated pneumonia, and seizures that were difficult to control despite multiple antiepileptic drugs. After 13 months, there was a very slow improvement in his level of consciousness, such that a slow weaning of respiratory support could be attempted. He could successfully maintain his own ventilation during the day (though with an ataxic respiratory pattern), but remained dependent on nocturnal mechanical ventilation.

The patient was discharged to the ward from intensive care in the 15th month of admission, where he continued to make slow but definite progress. There was gradual recovery of some distal power in his upper and lower limbs and he developed the ability to communicate with head movements. He was discharged to a rehabilitation facility 22 months after admission, where there has been ongoing gradual improvement. He now has antigravity power in his limbs and is capable of more complex non-verbal communication.


Angiostrongylus cantonensis, also known as the rat lungworm, is the most common cause of eosinophilic meningitis globally. This condition generally follows a benign, self-limited course.1 Rarely, the parasite causes meningoencephalitis, which should be considered a related but distinct clinical entity with a dramatically poorer prognosis. The mortality rate has been reported at 79%2 and, of patients who become comatose, at least 90% do not survive.3

A. cantonensis is endemic in South-East Asia and the Pacific region, and has spread down the eastern coast of Australia over the past 50 years.4 In Australia, it has been observed that cases tend to be particularly severe. This reflects the higher total larval load ingested from terrestrial hosts, which feed on rat faecal pellets harbouring thousands of larvae. In comparison, aquatic snails, which commonly cause the disease in South-East Asia, generally carry a smaller larval load.5,6 The first reported human case acquired in Sydney occurred in 2001,7 in the remarkably similar circumstances of a young man accepting a dare to eat a slug, highlighting the importance of specific questioning in the patient’s history. Our patient’s case is only the second reported case acquired in Sydney and, internationally, our patient is the first with the disease of this severity to have survived.

Recent investigations have sought to identify factors associated with the development of clinically severe angiostrongyliasis. In one study, clinical features including headache, abnormal CSF pressure and abnormal peripheral blood eosinophil count were associated with severe disease.8 An Activation Criteria for Angiostrongyliasis (ACA) scoring system, incorporating these factors, was proposed and validated in a population of Chinese patients, with a score of ≥ 7 predictive of severe disease. If we had used the presenting eosinophil count, our patient would only have had an ACA score maximum of 5, and most likely lower than this if his CSF opening pressure had been recorded at the first lumbar puncture. He would have scored 8 if his peak peripheral eosinophil count and his highest recorded CSF pressure had been used.

A second study investigated factors specifically associated with the development of the encephalitic form of the disease.2 In a cohort of 94 patients with angiostrongyliasis, of whom 14 developed encephalitis, it was found that the clinical factors predictive of encephalitis were temperature > 38°C at presentation, older age and longer duration of headache. Fever at presentation was associated with a remarkable 37-fold risk of encephalitis. Interestingly, other variables such as CSF opening pressure, peripheral or CSF eosinophil counts or paraesthesia were not predictive of encephalitis in this study. Our case indicates that caution should be used when applying the predictive factors reported in these studies, and suggests that peak eosinophil count and delayed CSF pressure results may be more useful when calculating the ACA.

The initial difficulty with diagnosis in this case emphasises the need for clinical suspicion of this condition in the setting of acute-onset neurological symptoms and peripheral eosinophilia in endemic areas, including the eastern coast of Australia. It is essential to seek a history of consuming raw or undercooked food, and specifically any ingestion of molluscs. The case illustrates the importance of repeat CSF examination if the diagnosis is suspected and the initial CSF test results are negative. It also highlights the need to request specific CSF examination to ensure any eosinophils are not mistaken for neutrophils.

The optimal treatment for Angiostrongylus meningoencephalitis remains poorly defined. Corticosteroids are commonly used, with the rationale of dampening the inflammatory reaction to the nematode, and have been shown in a double-blind, placebo-controlled trial to provide symptomatic relief in eosinophilic meningitis.9 However, studies of patients with the encephalitic form of the disease have not found corticosteroids to be effective.3 Anthelmintics are generally not used due to the theoretical possibility of exacerbating cerebral inflammation and damage as a result of larval death in the central nervous system (CNS), and the lack of evidence of their efficacy.9,10 We used albendazole when there was little to lose and, perhaps as expected, it did not lead to any appreciable benefit. In the absence of effective treatment of angiostrongyliasis, it is important in endemic areas that the public understand the small but very serious risks associated with ingestion of uncooked molluscs.

It is known that time spent in a minimally conscious state following traumatic brain injury does not correlate with the chance of functional recovery.11 This observation may extend to patients with diffuse brain injury caused by severe cerebral infection or inflammation. This case shows the potential for the CNS to recover following a severe, generalised insult in a young patient with supportive care. It is important for doctors to appreciate this capacity when wrestling with difficult decisions about continuation of care for critically unwell patients.

Source: MJA

Is Herpes Simplex Encephalitis in Immunocompromised Patients Different?

A comparison of clinical findings, neuroimaging, and outcomes in immunocompromised versus immunocompetent patients with HSE suggests important differences.

Herpes simplex encephalitis (HSE) is a very serious disease with an incidence of 1 in 250,000 to 1 in 500,000. With the introduction of new and more potent immunosuppressive therapies, HSE is seen more often with an atypical presentation. In this retrospective case-control review of adult patients with HSE diagnoses, researchers compared features and outcomes in 14 patients who were immunocompromised and 15 who were immunocompetent.

Clinical features, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) findings were different in the two groups. Fewer immunocompromised patients had prodromal symptoms (29% vs. 80%) and focal deficits (about 28% vs. 73%). Mean time between symptom onset and presentation to the hospital was shorter in the immunocompromised group (3.4 vs. 4.9 days). Whereas all immunocompetent patients had mononuclear cells in the CSF and one had no CSF pleocytosis, three immunocompromised patients had polymorphonuclear predominance and another three had normal profiles. Whereas all immunocompetent patients had MRI abnormalities in the temporal lobe, immunocompromised patients tended to have more diffuse cortical involvement, with cerebellar and brainstem compromise in some. Two of the immunocompromised patients and none of the immunocompetent patients had recurrent HSE, and 5 of the 14 immunocompromised patients died, versus 1 of the 15 immunocompetent patients. Similar numbers of patients in each group completed a 21-day treatment with acyclovir (30 mg/kg/day). Five immunocompetent patients completed a 14-day course.

Comment: Although this study is limited by its retrospective nature and its size, this is the largest published series on HSE in immunocompromised patients and the first to compare the presentation in immunocompromised and immunocompetent states. The findings should raise awareness of the potential increased risk, atypical presentations, and worse outcomes among immunocompromised patients. Early recognition of the disease is critical, because delay in treatment may be associated with severe morbidity and mortality. Early diagnosis and administration of acyclovir is associated with a better outcome.

Source: Journal Watch Neurology

Shunting with gravitational valves—can adjustments end the era of revisions for overdrainage-related events?

Overdrainage of CSF remains an unsolved problem in shunt therapy. The aim of the present study was to evaluate treatment options on overdrainage-related events enabled by the new generation of adjustable gravity-assisted valves.


The authors retrospectively studied the clinical course of 250 consecutive adult patients with various etiologies of hydrocephalus after shunt insertion for different signs and symptoms of overdrainage. Primary and secondary overdrainage were differentiated. The authors correlated the incidence of overdrainage with etiology of hydrocephalus, opening valve pressure, and patient parameters such as weight and size. Depending on the severity of overdrainage, they elevated the opening pressure, and follow-up was performed until overdrainage was resolved.


The authors found 39 cases (15.6%) involving overdrainage-related problems—23 primary and 16 secondary overdrainage. The median follow-up period in these 39 patients was 2.1 years. There was no correlation between the incidence of overdrainage and any of the following factors: sex, age, size, or weight of the patients. There was also no statistical significance among the different etiologies of hydrocephalus, with the exception of congenital hydrocephalus. All of the “complications” could be resolved by readjusting the opening pressure of the valve in one or multiple steps, avoiding further operations.


Modern adjustable and gravity-assisted valves enable surgeons to set the opening pressure relatively low to avoid underdrainage without significantly raising the incidence of overdrainage and to treat overdrainage-related clinical and radiological complications without surgical intervention.

Source: Journal of neurosurgery.




Spinal Fluid Test Predicts Alzheimer Disease

Patients may ask about a widely reported Archives of Neurology study that shows high accuracy in diagnosing Alzheimer disease (AD) based on protein patterns in the cerebrospinal fluid.

Researchers sought to identify biomarkers for AD without regard to clinical diagnostic information, such as cognitive testing. Measuring the spinal fluid concentrations of beta-amyloid protein 1-42 and phosphorylated tau181P protein, the researchers found that AD presented a “signature” pattern of low beta-amyloid levels and increased phosphorylated tau. The pattern was found in 90% of AD patients, 72% of those with mild cognitive impairment, and 36% of the cognitively normal.

The researchers conclude that AD apparently manifests itself earlier than previously believed and that the current diagnostic criteria for the disease should be revised.

Editorialists “strongly recommend” that the analyses be undertaken when a definitive diagnosis of AD will help counsel patients about work and driving.