Details

Dr Robert Rust

News

Published: 25 December 2012

Hits: 3988

 Robert Ouvrier was born on 17 May, 1940 to parents whose families had migrated to Australia in the early 19^th Century. His father had been among the Australian soldiers who served with considerable distinction in combat at the Franco-Belgian front during the First World War. Not long after Robert’s birth his father was called up to serve in the Second World War as well.  

 Robert distinguished himself throughout his pre-collegiate education. A keen reader and student of languages, he graduated with Honors in Latin and French. His B. Sc in Medicine with Honors in Physiology was granted by the University of Sidney in 1961. M.B. and B.S degrees with Honors were granted by the University of Sydney in 1964. Dr. Ouvrier’s standing was 9^th in a class of 220 and he was in addition awarded the Gillies Prize for Pathology.

Dr. Ouvrier served with distinction at successive residencies and registrarships in medicine and pediatrics that included appointments at the Royal Prince Alfred Hospital and the Royal Alexandra Hospital for Children (Sydney), the Princess Margaret Hospital (Perth), and the Royal Children’s Hospital (Melbourne), as well as six months as Registrar and then Consultant Pediatrician in New Guinea. In 1967, Dr. Ouvrier was elected a Member, the Royal Australian College of Physicians. In 1967, he was designated an Honorary Physician and Fellow in Neurology at the Royal Children’s Hospital, Melbourne. 

In 1968 Dr. Ouvrier was honored with the Nestlé Pediatric Traveling Scholarship and in 1969 with the Postgraduate Medical Scholarship of the University of Sydney. Dr. Ouvrier chose, as did a number of particularly accomplished and pioneering Australians and at least one Englishman to pursue additional training in child neurology with David Clark at the University of Kentucky.

Unlike the Englishman, Dr. Ouvrier did not arrive with a tightly furled umbrella and bowler hat. Not unlike his contemporary Australians, Dr. Ouvrier was keen to appreciate the rural Southern culture in which he found himself and to find out what there was to learn from the cheerful purveyor of sometimes lengthy patient-centered “clinical feasts” consisting not only of clinical neurology but generous helpings of neuropathology and neuroanatomy. To this was added the humor, charm and deeply humane personality of David Clark—qualities not unlike those that have marked the career of Dr. Ouvrier.

Dr. Ouvrier’s deep classical scholarship represented another shared attainment of the mentor and mentee—Dr. Clark was known from time to time to softly pronounce from memory through his abundant moustache suitably sly-witted passages from the Roman lyric poets such as Horace. The spontaneous rich mixture of Dr. Clark’s remarks, his keen powers of observation, intellectual depth, equanimity, wisdom, and his care of and about his patients either in Lexington or in the rural outreach clinics were legendary. The rounding experience generated discussions in a manner that Dr. Clark often celebrated as an enthusiastically consumed “clinical feast” the duration of which was unpredictable though unfailingly stimulating.

Whether intrinsic or due in part to mentorship, Dr. Ouvrier’s career has been marked by these same characteristics, including personal warmth, subtle sense of humor, devotion to patients, students, fellows, colleagues, to deep learning. Whether these shared characteristics were intrinsic or due in any degree to the example of Dr. Clark, Dr. Ouvrier was understandably very much at home during nearly three years in Kentucky.

His ensuing devotion to teaching, patient care and to scientific productivity has been perhaps less voluble and more focused and selective than was at times attained in the rich interchanges of Dr. Clark’s “clinical feasts, but partakes quite similarly of the atmosphere of intellectual excitement and purpose that worked such remarkable effects on all those that trained under David Clark. A final American year was spent in Baltimore under Doctors Guy McKhann and the late John M. Freeman and in learning all that might be learned from the other distinguished members of the Johns Hopkins neurology faculty.

To these experiences has subsequently been added—as had been the case for a number of Australian child neurologists, lengthy intervals of additional rich clinical and scientific experience and mentorship in France. This “French Connection” of Australian child neurology has depended in part on the linguistic talents and appreciation of the French perspective and accomplishments of a number of Australian child neurologists that resulted in the establishment of the Association Medicale Francophone d’Australie, of which Dr. Ouvrier was elected President in 1992.

Dr. Ouvrier returned to Australia in 1972 where he was elected Fellow of the RACP and assumed a position at the Royal Alexandra and Royal Prince Alfred Hospitals. Additional appointments followed at the University of Sydney, the Royal Newcastle Hospital, the Women’s Hospital of Sydney, the Sydney Eye Hospital, and the Westmead Hospital. In 1978 he was appointed Head of the Royal Alexandra Department of Neurology and Neurosurgery, a position he was to hold for 21 years.

In 1999 he was appointed Head of the Institute of Neuromuscular Research at the Royal Alexandra Hospital for Children, serving in that position for the ensuing decade. In 2001 Dr. Ouvrier was awarded the Petre Foundation Endowed Professorship of Pediatric Neurology at the University of Sydney. A member of the Royal Australian College of Physicians since 1967, he served for eight years as a member of the Special Advisory Committee in Neurology and for seven years as a member of the Pediatrics Written Examinations Committee.

Dr. Ouvrier’s research career has been supported by seven competitive grants aimed at objectives the have included expanding understanding antiepileptic drug metabolism and utilization, four designed to study the natural history and pathophysiology of peripheral neuropathic conditions, carrying out at the same time two studies designed to develop a sophisticated screening test for impairments of higher mental function in children.

For the studies of neuromuscular conditions, Dr. Ouvrier was awarded the degree of Doctor of Medicine in the University of Sydney in 1986. The data and perspective were richly represented, along with considerable ensuing observations and discoveries of Dr. Ouvrier and his colleagues in the celebrated textbook Peripheral Neuropathy in Childhood (Ouvrier RA, McLeod JG, Pollard JD, 1990). The monograph was enlarged into a second edition in 1999. In addition to these investigations Dr. Ouvrier has directed research concerning the significance of CSF amino-acids and neurotransmitters in epilepsy. His interest in epilepsy resulted in his editing a valuable book concerning Controversies in Childhood Epilepsy in1986. Dr. Ouvrier’s distinction in these and various other fields resulted in invitations to serve as an Editorial Board Member of five journals: Brain and Development (Japan), Journal of Child Neurology (USA), Pediatric Neurology (USA, Journal of Pediatric Neurology (Turkey), and Neuromuscular Disorders (Great Britain).

Dr. Ouvrier has published 131 original full-length papers to date. They have concentrated in particular on providing enlightenment concerning peripheral neuropathic (46 papers) or myopathic/myositic (14 papers) conditions. In total to date, these papers have been cited1838 times in the original publications of other scientists and clinicians. Of the thirty papers that Dr. Ouvrier has contributed to the understanding of the genetic aspects of neurological disease, most concern nerve and muscle. Several sub-concentrations are to be found. The most extensively investigated concentration has involved two forms of the hereditary sensorimotor neuropathies first recognized by the French have received sustained attention much to the enrichment of our understanding. Three remarkable papers that consider Type III (Dejerine-Sottas disease) have together received 283 citations.

Twenty-one papers considering Type I (Charcot-Marie-Tooth) including a wonderful summary review of 80 cases published in 1987 have together been cited a total of 294 times. An additional related and particular sustained concentration of Dr. Ouvrier and his associates has resulted in twenty-one papers that have extensively investigated the progressive pes cavus deformity, to which has been added similarly detailed investigation of contractures of the hand due to progressive heritable neuropathic conditions. Dr. Ouvrier and his associates are deeply concerned, beyond questions of clinical and genetic diagnosis, first to better understand and scientifically quantify the natural history of these results of progressive peripheral neuropathic conditions.

Upon the basis of that understanding they have established novel approaches to quantification of degree of deformity and disability that have in turn afforded the opportunity scientifically to improve the design of orthoses and evaluate the effects these and other forms of therapy on slowing and ameliorating dysfunction of gait and hand use. Not least, this approach has also provided new insight into the manner in which that age-old duty and objective of the physician, the alleviation of pain. The sustained and intelligent concentration on this subject demonstrates an essential characteristic of Professor Ouvrier: the desire to leave everything he encounters professionally better for having passed through is mind and hands. He has instilled or encouraged this same sense of devotion in those whom he has trained.

Other subjects considered with similar elegance and practical importance in the original papers that Professor Ouvrier and his colleagues have published are conditions involving CNS inflammatory or infectious conditions (9 papers), movement disorders (7), endocrinopathies (4), toxicology (5), as well as developmental, embryopathic and dysmorphic conditions. Others concern screening for cognitive dysfunction (8), peripheral nerve pathology (10), heritable metabolic conditions (7), conversion disorders (2), diagnosis and treatment of epilepsy (7), opthalmological disorders (5) and so on. Among the earliest papers was an important 1970 consideration together with Ian Hopkins of stroke in children that has been cited 36 times.

Dr. Ouvrier’s 1978 description of the ocular features of Aicardi syndrome has been cited 52 times. The quite well-known first description of paroxysmal tonic upgaze by Professors Ouvrier and Billson (1988) has been cited 22 times. The stimulating paper on the quite distinctive Australian form of tick paralysis by Professors Grattan-Smith and Ouvrier has been cited 50 times. The significance of the citation figures provided here should be considered against the fact that sadly--excepting self-citation--most of the world’s medical and scientific papers achieve few if any citations.

Dr. Ouvrier’s 26 excellent book chapters organize and concentrate quite a considerable body of knowledge with precision and compelling logic that render each of them a masterly model of the approach to diagnosis and management of neurological diseases. Fourteen consider neuropathic conditions; six consider epilepsy and its treatment, while others consider infectious conditions, cerebral palsies, movement disorders, neurometabolic disorders, degenerative conditions, or Australian tick paralysis.

Prof. Ouvrier and Prof Chugani at the ICNC2012 Brisbane CongressTo his American and French experiences and Asian/Oceanian experiences from the outset of his career, Dr.Ouvrier has added quite remarkable professional interactions with most of the rest of the world. His lengthy service to the International Child Neurology Association has included serving as Vice President from 1975-79, assumption of a critical role during his Chairmanship of the Executive Committee and in the organization of the Second International Child Neurology Congress in Sydney in 1979. He was an ICNA Councilor from 1986-1990, Convener of the ICNA International Training Committee in 1993, and as member of the Steering Panel for the International Training and Education Committee from 1997-99. He was Editor of the ICNA Newsletter from 1994-2006. He served as ICNA President from 2006-2010.

Dr. Ouvrier has been similarly quite active in the Asian Oceanian Child Neurology Association, serving as the Australian Delegate from 1983 to the present, as Member of the Steering Committee of the 2^nd Asian Oceanian Child Neurology Congress in 1986, as Vice-President of the AOCCN from 1987-1994 Member of the AOCCN Programme Committee in 1990 and 1994, and as Chairman of the Constitution Committee from 1999 to the present. Among other international responsibilities has been Dr. Ouvrier’s service in 2010 as Member of the WHO Advisory Working Group for Revision of the ICD-10 Diseases if the Nervous System.

Few child neurologists from any country have exerted over so long an interval an impact on the International child neurology movement. He has delivered sixty-one prestigious invited lectureships throughout the world Asia, Europe, North America, South America, the Middle East, Africa, and throughout Oceania since 1977. During his Presidency of ICNA he traveled as lecturer, advisor, and organizer for the advancement of child neurology throughout the world, traveling many hundreds of thousands of miles to advance the international child neurology movement throughout the world. He has been an absolutely critical figure in the realization of the concept of which he has written movingly: enriching not only the scientific and clinical quality of ICNA, but enlarging the role the ICNA plays as an open door for the child neurology community to citizenship of the world. No one who knows Professor Ouvrier personally is at all puzzled as to why he has succeeded in achieving so much for the advancement of our international movement.

Among other reasons is the fact that almost everyone who has met him quickly attains memorable personal knowledge of his character. Open and forthright, warmly encouraging to all, a keen listener and observer, he is as the poet says, “a man who loves his fellow man”—and perhaps even more the countless children he has encountered professionally. He is a man of integrity—by which is meant the manner in which each honest element of his personality, intentions, and character fit together seamlessly into a person that has so greatly enriched the clinical and scientific substance and the worthy international objectives of our profession.

How this can be done when in fact he has for so long quietly assumed tremendous personal responsibility for the advancement of so many good ideas, so many organizations and programs, and so many individuals in need of care for their neurological problems. Yet somehow, his ever-constructive availability to all that he encounters lasts for each individual at least just long enough to form an inspirational and lasting friendship that places each individual shoulder to should with Professor Ouvrier in advancing care and understanding of many sorts throughout the world.

To these activities are added the nonprofessional interests that Professor Ouvrier has cultivated throughout his life. He is an avid sportsman—tennis, skin-diving, surfing, and others, he has remained throughout his life as did David Clark a Latin scholar up to the challenge of even the most difficult Roman lyric poets. He is exceptionally knowledgeable of Western classical music—with particular keenness for Sibelius, and he has understanding in depth of history of science, medicine, and the history of the world. Such richness of attainment is a private matter to him—he hasn’t the slightest degree of ponderous exhibitionism in sharing all of the things that he knows. But these facts, as with the facts that constitute his knowledge of medicine and science, are ready quietly to be added as needed with modesty to enrich one or another particular conversation or answer a particular important question.

In addition to Professor Ouvrier’s other achievements, honors, and awards, several honors were quite extraordinary. In 2001 he was named Chevalier de l’Ordre National du Mérite, Republic of France and has subsequently designated Chevalier de l’Ordre de la Legion d’Honneur, Republic of France. In 2004 he was decorated with the Order of Australia. Yet there is on even greater attainment and it is a shared one that has enriched the whole of his professional life. It dates back to the acceptance of his proposal of marriage to Margo, a nurse who became his wife.

Together this pair has garnered the respect and love of an international collection of friends and colleagues. Together they raised a family of three children who have grown into accomplished adults—Sarah, Priscilla, and Richard. To date there are as well there are three grandchildren

Read More

Details

ICNA

News

Published: 23 November 2012

Hits: 526

Preliminary results from the FEBSTAT study has revealed that within days of a prolonged fever-related seizure, some children have signs of acute brain injury, abnormal brain anatomy, altered brain activity, or a combination.Febrile Seizures affect 3 to 4 percent of all children. Most such children recover rapidly and do not suffer long-term health consequences. However, having one or more prolonged febrile seizures in childhood is known to increase the risk of subsequent epilepsy which is estimated to be about 30-40 percent following febrile status epilepticus (FSE).

The Consequences of Prolonged Febrile Seizures in Childhood (FEBSTAT) study is focused specifically on FSE and the risk of temporal lobe epilepsy.Within days of FSE, the children in the study underwent magnetic resonance imaging (MRI) and electroencephalography (EEG). The MRI findings were reported in July 2012, and the EEG findings were reported in November 2012. Both papers were published in Neurology.

FEBSTAT began almost 10 years ago. 199 Children, aged between one month and six years with FSE were enrolled from 2003-2010 at five sites: Montefiore Medical Center and Jacobi Hospital in the New York City; Lurie Children's Hospital in Chicago; Duke University Medical Center in Durham, N.C.; Virginia Commonwealth University Hospital in Richmond; and Eastern Virginia Medical School in Norfolk.A further 96 children who had experienced a single, simple febrile seizure (lasting 10 minutes or less) were also recruited and served as the comparison (control) group.

The children underwent blood tests, a neurological exam, MRI, and EEG within 72 hours of being seen in the emergency room for FSE. The blood samples are being analyzed for viral infections linked to febrile seizures and for the presence of gene mutations that could contribute to epilepsy. The children continue to receive neurological exams, MRI and EEG at regular intervals.

The MRI scans revealed that FSE is sometimes associated with abnormalities in the hippocampus. Of 191 children with FSE, 22 (11.5 percent) had signs of hippocampal injury on MRI, and 20 (10.5 percent) had developmental abnormalities of the hippocampus. Abnormal MRI results were rare among children with simple febrile seizures, defined as lasting 10 minutes or less. Out of 96 children with such seizures, only two (2.1 percent) had developmental abnormalities of the hippocampus and none had signs of brain injury.

Nearly half (45.2 percent) of the children with FSE had abnormal EEG findings. There was also a correlation between the MRI and EEG findings. Children with evidence of acute brain injury after FSE were more than twice as likely to have abnormal EEG findings. The results suggested that in some children prolonged febrile seizures do result in brain injury. In some others pre-existing brain abnormalities may increase the susceptibility to febrile seizures. Both these situations could eventually lead to epilepsy. But it will take more time for the study to confirm this, especially as it usually takes between 8 and 11 years for TLE to develop following FSE.

Temporal lobe epilepsy can cause memory loss, and neuroimaging of adults with temporal lobe epilepsy have sometimes revealed shrinkage and cell loss within the temporal lobe and hippocampus. Many adults with the disorder also report a history of FSE.

If MRI and EEG findings associated with FSE ultimately do correlate with epilepsy, they could be used to identify kids who are at risk and who might benefit from research on preventative therapies for epilepsy.

FEBSTAT is supported by grant NS043209 to Dr. Shinnar. Data from children with simple febrile seizures were taken from a study led by Dale C. Hesdorffer, Ph.D., of Columbia University in New York. That study ended in 2004, and was supported by grant HD036867 from NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development.

References:

1. M. J. Berg, B. Abou-Khalil. Childhood febrile status epilepticus: Chicken or egg? Does it matter? Neurology, 2012; 79 (9): 840 DOI: 10.1212/WNL.0b013e3182684559
2. S. Shinnar, J. A. Bello, S. Chan, D. C. Hesdorffer, D. V. Lewis, J. MacFall, J. M. Pellock, D. R. Nordli, L. M. Frank, S. L. Moshe, W. Gomes, R. C. Shinnar, S. Sun. MRI abnormalities following febrile status epilepticus in children: The FEBSTAT study. Neurology, 2012; 79 (9): 871 DOI: 10.1212/WNL.0b013e318266fcc5

Details

ICNA

News

Published: 23 November 2012

Hits: 554

Prof Dimitri Kullmann's team from University College London (UCL) writing in the November 2012 issue of Science Translational Medicine,reports the potential efficacy of gene therapy in focal neocortical epilepsy using a rodent model.

The authors created a rat model of focal neocortical epilepsy where they induced epilepsy by injecting tetanus toxin into the rat motor cortex. In this model the animals show motor seizures and epileptic activity similar to Epilepsia Partialis Continua.

They then injected a lentiviral vector carrying the gene NpHR which encodes for the light-activated chloride ion pump halorhodopsin along with tetanus toxin. A miniaturized wireless system was used to record the EEG activity.A week later, through an optic fiber inserted into the epileptogenic region of the rat brain a laser light in 20-s pulses was delivered to activate halorhodopsin expressed by excitatory principal neurons .When the haloorhodopsin channels are activiated, chloride ions flow into the neurons resulting in membrane hyperpolarization, decreased neuronal excitability and epileptic activity. The controls rats who were not exposed to light did not show any activation of halorhodopsin no suppression of epileptic activity.

In another method using gene therapy they injected a lentiviral vector carrying the gene KCNA1 which encodes Kv1.1 the potassium ion channel.Kv1.1 expression results in an outward flow of potassoim ions, resulting in membrane hyperpolarisation and reduced neuronal excitability.In this situation there was no need for activation using an external light source. They found that following injection of the virus carryin the KCNA1 gene, the animals who have been injected with the tetanus toxin showed a steady reduction in epileptic actiivty. The epileptic activity eventually stopped completely with no resulting motor or behavioural deficits.

Gene therapy approaches has several advantages over drug treatment, in that their action is very specific by delivering the therapeutic gene to a small group of neurons in a specific brain region. Epileptogenic circuits in the brain often results in altered expression of multiple genes resulting in down-regulation of ion channels thereby making AEDs that work by targeting receptors or ion channels less effective.

This study is proof-of-concept that gene therapy can have disease-modifying effects in epilepsy. However this is still in a very early phase of research, and the challenge will be to translate these results into effective treatment for epilepsy.

The optogenetics approach,is disadvantageous in that it necessitates insertion of an optic fiber to deliver the laserlight which activates the injected gene. Besides there are safety issues in inducing the expression of a foreign protein like halorhodopsin. It is also not known for how long halorhodopsin delivered by gene therapy will be expressed by excitatory neurons and whether there are any side effects from long term expression of the halorhodopsin.

At present it is not certain whether viral transfection does not cause any long term risk . It is also not known whether the expression of Kv1.1 channels by principal neurons diminish over time.

This approach also needs to be validated in other animal models of epilepsy, such as temporal lobe epilepsy(TLE), since TLE invovles multiple epileptogenic regions and would require multiple injections of the viral vector. These advances are in the very early stages still and many questions remain unanswered, but certainly opens up exciting prospects for the future.

Fig. 1. Gene therapy for treating epilepsy.
(Top) Acquired epilepsies (in contrast to inherited epilepsies) may occur after an insult to the brain, such as trauma or meningitis. In response to the insult, specific neuronal networks in the brain become reorganized (hashed circle) in a process called epileptogenesis. Epileptic seizures are not yet apparent and this latent period can last for decades. At some point, the reorganized networks start to generate spontaneous seizures and full-blown epilepsy emerges (chronic period).

(Middle) Current antiepileptic drugs have many limitations. These drugs only control seizures in 70% of patients, with 30% of patients remaining refractory to drug treatment. None of the current antiepileptic drugs prevent the formation of epileptogenic networks and they often have severe side effects because they act nonspecifically in the brain.

(Bottom) Gene therapy for treating epilepsy specifically targets the affected brain region. In new work, Wykes et al.use two different gene therapy approaches to treat focal epilepsy induced in rat brain by injection of tetanus toxin into the motor cortex.

(A) Using an optogenetics approach, these investigators injected a viral vector carrying the gene for the light-sensitive chloride pump halorhodopsin (pink channels) together with tetanus toxin into rat brain. They used laser light delivered through an optic fiber to activate halorhodopsin expressed by excitatory principal neurons in the epileptogenic region. Activated halorhodopsin allowed chloride ions to flow into the neurons, membrane hyperpolarization, and a decrease in neuronal excitability leading to a reduction in epileptic activity.

(B) The second gene therapy approach involved injecting a viral vector carrying a gene encoding the native potassium ion channel Kv1.1 into rat brain. Overexpression of Kv1.1 (blue channels) by rat excitatory principal neurons resulted in an outward flow of potassium ions, increased membrane hyperpolarization, and decreased neuronal excitability. When virus with Kv1.1 was injected into rat brain at the same time as tetanus toxin, epileptogenesis was prevented.

When virus with Kv1.1 was injected into rat brain after epilepsy had been established, epileptic activity was progressively suppressed over several weeks, ultimately resulting in a normal EEG.

CREDIT: Y. HAMMOND/SCIENCE TRANSLATIONAL MEDICINE

Citations:

Wykes RC, Heeroma JH, Mantoan L, Zheng K, Macdonald DC, Deisseroth K et al. (2012) Optogenetic and Potassium Channel Gene Therapy in a Rodent Model of Focal Neocortical Epilepsy. Sci Transl Med ():. DOI: 10.1126/scitranslmed.3004190 PMID: 23147003.

Details

ICNA

News

Published: 19 November 2012

Hits: 577

In The Lancet, David Neal Franz and colleagues from Cincinnati Children’s Hospital Medical Center report on an international, double-blind, placebo-controlled phase 3 trial of the efficacy of the mTORC1 inhibitor everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex. Everolimus is a rapamycin analogue with improved bioavailability compared with sirolimus. 

This study is the latest to to show the effectiveness of everolimus in slowing the cell growth that is overactive in patients with TSC.

The phase III study was conducted among 117 patients with TSC who were randomly assigned to either everolimus or a placebo. Patients were 9 ½ years old on average but ranged from infants to adults. No patient on placebo showed improvement in their tumors. Tumor volume was measured by MRI assessment of the brain.Thirty-five percent of patients in this study on everolimus had at least a 50 percent reduction in tumor volume after an average of 42 weeks on medication.

Every patient in this study experienced a decrease in size of their tumors, and no patient required surgery for their tumors after treatment with everolimus. The earlier phase II study of everolimus by the same group was published in The New England Journal of Medicine in 2010. Based on that data, the U.S. Food and Drug Administration granted accelerated approval of everolimus for patients with subependymal giant cell astrocytomas, or SEGAs. The new, placebo-controlled study was conducted to confirm these earlier results.

In the current trial the patient reported quality of life, as measured by a validated quality of life and neuropsychological assessments, also improved at three months and six months after treatment with everolimus. The investigators also found that more patients had mutations in the TSC2 gene than in the TSC1 gene, and that TSC2 mutations correlated with lower response of the subependymal giant cell astrocytomas, which is in keeping with the results of earlier studies showing an increased severity of symptoms in patients with mutations in TSC2

Advances in the knowledge about tuberous sclerosis complex have shown that inactivating mutations in the Tsc1 and Tsc2 tumour suppressor genes leading to constitutive activation of the mammalian target of rapamycin (mTOR) as one of the main causes of astrocytomas.mTOR functions as an integrator of signalling within two multiprotein complexes (mTORC1 and mTORC2) leading to increased protein synthesis, and thus cell proliferation and survival. In the brain, growth of subependymal giant cell astrocytomas can cause life-threatening symptoms eg, hydrocephalus, requiring surgery. The same mTOR pathway associated with overactive cell growth in TSC also is implicated in other cancers and neurological conditions, such as Alzheimer’s disease, type 2 diabetes, Parkinson’s disease, Huntington’s disease and autism. This makes everolimus, an mTOR inhibitor, a potential candidate to treat these mTOR-associated disorders

Based on studies by John Bissler, MD, a nephrologist at Cincinnati Children’s, the US Food and Drug Administration (FDA) earlier this year approved everolimus as the first medication to shrink non-cancerous kidney tumors that strike up to 80 percent of people with TSC. This allows many patients to maintain kidney function for years to come without the need for repeated surgical intervention.Prior to FDA approval, surgery was considered standard therapy for SEGAs, but everolimus has now become a potential alternative to surgery and the first targeted medical therapy for TSC.

Citation: Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2012; published online Nov 14. (12)61134-9.[abstract]