Pioneers of Neurosurgery in Germany



Ernst von Bergmann

Ernst von Bergmann (1836 – 1907) was one of the most famous and successful surgeons in Europe at the end of the 19th century.  He developed procedure for the treatment of gunshot wounds, particulary of the joints and the skull. As professor and head of the surgical department at the Universities of Dorpat (1871-1878), Würzburg (1878-1882) and Berlin (1882-1907), he published a huge number of internationally approved scientific articles. In addition to his very time-consuming clinical activities von Bergmann became initiator of the surgical asepsis and developed operative methods valid up to this day in traumatology, abdominal, tumour and, above all, in neurological surgery. Being member or chairman of different medical associations and editor of prestigious periodicals, he started an effective post-graduate training for interested colleagues and arranged the first qualified exhaustive rescue service in the German capital.

In 1880, he authored 1st Textbook on surgery on nervous system, which  described missile ballistics and animal experiments first demonstrating the physiological response later known as "the Cushing reflex" and advocated meticulous intracranial debridement with thorough closure after cranial trauma. Twenty years later, as senior editor of the massive System of Practical Surgery, his contributions included pediatric neurosurgery, successful treatment of abscesses and tumors, diagnostic radiography, and cerebral localization using external landmarks and the neurological examination. 

 

Fedor Krause (1857-1937)

Fedor Krause

Within a few months of Wilhelm Conrad Röntgen's discovery of x-rays in 1895, Fedor Krause acquired an x-ray apparatus and began to use it in his daily interactions with patients and for diagnosis. He was the first neurosurgeon to use x-rays methodically and systematically. In 1908 Krause published the first volume of text on neurosurgery, Chirurgie des Gehirns und Rückenmarks (Surgery of the Brain and Spinal Cord), which was translated into English in 1909.  This was the first published multivolume text totally devoted to neurosurgery. He devised neurosurgical approaches (the "Krause operations)  for exposure of the trigeminal ganglion and root, of the cerebellopontine angle, and of the pituitary (transfrontal) and the pineal (supracerebellar) regions.

 

Otfried Foerster (1873-1941): German neurologist, neurosurgeon and system physiologist.

Otfrid Foerster was a neurosurgeon, an innovative experimental neurophysiologist and a neurologist.  His contributions included description of the dermatomes , conceptualizing rhizotomy as a cure for spasticity, anterolateral cordotomy for pain, the hyperventilation test in epilepsy, Foerster's syndrome, and the first electrocorticogram of a brain tumor. Foerster was able to excise intraventricular, hypophyseal, and quadrigeminal lesions and to perform epilepsy surgery under primitive conditions without clips, diathermy, or suction. He published more than 300 scientific monographs encompassing every aspect of the nervous system, including tabes, movement disorders, spasticity, extrapyramidal diseases, dermatomes, epilepsy, cortical localization, brain tumors, peripheral nerve injuries, and pain.

Following Fedor Krause and Otfrid Foerster, pioneers of neurosurgery in Germany, Emil Heymann was one of the outstanding promoters of the young surgical section, before it emerged as an independent specialty. As successor to Fedor Krause at the Augusta-Hospital, Berlin, he consistently improved techniques of investigation and operative treatment of intracranial and spinal tumors.

Fritz König (1866-1952), pioneer of modern neurosurgery in Germany.  Fritz König  enabled his resident Wilhelm Tönnis to be educated by Herbert Olivecrona in his Department of Neurosurgery in Stockholm. After his return from Sweden the first independent Department of Neurosurgery was founded for Wilhelm Tönnis in Würzburg. His scientific journal, "Zentralblatt für Neurochirurgie" was founded in 1936, which consolidated the scientific bond between all neurosurgeons of the world.

Klaus Joachim Zülch (1910-1988) as head of a department of the German Max-Planck-Society, deeply influenced the neurological sciences in post-war Germany. The department with the name Abteilung für allgemeine Neurologie (i.e. department of general neurology) constituted a section of the renowned Max-Planck-Institut für Hirnforschung (i.e. institute for brain research). At the same time he was in charge of the local neurology unit of the municipal Cologne hospital. He worked on  raised intracranial pressure, brain swelling and edema, brain and spinal chord circulation disturbances, head injuries and - in the first line - tumors of the central nervous system. His first contact with neurology specialty took place in Otfrid Foersters neurological clinic in Breslau, today in Poland, before World War II. Otfrid Foerster, a neurological encyclopedist, exerted a deep influence upon Klaus Joachim Zülch lifelong. Here he also came in contact with Percieval Bailey with whom he shared the obsession to classify brain tumors since then. This preoccupation became fruitful when he started collaboration with Wilhelm Tönnis . His association with Wilhelm Tönnis may well be compared to the team formed by Harvey Cushing and Percieval Bailey. Their respective philosophies were equally identical, namely to classify tumors of the central nervous system through a pragmatic approach that would facilitate the communication between neuropathologist, neurosurgeon, neurologist and of course be ultimately as helpful as possible to the patient.

Resources

PubMed abstracts, Wikipedia

Zimmermann  M.   Life and work of the surgeon Ernst von Bergmann (1836-1907), long-term editor of the "Zentralblatt für Chirurgie". Zentralbl Chir. 2000;125(6):552-60.

Hanigan WC, Ragen W, Ludgera M.Neurological surgery in the nineteenth century: the principles and techniques of Ernst von Bergmann. Neurosurgery. 1992 May;30(5):750-7.


Wallesch CW. Otfrid Foerster (1873-1941): German neurologist, neurosurgeon and system physiologist.Cortex;43:4 2007 May pg 491-3

Kuhlendahl H. Beginnings of neurosurgery in Germany: Fedor Krause. With comments on the understanding of medical history. Zeitschrift für Neurologie 204:3 1973 May 17 pg 159-63


Rosegay H. The Krause operations. Journal of neurosurgery 76:6 1992 Jun pg 1032-6
   
  

 

 


 


Sir William Macewen ( 1848-1924) : Pioneer Scottish Neurosurgeon, First Brain surgery

Sir William Macewen( 22^nd June 1848 - 22^nd March, 1924): Pioneer Scottish Neurosurgeon. He studied medicine at University of Glasgow & received medical degree in 1872. After 3 years he joined as surgeon at the Glasgow Royal Infirmary. In 1881 he was appointed lecturer on Systematic Surgery at the Royal Infirmary School of Medicine. In 1883 he was appointed as Surgeon to the Royal Hospital for Sick Children in Glasgow. In 1892 Macewen became Regius Professor of Surgery at the University of Glasgow (the post which Lister had held when Macewen was a student).

By following principles of antisepsis of Joseph Lister and adopting systematically the use of scrubbing & sterilization of surgical instruments, use of surgical gowns, and anesthesia Macewen became one of the most innovative surgeons of his time and was able to greatly advance modern surgical techniques.

Following the work of John Hughlings Jackson (1835–1911) and David Ferrier (1843–1924) on neurological mapping of functions in the brain, Macewen demonstrated in 1876 that it was possible to use a precise clinical examination to determine the possible site of a tumor or lesion in the brain, by observing its effects on the side and extension of alterations in motor and sensory functions. Thus, in 1876 he diagnosed an abscess in the frontal lobe of a boy, but the family refused permission to operate. When the patient died his diagnosis and localisation were found to be correct.

He performed the first successful intracranial surgery where the site of the lesion (a left frontal meningioma) was localised solely by the preoperative focal epileptic signs (twitching of the face and arms in the opposite site of the lesion). A trephined hole in the skull near the purported site of the lesion showed a big subdural tumor. The patient, a teenage girl, lived for eight more years, and a subsequent autopsy showed no trace of the tumor. He later used this many times to successfully operate on brain abscesses (in 1876) and hematomas and on the spine.

One of his earliest contributions while at the Royal Infirmary, in 1877, was in orthopaedics, by means of the development of the first bone grafts, but also in knee surgery using a special instrument (Macewen's osteotome) both techniques becoming key treatments for the highly prevalent disease of rickets. He developed surgical treatments for mastoid disease and pyogenic cysts of the temporal bone and has identified an anatomical structure in this bone, the foveola suprameatica, which was named MacEwen's triangle in his honour.

In 1916 Macewen helped to found the Princess Louise Scottish Hospital for Limbless Sailors and Soldiers in Erskine (now the Erskine Hospital), near Glasgow, which was urgently needed to treat the thousands of military that lost their limbs in the First World War. He helped in designing the Erskine artificial limb.

His method of surgical removal of lungs became a major medical weapon in the treatment of tuberculosis and lung cancer, thus saving many patients. His name was also immortalised in Medicine in two other instances: the Macewen's operation for inguinal hernia and the Macewen's sign for hydrocephalus and brain abscess.

Another important contribution by Macewen to modern surgery was the technique of endotracheal anaesthesia with the help of orotracheal intubation, which he described in 1880, and still in use today.

Macewen was noted for his early and creative use of photographs for documenting patients cases and for teaching surgery and medicine. He illustrated cranial anatomy in  in his Atlas of Head Sections. He pioneered the use of photos of body parts and pathological specimens, as well as photos taken before, after surgery. He was knighted in 1902. He was President of the British Medical Association in 1922. He was  Honorary Surgeon to the King in Scotland.

Sources:

http://en.wikipedia.org/wiki/William_Macewen

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2304086/pdf/brmedj05807-0045.pdf

Investigations and Treatment of Cancer Metastasis to Brain

About twenty five years back, as a medical student, I used to feel pity about anybody who was diagnosed with brain tumour, as I thought that all brain tumour patents had dismal prognosis. But, now as a neurosurgeon in year 2018, I understand and know that some brain tumours have favourable surgical outcome and carry good prognosis. Any, very often surgery for the brain tumour is very rewarding for the doctor as well as for the patients and their family members. Like, a patient with large frontal convexity meningioma can be operated safely and whole tumour can be excised without any need for chemotherapy or radiotherapy. So, the patient as well as the neurosurgeon are happy with the favourable outcome. This happiness is sustained even several years after the surgery as there may be no chance of recurrence due to complete excision.

So, as a medical student with initial posting in clinical departments I was like a lay person, observing the plight of patients and their relatives, I was pessimistic about this disease. However, about 13 years ago during my neurosurgical training,  I had experienced  similar feelings  for patients with brain metastasis. I thought that if cancer has spread to the brain of the patient, there would be very bad prognosis. Initially as a trained neurosurgeon I fad operated few patients with that notion, but his presumption was misfounded. Because, there were good prognosis in few patients of brain metastasis.

So, one reason for writing this article is to share my optimism and enthusiasm of managing patients with brain metastasis.

Another reason for writing this topic is to bring to the notice of readers about all available resources for the appropriate and tailor made approach to treat effectively any patient diagnosed with brain metastasis. Because, many medical professionals may not be aware about the favourable outcome in some patients with metastases to the brain.

Last reason is very simple. Most common brain tumour, definitely requires maximum attention. Such lesions with worst prognosis is a challenge and demands amalgamation of all available therapeutic modalities for providing best possible benefits to the patient.

The development of new diagnostic tools and therapeutic interventions in last two decades must be channelized and focussed on managing such cases, so the prognosis of brain metastasis becomes very good. This can be achieved now. If not now, atleast in next few years. This article is an attempt to achieve good neurosurgical outcome of patients with brain metastasis.

Brain metastasis is the commonest brain tumour in adults as almost all cancers metastasize to the brain.  A lot to be explored to understand about the disease process, early detection and effective treatment of this disease. With use of even the best available technologies, many patients die of this illness without diagnosis. In many patients brain metastasis is detected at the time of autopsy.

Although, many institutions are equipped with advanced machines and have good infrastructure for managing primary systemic cancers, but very few are having facility to treat cases with brain metastases. It may in part, due to preconception among physicians about the presumption that any patient harbouring multiple metastases has dismal chances of survival. So, to change the conception a paradigm shift is required. This manuscript may be a precursor for much mor clinical works in this field and will guide clinicians for managing a patient with brain metastasis.

Many advances have occurred in past few decades leading to better understanding of this disease. But, there is need to converge the outcome of different basic research , translational research, diagnostic studies and clinical studies of different specialities for the concerted effort to treat brain metastasis. Approach of all stakeholders who are involved in basic, paraclinical and clinical study and management should not be egocentric , but patient centric. These patients require multidisciplinary care . Multidiscilinary approach will definitely advance our understanding about biologyof brain metastasis, different therapeutic options , application of newer diagnostic tools and tailor made approach for managing each and every patient with brain metastasis. Contributions of basic science researcher and people involved in palliative care are equally important.

Brain metastasis is a major cause of morbidity and mortality in patients with systemic malignancies. Newer imaging and treatment modalities have improved clinical outcome in last few decades.

In last 50 years, there has been nearly a five-fold increase in the overall prevalence of brain metastases; the ratio between metastatic to primary brain tumor is now almost 50:50 . The incidence of metastases is rising due to early detection by advanced neuroimaging modalities and effective treatment regimens of systemic malignancies .

Up to 30% of patients with cancer develop cerebral metastasis. Autopsy studies of patients who die of cancer revealed  that CNS metastases occur in about 25% of patients. In patients with no history of cancer a cerebral metastasis was the presenting symptom in 15% ( EFNS, 2006). Highest incidence of brain metastases is seen in 5^th to 7^th decade of life. 

Metastases  most commonly spread via through hematogenous route. The brain parenchyma is the most common site (80%), followed by the skull and dura (15%). Direct extension to brain from a cancer of adjacent structures like cancers of nasopharynx, paranasal sinuses, middle ear (e.g. squamous cell carcinoma, esthenioneuroblastoma) is much less common than hematogenous spread . Diffuse leptomeningeal (pial) and subarachnoid space infiltrations are relatively uncommon, accounting for just 5% of all cases. Brain metastases are preferably located in arterial border zones and at the junction of cerebral cortex and subcortical white matter.  Only about 3-5% occur in basal ganglia region.  About 15% of metastases are found in the cerebellum. The midbrain, pons and medulla oblongata are uncommon sites and account for less than 1% of metastases.  Other rare sites include the choroid plexus, ventricular ependyma, pituitary gland and retinal choroid. The metastasis may also occur through the CSF pathway and may present as drop metastasis. Primary brain tumors like germinoma and medulloblastoma may spread along CSF pathways. Some systemic cancer like lymphomas and leukemias involve leptomeninges and is known as meningeal carcinomatosis. It is a diffuse metastasis in the leptomeninges by carcinomatous infiltration.

Single metastasis accounts for one third to one quarter of patients with brain metastasis. About 20% of patients have two lesions, 30% have three or more and only 5% have more than 5 lesions.   

The most common sources of brain metastases in adults are, in descending order, lung cancer (especially small cell and adenocarcinoma),  breast cancer, melanoma, renal carcinoma and colon cancer . In children in descending order of frequency , they are leukemia, lymphoma and sarcoma ( osteogenic sarcoma, rhabdomyosarcoma and Ewing sarcoma).  Melanoma, although constitute only 4% of all cancers, has the highest propensity to result in brain metastasis.

The average period required for the development of brain metastasis from lung cancer is 4 to 10 months, whereas it is approximately 3 years in breast cancer.

Histopathology of the lesion usually reflects the tissue of origin, i.e., the primary site of cancer. The histological features are as diverse as in the primary tumors from which they arise.  Metastatic choriocarcinoma should be considered in the differential diagnosis of hemorrhagic intracranial masses in females of child bearing age and surgically resected blood clot should be examined histologically for determining the etiology.

As with other intracranial space occupying lesions the symptoms and signs depend on the size and site of the lesion, raised intracranial pressure, hemorrhage, meningeal irritation and hydrocephalus. Headache, seizures and focal neurologic deficits are the most common presenting symptoms of parenchymal metastases. Detailed neuropsychological testing demonstrates cognitive impairment in 65% of patients with brain metastsasis.

Preoperative metastatic work up includes detailed history and systemic examination to detect the primary cancer , metastases elsewhere in the body and  to rule out other diagnosis like brain abscess, tuberculosis, toxoplasmosis, neurocysticercosis, resolving hematoma, lymphoma, hemangioblastoma and glioblastoma.

Chest X-ray, radiograph of the spine, ultrasound of abdomen and pelvis, trans rectal ultrasound, mammography, bronchoscopy, upper GI and lower GI endoscopy, bone marrow examination, radionuclide bone scan, serum electrophoresis, intravenous pyelogram (IVP), CT scan of the brain, chest, abdomen and pelvis, positron emission tomography ( PET)-CT or PET-MRI may be required for detection of the systemic cancer. Other important investigations include erythrocyte sedimentation rate (ESR), C- reactive protein (CRP) as markers of infection, Western Blot Test for HIV status, Gram stain, and blood and urine culture to identify hematogenous origin to an abscess. Few investigations are very costly and associated with risks and are required in very rare circumstances.

CT scan and MR are the most commonly used techniques for detecting brain metastases. Brain metastasis appears discrete ring or disc like at subcortical location, at the junction of grey and white matter, with enhancement and extensive surrounding edema which is disproportionate to the size of the lesion. FLAIR image, contrast image, magnetization transfer( MT), MR angiography (MRA), Diffusion weighted imaging (DWI),  fat suppression, MR spectroscopy further enhance the value of MRI as the investigation of choice for detecting CNS metastasis.

In carcinomatous meningitis MRI may reveal nodular contrast enhanced lining along the CSF pathways with or without hydrocephalus. FLAIR sequence is of particular value as it may reveal the neoplastic spread along the spinal cord and spinal nerves.

Prominent lipid signal is the dominating peak on MRS in the majority of brain metastases. However, lipid is also common in cellular processes including inflammation and necrosis. Choline is generally elevated, and Cr is depressed or absent in most metastases.

CSF examination may reveal carcinomatous cells. Meningeal biopsy is indicated when imaging fails to support the diagnosis but this disease is strongly suspected.

About 11% patients with known primary cancer do not have metastatic lesion, despite the fact that CT scan or MRI suggest so. Half of these patients can have potentially curable inflammatory and so a histopathological confirmation must be obtained before planning treatment.

Whole body PET-CT scanner can detect any significant residual or recurrent FDG avid lesion at the primary cancer site, or status of the lymph nodes, lungs, liver, spleen, kidneys, urinary bladder and other organs and systems like skeletal system. PET is used to evaluate the therapy response and to assess the disease status. However, PET does not distinguish secondary from primary neoplasms and may be false positive in some benign lesions of the brain.

Therapeutic approaches include steroid therapy, stereotactic biopsy, neurosurgical resection, brachytherapy, SRS, WBRT, chemotherapy and combinations of treatment. Patient selection for a particular type of treatment is paramount in order to maximize survival and neurologic function whilst avoiding unnecessary treatment. Clinical and  radiographic prognostic factors and histology of the lesion are the most important determinants of the outcome. Good prognostic indicators include Karnofsky performance status (KPS) of more than 70, age less than 65 and controlled primary tumor and no extracranial metastasis. Other prognostic factors include the sensitivity of the tumor to therapy and number and location of CNS metastases.

Anti edema measures like Frusemide, Mannitol , Glycerol, Acetazolamide and Dexamethasone reduce the raised ICP. Steroids have an oncolytic effect and cause shrinkage of metastatic lymphomas. The mainstay of treatment for brain metastsasis over the past 5 decades has been corticosteroids and WBRT. Non randomized studies suggest that WBRT increases the median survival time by 3-4 months over approximately 1 month without treatment and 2 months with corticosteroids.

Radiotherapy can be delivered by fractionated external beam irradiation, small field streotactic irradiation (stereotactic radiotherapy) or interstitial implantation (brachytherapy) (Dagnew et al, 2007, Patchell et al 1998) . For whole brain radiation therapy (WBRT), the most common regimen employed is 35 Gy delivered in 2.5 Gy fractions over 14 treatment days. Daily fraction of more than 3 Gy likely increases the risk of neurotoxicity.

Stereotactic radiotherapy (SRT) is delivered using a linear accelerator. A fractionated schedule is followed maintaining the targeting technique of SRS.

For neoplastic spread to the spinal cord, treatment involves the irradiation of the entire neuraxis with chemotherapy including methotrxate, cytosine arabinoside, and thiotepa. Intra-CSF drug therapy can also also be given. Topotecan, an inhibitor of totpisomerase-1, crosses the blood brain barrier (BBB) and may be effective in treatment of brain metastasis from small cell lung and breast cancer. Temozolamide, an oral alkylating agent also crosses BBB is useful in treating brain metastasis.  

Stereotactic radiosurgery (SRS) is a relatively recent therapeutic option that has significantly improved the effectiveness of and morbidity associated with radiation therapy. SRS may use gamma knife (GK) or linear accelerator (LINAC, CyberKnife) delivers a single large dose of focused radiation to lesions localized by stereotaxy. SRS is useful for lesions less than 3 cm  to 4 cm where a radiation of 1,600 – 3,500 cGy is delivered in a single sitting. A major advantage of this technique over conventional surgery is that it can treat surgically inaccessible tumors in the eloquent area of the brain. SRS is a safe alternative to surgical excision in elderly frail patients with associated medical conditions, such as diabetes mellitus, hypertension.  SRS is a non invasive procedure and it obviates the need of multiple craniotomies in a patient with multiple metastases. Some tumors are very sensitive to radiation like metastasis from lymphoma, germ cell tumor and small cell lung cancer where SRS is the treatment of choice.

Surgical resection is the treatment of choice in all the patients where lesion is surgically accessible, associated with significant mass effect and hydrocephalus. If the lesion is more than 4 cm in size, or highly cystic then surgical intervention is definitely better than SRS. If a patient presents with mass effect, local irritation of the adjoining brain tissue, raised intracranial pressure and tumor is in surgically accessible area of the brain then immediate tumor excision or decompression should be done. If the primary cancer is controlled and the life expectancy is more than 3 months, the surgery is indicated. Surgery is life saving and helps in establishing the histopathological diagnosis. The importance of diagnosis is paramount when the diagnosis of brain metastasis is in question. This is important because as many as 10%-15% of patients with a clinical diagnosis of metastasis may actually have non metastatic lesions such as abscess.

Surgical excision should be considered for patients with good KPS score, minimal or no evidence of extracranial disease and surgically accessible brain metastasis. Surgery is needed in cancers which are resistant to radiation like thyroid carcinoma, renal cell carcinoma and melanoma. A certain, immediate and predictable outcome of surgical resection and long term local control metastatic lesion are major advantages over radiation based treatment modalities.

                                       Intraoperative photograph of a frontal lobe metastasis

                             

                      Intraoperative photograph showing frontal lobe after excision of metastasis

Stereotactic biopsy should be an option for lesions located in inaccessible and eloquent area of the brain.

After surgery or SRS, adjuvant WBRT is recommended. It is an effort to erradicate residual cancer cells at the resected site and to eliminate microscopic foci at distant sites within the brain, thereby, reducing the risk of tumor recurrence.

Long term follow up of the patient is mandatory for evaluation of neurological status, complications of chemoradiation therapy, detection of recurrence or appearance of any new lesion, neurocognitive impairment and for neurorehabilitation and supportive care.

              A middle age female patient had presented with swelling in the head and history of seizures

MRI of brain the above mentioned patient showing scalp swelling and involvement of the cranium and intracranial cystic lesion with enhancement

This middle aged female had multiple intracranial metastses without detectable systemic primary cancer. 

 Intraoperative image shows defect in the cranial bone as seen after excision of the soft to firm swelling just beneath the scalp incision. Tumor was adherent to dura also. Intracranial lesion was mainly cystic with soft, suckable and moderately vascular surrounding solid compnent of the metastatic lesion.

Conclusion

In a suspected case of brain metastasis choice of investigation, neuroimaging and therapy must be decided by the treating team based on a firm understanding of the prognostic indicators and other parameters. Patient selection is the cornerstone of management with brain metastasis. Prompt decision and aggressive management with combined modality of treatment minimizes cost of care, maximizes the clinical outcome and reduces the mortality and morbidity of patients with brain metastases.

References

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[2]        Chapter : Metastatic Brain tumors, Ramamurthy R, Harinivas in Ramamurthy & Tandon’s Manual of Neurosurgery, P.N.Tandon, Ravi Ramamurthy, Pradeep Kumar Jain N., First Edition, ISBN 978-93-5152-192-1(2014) pp 1049-1064.

[3]        Anne G. Osborn. Osborn Brain imaging, pathology and anatomy., 2^nd edition ( Amirsys) 

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[9]        Ramamurthy, K. Sridhar, M.C.Vasudevan.  Textbook of operative neurosurgery, Ed Vol.1, B.I. Publication Pvt Ltd , New Delhi. Chapter: Surgical management of brain metastasis, By V.K.Khosla, B.S.Sharma.

[10]      Alexander Chi, Ritsuko Komaki. Treatment of brain metastasis from lung cancer, Cancer 2010, 2,2100-2137.

[11]      Andrew D. Norden, Patrick Y. Wen and Santosh Kesari.  Brain metastases. Current Opinion in Neurology, 2005, 18;654-661.

[12]      Remi Nader , Abdulrahman J. Sabbagh, Thieme.  Neurosurgery Case review Questions and Answers ,.Chapter, Case 17 : single brain metastases Joseph A. Shehadi and Brian Seaman, Chapter, Case 18: Multiple brain metastases. Ramez Malak and Robert Moumdijian.

[13]      Timothy Siu, Frederick F. Lang. Surgical management of cerebral metastasis. Page 178-91.Chapter in Textbook : Schmidek & Sweet operative Neurosurgical techniques, indications, methods and results, Alfredo Quinones- Hinojosa, 6^th edition, ( Elsevier Saunders). 

[14]      Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis ( RPA) of prognostic factors in three Radiation Therapy Oncology Group ( RTOG ) brain metastases trials . International Journal of Radiation Oncology, Biology, Physics 1997; 37: 745-751.

[15]      Wong ET, Berkenbit A. The role of topotecan in the treatment of brain metastasis. Oncologist , 2004; 9:68-79.

[16]     Dagnew E, Kanski J, Mc Dermott MW, et al. Management of newly diagnosed single brain metastasis using resection and permanent iodine-125 seeds without initial whole-brain radiotherapy: a two institution experience. NeurosurgFocus 2007; 22(3):E3

[17]      Patchell RA, Tibbs PA, Regine WF, et al. Postoperative radiotherapy on the treatment of single metastasis to the brain: a randomized trial JAMA 1998; 280: 1485-1489.