Epilepsy: The delayed sequelae to early head traumas!

Introduction:

Since age 14, when my younger brother in the early morning hours had his first fit of seizure, that shook us by surprise and terror, our family life changed for ever! Every day and every minute we were in anticipation of him having a fit, at the breakfast table in the morning, that happened the most, or during the day in school while we were not present to protect and taking him to medical attention. It took years until the seizure slowed down and came under control after many trials of anti-epileptics. At the time, nobody, even the medical experts knew the cause of a very common and ancient malady of humans. But while I was not yet even in medical school, I knew that during his childhood, he had several falls with head traumas, though I could not put things together and make a sense of the trauma as a common cause of epilepsy, that then was called “idiopathic”, meaning unknown cause!

 Epilepsy or seizure that has been recorded as one of the oldest disease of the humans, as far back as 2000 BC in Akkadian records in Mesopotamia, has been affected commons and greats such as Julius Caesar and Alexander the Great. The disease for centuries had been known through ignorance as caused by “possession by evil spirits”, or named the “sacred disease”. First it was Hippocrates, the father of medicine who in the fifth century BC, rejected the idea that the disease was caused by spirits, and proposed that epilepsy was not divine or satanic in origin, but a medically treatable disease of the brain. He also proposed, heredity an important cause, and described worse outcomes if the disease presents at an early age, and instead of referring to it as the sacred disease, he called it the “great disease” giving rise to the modern term “grand mal” used for tonic–clonic seizures. Despite this landmark ancient work of the father of medicine, evil spirits continued to be blamed until at least the 17th century, and inflicted people with epilepsy were stigmatized, shunned, or even imprisoned, or put in asylums side by side with the mentally ills, or the criminally insanes. This was resolved and epilepsy was accepted as a disease of the brain only when in the mid-1800s, the first effective anti-epileptic medication, “bromide” relatively treated some cases. (1)

Epilepsy is classified into six types: Tonic, clonic, tonic-clonic, myoclonic, absence and atonic seizures. The most common type in about 60% is tonic-clonic or generalized or grand mal seizure that involves the convulsion of one part of body, spreading to the whole body, that is the result of spreading electrical discharges of cortical neurons on both brain hemispheres. After the convulsion, the inflicted individuals loses consciousness for about 10-30 minutes with the usual loss of bladder and at times bowel control. Tonic and clonic alone are focal or partial seizures that involve one cortical hemisphere and does not generalize, so does not lead to the loss of consciousness. These seizures can at times occur to patients suffering from grand mal or generalized tonic-clonic epilepsy, when they have only partial not complete seizures, for example due to partial treatment with anti-epileptics. Myoclonic seizures involve muscle spasm of one or a few areas of the body without generalization or loss of consciousness. “Absence” is lapse in attention for a few seconds to minutes, mostly occurring in children, appearing as the child staring into space and does not hear or react when spoken to. “Atonic seizure” is the sudden loss of muscle tone, leading the person to fall without loss of consciousness. (2)

 In search of a cause:

Several medical conditions, such as fever causing febrile convulsions specially in infants where their brain is very sensitive, or metabolic conditions such as liver failure or jaundice by causing hyperbilirubinemia, brain infections and tumors can cause seizures, and these mostly treatable causes need to be ruled out specially in both extremes of age. But majority of epilepsy in otherwise healthy people start in childhood or youth who have none of the above medical conditions with not much genetic risk in the family. This common epilepsy that is still labeled as “idiopathic”, meaning with no known causes, are latent consequences of an early brain trauma, mostly in childhood, that I will detail here.

 Trauma as a causation of epilepsy and seizure or “post-traumatic epilepsy”, is recorded as early as 3000 BC. Trepanation, or cutting a hole in the skull, as a treatment of such epilepsy have also been used in ancient cultures, that continued as the mainstay treatment until late 19th century and the discovery and treatment of bromide as the first anti-epileptic. These operations were mostly performed on the patients with obvious acute or sub-acute history of brain traumas, where the skull at the site of injury would be opened, debriding injured tissue, and draining the blood or fluid from under the dura mater, so releasing pressure on the part of the cortex, that had caused the seizure. (4-5)

 The earliest study and record of late onset of epilepsy from trauma is a case study by Herman Mynter, a surgeon from the Niagara University and the Sisters of charity hospital in Buffalo in 1894. (6) Dr. Mynter reported a 24 years old man who at age 12 had a head trauma that led him to brief unconsciousness then, but no consequences until six years later at age 18, when he slowly developed seizures. His fits were absence like with dullness in alertness and staring into space mostly upon awakening in the morning, that over time evolved into convulsive attacks, day and night and finally “status epilepticus”, meaning uninterrupted seizures, for 30 hours. He was referred to Dr. Mynter, the surgeon who found a large depression under a scar over his head at the site of his old trauma, that by opening and cleaning the debris, he recovered fully from his convulsive attacks the next day. The young man had no attacks for 17 months, returned to work and got married, until again became convulsive. The epileptic attacks grew faster and uninterrupted soon in the state of “status epilepticus”! A second operation in the skull was performed and another hypertrophied bony edge was removed from deeper area of the initial traumatic site of his head and he again recovered totally from his seizures in 24 hours. He reportedly had been seizure free since!

 The epilepsy due to closed head traumas or concussions, not open traumas with skull fractures as the original case above, has been reported in the literature as early as 1947. (7-8) The first recorded case of latent epilepsy after trauma, has been reported by Mann (9) in 1949 of a case developing seizures, 24 years after an earlier trauma. The role of birth traumas and asphyxia in the causation of infants and children seizures also have been documented as early as 1949, 1951. (10-11) One of the earliest review studies of more than one case studies of the link of traumas to epilepsy has been reported by Russell and Shitty in 1953 who out of 360 such cases, they described the detail of 85 cases. (12) Dr. Jennett in his lecture delivered at the Royal College of Surgeons of England on 23rd March 1961 (13), presents a review of 282 cases of traumatic epilepsy that starts with the following surprising comment: “It has been asserted almost universally that trauma may cause epilepsy; I have never been able to understand why.” Dr. Jennet continues “Those are the words of Dr. Kinnier Wilson, speaking in 1923, referring to the link between head injury and subsequent fits which has been assumed since Hippocartic times. Few seemed to share Wilson’s skepticism, though few either have been able to discern any consistent pattern in the relationship between trauma and epilepsy.” This perhaps was the first large study of latent epilepsy with a follow up of cases for several years, show that ¼ of cases develop seizures after 4 years.

 The mystery of “Idiopathic epilepsy”:

Unfortunately the mystery of “Idiopathic epilepsy” still to this date is unsolved, as seizures due to head traumas, are mostly due to moderate and severe ones and open or penetrating injuries with an acute onset of epileptic manifestation. Moreover the risk of post-traumatic epilepsy in mild head injuries are estimated not to be greater than the general population. (14-15) In comparison with penetrating head injuries that half give rise to seizure in a short period of time, often less than 6 months, non-penetrating head traumas by causing focal brain contusions and intracranial hemorrhages, is associated with a risk of posttraumatic epilepsy up to 30%. These closed head injury often produces diffuse concussive injuries, with shearing of axons and selective damage to vulnerable brain regions, such as the hippocampus. (16) But since most of these concussions are moderate to severe and occur in sport injuries, the impact of minor repetitive injuries in causation of epilepsy, specially the common “idiopathic” one is not well known! Before opening my argument of the possibility of the cause of idiopathic epilepsy by minor repetitive head traumas, two important topics in that relation, need to be explored: 1. The consequences of repetitive head injuries and multiple concussions that have been documented mostly in sport medicine and are of moderate to severe type traumas. 2. The age of impact as the brain reaction at different ages are not the same.

Repetitive head traumas and multiple concussions, an emerging diagnostic entity in sport injuries and combat zones, have recently been of interest for causing chronic traumatic encephalopathy (CTE) over time and several other neuropathologies. (17-18) The list of these pathologies range from simple headache to mild cognitive impairments to dementias including Alzheimer’s disease, and in different contact sports from soccer to football and boxing. But majority of these studies have been done in high school and college sports, the age group with a more developed and less sensitive brains for developing seizures, but more aging pathologies such as cognitive and dementing disorders. (19-22) Nevertheless, repetitive head injuries, even mild ones in these age groups and in animal models have shown reactive astrocytosis throughout the cortical layers and axonal swellings, and metabolic derangements in the brain including glycolysis, all increased with repetition of traumas. (23-27) Despite all these, animal studies show that the post-morbid pathologies after head injuries, differ in myelinated versus unmyelinated fibers (28) which may suggest that myelin provides some protection against concussive injury so that the immature brain with less myelin may be more vulnerable to brain trauma. (29) Unfortunately, there is not yet any evidence from imaging studies of greater or more sustained diffuse axonal injury in children relative to older individuals. In the following and in presenting of my hypothesis of repetitive mild head traumas as the suspicious cause of “idiopathic epilepsy”, the sensitive brain at the age-window of childhood and the more common traumas at this age range will be explored, then linked with the possible neuropathophysiology of this common epilepsy.

Neuronal or Glial?:

The current pathophysiology of idiopathic epilepsy, though it is largely unknown, is centered and perceived as a neuronal de-synchronization. This theory posits that the resistance of excitatory neurons to fire in epilepsy is decreased, that in turn has been triggered by changes in ion channels or inhibitory neurons not functioning properly. This then results in a specific area from which seizures may develop, known as a “seizure focus”. (30) Another mechanism of epilepsy may be the up-regulation of excitatory circuits or down-regulation of inhibitory circuits following an injury to the brain. These secondary epilepsies occur through processes known as eipleptogenesis. (31) This current causation theory, clearly is insufficient as approximately one-third of epileptic patients do not respond to the current anticonvulsive drugs that target neurons or neuronal circuits.

 In the past few years, the pathophysiological theory of epilepsy has shifted its focus from neurons to astrocytes. Astrocytes or glia cells by secreting and controlling the most abundant brain neurotransmitters, the excitatory amino acid glutamate, and the inhibitory γ-aminobutyric acid (GABA), are in charge of the brain synchronization and stability. Many neurologic and psychiatric conditions, particularly

epilepsy, are accompanied by the development of reactive gliosis, or pathological proliferation of these cells. Among the biochemical changes evident in reactive astrocytes is a downregulation of several of the important regulators of the glutamine-glutamate cycle, including glutamine synthetase, and possibly glutamate transporters. This downregulation may have significance in contributing both to the aberrant excitability and to the altered neuropathology characterizing epilepsy. (32) Proliferation of reactive astrocytes (gliosis) has long been accepted as the pathophysiology underlying obvious post-traumatic seizures and the temporal lobe epilepsy (TLE). Even though many patients with TLE are refractory to antiepileptic drugs, some can be successfully treated with surgical resection of the anteromedial temporal lobe, where mostly exhibit mesial temporal sclerosis. This pathology is recognized by patterned neuronal loss and proliferation of reactive astrocytes in mesial temporal lobe structures, parts of hippocampus, the entorhinal cortex, and amygdala. (33-35)

 It is well established that metabolic fuels can either prevent or trigger epileptic seizures. For example, prolonged fasting or consistent intake of a low carbohydrate, high fat – ketogenic – diet leads to significant reductions in the frequency of many types of epileptic seizures. While the mechanisms underlying these effects are not completely understood, there is evidence to suggest that astrocytes and the glutamine-glutamate-GABA metabolic cycle may be involved (36). The perivascular astrocyte end feet are positioned between the endothelial cells of blood vessels and the rest of the brain; thus, blood-derived metabolic fuels normally enter the endothelial cell and astrocyte compartments first. It is therefore possible that the sclerotic hippocampal formation in TLE is deficient in ketone bodies under euglycemic conditions and that this deficiency may promote excitability due to the relative abundance of carbohydrate fuels, that could be reversed with a ketogenic diet. (37) Ketone bodies increase the brain energy stores, stabilize the neuronal membrane potential, enhance GABA-mediated inhibition and possibly decrease glutamate-mediated excitation. Furthermore, ketone bodies rather than glucose may increase the energy stores preferentially in GABAergic neurons, thus resulting in more sustained GABA-mediated inhibition. (38-39)

In addition to traumas, triggering astrocytosis or gliosis, causing seizures and epilepsy, other foreign insults such as virals, have been shown to induce gliosis in the hippocampus on inhibitory and excitatory synaptic function, as well as circuit excitability in animal models. Injection of high titer, astrocytes-specific viral particles has caused anatomic alterations in astrocytes consistent with gliosis, including hypertrophy, as well as reduced expression of glutamine synthetase, that could be reversed by application of exogenous glutamine. (40)

As a proof of concept and showing if reactive astrocytosis is a primary disease contributor, or epileptogenic, or a consequence of epileptogenesis, Robel et al. (41) in 2015, genetically induced widespread chronic astrogliosis in a mouse model. These researchers were able to prove that astrogliosis induced in the lab mice in the absence of other pathologies and without breaching the blood brain barrier (BBB) or significant inflammation, electroencephalographically and with simultaneous video recording, that these mice develop spontaneous seizures during the first six postnatal weeks of life and brain slices show neuronal hyperexcitability. These frontier researchers have most recently in 2016, based on their findings, have challenged the current neuronal theory of epilepsy and invited the pathophysiological research in acquired epilepsy or “idiopathic epilepsy” to consider the contribution of glial cells as drivers of epileptogenesis. (42)

 Conclusion:

Since epilepsy like so many other neurological and psychiatric diseases is short of any genetic cause, with only 50% risk in identical twins and only 15% in non-identical twins (43), exogenous causes need to be explored. (43) Moreover seizures are the most common in the extremes of age, 50% in children and adolescence, with a rarity in adulthood unless having a clear known cause or trigger, and almost half at the other extreme of life, the old age. (44-48) Therefore, an exogenous trigger, cause or insult on a fragile or sensitive brain are the right ingredient or pathophysiological formulation of idiopathic epilepsy. Henceforth, like other types of epilepsy with known causes, that are basically traumatic or metabolic, in one way or another exogenous, the “idiopathic epilepsy” needs to come out of the closet of unknown and to be known having cause and trigger. As discussed in detail throughout this article, the cause and trigger of the common epilepsy of yet known as “idiopathic” is the physical trauma or microbial insult in a time-sensitive window of the brain, mostly in childhood. Since these traumatic events have been mild, but probably repetitive, they have skipped the medical and research attentions and is still known as “idiopathic”. Now that we know the pathophysiology of common epilepsy is laid in gliosis and abnormal astrocytes proliferations, and not neuronal as perceived for long, it is time to delineate the cause (s) of these glioses, that lead to hyper-excitements of the brain and loss of its inhibition or synchronization. This important recognition, not only is a huge step forward in the classification and knowledge on the etiology of the common epilepsy and its efficacious treatment, it has the most value in the step forward to the prevention of this common neurological condition that changes the inflicted person and his or her families at large, like ours in the case of my brother!          

Dr.Mostafa Showraki, MD, FRCPC                                                                  Lecturer, School of Medicine, University of Toronto,Author: “ADHD:Revisited” Book/ “adhdrevisited.com”/”medicinerevisited.com”

Reference:

  1. Magiorkinis E, Kalliopi S, Diamantis A (January 2010). “Hallmarks in the history of epilepsy: epilepsy in antiquity”. Epilepsy & behavior : E&B 17 (1): 103–108.
  2. Chang BS, Lowenstein DH (2003). “Epilepsy”. Engl. J. Med. 349 (13): 1257–66.
  3. Holmes, Thomas R. Browne, Gregory L. (2008). Handbook of epilepsy (4th ed.). Philadelphia: Lippincott Williams & Wilkins.
  4. Eadie MJ, Bladin PF (2001). A Disease Once Sacred: A History of the Medical Understanding of Epilepsy. London: John Libbey. pp. 215–216.
  5. Young B (1992). “Post-traumatic epilepsy”. In Barrow DL. Complications and Sequelae of Head Injury. Park Ridge, Ill: American Association of Neurological Surgeons. pp. 127–132.
  6. Mynter H. III. Contribution to the Study of Head Injuries, and of the Results of Trephining for Subdural Haemorrhage, Abscess of Brain, and Epilepsy. Ann Surg. 1894 May;19(5):539-45.
  7. MARKS M, SPIEGEL-ADOLF M, SPIEGEL EA. Effect of cerebral concussion upon chemically induced convulsions. Fed Proc. 1947;6(1 Pt 2):231.
  8. WYCIS HT, MARKS M, SPIEGEL EA. Effect of cerebral concussion upon the threshold of electrically induced convulsions. Fed Proc. 1947;6(1 Pt 2):163.
  9. MANN LB Jr. Posttraumatic epilepsy; report of a case with a 24 year interval between injury and the onset of seizures. Bull Los Angel Neuro Soc. 1949 Sep;14(3):187-9.
  10. PENFIELD W, LIVINGSTON S. Birth injury, focal epilepsy and cortical excision; case report.Pediatrics. 1949 Aug;4(2):157-62.
  11. NIELSEN JM, COURVILLE CB. Role of birth injury and asphyxia in idiopathic epilepsy. Neurology. 1951 Jan-Feb;1(1):48-52.
  12. RUSSELL WR, WHITTY CW. Studies in traumatic epilepsy. II. Focal motor and somatic sensory fits: a study of 85 cases.J Neurol Neurosurg Psychiatry. 1953 May;16(2):73-97.
  13. JENNETT WB. Late epilepsy after blunt head injuries: a clinical study based on 282 cases of traumatic epilepsy. Ann R Coll Surg Engl. 1961 Dec;29:370-84.
  14. Annegers JF, Grabow JD, Groover RV, Laws ER Jr, Elveback LR, Kurland LT. Seizures after head trauma: a population study. Neurology. 1980 Jul;30(7 Pt 1):683-9.
  15. Bazarian JJ, Cernak I, Noble-Haeusslein L, Potolicchio S, Temkin N. Long-term neurologic outcomes after traumatic brain injury.J Head Trauma Rehabil. 2009 Nov-Dec;24(6):439-51.
  16. Diaz-Arrastia R, Agostini MA, Madden CJ, Van Ness PC. Posttraumatic epilepsy: the endophenotypes of a human model of epileptogenesis. Epilepsia. 2009 Feb;50 Suppl 2:14-20.
  17. Meehan W 3rd, Mannix R, Zafonte R, Pascual-Leone A. Chronic traumatic encephalopathy and athletes.Neurology. 2015 Oct 27;85(17):1504-11.
  18. Stein TD, Alvarez VE, McKee AC. Concussion in Chronic Traumatic Encephalopathy.Curr Pain Headache Rep. 2015 Oct;19(10):47.
  19. Collins MW, Lovell M, Iverson G, Cantu R, Maroon J, Field M. Cumulative effects of concussion in high school athletes. Neurosurgery. 2002;51(5):1175–1179.
  20. Schatz P, Moser RS, Covassin T, Karpf R. Early indicators of enduring symptoms in high school athletes with multiple previous concussions. Neurosurgery. 2011;68(6):1562–1567.
  21. Covassin T, Stearne D, Elbin R. Concussion history and postconcussion neurocognitive performance and symptoms in collegiate athletes. Journal of Athletic Training. 2008;43(2):119–124.
  22. Elbin RJ, Covassin T, Hakun J, Kontos AP, Berger K, Pfeiffer K, Ravizza S. Do brain activation changes persist in athletes with a history of multiple concussions who are asymptomatic. Brain Injury. 2012;26(10):1217–1225.
  23. Huh JW, Widing AG, Raghupathi R. Basic science; repetitive mild noncontusive brain trauma in immature rats exacerbates traumatic axonal injury and axonal calpain activation: A preliminary report. Journal of Neurotrauma. 2007;24(1):15–27.
  24. Friess SH, Ichord RN, Ralston J, Ryall K, Helfaer MA, Smith C, Margulies SS. Repeated traumatic brain injury affects composite cognitive function in piglets. Journal of Neurotrauma. 2009;26(7):1111–1121.
  25. O’Connell MT, Seal A, Nortje J, Al-Rawi PG, Coles JP, Fryer TD, Menon DK, Pickard JD, Hutchinson PJ. Glucose metabolism in traumatic brain injury: A combined microdialysis and [18F]-2-fluoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET) study. Acta Neurochirurgica Supplement. 2005;95:165–168.
  26. Prins ML, Alexander D, Giza CC, Hovda DA. Repeated mild traumatic brain injury: Mechanisms of cerebral vulnerability. Journal of Neurotrauma. 2013;30(1):30–38.
  27. Barkhoudarian G, Hovda DA, Giza CC. The molecular pathophysiology of concussive brain injury. Clinics in Sports Medicine. 2011;30(1):33–48.
  28. Reeves TM, Phillips LL, Povlishock JT. Myelinated and unmyelinated axons of the corpus callosum differ in vulnerability and functional recovery following traumatic brain injury. Experimental Neurology. 2005;196(1):126–137.
  29. Shrey DW, Griesbach GS, Giza CC. The pathophysiology of concussions in youth. Physical Medicine and Rehabilitation Clinics of North America. 2011;22(4):577–602.
  30. Hammer, edited by Stephen J. McPhee, Gary D. (2010). “7”. Pathophysiology of disease : an introduction to clinical medicine (6th ed.). New York: McGraw-Hill Medical.
  31. Goldberg, EM; Coulter, DA (May 2013). “Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction.”. Nature reviews. Neuroscience 14 (5): 337–49.
  32. Coulter DA, Eid T. Astrocytic regulation of glutamate homeostasis in epilepsy. Glia. 2012 Aug;60(8):1215-26.
  33. Eid T, Williamson A, Lee TS, Petroff OA, de Lanerolle NC. Glutamate and astrocytes–key players in human mesial temporal lobe epilepsy? 2008; 49 Suppl 2():42-52.
  34. de Lanerolle NC, Kim JH, Williamson A, Spencer SS, Zaveri HP, Eid T, Spencer DD. A retrospective analysis of hippocampal pathology in human temporal lobe epilepsy: evidence for distinctive patient subcategories. 2003 May; 44(5):677-87.
  35. Gloor P. Mesial temporal sclerosis: Historical background and an overview from a modern perspective. In: Luders H, editor. Epilepsy Surgery. New York: Raven Press; 1991. pp. 689–703.
  36. Stafstrom C, Vining EPG, Rho JM. Ketogenic diet. In: Engel J, Pedley TA, editors. Epilepsy: a comprehensive textbook. Lippincott Williams & Wilkins; 2007. pp. 1377–1386.
  37. Leino RL, Gerhart DZ, Duelli R, Enerson BE, Drewes LR. Diet-induced ketosis increases monocarboxylate transporter (MCT1) levels in rat brain. Neurochem Int. 2001 May; 38(6):519-27.
  38. Bough K. Energy metabolism as part of the anticonvulsant mechanism of the ketogenic diet. 2008 Nov; 49 Suppl 8():91-3.
  39. Yudkoff M, Daikhin Y, Nissim I, Lazarow A, Nissim I. Ketogenic diet, brain glutamate metabolism and seizure control. Prostaglandins Leukot Essent Fatty Acids. 2004 Mar; 70(3):277-85.
  40. Ortinski PI, Dong J, Mungenast A, Yue C, Takano H, Watson DJ, Haydon PG, Coulter DA. Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat Neurosci. 2010 May; 13(5):584-91.
  41. Robel S, Buckingham SC, Boni JL, Campbell SL, Danbolt NC, Riedemann T, Sutor B, Sontheimer H. Reactive astrogliosis causes the development of spontaneous seizures. J Neurosci. 2015 Feb 25;35(8):3330-45.
  42. Robel S, Sontheimer H. Glia as drivers of abnormal neuronal activity.Nat Neurosci. 2016 Jan;19(1):28-33. doi: 10.1038/nn.4184.
  43. Pandolfo, M. (Nov 2011). “Genetics of epilepsy.”. Semin Neurol 31 (5): 506–18.
  44. BlomS,HeijbelJ,BergforsPG.Incidenceofepilepsyinchildren:afollow-up study three years after the first seizure. Epilepsia. 1978;19(4):343–350.
  45. Cowan LD, Bodensteiner JB, Leviton A, et al. Prevalence of the epilepsies in children and adolescents. Epilepsia. 1989;30(1):94–106.
  46. Camfield CS, Camfield PR, Gordon K, et al. Incidence of epilepsy in childhood and adolescence: a population-based study in Nova Scotia from 1977 to 1985. Epilepsia. 1996;37(1):19–23.
  47. Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984. Epilepsia. 1993;34(3):453–468.
  48. Olafsson E, Ludvigsson P, Gudmundsson G, et al. Incidence of unprovoked seizures and epilepsy in Iceland and assessment of the epilepsy syndrome classification: a prospective study. Lancet Neurol. 2005;4(10):627–634.

 

Welcome to a new Medicine site

Translate »