J Neurol (2014) 261:283–290 DOI 10.1007/s00415-013-7185-7
ORIGINAL COMMUNICATION
Can lesions to the motor cortex induce amyotrophic lateral sclerosis? Angela Rosenbohm • Jan Kassubek • Patrick Weydt • Nicolai Marroquin • Alexander E. Volk • Christian Kubisch • Hans-Ju¨rgen Huppertz • Markus Weber • Peter M. Andersen • Jochen H. Weishaupt • Albert C. Ludolph The ALS Schwaben Register Group
•
Received: 2 September 2013 / Revised: 5 November 2013 / Accepted: 5 November 2013 / Published online: 20 November 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract A recent staging effort for amyotrophic lateral sclerosis (ALS) has demonstrated that the TDP-43 neuropathology may initiate focally in the motor cortex in the majority of patients. We searched our data bank for patients with lesions of the motor cortex which preceded disease onset. We performed a search of our patient- and MRI-data bank and screened 1,835 patients with amyotrophic lateral sclerosis for frontal lobe/motor cortex lesions. We found 18 patients with definite ALS who had documented and defined lesions of the motor cortex, which preceded the initial ALS symptoms by 8–42 years. In the vast majority (15/18) of the patients, the onset of ALS was closely related to the focal lesion since it started in a body region reflecting the damaged cortical area. The findings suggest that initial lesions to the motor cortex may be a contributing initiating factor in some patients with ALS or
A. Rosenbohm J. Kassubek P. Weydt P. M. Andersen J. H. Weishaupt A. C. Ludolph (&) Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany e-mail: [email protected] N. Marroquin A. E. Volk C. Kubisch Institute of Human Genetics, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany H.-J. Huppertz Swiss Epilepsy Centre, Zu¨rich, Switzerland M. Weber Muskelzentrum/ALS Clinic, Kantonsspital St. Gallen, Greithstraße 20, 9007 St. Gallen, Switzerland P. M. Andersen Department of Clinical Neuroscience, Umea˚ University, Umea˚, Sweden
determine the site of onset in individuals pre-disposed to ALS. Keywords Frontal lobe lesions Motor cortex lesions Amyotrophic lateral sclerosis Motor neuron disease
Introduction A remarkable clinical feature of the majority of patients with amyotrophic lateral sclerosis (ALS) is focal onset in one or more myotomes with successive propagation to adjacent muscle groups, eventually encompassing most skeletal myotomes of the body [1–3]. This implies that the clinical progression may be complementary to the pathological process as described by Braak et al. [4–6] for Parkinson’s and Alzheimer’s diseases––a continuous disease process that systematically affects neuronal populations and may be described formally in preclinical and clinical stages. Furthermore, experimental evidence in vitro suggests that the pathogenesis of sporadic and familial ALS may be explained by a ‘‘multiple hit’’ scenario [7, 8]. The wide range of ages of onset of ALS in individuals carrying the same mutation (20–94 years for patients with the D90A SOD1 mutation [9]) and the frequent occurrence of reduced disease penetrance for mutations in carriers for some of the most common ALS genes C9ORF72, SOD1, FUS/TLS, TDP43 are factors suggesting that non-genetic exogenous or endogenous environmental factors play a role in ALS [10]. Yet, the only widely accepted non-genetic risk factors for sporadic ALS are increasing age and male gender [11]. Of note, in a case–control study ALS patients reported more
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frequently than controls to have experienced head injuries consistent with a meta-analysis of previous studies. No correlation was found to injuries of other parts of the body [12]. Lesions of the motor system including the frontotemporal lobes which often show early deficits that in some patients seem to precede the motor decline [13] may thus be a predisposing factor for ALS. On the basis of the results of staging efforts for ALS, we hypothesized that focal brain lesions may in some patients trigger the spread of ALS [14] and this can be documented by histories of individual patients, lesions visible in MRI, and a complementary clinical disease course. To test this hypothesis, we systematically searched our MRI bank for frontotemporal lesions in ALS patients. We present 18 patients who developed sporadic ALS following frontotemporal cerebral lesions, of which the majority displayed lesions of the motor cortex contralateral to the site of symptomatic ALS disease onset.
Methods We performed a retrospective chart review of patients presenting to the ALS outpatient clinic at the Department of Neurology, University of Ulm, Germany and the regional ALS register (‘ALS Register Schwaben’) between 2007 and 2012. In total, N = 855 patients who had presented to the outpatient clinic at Ulm University were screened. Additionally, all patients recruited in the ALS Register Schwaben since October 2008 were screened for MRI-positive cerebral lesions (N = 550). Another 430 patients were screened in the Kantonsspital St. Gallen, Switzerland; these individuals had presented there between 2002 and 2012. All screened patients had received an MRI of the brain, neurophysiology and clinical examination for the diagnosis of ALS and primary lateral sclerosis (PLS), respectively, by an experienced neurologist, and diagnostic confirmation had been obtained according to the revised El Escorial criteria. In order to be included in the study, the patient’s MRI had to show a well defined frontotemporal cerebral lesion on MRI/CT. The interval between lesion and motor neuron disease was defined as the latency between the first clinical symptom of a lesion (e.g. paresis, epileptic seizure) and first paresis as a symptom of MND. In some cases, an interval could not be defined as indicated in (Table 1). Out of 18 cases with brain lesions who were retrospectively identified by the screening procedures, 15 patients showed hemispheric frontal/temporal lesions contralateral to the first symptoms of ALS, while the remaining three patients had an ipsilateral lesion of the frontal cortex.
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Additional morphometric analysis In order to test the hypothesis that abnormalities in frontal cortical areas are frequent in ALS, the 3D MRI data of a sample of 200 ALS patients with definite or probable ALS from the MRI data bank of the Department of Neurology, University of Ulm were subjected to morphometric MRI analysis, a voxel-based image processing method comparing individual brain anatomy with a normal database. Each T1-weighted MRI volume data set was normalized, simultaneously bias corrected for intensity inhomogenities, and segmented in different tissue compartments (statistical parametric mapping software (SPM5); http://www.fil.ion. ucl.ac.uk/spm). The distribution of grey and white matter was analyzed on a voxel-wise basis and compared with a normal data base of MRIs of healthy controls. This data base, which has already been described elsewhere [15], consists of 150 controls (70 female, 80 male, age range 15–77 years) with MRIs acquired on five different MRI scanners and are found to be free of structural abnormalities. Based on this analysis, three new feature maps (i.e. z score maps) were created in which brain structures which deviate from the normal database going along with higher z scores, thereby highlighting cortical abnormalities, as described in detail elsewhere [16]. By highlighting suspicious cortical regions, the results of this Morphometric Analysis Program (MAP) can guide a second look at the MRI and thereby increase the sensitivity of MRI evaluation [17].
Results Eighteen patients matched our criteria, fourteen presented with ALS and four patients presented initially with primary lateral sclerosis (PLS). The mean age at presentation was 58 years (range 28–85 years). The latency to develop motor neuron disease in those patients with clinically symptomatic brain lesions ranged between 8 and 42 years with a mean interval of 17.6 years. Fourteen of the 18 patients had limb and two had bulbar onset, while in two patients it was uncertain whether the initial symptoms were bulbar or spinal. The spreading patterns of motor symptoms are summarized in (Table 1). A formal neuropsychological examination was only done in patients who presented frontal signs on clinical examination. This was the case only in one patient (No. 7) who then received a neuropsychological test, suggesting ALS-FTD, with FTD features being relatively stable in the further disease course compared to motor decline. None of the other patients had clinically apparent frontal deficits. Also, none of the patients reported a family history for ALS or frontotemporal dementia. Genetic testing of the
M/28
F/40
M/56
M/36
M/66
F/68
F/76
F/32
M/38
M/61
M/75
F/70
M/35
M/85
M/81
F/69
M/46
F/56
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
PLS
ALS
ALS
ALS
ALS
ALS
ALS
ALS
ALS
ALS
ALS
ALS-FTD
ALS
ALS
PLS
PLS
PLS
ALS
MND
White matter lesion (contusion?)
AVM
Ischemia MCA
Meningioma
Infarction ACA
White matter lesion (contusion?) frontopolar
Meningioma frontobasal, infarction left PICA
Ischemia: MCA bilaterally, left PCA
White matter lesion (contusion?)
AVM
AVM
Cavernoma
Astrocytoma
TBI: contusion and hemorrhage
Perinatal Ischemia
TBI: frontal contusion
TBI: bilateral contusion
AVM
Brain lesion
Right centromedial region
Gyrus cinguli
Frontotemporal
Left frontal region
Frontal
Frontopolar
Frontobasal midline
Bilateral
Frontopolar
Central region
Frontal lobe
Frontal lobe
Gyrus frontalis superior
Parietotemporal region
Anterior capsula interna and basal ganglia
Frontal region
Central region
Gyrus frontalis
Site of brain lesion
Right
Left
Right
Left
Right
Right
Midline ? left
Bilateral
Left
Left
Left
Right
Right
Right
Left
Right leg/1 ? 2
Left leg/1
Right leg/2 ? 1
Right arm/1 ? 2
Bulbar/2
Left arm/2
Bulbar/1 ? 2
Left arm/2 ? 1
Right arm/2 ? 1
Right leg/1 ? 2
Right arm/1 ? 2
Bulbar/2 and left arm/1 ? 2
Bulbar/1 ? 2 and left arm/1
Left arm/2
Right leg/1 ? 2
Right leg/1 ? 2
Left leg/1
Right [ left Left
Right arm/1
Onset paresis of MND
Left
Lesion hemisphere
For the calculation of the latency, first symptoms or first detection in MRI of the underlying pathology was taken into account
Gender/age (in years) of ALS onset
Case no.
Arm ipsilateral/1 ? 2
Leg contra-lateral/2 ? 1, arm ipsilateral/1 ? 2
Leg contralateral/1 ? 2
Trunk, arm contralateral/2 ? 1
Arm bilateral/1 ? 2, leg bilateral/1 ? 2
Arm contralateral/2, legs/2 ? 1
Arm right/1 ? 2
Arm contralateral/2 ? 1, leg bilatera/2, bulbar/ 2
Arm contralateral/2 ? 1, leg bilateral/2
Arm ipsilateral/1 ? 2, leg contralateral/2 ? 1, arm contralateral/1 ? 2, bulbar/2
Bulbar/2, leg ipsilateral/1 ? 2, arm contralateral/2 ? 1, leg contralateral/1 ? 2
Arm contralateral/1 ? 2
Arm contralateral/1 ? 2
Leg ipsilateral/2 ? 1
Arm ipsilateral/1, arm contralateral/1, bulbar/2
Leg contralateral/1
Arm ipsilateral/1, leg contralateral/1 ? 2
Leg ipsilateral/1, bulbar/2, arm contralateral/ 1 ? 2, leg contralateral/2 ? 1
Spreading pattern
nd
14
42
nd
nd
nd
nd
8
nd
11
14
[9
nd
13
35
13
12
14
Interval between lesion and MND (years)
Table 1 Clinical/historical details of patients with hemispherical cerebral lesions, upper motor neuron (UMN) = 1, lower motor neuron (LMN) = 2, nd not determined
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GGGGCC-repeat expansion of C9ORF72 and the coding regions of TARDBP (TDP-43), SOD1, and FUS/TLS was performed with negative results in nine patients. In patients 4, 5, 6, 9, 10, 12, 13, 17 and 18, however, genetic testing could not be performed as either they did not consent to genetic testing or DNA was not available for patients who had already died. Out of the 18 patients, three patients had a history of cerebral contusions, four had an arteriovenous malformation, one a frontal astrocytoma, one perinatal ischemia, three frontal/frontotemporal infarctions, two meningioma, and one a frontal cavernoma (Table 1; Fig. 1). Three patients had a frontal white matter lesion resembling contusion but no overt history of traumatic brain injury. Eight patients showed left-hemispheric, seven patients righthemispheric lesions, one patient had predominantly rightsided bilateral lesions, one patient showed a central lesion, and one patient bilateral infarctions. Interestingly, five of our patients (patients 1, 2, 8, 9, 16) showed evidence of cortical hyperexcitability clinically presenting with predominantly focal epileptic seizures. In the following, we present three representative histories. Patient 1 After an epileptic seizure at the age of 14, an AVM of the gyrus frontalis on the left side was diagnosed in this Swiss male. The seizures were treated with phenytoin and the AVM was embolised five times at the age of 14, 15, 19, 23 and 28 years because of relapsing paresis of the right hand. One month after the last embolisation, i.e. 14 years after the AVM had become symptomatic, the patient showed impairment of skilled finger movements and upper motor neuron signs in his right hand. The disease rapidly progressed to the right leg within a month and the patient was dependent on a walking aid 3 months later. Neurological examination revealed a right-sided brachially pronounced hemiparesis with brisk deep tendon reflexes and positive Babinski’s sign. The palmomental reflex was positive. The gait appeared spastic-ataxic, fasciculations were not visible during examination but were reported. Somatosensory signs were absent. Primary lateral sclerosis (PLS) was diagnosed. The disease progressed to both the thoracoabdominal muscles causing inability to rise from bed, and shortly later the bulbar region was affected. Pathological laughter, dysphagia and dysarthria occurred. One month later, the left arm was affected, another month later the left leg. The patient had bulbar palsy with dysphagia 8 months after symptom onset. After a disease duration of 18 months, electrophysiological examination revealed affection of the second motor neuron. Four months later, a percutaneous endoscopic gastrostomy (PEG) was considered but rejected
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Fig. 1 Representative slices of the brain magnetic resonance imaging (MRI) data in single cases, demonstrating the underlying lesions. All MRI are shown in radiological convention, i.e. the left side in the image represents the right side of the brain. a Transaxial T2-weighted (T2w) MRI of patient 2. The extensive postcontusional frontoparietal lesion is shown, spreading bilaterally over the pericentral areas with right-sided predominance, involving both cortical and subcortical areas. b Transaxial T2w MRI of patient 3. The large postcontusional lesions spread across frontal areas bilaterally with left-hemispheric predominance. Both cortical and subcortical areas are affected, with secondary enlargement of the anterior horn of the left lateral ventricle. c Transaxial fluid-attenuated inversion recovery (FLAIR) MRI of patient 4. A postischemic lesion, probably following perinatal ischemia, in the supply area of the left middle cerebral artery anterior is shown, with damage to the internal capsule and basal ganglia. The lesion has a cyst-like appearance with marked gliosis and a secondary enlargement of the anterior horn of the left lateral ventricle. d Transaxial T2w MRI of patient 5. The large postcontusional lesion is located cortically and subcortically in the right-sided parietal and temporal areas. The posterior horn of the right lateral ventricle is enlarged, and an additional subcortical microlesion is shown in the right-hemispheric periventricular white matter. e Transaxial FLAIR MRI of patient 6, showing the astrocytoma located in the frontal lobe, mainly involving the gyrus frontalis superior. f Transaxial T1-weighted (T1w) contrast-enhanced MRI of patient 7. Cavernoma in the right-sided frontal lobe is shown, including an associated deep venous anomaly and signs of prior intralesional bleeding
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by the patient. Another month later, the patient was admitted to the clinic because of aspiration pneumonia. The patient presented with dysarthrophonia, bulbar signs like tongue atrophy and fasciculations, tetraparesis with severe spasticity of the arms, atrophy of all extremities and brisk deep tendon reflexes. At this time, the patient chose physician-assisted suicide, after a disease duration of about 2 years at the age of 30 years. Autopsy revealed symmetric degeneration of the pyramidal tract. Skein-like inclusions and Lewy Body-like inclusions were visible in the nucleus hypoglossus and nucleus facialis. Furthermore, a reduction of the number of anterior horn cells in the cervical and thoracal spine was recognized. In the cervical area Bunina bodies and lumbar ubiquitin-positive intracytoplasmatic inclusions were detected. The autopsy findings confirmed the clinical diagnosis of ALS. No examination of TDP-43 or Tau pathology was done.
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leg muscles. At admission, the left leg was also affected, causing pronounced difficulty walking. The patient presented with a bilateral upper motor neuron syndrome with mild paraparesis. There was no paresis in the arms but brisk tendon reflexes bilaterally. Neurophysiology revealed absence of denervation and normal neurography. The patient was diagnosed with PLS. Morphometric analysis In our morphometric MRI analysis of the 200 ALS patients, we did not observe any cortical malformation. In none of these patients, focal cortical dysplasia or any other form of cortical malformation (e.g. polymicrogyria, subependymal or subcortical heterotopia) could be discovered (data not shown).
Discussion Patient 2 At the age of 12 years, the female patient fell head first down a 10 m cliff, resulting in an open-skull head injury with a cerebral contusion of the bilateral frontoparietal region with an initial hemiparesis on the left side. The left leg was most severely affected (Fig. 1a). This paresis resolved almost completely with physiotherapy. Twelve years later, the patient noticed increasing spasticity of the left leg. Fifteen years after the trauma, focal left-sided sensorimotor seizures occurred, successfully treated with carbamazepine and later with lamotrigine. Another 8, 9 and 13 years later, respectively frontal seizures re-occured, accompanied by a subsequent deterioration of spastic hemiparesis of the left leg and arm. In the meantime, the disease had progressed to the right leg. Electrophysiology showed normal neurography at the age of 40 years, electromyography revealed acute and chronic denervation on the cervical and lumbar level. Cerebrospinal fluid examination was normal. The diagnosis of ALS with predominant upper motor neuron involvement was given at the age of 40 years. Patient 3 Thirteen years before the first contact, the 56 year-old male patient fell from a ladder resulting in a severe head injury with predominantly left frontal brain damage (Fig. 1b). Initially the patient was comatose and had weakness of the right leg. The patient recovered completely from his deficits and worked successfully as an engineer. More than 12 years later, about half a year before admission, the patient first noticed that he constantly stumbled with his right leg, and weakness progressed to the more proximal
In this systematic retrospective chart review, we identified 18 patients between 30 and 85 years who developed MND after frontal contusions or other frontal intracranial lesions with a latency of 8–42 years. Fourteen patients developed ALS and four patients initially presented with PLS. The spreading pattern of symptoms in these patients was onset at one limb in 14 cases with spreading to the contralateral (n = 7) or ipsilateral upper/lower limb (n = 7), bulbar onset in four cases with spreading to the arms. Remarkably, the site of onset was contralateral to the lesion site in the vast majority (15/18; 83.3 %) of our cases. Several studies support the notion that head injuries may increase the risk of ALS [18] whereas other reports could not find such a relation [19]. We saw this study as a ‘‘proof of principle’’ observational study, and we, therefore, did not intend to obtain epidemiological data. Since recollection bias might occur in retrospectively obtained data, we limited our study to patients with clear-cut morphological evidence of injury to frontotemporal brain structures. Based on the interpretation that ALS is an initial focal disease which spreads secondarily [3], our observations support the view that a spreading of neuropathology starting in the frontal cortex might also occur in ALS according to the pathological studies of Brettschneider et al. [14]. From the neuropathological point of view, a single traumatic brain injury can lead to ongoing white matter degradation via initial inflammatory pathology even many years after the trauma [20, 21]. Although 18/1,835 patients seem to be a small subgroup from the epidemiological point of view, the findings of mostly contralateral clinical spreading initiation may point to a focal central nervous onset and support an initiation of the degenerative process in the damaged brain region.
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In order to test the additional hypothesis that abnormalities in frontal cortical areas may be frequent in ALS, the 3D MRI data of a sample of 200 ALS patients were subjected to computer-based morphometric MRI analysis, but not a single case of any form of cortical malformation could be identified so that we rejected the hypothesis that frontal cortical malformations might serve as a cofactor. However, epidemiological data for the incidence of head injuries clearly demonstrate that this ‘‘hit’’ alone does not lead frequently to ALS. There must be additional genetic and non-genetic susceptibility factors to explain ALS (‘‘multiple hits’’). Although additional, yet unknown, genetic modifiers may exist, we looked for possible ‘‘second hits’’ by testing for the most common genes involved in the etiology of ALS but did not find any mutation in the C9ORF72, SOD1, FUS and TDP-43 genes. It is known that neuronal injury results in cytoskeletal alterations. TDP-43 serves as a mediator for the cytoskeletal changes observed after neuronal lesions [22–24]. Thus, one of the explanations for the co-occurrence of preceding cerebral lesion and ALS may be cytoskeletal changes as the consequence of the cerebral lesion. There is also evidence for a TDP-43-positive proteinopathy in chronic traumatic encephalopathy sometimes associated with motor neuron disease [25]. Remarkably, five of our patients (patients 1, 2, 8, 9 and 16) showed cortical hyperexcitability as these patients presented with focal sensorimotor seizures in the brain region representing the limb where, later, the first ALS symptoms began. Such cortical hyperexcitability could be induced by downregulation of inhibitory neurotransmitters like GABA and glycine [26], analogous to rare forms of epilepsy caused by an impairment/mutation of the inhibitory glycine pathways [27, 28]. Therefore, although highly speculative at this point, it is a testable hypothesis that our patients develop MND since primary cortical inhibition fails because of loss or dysfunction of inhibitory GABAergic neurons and/or glycine, as supported by a dysbalance of the cortical the GABAergic system reported earlier in ALS patients [29–31]. Taken together, this observational study provides a rationale to experimentally test the hypothesis that focal frontal lesions may (1) trigger pathogenic processes leading to ALS in possibly pre-disposed individuals and (2) determine the site of onset in ALS patients. Cortical frontal lesions could thereby serve as one ‘‘hit’’ in addition to other, genetic and non-genetic factors contributing to the etiology and pathogenesis of ALS. Acknowledgments This study was supported by the German Research Council (Deutsche Forschungsgemeinschaft, DFG Grant Number LU 336/15-1) and the German Network of ALS (BMBF 01GM1103A).
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J Neurol (2014) 261:283–290 Conflicts of interest of interest.
The authors declare that they have no conflict
Ethical standards All persons gave their informed consent prior to their inclusion in the ALS Schwaben register. The ALS Schwaben Register was approved by the local ethics committee of the University of Ulm (No. 11/10).
ALS Schwaben Register Group Adam T, Praxis EMSA Singen Arnold G, Klinikum Sindelfingen-Bo¨blingen, Department of Neurology Baier H, ZFP Su¨dwu¨rttemberg, Department of Epileptology Ba¨zner H, Bu¨rgerhospital Stuttgart, Department of Neurology Beattie J, Ostalb-Klinikum Aalen, Department of Neurology Behne F, ZFP Su¨dwu¨rttemberg, Department of Epileptology Bengel D, Oberschwabenklinik Ravensburg, Department of Neurology Bluthardt M, Department of Neurology, Ludwigsburg Bo¨rtlein A, Bu¨rgerhospital Stuttgart, Department of Neurology Dettmers C, Schmieder Kliniken Konstanz Eppinger B, Klinikum am Gesundbrunnen Heilbronn, Department of Neurology Gold H-J, Klinikum am Gesundbrunnen Heilbronn, Department of Neurology Hecht M, Bezirkskrankenhaus Kaufbeuren, Department of Neurology Heimbach B, University of Freiburg, Department of Neurology Hendrich C, Klinikum Friedrichshafen, Department of Neurology Herting B, Diakonie-Klinikum Schwa¨bisch Hall, Department of Neurology Huber R, Klinikum Friedrichshafen, Department of Neurology Hu¨lser P-J, Fachklinik Wangen, Department of Neurology Kaendler S, Kliniken Landkreis Heidenheim, Department of Neurology Kaspar A, Oberschwabenklinik Ravensburg, Department of Neurology Kimmig H., Kliniken Schwenningen, Department of Neurology Klo¨tzsch C, Schmieder Kliniken Allensbach, Bodensee Klinikum Hegau Konstanz
J Neurol (2014) 261:283–290
Ku¨hne J, Schmieder Kliniken Allensbach, Bodensee Klinikum Hegau Konstanz Lewis D, Marienhospital Stuttgart, Department of Neurology Lichy C, Klinikum Memmingen, Department of Neurology Lindner A, Marienhospital Stuttgart, Department of Neurology Lorenzl S, LMU Mu¨nchen, Department of Neurology Lutz-Schuhbauer S, Department of Neurology, Dietenbronn Ma¨urer M, Caritas Krankenhaus, Bad Mergentheim, Department of Neurology Meinck H M, University of Heidelberg, Department of Neurology Meudt O, Klinikum Memmingen, Department of Neurology Mu¨ller vom Hagen J, Universita¨tsklinikum Tu¨bingen, Department of Neurology Na¨gele A, Christophsbad Go¨ppingen, Department of Neurology Naumann M, Klinikum Augsburg, Department of Neurology und Neurophysiologie Neher K-D, Vinzenz von Paul Hospital, Rottweil, Department of Neurology Neuhaus O, Kliniken Landkreis Sigmaringen, Department of Neurology Neusch C, Praxis EMSA Singen Niehaus L, Department of Neurology, Winnenden Patzner M, Fachklinik Wangen, Department of Neurology Peters J, Ostalb-Klinikum Aalen, Department of Neurology Poerschke Y, Bundeswehrkrankenhaus Ulm, Department of Neurology Raape J, ZFP Su¨dwu¨rttemberg, Neurologie Weissenau Ratzka P, Klinikum Augsburg, Department of Neurology und Neurophysiologie Reeh A, Kliniken Landkreis Heidenheim, Department of Neurology Rettenmayr C, Klinikum Esslingen, Department of Neurology Rothmeier J, ZFP Su¨dwu¨rttemberg, Neurologie Weissenau Sabolek M, Department of Neurology, Dietenbronn Schabet M, Department of Neurology, Ludwigsburg Scha¨ff-Vogelsang M, Diakonie-Klinikum Schwa¨bisch Hall, Department of Neurology Scho¨ls L, Universita¨tsklinikum Tu¨bingen, Department of Neurology Schweigert B, Caritas Krankenhaus, Bad Mergentheim, Department of Neurology
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Sommer N, Christophsbad Go¨ppingen, Department of Neurology Sperber W, Kliniken Esslingen, Department of Neurology Stroick M, Klinikum Memmingen, Department of Neurology Trottenberg T, Department of Neurology, Winnenden Weber F, Bundeswehrkrankenhaus Ulm, Department of Neurology Wessig C, University of Wu¨rzburg, Department of Neurology Will H-G, Kliniken Schwenningen, Department of Neurology Winkler A, TU Mu¨nchen, Department of Neurology
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23. Wu CH, Fallini C, Ticozzi N et al (2012) Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488(7412):499–503 24. Ingre C, Landers JE, Rizik N, Volk AE, Akimoto C, Birve A, Hu¨bers A, Keagle PJ, Piotrowska K, Press R, Andersen PM, Ludolph AC, Weishaupt JH (2013) A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic, and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts. Neurobiol Aging 34:1708.e1–1708.e7 25. McKee AC, Gavett BE, Stern RA et al (2010) TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J Neuropathol Exp Neurol 69(9):918–929 26. Kiernan MC, Petri S (2012) Hyperexcitability and amyotrophic lateral sclerosis. Neurology 78:1544–1545 27. Bohme I, Luddens H (2001) The inhibitory neural circuitry as target of antiepileptic drugs. Curr Med Chem 8:1257–1274 28. Harvey RJ, Carta E, Pearce BR et al (2008) A critical role for glycine transporters in hyperexcitability disorders. Front Mol Neurosci 1:1 29. Carunchio I, Mollinari C, Pieri M, Merlo D, Zona C (2008) GAB(A) receptors present higher affinity and modified subunit composition in spinal motor neurons from a genetic model of amyotrophic lateral sclerosis. Eur J Neurosci 28:1275–1285 30. Lorenzo LE, Barbe A, Portalier P, Fritschy JM, Bras H (2006) Differential expression of GABAA and glycine receptors in ALSresistant vs. ALS-vulnerable motoneurons: possible implications for selective vulnerability of motoneurons. Eur J Neurosci 23:3161–3170 31. Sasabe J, Aiso S (2010) Aberrant control of motoneuronal excitability in amyotrophic lateral sclerosis: excitatory glutamate/ D-serine versus inhibitory glycine/gamma-aminobutanoic acid (GABA). Chem Biodivers 7:1479–1490
ORIGINAL COMMUNICATION
Can lesions to the motor cortex induce amyotrophic lateral sclerosis? Angela Rosenbohm • Jan Kassubek • Patrick Weydt • Nicolai Marroquin • Alexander E. Volk • Christian Kubisch • Hans-Ju¨rgen Huppertz • Markus Weber • Peter M. Andersen • Jochen H. Weishaupt • Albert C. Ludolph The ALS Schwaben Register Group
•
Received: 2 September 2013 / Revised: 5 November 2013 / Accepted: 5 November 2013 / Published online: 20 November 2013 Ó Springer-Verlag Berlin Heidelberg 2013
Abstract A recent staging effort for amyotrophic lateral sclerosis (ALS) has demonstrated that the TDP-43 neuropathology may initiate focally in the motor cortex in the majority of patients. We searched our data bank for patients with lesions of the motor cortex which preceded disease onset. We performed a search of our patient- and MRI-data bank and screened 1,835 patients with amyotrophic lateral sclerosis for frontal lobe/motor cortex lesions. We found 18 patients with definite ALS who had documented and defined lesions of the motor cortex, which preceded the initial ALS symptoms by 8–42 years. In the vast majority (15/18) of the patients, the onset of ALS was closely related to the focal lesion since it started in a body region reflecting the damaged cortical area. The findings suggest that initial lesions to the motor cortex may be a contributing initiating factor in some patients with ALS or
A. Rosenbohm J. Kassubek P. Weydt P. M. Andersen J. H. Weishaupt A. C. Ludolph (&) Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany e-mail: [email protected] N. Marroquin A. E. Volk C. Kubisch Institute of Human Genetics, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany H.-J. Huppertz Swiss Epilepsy Centre, Zu¨rich, Switzerland M. Weber Muskelzentrum/ALS Clinic, Kantonsspital St. Gallen, Greithstraße 20, 9007 St. Gallen, Switzerland P. M. Andersen Department of Clinical Neuroscience, Umea˚ University, Umea˚, Sweden
determine the site of onset in individuals pre-disposed to ALS. Keywords Frontal lobe lesions Motor cortex lesions Amyotrophic lateral sclerosis Motor neuron disease
Introduction A remarkable clinical feature of the majority of patients with amyotrophic lateral sclerosis (ALS) is focal onset in one or more myotomes with successive propagation to adjacent muscle groups, eventually encompassing most skeletal myotomes of the body [1–3]. This implies that the clinical progression may be complementary to the pathological process as described by Braak et al. [4–6] for Parkinson’s and Alzheimer’s diseases––a continuous disease process that systematically affects neuronal populations and may be described formally in preclinical and clinical stages. Furthermore, experimental evidence in vitro suggests that the pathogenesis of sporadic and familial ALS may be explained by a ‘‘multiple hit’’ scenario [7, 8]. The wide range of ages of onset of ALS in individuals carrying the same mutation (20–94 years for patients with the D90A SOD1 mutation [9]) and the frequent occurrence of reduced disease penetrance for mutations in carriers for some of the most common ALS genes C9ORF72, SOD1, FUS/TLS, TDP43 are factors suggesting that non-genetic exogenous or endogenous environmental factors play a role in ALS [10]. Yet, the only widely accepted non-genetic risk factors for sporadic ALS are increasing age and male gender [11]. Of note, in a case–control study ALS patients reported more
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frequently than controls to have experienced head injuries consistent with a meta-analysis of previous studies. No correlation was found to injuries of other parts of the body [12]. Lesions of the motor system including the frontotemporal lobes which often show early deficits that in some patients seem to precede the motor decline [13] may thus be a predisposing factor for ALS. On the basis of the results of staging efforts for ALS, we hypothesized that focal brain lesions may in some patients trigger the spread of ALS [14] and this can be documented by histories of individual patients, lesions visible in MRI, and a complementary clinical disease course. To test this hypothesis, we systematically searched our MRI bank for frontotemporal lesions in ALS patients. We present 18 patients who developed sporadic ALS following frontotemporal cerebral lesions, of which the majority displayed lesions of the motor cortex contralateral to the site of symptomatic ALS disease onset.
Methods We performed a retrospective chart review of patients presenting to the ALS outpatient clinic at the Department of Neurology, University of Ulm, Germany and the regional ALS register (‘ALS Register Schwaben’) between 2007 and 2012. In total, N = 855 patients who had presented to the outpatient clinic at Ulm University were screened. Additionally, all patients recruited in the ALS Register Schwaben since October 2008 were screened for MRI-positive cerebral lesions (N = 550). Another 430 patients were screened in the Kantonsspital St. Gallen, Switzerland; these individuals had presented there between 2002 and 2012. All screened patients had received an MRI of the brain, neurophysiology and clinical examination for the diagnosis of ALS and primary lateral sclerosis (PLS), respectively, by an experienced neurologist, and diagnostic confirmation had been obtained according to the revised El Escorial criteria. In order to be included in the study, the patient’s MRI had to show a well defined frontotemporal cerebral lesion on MRI/CT. The interval between lesion and motor neuron disease was defined as the latency between the first clinical symptom of a lesion (e.g. paresis, epileptic seizure) and first paresis as a symptom of MND. In some cases, an interval could not be defined as indicated in (Table 1). Out of 18 cases with brain lesions who were retrospectively identified by the screening procedures, 15 patients showed hemispheric frontal/temporal lesions contralateral to the first symptoms of ALS, while the remaining three patients had an ipsilateral lesion of the frontal cortex.
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Additional morphometric analysis In order to test the hypothesis that abnormalities in frontal cortical areas are frequent in ALS, the 3D MRI data of a sample of 200 ALS patients with definite or probable ALS from the MRI data bank of the Department of Neurology, University of Ulm were subjected to morphometric MRI analysis, a voxel-based image processing method comparing individual brain anatomy with a normal database. Each T1-weighted MRI volume data set was normalized, simultaneously bias corrected for intensity inhomogenities, and segmented in different tissue compartments (statistical parametric mapping software (SPM5); http://www.fil.ion. ucl.ac.uk/spm). The distribution of grey and white matter was analyzed on a voxel-wise basis and compared with a normal data base of MRIs of healthy controls. This data base, which has already been described elsewhere [15], consists of 150 controls (70 female, 80 male, age range 15–77 years) with MRIs acquired on five different MRI scanners and are found to be free of structural abnormalities. Based on this analysis, three new feature maps (i.e. z score maps) were created in which brain structures which deviate from the normal database going along with higher z scores, thereby highlighting cortical abnormalities, as described in detail elsewhere [16]. By highlighting suspicious cortical regions, the results of this Morphometric Analysis Program (MAP) can guide a second look at the MRI and thereby increase the sensitivity of MRI evaluation [17].
Results Eighteen patients matched our criteria, fourteen presented with ALS and four patients presented initially with primary lateral sclerosis (PLS). The mean age at presentation was 58 years (range 28–85 years). The latency to develop motor neuron disease in those patients with clinically symptomatic brain lesions ranged between 8 and 42 years with a mean interval of 17.6 years. Fourteen of the 18 patients had limb and two had bulbar onset, while in two patients it was uncertain whether the initial symptoms were bulbar or spinal. The spreading patterns of motor symptoms are summarized in (Table 1). A formal neuropsychological examination was only done in patients who presented frontal signs on clinical examination. This was the case only in one patient (No. 7) who then received a neuropsychological test, suggesting ALS-FTD, with FTD features being relatively stable in the further disease course compared to motor decline. None of the other patients had clinically apparent frontal deficits. Also, none of the patients reported a family history for ALS or frontotemporal dementia. Genetic testing of the
M/28
F/40
M/56
M/36
M/66
F/68
F/76
F/32
M/38
M/61
M/75
F/70
M/35
M/85
M/81
F/69
M/46
F/56
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
PLS
ALS
ALS
ALS
ALS
ALS
ALS
ALS
ALS
ALS
ALS
ALS-FTD
ALS
ALS
PLS
PLS
PLS
ALS
MND
White matter lesion (contusion?)
AVM
Ischemia MCA
Meningioma
Infarction ACA
White matter lesion (contusion?) frontopolar
Meningioma frontobasal, infarction left PICA
Ischemia: MCA bilaterally, left PCA
White matter lesion (contusion?)
AVM
AVM
Cavernoma
Astrocytoma
TBI: contusion and hemorrhage
Perinatal Ischemia
TBI: frontal contusion
TBI: bilateral contusion
AVM
Brain lesion
Right centromedial region
Gyrus cinguli
Frontotemporal
Left frontal region
Frontal
Frontopolar
Frontobasal midline
Bilateral
Frontopolar
Central region
Frontal lobe
Frontal lobe
Gyrus frontalis superior
Parietotemporal region
Anterior capsula interna and basal ganglia
Frontal region
Central region
Gyrus frontalis
Site of brain lesion
Right
Left
Right
Left
Right
Right
Midline ? left
Bilateral
Left
Left
Left
Right
Right
Right
Left
Right leg/1 ? 2
Left leg/1
Right leg/2 ? 1
Right arm/1 ? 2
Bulbar/2
Left arm/2
Bulbar/1 ? 2
Left arm/2 ? 1
Right arm/2 ? 1
Right leg/1 ? 2
Right arm/1 ? 2
Bulbar/2 and left arm/1 ? 2
Bulbar/1 ? 2 and left arm/1
Left arm/2
Right leg/1 ? 2
Right leg/1 ? 2
Left leg/1
Right [ left Left
Right arm/1
Onset paresis of MND
Left
Lesion hemisphere
For the calculation of the latency, first symptoms or first detection in MRI of the underlying pathology was taken into account
Gender/age (in years) of ALS onset
Case no.
Arm ipsilateral/1 ? 2
Leg contra-lateral/2 ? 1, arm ipsilateral/1 ? 2
Leg contralateral/1 ? 2
Trunk, arm contralateral/2 ? 1
Arm bilateral/1 ? 2, leg bilateral/1 ? 2
Arm contralateral/2, legs/2 ? 1
Arm right/1 ? 2
Arm contralateral/2 ? 1, leg bilatera/2, bulbar/ 2
Arm contralateral/2 ? 1, leg bilateral/2
Arm ipsilateral/1 ? 2, leg contralateral/2 ? 1, arm contralateral/1 ? 2, bulbar/2
Bulbar/2, leg ipsilateral/1 ? 2, arm contralateral/2 ? 1, leg contralateral/1 ? 2
Arm contralateral/1 ? 2
Arm contralateral/1 ? 2
Leg ipsilateral/2 ? 1
Arm ipsilateral/1, arm contralateral/1, bulbar/2
Leg contralateral/1
Arm ipsilateral/1, leg contralateral/1 ? 2
Leg ipsilateral/1, bulbar/2, arm contralateral/ 1 ? 2, leg contralateral/2 ? 1
Spreading pattern
nd
14
42
nd
nd
nd
nd
8
nd
11
14
[9
nd
13
35
13
12
14
Interval between lesion and MND (years)
Table 1 Clinical/historical details of patients with hemispherical cerebral lesions, upper motor neuron (UMN) = 1, lower motor neuron (LMN) = 2, nd not determined
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GGGGCC-repeat expansion of C9ORF72 and the coding regions of TARDBP (TDP-43), SOD1, and FUS/TLS was performed with negative results in nine patients. In patients 4, 5, 6, 9, 10, 12, 13, 17 and 18, however, genetic testing could not be performed as either they did not consent to genetic testing or DNA was not available for patients who had already died. Out of the 18 patients, three patients had a history of cerebral contusions, four had an arteriovenous malformation, one a frontal astrocytoma, one perinatal ischemia, three frontal/frontotemporal infarctions, two meningioma, and one a frontal cavernoma (Table 1; Fig. 1). Three patients had a frontal white matter lesion resembling contusion but no overt history of traumatic brain injury. Eight patients showed left-hemispheric, seven patients righthemispheric lesions, one patient had predominantly rightsided bilateral lesions, one patient showed a central lesion, and one patient bilateral infarctions. Interestingly, five of our patients (patients 1, 2, 8, 9, 16) showed evidence of cortical hyperexcitability clinically presenting with predominantly focal epileptic seizures. In the following, we present three representative histories. Patient 1 After an epileptic seizure at the age of 14, an AVM of the gyrus frontalis on the left side was diagnosed in this Swiss male. The seizures were treated with phenytoin and the AVM was embolised five times at the age of 14, 15, 19, 23 and 28 years because of relapsing paresis of the right hand. One month after the last embolisation, i.e. 14 years after the AVM had become symptomatic, the patient showed impairment of skilled finger movements and upper motor neuron signs in his right hand. The disease rapidly progressed to the right leg within a month and the patient was dependent on a walking aid 3 months later. Neurological examination revealed a right-sided brachially pronounced hemiparesis with brisk deep tendon reflexes and positive Babinski’s sign. The palmomental reflex was positive. The gait appeared spastic-ataxic, fasciculations were not visible during examination but were reported. Somatosensory signs were absent. Primary lateral sclerosis (PLS) was diagnosed. The disease progressed to both the thoracoabdominal muscles causing inability to rise from bed, and shortly later the bulbar region was affected. Pathological laughter, dysphagia and dysarthria occurred. One month later, the left arm was affected, another month later the left leg. The patient had bulbar palsy with dysphagia 8 months after symptom onset. After a disease duration of 18 months, electrophysiological examination revealed affection of the second motor neuron. Four months later, a percutaneous endoscopic gastrostomy (PEG) was considered but rejected
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Fig. 1 Representative slices of the brain magnetic resonance imaging (MRI) data in single cases, demonstrating the underlying lesions. All MRI are shown in radiological convention, i.e. the left side in the image represents the right side of the brain. a Transaxial T2-weighted (T2w) MRI of patient 2. The extensive postcontusional frontoparietal lesion is shown, spreading bilaterally over the pericentral areas with right-sided predominance, involving both cortical and subcortical areas. b Transaxial T2w MRI of patient 3. The large postcontusional lesions spread across frontal areas bilaterally with left-hemispheric predominance. Both cortical and subcortical areas are affected, with secondary enlargement of the anterior horn of the left lateral ventricle. c Transaxial fluid-attenuated inversion recovery (FLAIR) MRI of patient 4. A postischemic lesion, probably following perinatal ischemia, in the supply area of the left middle cerebral artery anterior is shown, with damage to the internal capsule and basal ganglia. The lesion has a cyst-like appearance with marked gliosis and a secondary enlargement of the anterior horn of the left lateral ventricle. d Transaxial T2w MRI of patient 5. The large postcontusional lesion is located cortically and subcortically in the right-sided parietal and temporal areas. The posterior horn of the right lateral ventricle is enlarged, and an additional subcortical microlesion is shown in the right-hemispheric periventricular white matter. e Transaxial FLAIR MRI of patient 6, showing the astrocytoma located in the frontal lobe, mainly involving the gyrus frontalis superior. f Transaxial T1-weighted (T1w) contrast-enhanced MRI of patient 7. Cavernoma in the right-sided frontal lobe is shown, including an associated deep venous anomaly and signs of prior intralesional bleeding
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by the patient. Another month later, the patient was admitted to the clinic because of aspiration pneumonia. The patient presented with dysarthrophonia, bulbar signs like tongue atrophy and fasciculations, tetraparesis with severe spasticity of the arms, atrophy of all extremities and brisk deep tendon reflexes. At this time, the patient chose physician-assisted suicide, after a disease duration of about 2 years at the age of 30 years. Autopsy revealed symmetric degeneration of the pyramidal tract. Skein-like inclusions and Lewy Body-like inclusions were visible in the nucleus hypoglossus and nucleus facialis. Furthermore, a reduction of the number of anterior horn cells in the cervical and thoracal spine was recognized. In the cervical area Bunina bodies and lumbar ubiquitin-positive intracytoplasmatic inclusions were detected. The autopsy findings confirmed the clinical diagnosis of ALS. No examination of TDP-43 or Tau pathology was done.
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leg muscles. At admission, the left leg was also affected, causing pronounced difficulty walking. The patient presented with a bilateral upper motor neuron syndrome with mild paraparesis. There was no paresis in the arms but brisk tendon reflexes bilaterally. Neurophysiology revealed absence of denervation and normal neurography. The patient was diagnosed with PLS. Morphometric analysis In our morphometric MRI analysis of the 200 ALS patients, we did not observe any cortical malformation. In none of these patients, focal cortical dysplasia or any other form of cortical malformation (e.g. polymicrogyria, subependymal or subcortical heterotopia) could be discovered (data not shown).
Discussion Patient 2 At the age of 12 years, the female patient fell head first down a 10 m cliff, resulting in an open-skull head injury with a cerebral contusion of the bilateral frontoparietal region with an initial hemiparesis on the left side. The left leg was most severely affected (Fig. 1a). This paresis resolved almost completely with physiotherapy. Twelve years later, the patient noticed increasing spasticity of the left leg. Fifteen years after the trauma, focal left-sided sensorimotor seizures occurred, successfully treated with carbamazepine and later with lamotrigine. Another 8, 9 and 13 years later, respectively frontal seizures re-occured, accompanied by a subsequent deterioration of spastic hemiparesis of the left leg and arm. In the meantime, the disease had progressed to the right leg. Electrophysiology showed normal neurography at the age of 40 years, electromyography revealed acute and chronic denervation on the cervical and lumbar level. Cerebrospinal fluid examination was normal. The diagnosis of ALS with predominant upper motor neuron involvement was given at the age of 40 years. Patient 3 Thirteen years before the first contact, the 56 year-old male patient fell from a ladder resulting in a severe head injury with predominantly left frontal brain damage (Fig. 1b). Initially the patient was comatose and had weakness of the right leg. The patient recovered completely from his deficits and worked successfully as an engineer. More than 12 years later, about half a year before admission, the patient first noticed that he constantly stumbled with his right leg, and weakness progressed to the more proximal
In this systematic retrospective chart review, we identified 18 patients between 30 and 85 years who developed MND after frontal contusions or other frontal intracranial lesions with a latency of 8–42 years. Fourteen patients developed ALS and four patients initially presented with PLS. The spreading pattern of symptoms in these patients was onset at one limb in 14 cases with spreading to the contralateral (n = 7) or ipsilateral upper/lower limb (n = 7), bulbar onset in four cases with spreading to the arms. Remarkably, the site of onset was contralateral to the lesion site in the vast majority (15/18; 83.3 %) of our cases. Several studies support the notion that head injuries may increase the risk of ALS [18] whereas other reports could not find such a relation [19]. We saw this study as a ‘‘proof of principle’’ observational study, and we, therefore, did not intend to obtain epidemiological data. Since recollection bias might occur in retrospectively obtained data, we limited our study to patients with clear-cut morphological evidence of injury to frontotemporal brain structures. Based on the interpretation that ALS is an initial focal disease which spreads secondarily [3], our observations support the view that a spreading of neuropathology starting in the frontal cortex might also occur in ALS according to the pathological studies of Brettschneider et al. [14]. From the neuropathological point of view, a single traumatic brain injury can lead to ongoing white matter degradation via initial inflammatory pathology even many years after the trauma [20, 21]. Although 18/1,835 patients seem to be a small subgroup from the epidemiological point of view, the findings of mostly contralateral clinical spreading initiation may point to a focal central nervous onset and support an initiation of the degenerative process in the damaged brain region.
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In order to test the additional hypothesis that abnormalities in frontal cortical areas may be frequent in ALS, the 3D MRI data of a sample of 200 ALS patients were subjected to computer-based morphometric MRI analysis, but not a single case of any form of cortical malformation could be identified so that we rejected the hypothesis that frontal cortical malformations might serve as a cofactor. However, epidemiological data for the incidence of head injuries clearly demonstrate that this ‘‘hit’’ alone does not lead frequently to ALS. There must be additional genetic and non-genetic susceptibility factors to explain ALS (‘‘multiple hits’’). Although additional, yet unknown, genetic modifiers may exist, we looked for possible ‘‘second hits’’ by testing for the most common genes involved in the etiology of ALS but did not find any mutation in the C9ORF72, SOD1, FUS and TDP-43 genes. It is known that neuronal injury results in cytoskeletal alterations. TDP-43 serves as a mediator for the cytoskeletal changes observed after neuronal lesions [22–24]. Thus, one of the explanations for the co-occurrence of preceding cerebral lesion and ALS may be cytoskeletal changes as the consequence of the cerebral lesion. There is also evidence for a TDP-43-positive proteinopathy in chronic traumatic encephalopathy sometimes associated with motor neuron disease [25]. Remarkably, five of our patients (patients 1, 2, 8, 9 and 16) showed cortical hyperexcitability as these patients presented with focal sensorimotor seizures in the brain region representing the limb where, later, the first ALS symptoms began. Such cortical hyperexcitability could be induced by downregulation of inhibitory neurotransmitters like GABA and glycine [26], analogous to rare forms of epilepsy caused by an impairment/mutation of the inhibitory glycine pathways [27, 28]. Therefore, although highly speculative at this point, it is a testable hypothesis that our patients develop MND since primary cortical inhibition fails because of loss or dysfunction of inhibitory GABAergic neurons and/or glycine, as supported by a dysbalance of the cortical the GABAergic system reported earlier in ALS patients [29–31]. Taken together, this observational study provides a rationale to experimentally test the hypothesis that focal frontal lesions may (1) trigger pathogenic processes leading to ALS in possibly pre-disposed individuals and (2) determine the site of onset in ALS patients. Cortical frontal lesions could thereby serve as one ‘‘hit’’ in addition to other, genetic and non-genetic factors contributing to the etiology and pathogenesis of ALS. Acknowledgments This study was supported by the German Research Council (Deutsche Forschungsgemeinschaft, DFG Grant Number LU 336/15-1) and the German Network of ALS (BMBF 01GM1103A).
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J Neurol (2014) 261:283–290 Conflicts of interest of interest.
The authors declare that they have no conflict
Ethical standards All persons gave their informed consent prior to their inclusion in the ALS Schwaben register. The ALS Schwaben Register was approved by the local ethics committee of the University of Ulm (No. 11/10).
ALS Schwaben Register Group Adam T, Praxis EMSA Singen Arnold G, Klinikum Sindelfingen-Bo¨blingen, Department of Neurology Baier H, ZFP Su¨dwu¨rttemberg, Department of Epileptology Ba¨zner H, Bu¨rgerhospital Stuttgart, Department of Neurology Beattie J, Ostalb-Klinikum Aalen, Department of Neurology Behne F, ZFP Su¨dwu¨rttemberg, Department of Epileptology Bengel D, Oberschwabenklinik Ravensburg, Department of Neurology Bluthardt M, Department of Neurology, Ludwigsburg Bo¨rtlein A, Bu¨rgerhospital Stuttgart, Department of Neurology Dettmers C, Schmieder Kliniken Konstanz Eppinger B, Klinikum am Gesundbrunnen Heilbronn, Department of Neurology Gold H-J, Klinikum am Gesundbrunnen Heilbronn, Department of Neurology Hecht M, Bezirkskrankenhaus Kaufbeuren, Department of Neurology Heimbach B, University of Freiburg, Department of Neurology Hendrich C, Klinikum Friedrichshafen, Department of Neurology Herting B, Diakonie-Klinikum Schwa¨bisch Hall, Department of Neurology Huber R, Klinikum Friedrichshafen, Department of Neurology Hu¨lser P-J, Fachklinik Wangen, Department of Neurology Kaendler S, Kliniken Landkreis Heidenheim, Department of Neurology Kaspar A, Oberschwabenklinik Ravensburg, Department of Neurology Kimmig H., Kliniken Schwenningen, Department of Neurology Klo¨tzsch C, Schmieder Kliniken Allensbach, Bodensee Klinikum Hegau Konstanz
J Neurol (2014) 261:283–290
Ku¨hne J, Schmieder Kliniken Allensbach, Bodensee Klinikum Hegau Konstanz Lewis D, Marienhospital Stuttgart, Department of Neurology Lichy C, Klinikum Memmingen, Department of Neurology Lindner A, Marienhospital Stuttgart, Department of Neurology Lorenzl S, LMU Mu¨nchen, Department of Neurology Lutz-Schuhbauer S, Department of Neurology, Dietenbronn Ma¨urer M, Caritas Krankenhaus, Bad Mergentheim, Department of Neurology Meinck H M, University of Heidelberg, Department of Neurology Meudt O, Klinikum Memmingen, Department of Neurology Mu¨ller vom Hagen J, Universita¨tsklinikum Tu¨bingen, Department of Neurology Na¨gele A, Christophsbad Go¨ppingen, Department of Neurology Naumann M, Klinikum Augsburg, Department of Neurology und Neurophysiologie Neher K-D, Vinzenz von Paul Hospital, Rottweil, Department of Neurology Neuhaus O, Kliniken Landkreis Sigmaringen, Department of Neurology Neusch C, Praxis EMSA Singen Niehaus L, Department of Neurology, Winnenden Patzner M, Fachklinik Wangen, Department of Neurology Peters J, Ostalb-Klinikum Aalen, Department of Neurology Poerschke Y, Bundeswehrkrankenhaus Ulm, Department of Neurology Raape J, ZFP Su¨dwu¨rttemberg, Neurologie Weissenau Ratzka P, Klinikum Augsburg, Department of Neurology und Neurophysiologie Reeh A, Kliniken Landkreis Heidenheim, Department of Neurology Rettenmayr C, Klinikum Esslingen, Department of Neurology Rothmeier J, ZFP Su¨dwu¨rttemberg, Neurologie Weissenau Sabolek M, Department of Neurology, Dietenbronn Schabet M, Department of Neurology, Ludwigsburg Scha¨ff-Vogelsang M, Diakonie-Klinikum Schwa¨bisch Hall, Department of Neurology Scho¨ls L, Universita¨tsklinikum Tu¨bingen, Department of Neurology Schweigert B, Caritas Krankenhaus, Bad Mergentheim, Department of Neurology
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Sommer N, Christophsbad Go¨ppingen, Department of Neurology Sperber W, Kliniken Esslingen, Department of Neurology Stroick M, Klinikum Memmingen, Department of Neurology Trottenberg T, Department of Neurology, Winnenden Weber F, Bundeswehrkrankenhaus Ulm, Department of Neurology Wessig C, University of Wu¨rzburg, Department of Neurology Will H-G, Kliniken Schwenningen, Department of Neurology Winkler A, TU Mu¨nchen, Department of Neurology
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