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J Neurol (2009) 256:898903 DOI 10.

1007/s00415-009-5037-2

ORIGINAL COMMUNICATION

Classical crossed brain stem syndromes: myth or reality?


Jurgen J. Marx Frank Thomke

Received: 25 November 2008 / Accepted: 28 January 2009 / Published online: 28 February 2009 Springer-Verlag 2009

Abstract Numerous crossed brain stem syndromes have been described, especially in the nineteenth century. While these syndromes are passed on in neurological textbooks, their relevance in clinical neurology remains to be elucidated. To investigate the prevalence of classical crossed brain stem syndromes in clinical practice, we prospectively recruited 308 consecutive patients with signs and symptoms indicative of acute brain stem infarction. Standardized high-resolution MR imaging and multimodal electrophysiological brain stem testing were applied to localize the site of the acute lesion. We performed a computer-based correlation of clinical signs and symptoms of our patients to those reported in the original historical publications for more than 25 crossed brain stem syndromes. Fourteen cases matched the clinical criteria of Wallenbergs syndrome, two patients had Babinski-Nageottes syndrome, two had Raymond-Cestans, one showed Webers, and one Claudes syndrome. All other tested syndromes were not present in the cohort. More than 20% of patients showed different, so far unnamed crossed symptom combinations. In conclusion, except for Wallenbergs syndrome, classical crossed brain stem syndromes do not seem to play a relevant role in clinical neurology. Other syndromes may serve as theoretical models only that illustrate possible neuroanatomical connections in the human brain stem. This is complicated, however, by considerable topographic and terminological inconsistencies.

Keywords History of neurology Neuroepidemiology Brain stem Cerebrovascular disease MRI Background A considerable variety of crossed brain stem syndromes has been described in the neurological literature, especially in the nineteenth century. Most of these syndromes comprise ipsilateral cranial nerve lesions and contralateral signs of long tract involvement, such as hemiparesis or a hemisensory decit. More than 25 corresponding syndromes have been named according to their rst describer so far. They are usually used as eponyms to characterize a complex neurological state like in the classical case of Wallenbergs syndrome [17]. While hardly anything is known about the prevalence of these syndromes, denitions in modern neurological literature are often inaccurate and show growing topodiagnostic as well as terminological inconsistencies [4, 7, 13]. It is even debated whether some of these syndromes actually exist at all as a correlate of brain stem dysfunction [5]. Nevertheless, the majority of these eponyms are repeatedly cited in neurological textbooks and even in modern neurological literature. In order to investigate the prevalence and clinical relevance of a variety of brain stem syndromes, we performed a computer-based analysis of symptom distribution in more than 300 prospectively recruited patients with acute signs of brain stem ischemia at an academic neurological center with a long tradition of anatomical/structural brain stem mapping. Patients and methods Over a 3-year period, we prospectively recruited 308 consecutive patients with acute signs and symptoms of

J. J. Marx (&) F. Thomke Department of Neurology, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55101 Mainz, Germany e-mail: marx@neurologie.klinik.uni-mainz.de

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vertebrobasilar ischemia. We rated acute ocular motor disorders, cranial nerve lesions and limb, trunk, stand or gait ataxia as indicators of vertebrobasilar dysfunction. Approval of the study was granted by the university ethics committee, and patients gave informed consent to the procedures. Clinical investigation A detailed clinical investigation was done within 24 h after onset of symptoms using standard clinical procedures with a focus on ocular motor disorders, cranial nerve lesions or signs of long tract involvement like pyramidal tract lesions, lemniscal or pain/temperature sensory decits, hemiataxia or lateropulsion. All signs and symptoms were entered in a specially designed ACCESS database for further statistical analysis. The patient had to fulll all cited criteria for a positive match with the syndromes according to their historical description (Table 3). Only for the more extensive medullary syndromes of Babinski-Nageotte, Wallenberg, and Reinhold was one missing ipsilateral clinical sign accepted. Electrophysiological investigations For detailed assessment of brain stem dysfunction, a battery of functional electrophysiological brain stem testing was applied in all patients in whom the clinical condition allowed functional testing. This comprised brain stem reexes (blink reex, jaw jerk, masseter inhibitory reex), auditory evoked potentials (AEPs), and electrooculography with caloric stimulation. Electrophysiological testing was used to prove a functional brain stem lesion in patients with normal MRI, but with clinical rating of brain stem ischemia as the best nal diagnosis. MR imaging Biplanar T2- and diffusion-weighted (DWI) MRI was done within 48 h after onset of symptoms with a 1.5-T superconducting system (Magnetom Vision, Siemens, Erlangen, Germany). We used DW-echo planar imaging with separately applied diffusion gradients in the three spatial axes to prove the acuity of the lesion. Axial and sagittal highresolution T2/T1-weighted imaging before and after intravenous gadolinium was done as soon as patients could tolerate the longer lasting MRI scan (median 6.5 days after onset of symptoms). To ensure standardized imaging, slice orientation was parallel (sagittal sections) and perpendicular (axial sections) to the sagittal brainstem cuts of the stereotactic anatomical atlas of Schaltenbrand and Wahren [12].

Results Patient data MR imaging was impossible in 27 of the 308 patients with clinical signs and symptoms indicative of vertebrobasilar ischemia due to claustrophobia, the clinical condition or metal implants. In 36 of the remaining patients, MRI or further investigations revealed a diagnosis other than brain stem infarction: pure cerebellar ischemia (14), tumor (3), vestibular neuritis (6), inammatory disease (6), or others (7). In the remaining 245 patients an acute brain stem ischemia was rated as the best nal diagnosis according to clinical investigation, MRI, and electrophysiological brain stem testing. Of the 245 patients, 189 (77.1%) showed an acute brain stem infarction in MRI. Lesion location was mesencephalic in 18 patients (9.5%), pontomesencephalic in 34 (18.0%), pontine in 69 patients (36.5%), pontomedullary in 32 (16.9%), and medullary in 36 cases (19.0%). Fourteen patients (7.4%) had multiple acute vertebrobasilar infarcts. In 56 (22.9%) of the 245 patients, the diagnosis of an acute brain stem lesion was based on the results of functional testing alone, while MRI failed to show the expected brain stem ischemia. Electrooculography (26.2%) and the jaw jerk (22.8%) were the functional tests most frequently affected. See Table 1 for the number of pathological ndings in serial electrophysiological investigations. In 214 of these patients a complete diagnostic workup was available. Sonography and MR-angiography detected occlusion or stenosis of a vertebral artery in 46 patients (21.5%). Four patients had a vertebral artery dissection, in two cases following a chiropractic maneuver. Seventy-one patients (33.2%) had multiple vascular risk factors, and sonography demonstrated atherosclerosis of the extracranial arteries, but no vertebral artery stenosis or occlusion. Forty-three patients (20.1%) had cardioembolic infarction due to atrial brillation or a patent foramen ovale with combined atrial septal aneurysm. Two patients had Wegners granulomatosis. In 48 patients (22.4%), the etiology of the infarction remained unclear. The most common clinical sign was gait ataxia in 60.8% of the 245 patients. Ipsilateral cranial nerve lesions were

Table 1 Pathological ndings in serial electrophysiological tests Test Electrooculography Jaw jerk Blink reex Masseter inhibitory reex Auditory evoked potentials Pathological ndings 52/198 (26.2%) 49/215 (22.8%) 40/208 (19.2%) 38/215 (17.7%) 21/221 (9.5%)

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present in 18.8% of patients, while the most common cranial nerve decit was that of the 5th nerve (11.4%). Motor hemiparesis was the most common long tract sign contralateral to lesion location (21.6%). See Table 2 for further clinical characteristics. According to the computerbased symptom mapping analysis, 14 cases matched the clinical criteria of Wallenbergs syndrome, 2 patients had Babinski-Nageottes syndrome, 2 had Raymond-Cestans, 1 Webers and 1 Claudes syndrome. See Tables 3 and 4 for more detailed clinical data in the 19 patients matching one of the crossed brain stem syndromes. When regarding symptom combinations apart from described crossed brain stem syndromes, the most frequent syndromes in our cohort were gait ataxia combined with hemiataxia (15.1%) and gait ataxia with dysarthria (6.5%) as typical signs in dorsal/lateral medullary infarctions. Moreover, dysarthria combined with motor hemiparesis (8.6%) was a frequent correlate of ventral pontine ischemia. When regarding crossed syndromes, trigeminal decits combined with hemiataxia (7.8%), or impaired contralateral pain/temperature sensation (4.9%), as well as Horners syndrome combined with contralateral hemiataxia (6.5%) or impaired pain/temperature sensation (4.5%) were frequent symptom combinations, all typical in dorsal/lateral medullary infarction.

Discussion According to our ndings, only Wallenbergs syndrome seems to be of clinical importance, whereas the remaining classical crossed brain stem syndromes are missed in clinical practice (Fig. 1). Some others may occur
Table 2 Clinical signs in patients with brain stem ischemia (n = 245) Gait ataxia Dysarthria Nystagmus Skew deviation Ipsilateral Cranial nerve lesion 5th nerve 6th nerve 7th nerve Internuclear ophthalmoplegia Contralateral Motor hemiparesis Hemiataxia Sensory decit pain/temperature Sensory decit light touch 53 (21.6%) 25 (10.2%) 32 (14.3%) 18 (7.3%) 46 (18.8%) 28 (11.4%) 11 (4.5%) 8 (3.3%) 27 (11.0%) 149 (60.8%) 55 (22.4%) 42 (17.1%) 24 (9.8%)

occasionally, such as the syndromes of Weber, Claude, Raymond-Cestan, and Babinski-Nageotte. Even in Wallenbergs syndrome, nearly half of our patients did not fulll all symptoms described by Wallenberg or had additional symptoms of brain stem dysfunction [17]. Wallenbergs syndrome is a clinical correlate of classical lateral medullary infarction, which is a frequent area of ischemia due to the vascular architecture of the brain stem [2]. Most of the crossed brain stem syndromes have been described in the nineteenth and few in the early twentieth century on the basis of single case studies, sometimes with correlation to autopsy ndings. At that time, imaging of the central nervous system or elaborate functional testing was not available to prove the suspected acute brain stem lesion in vivo. While these syndromes are generally cited in textbooks on clinical neurology and in modern literature, several of the eponyms used in clinical diagnosis today do not exactly correspond to the rst descriptions of the nineteenth century anymore. Investigations on the prevalence of these syndromes and their growing terminological inconsistencies are rare. Corresponding publications are mainly published in German language, and their access is limited [4, 5, 13]. Over the decades, syndromes have been simplied or have been extended by terms like Wallenberg-plus [11]. Parinauds syndrome is often used as a synonym for a dorsal midbrain syndrome, which does not correspond to the original description [10, 13]. Modern citations of the Avellis syndrome do not correspond to the historical description of the crossed medullary syndrome [1], while other syndromes like those of Foville or MillardGubler are occasionally mixed up with each other in the literature [3, 6, 9, 15]. Moreover, some syndromes have probably never been described by the authors to whom they are attributed. This applies for example to the syndromes that are attributed to Gasperini or to Grenet [6]. Other syndromes, like those of Schmidt [14] or Vernet [16], have actually never been described as a correlate of a brain stem lesion and probably represent multiple cranial nerve lesions instead [5]. All these limitations restrict the clinical value of the historical crossed brain stem syndromes in neurological practice. Moreover, according to our data, most of the syndromes do not exist at all in clinical practice, even at specialized academic neurological centers. Other crossed syndromes like that of an ipsilateral trigeminal decit combined with a pure contralateral hemiataxia are far more frequent, but have never been named accordingly. To the best of our knowledge, this is the largest prospectively recruited unselected cohort of patients with brain stem infarctions. Our investigation is limited in that it is based on ischemic brain stem lesions alone. Brain stem ischemia is, however, by far the most frequent cause of acute brain

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Table 3 Prevalence of crossed brain stem syndromes according to the computer-based mapping analysis Syndrome name Mesencephalon Benedikt 3rd nerve palsy Hemiataxia Hyperkinesia Rigor Claude Weber Nothnagel 3rd nerve palsy 3rd nerve palsy 3rd nerve palsy Hemiataxia Hemiparesis Hemiataxia Ptosis M. rectus superior paresis Pons Grenet Gasperini Trigeminal decit Trigeminal decit 7th nerve palsy Gaze palsy Raymond-Cestan Gaze palsy Hemiataxia Hemiparesis Hemihypaesthesia Raymond Millard-Gubler Brissaud-Sicard Foville (superior) Foville (inferior) Pierre-Marie-Foix 6th nerve palsy 6th nerve palsy 7th nerve palsy Facial spasm 6th nerve palsy 6th nerve palsy 7th nerve palsy 6th nerve palsy 7th nerve palsy Horners syndrome Gelle Medulla oblongata Babinski-Nageotte Trigeminal decit Horners syndrome Hemiataxia Vail paresis Vocal cord paresis Wallenberg Trigeminal decit Horners syndrome Hemiataxia Vail paresis Vocal cord paresis Cestan-Chenais Trigeminal decit Horners syndrome Vail paresis Vocal cord paresis Hemiparesis Hemihypalgesia Hemithermhypaesthesia 0 Hemihypalgesia Hemithermhypaesthesia 14 Hemiparesis Hemihypalgesia Hemithermhypaesthesia 2 Hypakusis/tinnitus Vertigo Hemiparesis 0 Hemiparesis Hemiparesis Hemihypaesthesia Hemiparesis Hemihypaesthesia Hemiparesis Hemihypaesthesia 0 0 0 Dejerine Spiller Hemiparesis Hemiparesis 0 0 Jackson 2 Hemihypalgesia Hemithermhypaesthesia Hemihypaesthesia 0 Vernet 0 Tapia 1 1 0 Schmidt Avellis 0 Ipsilesional Contralesional No.

901 Table 3 continued


Syndrome name Reinhold Ipsilesional Contralesional No.

Trigeminal decit Horners syndrome Vail paresis Vocal cord paresis Hemiataxia Hypoglossal paresis Vail paresis Vocal cord paresis Vail paresis Vocal cord paresis 11th nerve palsy 12th nerve palsy Vail paresis Vocal cord paresis 12th nerve palsy Vail paresis 11th nerve palsy Hemiageusia posterior tongue Pharyngeal hemihypaesthesia Vail paresis Vocal cord paresis 12th nerve palsy 12th nerve palsy 12th nerve palsy

Hemiparesis Hemihypalgesia Hemithermhypaesthesia Hemihypaesthesia

Hemiparesis Hemihypaesthesia Hemiparesis

0 0

Hemiparesis

Hemiparesis

Hemiparesis

Hemiparesis Hemiparesis Hemihypaesthesia

0 0

stem lesions, and most of the cited syndromes have been initially described as a sequel of brain stem infarction. Tumors in the posterior fossa are rare, and brainstem lesions in inammatory diseases are usually multitopic and thus unsuitable for topographic studies in oligosymptomatic syndromes. According to earlier investigations, routine MR imaging is able to detect only about 80% of functional brain stem lesions [8]. Therefore, we included a broad battery of electophysiological brain stem tests to prove a central brain stem affection in our patients with acute vertebrobasilar symptoms. Another drawback of our study is the fact that the mechanisms of ischemia were multiplex in our cohort, whereas most of the named brainstem syndromes are penetrator syndromes or territorial infarcts involving several penetrating arteries. This cohort does, however, represent clinical practice as it is based on consecutive patients prospectively recruited over a 3-year period of time. In conclusion, crossed brain stem syndromes other than Wallenbergs syndrome do not seem to have a major

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902 Table 4 Clinical characteristics in patients matching crossed brain stem syndromes Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Syndrome Wallenberg Wallenberg Wallenberg Wallenberg Wallenberg Wallenberg Wallenberg Wallenberg Wallenberg Wallenberg Wallenberg Wallenberg Wallenberg Wallenberg Babinski-Nageotte Babinski-Nageotte Raymond-Cestan Raymond-Cestan Claude Vail paresis Vail paresis Horners sign Vocal cord paresis Cerebellum Facial weakness Cerebellum Skew deviation Cerebellum Horners sign Facial weakness Skew deviation Cerebellum Cerebellum Vocal cord paresis Vail paresis Missing signs Additional signs Facial weakness

J Neurol (2009) 256:898903

Additional lesion Cerebellum

Aetiology VA dissection RF, AS Unclear Cardioembolic VA occlusion Wegeners disease VA occlusion Unclear VA occlusion Cardioembolic Unclear Cardioembolic RF, AS Cardioembolic RF, AS VA occlusion Unclear VA stenosis RF, AS

VA vertebral artery, RF vascular risk factors, AS atherosclerosis

Fig. 1 Typical lateral medullary lesion in patient 4 with Wallenbergs syndrome (a) and in patient 15 with BabinskiNageotte syndrome (b), transversal T2-weighted image

clinical importance. They may serve as theoretical constructs illustrating the functional neuroanatomy of the brain stem for educational purposes. This is, however, considerably complicated by multiple terminological and topographic inconsistencies when regarding the historical descriptions.
Acknowledgments The study was supported by the DFG (Deutsche Forschungsgemeinschaft: Ho293/10-2).

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