Cortical Spreading Ischaemia and
Delayed Ischaemic Neurological Deficits
after Subarachnoid Haemorrhage

Habilitationsschrift

zur Erlangung der Lehrbefähigung
für das Fach


Neurologie

vorgelegt dem Fakultätsrat der Medizinischen Fakultät Charité
der Humboldt-Universität zu Berlin

von

Herrn Dr. Jens P. Dreier


geboren am 11.09.1965 in Kassel

Präsident: Prof. Dr. rer. nat. J. Mlynek

Dekan: Prof. Dr. Joachim W. Dudenhausen

eingereicht am:12/2002

Öffentlich-wissenschaftlicher Vortrag am: 21.07.2003

Gutachter:
1. Herr Prof. Dr. rer. nat. Heiko Luhmann
2. Herr Prof. Dr. med. Peter Schmiedek

Abstract

The coupling between neuronal activity and cerebral blood flow is a fundamental process, which underpins all cerebral functions. The topic of my Habilitation is the discovery of a new variant of ischaemia in which neuronal activation triggers a cerebral ischaemic event through the inversion of the coupling between neuronal activation and cerebral blood flow. This inversion occurs when red blood cell products are present in the subarachnoid space. The most distinct feature of this variant of ischaemia is its propagation in the cerebral cortex together with the wave of neuronal activation. Therefore, I named the phenomenon ‘cortical spreading ischaemia’. The presented animal model may have implications for the delayed ischaemic neurological deficits after subarachnoid haemorrhage. The link with this clinical syndrome has been based: (a) on the induction of cortical spreading ischaemia by red blood cell products in the subarachnoid space, (b) the correspondence between the characteristic patterns of the cortical ischaemic lesions, and (c) the therapeutic effects of nimodipine and moderate hypervolaemic haemodilution in clinical syndrome and animal model. With the aid of this model, it was possible to experimentally confirm the hypothesis that red blood cell products can induce cerebral ischaemia. I hope that the model will contribute to develop new strategies for the treatment of patients with subarachnoid haemorrhage.

Keywords: Spreading Depression, cerebral ischemia, subarachnoid hemorrhage, cortical spreading ischemia

Zusammenfassung

Die Kopplung zwischen neuronaler Aktivität und cerebralem Blutfluss ist ein fundamentaler Prozess, der alle cerebralen Funktionen begleitet. Das Thema meiner Habilitation ist die Entdeckung einer neuen Ischämievariante, bei der neuronale Aktivierung eine cerebrale Ischämie auslöst, indem sich die Kopplung zwischen neuronaler Aktivierung und cerebralem Blutfluss umkehrt. Diese Umkehrung wird durch Produkte roter Blutkörperchen im Subarachnoidalraum hervorgerufen. Die eigentümlichste Eigenschaft dieser Ischämievariante ist ihre Wanderung im cerebralen Cortex gemeinsam mit der Welle neuronaler Aktivierung. Deshalb habe ich das Phänomen ‘cortical spreading ischaemia’ genannt. Das vorgestellte tierexperimentelle Modell könnte für die verzögerten ischämischen neurologischen Defizite nach Subarachnoidalblutung Implikationen besitzen. Die Verbindung mit diesem klinischen Syndrom basiert auf: (a) der Induktion der cortical spreading ischaemia durch Produkte roter Blutkörperchen im Subarachnoidalraum, (b) der Übereinstimmung im Läsionsmuster mit corticalen ischämischen Infarkten, und (c) den therapeutischen Effekten von Nimodipin und mässiger hypervolämischer Hämodilution im klinischen Syndrom und im Tiermodell. Mit Hilfe dieses Modells ist es zum ersten Mal gelungen, experimentell die Hypothese zu bestätigen, dass Produkte roter Blutkörperchen eine cerebrale Ischämie induzieren können. Ich hoffe, dass das Modell dazu beitragen wird, neue Strategien bei der Behandlung von Patienten mit Subarachnoidalblutung zu entwickeln.

Eigene Schlagworte: Spreading Depression, cerebrale Ischämie, Subarachnoidalblutung, cortical spreading ischemia

Inhaltsverzeichnis

• 1.  DELAYED ISCHAEMIC NEUROLOGICAL DEFICITS (DIND) AFTER ANEURYSMAL SUBARACHNOID HAEMORRHAGE
  • 1.1.  Epidemiology
  • 1.2.  Clinical presentation
  • 1.3.  Risk factors
  • 1.4.  Differential diagnosis
    • 1.4.1.  Re-bleeding
    • 1.4.2.  Hydrocephalus
    • 1.4.3.  Hyponatraemia
    • 1.4.4.  Peri- and intra-operative complications associated with aneurysm clipping
    • 1.4.5.  Ischaemic stroke unrelated to surgical complications or DIND in the post-operative course
  • 1.5.  Pathoanatomy
  • 1.6.  Treatment
    • 1.6.1.  Relative risk reduction of poor outcome after SAH by nimodipine
    • 1.6.2.  Systemic blood volume and DINDs
  • 1.7.  Animal models
• 2.  SUMMARY OF OUR OWN RESULTS
  • 2.1.  Dreier JP, Körner K, Görner A, Lindauer U, Weih M, Villringer A, Dirnagl U. Nitric oxide modulates the CBF response to increased extracellular potassium. J Cereb Blood Flow Metab. 1995 15:914-919.
  • 2.2.  Dreier JP, Körner K, Ebert N, Görner A, Rubin I, Back T, Lindauer U, Wolf T, Villringer A, Einhäupl KM, Lauritzen M, Dirnagl U. Nitric oxide scavenging by hemoglobin or nitric oxide synthase inhibition by N-nitro-L-arginine induces cortical spreading ischemia when K+ is increased in the subarachnoid space. J Cereb Blood Flow Metab. 1998 18:978-990.
  • 2.3.  Dreier JP, Ebert N, Priller J, Megow D, Lindauer U, Klee R, Reuter U, Imai Y, Einhäupl KM, Victorov I, Dirnagl U. Products of hemolysis in the subarachnoid space inducing spreading ischemia in the cortex and focal necrosis in rats: a model for delayed ischemic neurological deficits after subarachnoid hemorrhage? J Neurosurg. 2000 93:658-666.
  • 2.4.  Dreier JP, Petzold G, Tille K, Lindauer U, Arnold G, Heinemann U, Einhäupl KM, Dirnagl U. Ischaemia triggered by spreading neuronal activation is inhibited by vasodilators in rats. J Physiol (Lond). 2001 531(Pt 2):515-526.
  • 2.5.  Dreier JP, Sakowitz OW, Unterberg AW, Benndorf G, Einhäupl KM, Valdueza JM. Migrainous aura starting several minutes after the onset of subarachnoid hemorrhage. Neurology. 2001 57:1344-1345.
  • 2.6.  Dreier JP, Kleeberg J, Petzold G, Priller J, Windmuller O, Orzechowski HD, Lindauer U, Heinemann U, Einhaupl KM, Dirnagl U. Endothelin-1 potently induces Leao's cortical spreading depression in vivo in the rat: a model for an endothelial trigger of migrainous aura? Brain. 2002 125:102-112.
  • 2.7.  Dreier JP, Windmüller O, Petzold G, Lindauer U, Einhäupl KM, Dirnagl U. Ischemia triggered by red blood cell products in the subarachnoid space is inhibited by nimodipine administration or moderate volume expansion/hemodilution in rats. Neurosurgery. 2002 51:1457-1467.
  • 2.8. Dreier JP, Sakowitz OW, Harder A, Zimmer C, Dirnagl U, Valdueza JM, Unterberg AW. Focal laminar cortical MR-signal abnormalities after subarachnoid hemorrhage. Ann Neurol. 2002 52:825-829.
• 3.  ASSESSMENT
• References
• EIDESSTATTLICHE VERSICHERUNG

Bilder

• Figure 1 A and B The upper two pictures are diagrammatic representations of macroscopic and microscopic cerebral infarction in a 37-year old man with DIND at day 8 after subarachnoid haemorrhage. The DIND was characterised by a rapid deterioration with development of paraplegia. The patient died 4 days later. The pictures are taken from a paper of 8 cases selected from a larger autosy series by Sheila Birse and Mary Tom published in Neurology in 1960. The lower two pictures are turbo inversion recovery magnitude magnetic resonance images from a 33-year old man who developed a DIND with mental status changes and right-sided hemiparesis about 6 days after subarachnoid haemorrhage (Dreier et al. 2002b). The patient was treated in the intensive care unit with a good recovery. In both patients, the aneurysm was un-operated at the time point when the pictures were made so that the lesions represent the typical pattern occurring in the natural course of the disease. The most characteristic feature of the lesions is their distribution in the cortex band around a sulcus (arrows in A) or a fissure (arrows in B). In both patients, the aneurysm was located at the anterior communicating artery in which case the blood is typically pushed upwards along the interhemispheric fissure. C A similar focal laminar cortical necrosis is observed after cortical spreading ischaemia in response to the red blood cell products haemoglobin and increased subarachnoid K+ in the rat (*). The bar illustrates size and position of the cranial window. It is unclear why the lesion can extend beyond the borders of the window. Likely, haemoglobin and K+ have diffused to areas neighbouring the window (Dreier et al. 2000).
• Figure 2 Under physiological conditions, a cortical spreading hyperaemia (upper trace, left part) (CBF = cerebral blood flow) is coupled to a spreading neuronal depolarisation wave (lower trace, left part) (DC = slow direct current potential) propagating from cranial window 1 to cranial window 2. However, when red blood cell products, haemoglobin and increased K+, are in the subarachnoid space, the coupling between neuronal activation and cerebral blood flow is inverted so that a cortical spreading ischaemia (upper trace, right part) is coupled to the spreading neuronal depolarisation wave (lower trace, right part). Due to a vicious circle, both depolarisation wave and its CBF response are prolonged under this condition (see text).
• Figure 3 Comparison of cerebral blood flow (CBF)- and direct current (DC)-responses to the spreading neuronal/astroglial depolarisation wave (SND). While the upper two traces represent CBF at two different laser-Doppler positions, the lower trace gives the DC-potential at one cranial window. A Physiological artificial cerebrospinal fluid (ACSF) topically, 0.9% saline intravenously (control): The depolarisation wave is associated with a cortical spreading hyperaemia (CSH) under physiological conditions (= cortical spreading depression (CSD) of Leão). B ACSF containing haemoglobin ([Hb]ACSF ) and elevated K+ ([K+ ]ACSF ) topically, 0.9% saline intravenously: Cortical spreading ischaemia (CSI) in response to the depolarisation wave. C ACSF containing the red blood cell products topically, nimodipine is given intravenously at a dose of 2 µg/kg bodyweight/min (i.v.): Cortical spreading ischaemia reverts to a cortical spreading hyperaemia in presence of nimodipine. Only a short initial hypoperfusion (*) preceding cortical spreading hyperaemia indicates the presence of the red blood cell products in the subarachnoid space. The effect of moderate hypervolaemic haemodilution was similar to that of nimodipine.