Die Bedeutung des Liquorbefundes in der Diagnostik der Multiplen Sklerose

Zusammenfassung

Die Liquordiagnostik ist ein wesentlicher Bestandteil der Diagnose „Multiple Sklerose“ (MS), insbesondere um differenzialdiagnostisch andere Erkrankungen des ZNS auszuschließen. Mit Ausnahme der Hirnbiopsie kann nur die Liquordiagnostik den entzündlichen Charakter der Erkrankung beweisen. Durch einen „positiven Liquorbefund“ kann die Diagnose MS nach den McDonald-Kriterien in vielen Fällen deutlich früher gestellt werden.

Das MS-typische Liquorprofil besteht aus 1. oligoklonalen IgG-Banden, 2. lymphomonozytärem Zellbild (normal bis leicht erhöhte Zellzahl), 3. intakter bis leicht gestörter Blut-Liquorschrankenfunktion und 4. dem Nachweis einer polyspezifischen Immunantwort („MRZ-Reaktion“). Ähnlich dem MRT hat der MS-typische Liquorbefund einen hohen prädiktiven Wert hinsichtlich der Entwicklung einer MS nach einem klinischen Erstereignis.

Keiner der genannten Liquorparameter ist jedoch pathognomonisch. Auch ist das Liquorprofil im Verlauf der MS nahezu konstant, es erlaubt keine Aussage über die Krankheitsaktivität beziehungsweise Schwere der Behinderung und differenziert nicht zwischen Verlaufstypen. Unter der Therapie mit Kortikosteroiden und immunmodulatorischen Substanzen ist keine Änderung dieses diagnostischen Liquorprofils zu beobachten.

Gegenstand der Forschung ist die Identifizierung Prozessspezifischer Surrogatmarker (Zytokine, Adhäsionsmoleküle, Myelinabbauprodukte, gliale und neuronale Proteine), die unterschiedliche Aspekte der MS-Pathologie reflektieren und zum Teil eine Erfassung von Krankheitsaktivität und Therapieerfolg ermöglichen.

Summary

Analysis of cerebrospinal fluid (CSF) is highly important to establish the diagnosis of MS, especially by recognizing or ruling out non-MS diseases. Except for brain biopsy, only CSF findings may confirm the inflammatory nature of MS. Moreover, a typical CSF pattern improves the probability of an early diagnosis of MS according to the McDonald criteria. The MS-typical CSF profile consists of 1. presence of oligoclonal IgG bands, 2. mononuclear cells (normal or mildly elevated leukocyte count), 3. normal or mildly disturbed blood-CSF barrier function and 4. presence of polyspecific humoral immune response („MRZ-reaction”). As for MRI, CSF findings show high predictivity with regard to conversion to definite MS following a first clinical event.

None of the single CSF parameters is pathognomonic for MS. Furthermore, the CSF profile remains constant over disease course without correlation to disease activity or severity, it does not allow differentiation of disease subtypes, and it is not influenced by treatment with corticosteroids or immunmodulatory drugs.

It is subject of ongoing research to identify process-specific surrogate markers (cytokines, adhesion molecules, myelin degradation products, glial and neuronal proteins) related to different aspects of MS pathology. Such markers correlate in part with disease activity and treatment response.

Schlüsselwörter

Liquor cerebrospinalis - Multiple Sklerose - Prozesspezifische Surrogatmarker

Keywords

Cerebrospinal fluid - multiple sclerosis - process-specific surrogates

• Literatur

• 1 Bahner D, Klucke C, Kitze B. et al. Interferon-beta-1b increases serum interleukin-12 p40 levels in primary progressive multiple sclerosis patients. Neurosci Lett 2002; 326: 125-8.
• 2 Barkhof F, Frequin ST, Hommes OR. et al. A correlative triad of gadolinium-DTPA MRI, EDSS, and CSF-MBP in relapsing multiple sclerosis patients treated with high-dose intravenous methylprednisolone. Neurology 1992; 42: 63-7.
• 3 Bartosik-Psujek H, Archelos JJ. Tau protein and 14–3–3 are elevated in the cerebrospinal fluid of patients with multiple sclerosis and correlate with intrathecal synthesis of IgG. J Neurol 2004; 251: 414-20.
• 4 Berger T, Rubner P, Schautzer F. et al. Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N Engl J Med 2003; 349: 139-45.
• 5 Brettschneider J, Ecker D. et al. The macrophage activity marker sCD14 is increased in patients with multiple sclerosis and upregulated by interferon beta-1b. J Neuroimmunol 2002; 133: 193-7.
• 6 Brettschneider J, Arda S, Claus A, Maier M. et al. Cerebrospinal fluid tau protein levels in multiple sclerosis. Multiple Sclerosis. 2005. in press:
• 7 Dumont D, Noben JP, Raus J, Stinissen P, Robben J. Proteomic analysis of cerebrospinal fluid from multiple sclerosis patients. Proteomics 2004; 4: 2117-24.
• 8 Elovaara I, Ukkonen M, Leppakynnas M. et al. Adhesion molecules in multiple sclerosis: relation to subtypes of disease and methylprednisolone-therapy. Arch Neurol 2000; 57: 546-51.
• 9 Fangerau T, Schimrigk S. et al. Diagnosis of multiple sclerosis: comparison of the Poser criteria and the new McDonald criteria. Acta Neurol Scand 2004; 109: 385-9.
• 10 Hammack BN, Fung KY, Hunsucker SW, Duncan MW, Burgoon MP, Owens GP, Gilden DH. Proteomic analysis of multiple sclerosis cerebrospinal fluid. Mult Scler 2004; 10: 245-60.
• 11 Jacobs LD, Beck RW, Simon JH. et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000; 343: 898-904.
• 12 Kapaki E, Paraskevas GP, Michalopoulou M. et al. Increased cerebrospinal fluid tau protein in multiple sclerosis. Eur Neurol 2000; 43: 228-32.
• 13 Kuhlmann T, Lingfeld G, Bitsch A. et al. Acute axonal damage in multiple sclerosis is most extensive in early disease stages and decreases over time. Brain 2002; 125: 2202-12.
• 14 Lamers KJ, van-Engelen BG, Gabreels FJ. et al. Cerebrospinal neuron-specific enolase, S-100 and myelin basic protein in neurological disorders. Acta Neurol Scand 1995; 92: 247-51.
• 15 Leppert D, Ford J, Stabler G. et al. Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis. Brain 1998; 121: 2327-34.
• 16 Lycke JN, Karlsson JE, Andersen O. et al. Neurofilament protein in cerebrospinal fluid: a potential marker of activity in multiple sclerosis. J Neurol Neurosurg Psychiatry 1998; 64: 402-4.
• 17 Massaro AR. Are there indicators of remyelination in blood or CSF of multiple sclerosis patients?. Mult Scler 1998; 4: 228-31.
• 18 McDonald WI, Compston A. et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121-7.
• 19 Patzold T, Sindern E, Ossege PL. et al. The soluble 60-kDa tumour necrosis factor receptor: no difference found between patients with relapsing-remitting multiple sclerosis and controls: increasing levels are associated with the recovery from Guillain- Barre syndrome. J Neurol 1998; 245: 803-8.
• 20 Petzold A, Eikelenboom MJ, Gveric D. et al. Markers for different glial cell responses in multiple sclerosis: clinical and pathological correlations. Brain 2002; 125: 1462-73.
• 21 Rieckmann P, Albrecht M, Kitze B. et al. Cytokine mRNA levels in mononuclear blood cells from patients with multiple sclerosis. Neurology 1994; 44: 152-6.
• 22 Rieckmann P, Altenhofen B, Riegel A. et al. Soluble adhesion molecules (sVCAM-1 and sICAM- 1) in cerebrospinal fluid and serum-correlate with MRI activity in multiple sclerosis. Ann Neurol 1997; 41: 326-33.
• 23 Rieckmann P, Toyka KV. Multiple Sclerosis Therapy Consensus Group. Immunomodulatory staged therapy of multiple sclerosis. New aspects and practical applications, March 2002. Nervenarzt 2002; 73: 556-63.
• 24 Rudick RA, Cookfair DL, Simonian NA. et al. Cerebrospinal fluid abnormalities in a phase III trial of Avonex (IFNbeta-1a) for relapsing multiple sclerosis. The Multiple Sclerosis Collaborative Research Group. J Neuroimmunol 1999; 93: 8-14.
• 25 Süßmuth S, Reiber H, Tumani H. Tau protein in cerebrospinal fluid: a blood-CSF barrier related evaluation in neurological diseases. Neurosci Lett 2001; 300: 95-8.
• 26 Tumani H, Tourtellotte WW, Peter JB. et al. Acute optic neuritis: combined immunological markers and magnetic resonance imaging predict subsequent development of multiple sclerosis. The Optic Neuritis Study Group. J Neurol Sci 1998; 155: 44-9.
• 27 Wandinger KP, Lünemann JD, Wengert O. et al. TNF-related apoptosis inducing ligand (TRAIL) as a potential response marker for interferone-beta treatment in multiple sclerosis. The Lancet 2003; 361: 2036-43.
• 28 Whitaker JN. Myelin basic protein in cerebrospinal fluid and other body fluids. Mult Scler 1998; 4: 16-21.
• 29 Yushchenko M, Weber F, Mader M. et al. Matrix metalloproteinase-9 (MMP-9) in human cerebrospinal fluid (CSF): elevated levels are primarily related to CSF cell count. J Neuroimmunol 2000; 110: 244-51.
• 30 Yushchenko M, Mader M, Elitok E, Bitsch A, Dressel A, Tumani H, Bogumil T, Kitze B, Poser S, Weber F. Interferon-beta-1 b decreased matrix metalloproteinase-9 serum levels in primary progressive multiple sclerosis. J Neurol 2003; 250: 1224-8.