Gray matter pathology is increasingly recognized as an important feature of multiple sclerosis (MS), but the nature of the immune response that targets the gray matter is poorly understood. Starting with a proteomics approach, we identified contactin-2/transiently expressed axonal glycoprotein 1 (TAG-1) as a candidate autoantigen recognized by both autoantibodies and T helper (Th) 1/Th17 T cells in MS patients. Contactin-2 and its rat homologue, TAG-1, are expressed by various neuronal populations and sequestered in the juxtaparanodal domain of myelinated axons both at the axonal and myelin sides. The pathogenic significance of these autoimmune responses was then explored in experimental autoimmune encephalitis models in the rat. Adoptive transfer of TAG-1-specific T cells induced encephalitis characterized by a preferential inflammation of gray matter of the spinal cord and cortex. Cotransfer of TAG-1-specific T cells with a myelin oligodendrocyte glycoprotein-specific mAb generated focal perivascular demyelinating lesions in the cortex and extensive demyelination in spinal cord gray and white matter. This study identifies contactin-2 as an autoantigen targeted by T cells and autoantibodies in MS. Our findings suggest that a contactin-2-specific T-cell response contributes to the development of gray matter pathology.cortical pathology ͉ experimental autoimmune encephalitis ͉ Th1/Th17 T cells ͉ node of Ranvier ͉ myelin glycoproteins

SYNOPSIS The clinical picture of 15 patients with “cervicogenic headache” is presented. The patients suffered from constant one‐sided headaches, upon which were superimposed acute attacks. The pain could be precipitated and intensified mechanically. It was accompanied in one third of the patients by ipsilateral lacrimation, conjunctival injection, lid edema and visual blurring. Other concomitant symptoms were phono‐ and photophobia, nausea and vomiting. A C2 blockade always led to temporary pain relief.Routine X‐rays of the cervical spine and functional radio‐graphs in flexion and extension did not reveal any findings specific for cervicogenic headache when compared to 18 control subjects. Hypotheses on the pathophysiology of cervicogenic headache are presented.

Headache related to the cervical spine is often misdiagnosed and treated inadequately because of confusing and varying terminology. Primary headaches such as tension-type headache and migraine are incorrectly categorized as "cervicogenic" merely because of their occipital localization. Cervicogenic headache as described by Sjaastad presents as a unilateral headache of fluctuating intensity increased by movement of the head and typically radiates from occipital to frontal regions. Definition, pathophysiology; differential diagnoses and therapy of cervicogenic headache are demonstrated. Ipsilateral blockades of the C2 root and/or greater occipital nerve allow a differentiation between cervicogenic headache and primary headache syndromes such as migraine or tension-type headache. Neither pharmacological nor surgical or chiropractic procedures lead to a significant improvement or remission of cervicogenic headache. Pains of various anatomical regions possibly join into a common anatomical pathway, then present as cervicogenic headache, which should therefore be understood as a homogeneous but also unspecific pattern of reaction.

While pain is a common problem in patients with multiple sclerosis (MS), it is not frequently mentioned by patients and a more direct approach is required in order to obtain information about pain from patients. Many patients with MS experience more than one pain syndrome; combinations of dysaesthesia, headaches and/or back or muscle and joint pain are frequent. For each pain syndrome a clear diagnosis and therapeutic concept needs to be established. Pain in MS can be classified into four diagnostically and therapeutically relevant categories: (i) neuropathic pain due to MS (pain directly related to MS); (ii) pain indirectly related to MS; (iii) MS treatment-related pain; and (iv) pain unrelated to MS. Painful paroxysmal symptoms such as trigeminal neuralgia (TN), or painful tonic spasms are treated with antiepileptics as first choice, e.g. carbamazepine, oxcarbazepine, lamotrigine, gabapentin, pregabalin, etc. Painful 'burning' dysaesthesias, the most frequent chronic pain syndrome, are treated with TCAs such as amitriptyline, or antiepileptics such as gabapentin, pregabalin, lamotrigine, etc. Combinations of drugs with different modes of action can be particularly useful for reducing adverse effects. While escalation therapy may require opioids, there are encouraging results from studies regarding cannabinoids, but their future role in the treatment of MS-related pain has still to be determined. Pain related to spasticity often improves with adequate physiotherapy. Drug treatment includes antispastic agents such as baclofen or tizanidine and in patients with phasic spasticity, gabapentin or levetiracetam are administered. In patients with severe spasticity, botulinum toxin injections or intrathecal baclofen merit consideration. While physiotherapy may ameliorate malposition-induced joint and muscle pain, additional drug treatment with paracetamol (acetaminophen) or NSAIDs may be useful. Moreover, painful pressure lesions should be avoided by using optimally adjusted aids. Treatment-related pain associated with MS can occur with subcutaneous injections of interferon-beta or glatiramer acetate, and may be reduced by optimizing the injection technique and by local cooling. Systemic (particularly 'flu-like') adverse effects of interferons, e.g. myalgias, can be reduced by administering paracetamol, ibuprofen or naproxen. A potential increase in the frequency of pre-existing headaches after starting treatment with interferons may require optimization of headache attack therapy or even prophylactic treatment. Pain unrelated to MS, such as back pain or headache, is common in patients with MS and may deteriorate as a result of the disease. In summary, a careful analysis of each pain syndrome will allow the design of the appropriate treatment plan using various medical and nonmedical options (multimodal therapy), and will thus help to improve the quality of life (QOL) of the patients.

Acquired pendular nystagmus (APN) is regularly accompanied by oscillopsia and impairment of static visual acuity. Therapeutic approaches to APN remain controversial, and there is no generally accepted therapeutic approach. We tested 14 patients who had suffered from APN caused by multiple sclerosis for several years; 12 patients presented with fixational pendular nystagmus (increasing during fixation) and 2 with spontaneous pendular nystagmus. All 11 patients with fixational pendular nystagmus who were given memantine, a glutamate antagonist, experienced complete cessation of the nystagmus. In contrast, scopolamine caused no (6 of 8) or only a minor (10-50%) reduction of the nystagmus (2 of 8). It was concluded that memantine is a safe treatment option for APN.