Headache and vascular inflammation?

No doubt, headaches may be related to vasospasm or carotid stenosis, but they may also be a typical symptom of an inflammatory arterial disease. Everybody has heard of atherosclerosis. Nevertheless few people know that vascular symptoms might be related to vascular wall inflammation, i.e. vasculitis. Degenerative atherosclerosis and its complaints develop slowly, over years (with the exception of an associated thrombotic event), whereas vasculitis acutely results in complaints and symptoms of a systemic inflammatory disease.

Patient with giant cell arteritis. On physical examination, a segment of the left temporal artery is thickened and nodular and the temporal artery is tender on palpation

Vasculitides are classified according to the size of the blood vessels involved. Large vessel vasculitis (LVV) is defined when large and medium vessels are involved. Giant cell arteritis (GCA) is one of the best known LVVs. Cranial GCA (75%) is the predominant form of GCA, when cranial vessels are involved, including extracranial branches of the external carotid artery such as the temporal arteries (temporal arteritis TA) with the typical symptom of a headache. The other form of GCA is Large Vessel GCA (25%), mainly involving the large and medium arteries of the trunk and extremities, especially the branches of the proximal aorta.

Diagnosis of GCA is based on the ACR criteria 1990, though revision of the criteria is in process. Differentiating GCA from other GCA-form presentations of diseases like tumours, infections and other autoimmune diseases is crucial, it is the task of specialists with rheumatology knowledge.  GCA almost exclusively affects patients aged ≥ 50 years. This is one reason for the association of GCA with polymyalgia rheumatica, an inflammatory rheumatic disease of the same population (see our next blog „PMR”).  GCA is a multifactorial disease, caused by genetic and environmental factors, infections and others, eg. UV radiation.  Nowadays, immune privilege is a highly frequented issue of autoimmune research, and GCA seems to be a failure of immune privilege. Tissue resident memory immune cells are deliberated, and pathogenic helper cells increase in numbers whereas regulatory cell deficiency develops. Interestingly, immune checkpoint inhibitors in the treatment of neoplastic diseases result in PMR/GCA -like symptoms.

Patients with GCA complain of a sudden onset, excruciating, bilateral, predominantly temporal headache (75-90%), accompanied by severe visual disturbances, eg. diplopia, scotoma, visual loss or blindness. Scalp tenderness occurs (33-50%) while brushing or combing the hair. Jaw claudication is highly specific for GCA (50%), due to ischaemia of the masseter muscle. Occasionally, intermittent claudication can affect the tongue or the muscles involved in swallowing.Constitutional symptoms, such as fever, anorexia, weight loss and fatigue, are present and sometimes prominent (33-66%). Fever is usually low grade, but it may exceed 38°C in about 10% of patients. In some cases, constitutional symptoms may be the only clinical manifestations of GCA, and some of them may fulfill criteria for fever of unknown origin. GCA is a major cause of irreversible visual loss. The incidence of ocular complications ranges from 14% to 70% in different series. The most common ophthalmic manifestation of GCA is anterior ischaemic optic neuropathy (AION). The clinical picture is described as a sudden painless loss of vision. Visual loss may present as a mist in the entire field or part of the visual field and evolve within 24–48 h to total blindness.

Physical examination in GCA may reveal tenderness, thickening, nodules and occasionally redness of the superficial temporal arteries. Temporal artery pulses may be decreased or absent, while in patients with large vessel involvement bruits may be heard, particularly in the supra-aortic branches.

Raised ESR and CRP have been considered a hallmark for the diagnosis of GCA, characteristic but not pathognostic. Raised inflammatory indices support, but normal ESR and CRP values make a diagnosis of GCA very unlikely.

Arthralgia and arthritis, polymyalgic symptoms (50%) associate the vascular symptoms.

GCA is diagnosed according to the ACR criteria 1990:1. Age at onset of the disease (≥ 50 years) 2. Newly onset localized headache, 3. Temporal artery tenderness, reduced pulses 4. Raised ESR 5. Pathognostic temporal artery biopsy (TAB). Three criteria are required. GCA diagnosis can be based on clinical symptoms only, but histology of the temporal artery remains the only definite sign.  Generally, temporal artery biopsy (TAB) is performed, histology shows giant cells (hence the name GCA), inflammatory cell infiltration of the vessel wall and disruption of the normal structure. Nowadays, vascular ultrasound (US) of the temporal artery is applied in an ever increasing number, the US results are somewhat similar to histology, non-compressible occlusion due to concentric vessel wall thickening is documented as the „halo-sign”.

On temporal artery histology: occlusion with concentrically thickened vascular wall caused by infiltration of inflammatory cells

There are pros and cons for both diagnostic methods. TAB is able to detect early signs of GCA, whereas US is a non-invasive method and gives us prompt results. Based on the enthusiastic work of US experts, Fast Track Clinics have been founded in England and Germany, in order to prevent severe complications, visual loss and irreversible blindness.

Examination by US:  halo sign: non-compressible occlusion (red) homogeneous hypoechoic wall thickening (black)

Other modalities of modern imaging can also used for diagnosis. If not the temporal, but other superficial cranial artery is involved, magnetic resonance image (MRI) would be a good choice. If GCA involvement is extracranial, the aorta and its branches, PET/CT should be advised.

Glucocorticoids (GC) remain the cornerstone in the treatment of GCA (GC). GC therapy should be started ad soon as the diagnosis is made. Severe complications, visual loss and blindness can be decreased with early GC treatment. The initial dose of methylprednisolone is 40-60 mg/die, later reduced slowly and gradually. GCs are generally needed for 1.5-2 years. Relapse of the disease is a real option if there is reduction or cessation of GC therapy before the appropriate time.

Long-term GC-related side effects are well known (obesity, diabetes, hypertension, hyperlipidaemia and osteoporosis). Effective drugs are needed to decrease cumulative GC dose. Attempts have been made to investigate different synthetic disease modifying drugs (DMARD) as glucocorticoid-sparing agents. Out of them Methotrexate has been proven the only one to have some significant effect in GC refracter disease.

Modern biological DMARDS are on trial. It seems, that a real breakthrough in the treatment of GCA has been achieved by the international GIACTA study, in which tocilizumab (TCZ), an IL 6R inhibitor for the first time proved to be successful and gained a sustained GC free remission with no severe adverse effects. The study was presented by J. Stone at the American  Congress of Rheumatology 2016, in Washington DC (see our previous post, click here).

Tocilizumab has been approved by the pharmaceutical agencies, the American Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of GCA. Tocilizumab has also been confirmed for the treatment of GCA in Hungary. Although the drug is very expensive, with the approval of individual applications the expenses are covered by the Hungarian National Health Fund.

Vacsulitis is a vascular disease and as such do not to forget about vascular physicotherapy,  Bemer pulse magnetotherapy (see our previous post, click here) as a complementerary treatment!