Headache and inflammatory disorders of the central nervous system

Neurol Sci (2004) 25:S148–S153 DOI 10.1007/s10072-004-0275-7 H E A D A C H E S A T T R I B U T E D T O N O N - VA S C U L A R I N T R A C R A N I A L D I S O R D E R S

L. La Mantia • A. Erbetta

Headache and inflammatory disorders of the central nervous system

Abstract The subcommittee of the International Headache Society for headache classification (ICHD-II) has recently recognised that secondary headaches may occur in patients affected by inflammatory diseases (ID) of the central nervous system (CNS), classifying them among the headaches attributed to non-vascular intracranial disorders. The aim of the study was to verify the association between headache and inflammatory non-infectious diseases of the CNS, by a review of the literature data on the topic, integrated by personal cases and data. Secondary headaches may occur in four main disorders: neurosarcoidosis (sec 7.3.1), aseptic (non-infectious) meningitis (7.3.2), other non-infectious ID (7.3.3) and lymphocytic hypophysitis (7.3.4). Headache and/or primary headaches are frequently reported in patients with neurosarcoidosis (30%), Behçet’s syndrome (BS) (55%) and acute disseminated encephalomyelitis (45–58%). Recent data show a high incidence of headache also in multiple sclerosis (MS) (58%) (not mentioned in ICHD-II). The association between headache and inflammatory dysimmune diseases of the CNS, in particular BS and MS, might suggest a pathogenetic relationship. Key words Headache • Inflammatory disease • Central nervous system • Neurosarcoidosis • Behçet’s syndrome • Multiple sclerosis

Introduction The subcommittee of the International Headache Society for headache classification (ICHD-II) has recently underlined that secondary headaches may occur in patients affected by inflammatory diseases (ID) of the central nervous system (CNS). Secondary headaches are recognised in 4 main non-infectious IDs: neurosarcoidosis (sec 7.3.1), aseptic (non-infectious) meningitis (7.3.2), other non-infectious ID (7.3.3) and lymphocytic hypophysitis (7.3.4) [1]. The aim of the study was to verify the association between headache and ID of the CNS, by a review of the literature data on the topic, with the focus on neurosarcoidosis, Behçet’s syndrome (BS), acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS).

Methods References were retrieved by electronic data base using the following key words: headache, migraine, tension headache, sarcoidosis, Behçet syndrome, ADEM and MS. The literature data were analysed in terms of incidence and characteristics of headache and integrated by personal cases. The review was performed following the ICHD-II classification.

Results of the review on secondary headache to CNS inflammatory non-infectious diseases L. La Mantia () MS Centre National Neurological Institute “C. Besta” Via Celoria 11, I-20133 Milan, Italy e-mail: [email protected] A. Erbetta Neuroradiological Department National Neurological Institute “C. Besta”, Milan, Italy

Headache attributed to neurosarcoidosis Sarcoidosis (NS) is a multisystem granulomatous disease of unknown cause, most commonly affecting young adults. Involvement of the CNS is clinically evident in 5% and silent in 10% of the cases with systemic sarcoidosis: it may occur at presentation in 10–30% of patients and more rarely is strictly confined to the CNS. Sarcoid lesions are non-

L. La Mantia, A. Erbetta: Headache in inflammatory diseases of the CNS

caseating epithelioid granulomas. Intracranial lesions, detectable by magnetic resonance imaging (MRI), appear as nodular or diffuse leptomeningeal thickening, mimicking various forms of meningitides, neoplastic seeding including carcinomatous and/or intra-parenchymatous lesions. MRI findings have been included in the diagnostic criteria [2]. Clinical aspects with focus on headache Any part of the CNS may be involved, resulting in a wide spectrum of clinical symptoms: headache is one of the most common neurological symptoms (see Table 1) [3]. Different kinds of headache are likely to occur, in relation to neuropathologic involvement: focal lesions, meningitis, cranial nerve palsies. No typical characteristics of headache are known: however, detailed information on these aspects is occasionally reported in the published studies. Occipital radiating frontally intractable headache with nausea and visual disturbances have been reported in patients with isolated supratentorial tumourlike lesions [4]. Diffuse or bifrontal pain is a more typical symptom of leptomeningeal involvement, associated or not to papilledema [5, 6]. Other forms of cranial pain may be related

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Table 1 Neurosarcoidosis. Clinical signs and symptoms of CNS [3] Symptoms

Percentage of affected cases

Cranial nerve palsies Headache Seizures Pituitary dysfunction Sensory and motor deficits Neuropsychological deficits Cerebellar symptoms Hydrocephalus Meningitis

50 30 10 10 10 10 10 5 5

to trigeminal or optic nerve involvement. Migraine has been also reported [7]. Case report A 56-year-old woman came to our observation for a painful paresis of the third right cranial nerve, neuropapillitis and transient trigeminal neuralgia on the right side. MRI showed a granulomatous lesion of the right cavernous sinus (Fig. 1).

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Fig. 1a–e Axial T1-weighted images (a, b) after contrast medium administration (c, d). The inflammatory process fills the right cavernous sinus. The enlarged cavernous sinus contains abnormal soft tissue isointense to grey matter (a, b), and enhancing after contrast medium administration (c, d). The CT scan shows abnormal soft tissue density in the orbital apex and gives more information about the actual extension of the granuloma (e). These features are commonly seen in meningioma or lymphoma too. Clinical history allows further precision in differential diagnosis

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Steroid treatment allowed pain remission within 3 months, but without effect on the neurological deficits. MRI showed a significant reduction of the lesion after therapy. The diagnostic work-up (angiotensin converting enzyme level, chest CT scan, BAL, gallium scintigraphy) allowed the diagnosis of probable neurosarcoidosis [2].

Headache attributed to other non-infectious inflammatory diseases Headache can be associated with but is not usually a presenting or dominant symptom of systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome, VogtKoyanagi-Harada syndrome [1]. The headaches reported in demyelinating disorders of the CNS, such as ADEM, BS and MS, have been analysed in the following sections. Acute disseminated encephalomyelitis ADEM is an uncommon, acute, demyelinating disorder of the CNS, typically occurring after infections or vaccina-

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tions. Autoimmune response to myelin basic protein triggered by infection or immunisation is considered to be a possible aetiologic factor. The diagnosis is based on clinical, MRI and CSF findings [8]. Clinical aspects with focus on headache Clinical features include sudden onset of multifocal neurological disturbances such as bilateral optic neuritis, aphasia, motor and sensory deficits, ataxia, movement disorders and signs of acute meningoencephalomyelopathy with meningism, decreased level of consciousness and seizures. Headache is a frequent symptom at onset, occurring in 45–58% of cases [9, 10]: it is usually severe, worsening within a few days, associated with vomiting, photophobia and meningism. Case report This 22-year-old woman was affected, 7 months before her hospitalisation in our institute, by an acute episode characterised by headache, confusional state and ataxia. Brain MRI revealed disseminated encephalomyelitis (Fig. 2), confirmed by cerebral biopsy. She was treated with high dosages of steroids with partial recovery. She complained of persistent

Fig. 2a–d Axial proton-density images (a, b) show large and scattered white matter lesions involving both hemispheres. Dense and irregular enhancement of portions of lesions is evident on T1-weighted images after gadolinium (c, d). Although there are large lesions, the mass effect is not prominent


frontal headache (chronic post-intracranial disorder headache). CSF examination was within normal limits. Behçet’s syndrome BS is a chronic multisystem T-cell mediated disorder, associated with HLA–B5 and B 51 antigens; vasculitis is the underlying pathogenetic process, which can be seen in the retina, brain and subcutaneous tissue. In 1990 the International Study Group for BS published the diagnostic criteria [11]. Clinical aspects with focus on headache Neurological involvement is reported in 22–50% of the cases (NeuroBehçet). Three main patterns have been identified: 1. Parenchymal CNS (65%) (brain stem syndrome, diffuse pseudobulbar and stroke-like); 2. Intracranial hypertension with papilledema (27.5%); 3. Meningitis-like (7.5%) [12].

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Headache is a frequent manifestation of the disease, its incidence ranging from 4 to 64% [12–16] (Table 2). It is the most common initial symptom of favourable prognostic value [15]. According to Evans [17], different types of headache may occur in BS, as in the general population, as related to specific neurological involvement and also to ocular manifestations. Case report This 47-year-old woman was affected by right uveitis associated with fronto orbital pain, and by oral and genital ulcers from 7 years. She complained of recurrent episodes of paraparesis and parestesias of the legs, gradually worsening from 2 years. CSF revealed oligoclonal bands. Brain and cervical spinal cord MRI showed demyelinating lesions (Fig. 3). She was treated with azathioprine with clinical stabilisation and remission of pain.

Table 2 Headache in BS Author

Incidence of headache No. cases/no. of patients (%)

Type of headache (%)

Serdaroglu, 1989 [14] Farah, 1998 [13] Al-Fahad, 1999 [12] Siva, 2001 [15] Ashjazadeh, 2003 [16]

26/323 (8) 1/24 (4) 22/40 (55) 296/460 (64) 80/96 (83.3)

Migraine (65), tension headache (19) nr nr Migraine (29.5), tension headache (57.5) nr

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Fig. 3a–c The neuroradiological features of the patient’s brain is weak and inconsistent. Axial T2-weighted image (a) reveals only three small, focal and punctate hyperintensities in the periventricular and subcortical white matter. The periventricular lesion is marked hypointense on T1-weighted image after gadolinium (b), consistent with loss of cerebral tissue. On the other hand, sagittal T2-weighted image (c) demonstrates several foci of high signal intensity in the cervical cord.

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Multiple sclerosis MS is a chronic inflammatory demyelinating disease of the CNS, characterised as having dissemination of lesions in both time and space. The diagnostic criteria have been recently revised [18]. Clinical aspects with focus on headache The signs and symptoms are quite various, as any part of the CNS may be involved in the different forms of the disease (remitting–relapsing, secondary and primary progressive). Pain is frequently reported in MS [19]. The relationship between MS and headache has been investigated with conflicting results. MS is not mentioned by ICDH-II among the IDs associated to secondary headaches. The lifetime prevalence of headache in MS patients is reported at between 4% and 58% [20, 21] and the frequency of headache as MS onset symptom is reported at between 1.6 and 26% [20, 22]. In a recent study we investigated the lifetime prevalence of headache and primary headache in

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137 patients with clinically definite MS. The prevalence of all headaches was 57.7%. Migraine was found in 25%; tension-type headache in 31.9% [23]. These figures are higher than that reported in the general population [24]. The role of MS treatments in exacerbating pre-existing headaches and triggering de novo headache syndromes has recently been emphasised [21, 25]. The headache is significantly more frequent in MS patients receiving interferon than placebo [26], although the presence of other comorbidities which may correlate with the presence or worsening of headache cannot be excluded. Case report This 31-year-old woman was affected by MS, which began 4 years before, with episodes of dysestesia of the left leg and arm and transient paraparesis. The MRI examination confirmed the diagnosis (Fig. 4). She was treated with Betaferon for one year and remained relapse-free. However, the treatment was interrupted for severe migraine without aura, flulike syndrome and sicca syndrome. Haematological examination revealed high autoantibodies levels.

Fig. 4a-d Axial T2-weighted images in acute MS (a, b) demonstrate large plaques in the periventricular white matter extending to the subcortical white matter with extensive oedema. Several months later, after beta interferon therapy, the lesions have almost completely resolved (c, d)


Conclusions Headache can be associated with, but is not usually a presenting or dominant symptom of ID of the CNS [1]. However headache is frequently reported in these diseases and namely neurosarcoidosis (30%), BS (55%), ADEM (45–58%) and MS (58%) (not mentioned in ICHD-II). Different types of headache may occur, as in the general population and as related to specific neuropathologic involvement. A common pathogenesis might be hypothesised in some cases (mainly BS and MS): the diseases are immune T-cell mediated and the brainstem is frequently involved [12, 27]. There is evidence that several brainstem areas are involved in the pathophysiology of migraine [28]. The diagnosis of secondary headaches should be revised according to ICHD-II criteria, in order to better understand the relationship between the two conditions.

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