Neurol Sci (2004) 25:S148–S153 DOI 10.1007/s10072-004-0275-7

HEADACHES ATTRIBUTED TO NON-VASCULAR INTRACRANIAL DISORDERS

L. La Mantia • A. Erbetta and inflammatory disorders of the central

Abstract The subcommittee of the International Headache Introduction Society for headache classification (ICHD-II) has recently recognised that secondary may occur in patients The subcommittee of the International Headache Society affected by inflammatory (ID) of the central ner- for headache classification (ICHD-II) has recently under- vous system (CNS), classifying them among the headaches lined that secondary headaches may occur in patients attributed to non-vascular intracranial disorders. The aim of affected by inflammatory diseases (ID) of the central ner- the study was to verify the association between headache vous system (CNS). Secondary headaches are recognised in and inflammatory non-infectious diseases of the CNS, by a 4 main non-infectious IDs: neurosarcoidosis (sec 7.3.1), review of the literature data on the topic, integrated by per- aseptic (non-infectious) (7.3.2), other non-infec- sonal cases and data. Secondary headaches may occur in tious ID (7.3.3) and lymphocytic hypophysitis (7.3.4) [1]. four main disorders: neurosarcoidosis (sec 7.3.1), aseptic The aim of the study was to verify the association (non-infectious) meningitis (7.3.2), other non-infectious ID between headache and ID of the CNS, by a review of the (7.3.3) and lymphocytic hypophysitis (7.3.4). Headache literature data on the topic, with the focus on neurosar- and/or primary headaches are frequently reported in coidosis, Behçet’s syndrome (BS), acute disseminated patients with neurosarcoidosis (30%), Behçet’s syndrome (ADEM) and (MS). (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 inflam- Methods matory dysimmune diseases of the CNS, in particular BS and MS, might suggest a pathogenetic relationship. References were retrieved by electronic data base using the fol- lowing key words: headache, , , sar- Key words Headache • Inflammatory • Central ner- coidosis, Behçet syndrome, ADEM and MS. The literature data were analysed in terms of incidence and characteristics of vous system • Neurosarcoidosis • Behçet’s syndrome • headache and integrated by personal cases. The review was per- Multiple sclerosis formed following the ICHD-II classification.

Results of the review on secondary headache to CNS inflammatory non-infectious diseases

L. La Mantia () Headache attributed to neurosarcoidosis MS Centre National Neurological Institute “C. Besta” Sarcoidosis (NS) is a multisystem granulomatous disease Via Celoria 11, I-20133 Milan, Italy of unknown cause, most commonly affecting young adults. e-mail: [email protected] Involvement of the CNS is clinically evident in 5% and A. Erbetta silent in 10% of the cases with systemic sarcoidosis: it may Neuroradiological Department occur at presentation in 10–30% of patients and more rarely National Neurological Institute “C. Besta”, Milan, Italy is strictly confined to the CNS. Sarcoid lesions are non- L. La Mantia, A. Erbetta: Headache in inflammatory diseases of the CNS S149

caseating epithelioid granulomas. Intracranial lesions, Table 1 Neurosarcoidosis. Clinical signs and symptoms of CNS [3] detectable by magnetic resonance imaging (MRI), appear as nodular or diffuse leptomeningeal thickening, mimicking Symptoms Percentage of affected cases various forms of meningitides, neoplastic seeding including carcinomatous and/or intra-parenchymatous lesions. MRI Cranial nerve palsies 50 Headache 30 findings have been included in the diagnostic criteria [2]. 10 Pituitary dysfunction 10 Clinical aspects with focus on headache Sensory and motor deficits 10 Neuropsychological deficits 10 Cerebellar symptoms 10 Any part of the CNS may be involved, resulting in a wide spec- 5 trum of clinical symptoms: headache is one of the most com- Meningitis 5 mon 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. to trigeminal or optic nerve involvement. Migraine has been No typical characteristics of headache are known: however, also reported [7]. detailed information on these aspects is occasionally reported in the published studies. Occipital radiating frontally Case report intractable headache with nausea and visual disturbances have been reported in patients with isolated supratentorial tumour- A 56-year-old woman came to our observation for a painful like lesions [4]. Diffuse or bifrontal is a more typical paresis of the third right cranial nerve, neuropapillitis and tran- symptom of leptomeningeal involvement, associated or not to sient on the right side. MRI showed a papilledema [5, 6]. Other forms of cranial pain may be related granulomatous lesion of the right cavernous sinus (Fig. 1).

a bc

d e 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 informa- tion about the actual extension of the granuloma (e). These features are com- monly seen in meningioma or lym- phoma too. Clinical history allows fur- ther precision in differential diagnosis S150 L. La Mantia, A. Erbetta: Headache in inflammatory diseases of the CNS

Steroid treatment allowed pain remission within 3 months, but tions. Autoimmune response to myelin basic protein trig- without effect on the neurological deficits. MRI showed a sig- gered by infection or immunisation is considered to be a nificant reduction of the lesion after therapy. The diagnostic possible aetiologic factor. The diagnosis is based on clini- work-up (angiotensin converting enzyme level, chest CT scan, cal, MRI and CSF findings [8]. BAL, gallium scintigraphy) allowed the diagnosis of probable neurosarcoidosis [2]. Clinical aspects with focus on headache Clinical features include sudden onset of multifocal neuro- logical disturbances such as bilateral , aphasia, motor and sensory deficits, ataxia, movement disorders and Headache attributed to other non-infectious inflammatory signs of acute meningoencephalomyelopathy with diseases meningism, decreased level of consciousness and seizures. Headache is a frequent symptom at onset, occurring in Headache can be associated with but is not usually a pre- 45–58% of cases [9, 10]: it is usually severe, worsening with- senting or dominant symptom of systemic lupus erythe- in a few days, associated with vomiting, photophobia and matosus (SLE), antiphospholipid antibody syndrome, Vogt- meningism. Koyanagi-Harada syndrome [1]. The headaches reported in demyelinating disorders of the CNS, such as ADEM, BS Case report and MS, have been analysed in the following sections. This 22-year-old woman was affected, 7 months before her hospitalisation in our institute, by an acute episode charac- Acute disseminated encephalomyelitis terised by headache, confusional state and ataxia. Brain MRI revealed disseminated encephalomyelitis (Fig. 2), confirmed ADEM is an uncommon, acute, demyelinating disorder of by cerebral biopsy. She was treated with high dosages of the CNS, typically occurring after infections or vaccina- steroids with partial recovery. She complained of persistent

a b

c d

Fig. 2a–d Axial proton-density images (a, b) show large and scattered white matter lesions involving both hemispheres. Dense and irregular enhancement of por- tions of lesions is evident on T1-weighted images after gadolinium (c, d). Although there are large lesions, the mass effect is not prominent L. La Mantia, A. Erbetta: Headache in inflammatory diseases of the CNS S151 frontal headache (chronic post-intracranial disorder Headache is a frequent manifestation of the disease, its headache). CSF examination was within normal limits. incidence ranging from 4 to 64% [12–16] (Table 2). It is the most common initial symptom of favourable prognostic Behçet’s syndrome value [15]. According to Evans [17], different types of headache may occur in BS, as in the general population, as BS is a chronic multisystem T-cell mediated disorder, associ- related to specific neurological involvement and also to ocu- ated with HLA–B5 and B 51 antigens; vasculitis is the under- lar manifestations. lying pathogenetic process, which can be seen in the retina, brain and subcutaneous tissue. In 1990 the International Study Case report Group for BS published the diagnostic criteria [11]. This 47-year-old woman was affected by right uveitis asso- ciated with fronto orbital pain, and by oral and genital Clinical aspects with focus on headache ulcers from 7 years. She complained of recurrent episodes Neurological involvement is reported in 22–50% of the cases of paraparesis and parestesias of the legs, gradually wors- (NeuroBehçet). Three main patterns have been identified: 1. ening from 2 years. CSF revealed oligoclonal bands. Brain Parenchymal CNS (65%) (brain stem syndrome, diffuse and cervical MRI showed demyelinating pseudobulbar and -like); 2. Intracranial hypertension lesions (Fig. 3). She was treated with azathioprine with with papilledema (27.5%); 3. Meningitis-like (7.5%) [12]. clinical stabilisation and remission of pain.

Table 2 Headache in BS

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

Serdaroglu, 1989 [14] 26/323 (8) Migraine (65), tension headache (19) Farah, 1998 [13] 1/24 (4) nr Al-Fahad, 1999 [12] 22/40 (55) nr Siva, 2001 [15] 296/460 (64) Migraine (29.5), tension headache (57.5) Ashjazadeh, 2003 [16] 80/96 (83.3) nr

a bc

Fig. 3a–c The neuroradiological features of the patient’s brain is weak and incon- sistent. Axial T2-weighted image (a) reveals only three small, focal and punctate hyperintensities in the periventricular and subcortical white matter. The periven- tricular 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. S152 L. La Mantia, A. Erbetta: Headache in inflammatory diseases of the CNS

Multiple sclerosis 137 patients with clinically definite MS. The prevalence of all headaches was 57.7%. Migraine was found in 25%; MS is a chronic inflammatory of the tension-type headache in 31.9% [23]. These figures are CNS, characterised as having dissemination of lesions in higher than that reported in the general population [24]. both time and space. The diagnostic criteria have been The role of MS treatments in exacerbating pre-existing recently revised [18]. headaches and triggering de novo headache syndromes has recently been emphasised [21, 25]. The headache is Clinical aspects with focus on headache significantly more frequent in MS patients receiving inter- The signs and symptoms are quite various, as any part of feron than placebo [26], although the presence of other the CNS may be involved in the different forms of the dis- comorbidities which may correlate with the presence or ease (remitting–relapsing, secondary and primary pro- worsening of headache cannot be excluded. gressive). Pain is frequently reported in MS [19]. The relationship Case report between MS and headache has been investigated with This 31-year-old woman was affected by MS, which began conflicting results. MS is not mentioned by ICDH-II 4 years before, with episodes of dysestesia of the left leg and among the IDs associated to secondary headaches. The arm and transient paraparesis. The MRI examination con- lifetime prevalence of headache in MS patients is report- firmed the diagnosis (Fig. 4). She was treated with Betaferon ed at between 4% and 58% [20, 21] and the frequency of for one year and remained relapse-free. However, the treat- headache as MS onset symptom is reported at between 1.6 ment was interrupted for severe migraine without aura, flu- and 26% [20, 22]. In a recent study we investigated the like syndrome and sicca syndrome. Haematological exami- lifetime prevalence of headache and primary headache in nation revealed high autoantibodies levels.

a b

c d

Fig. 4a-d Axial T2-weighted images in acute MS (a, b) demonstrate large plaques in the periventricular white matter extend- ing to the subcortical white matter with extensive oedema. Several months later, after beta interferon therapy, the lesions have almost completely resolved (c, d) L. La Mantia, A. Erbetta: Headache in inflammatory diseases of the CNS S153

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