Brainstem signs with progressing atrophy of medulla oblongata and upper cervical spinal cord

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Brainstem signs with progressing atrophy of medulla oblongata and upper cervical spinal cord Silvia Romano, Marco Salvetti, Isabella Ceccherini, Tiziana De Simone, Mario Savoiardo Lancet Neurol 2007; 6: 562–70 Department of Neurology and Centre for Experimental Neurological Therapy, S Andrea Hospital, University of Rome La Sapienza , Rome, Italy (S Romano MD, M Salvetti MD); Laboratory of Molecular Genetics, Institute G Gaslini, Genova, Italy (I Ceccherini PhD); Department of Neuroradiology, National Neurological Institute “C Besta”, Milan, Italy (T De Simone MD, M Savoiardo MD) Correspondence to: Dr Mario Savoiardo, Department of Neuroradiology, Instituto Nazionale Neurologico “C Besta”, Via Celoria 11, 20133 Milan, Italy [email protected]

Case presentation A 20-year-old man was admitted to hospital in May, 1998, because of episodic dysphagia and dysphonia. 18 years earlier, he had two generalised tonic-clonic seizures and was treated with valproic acid for 3 years; family history was unremarkable. On admission, neurological examination showed transient gaze-evoked nystagmus, episodic dysphagia, episodic dysphonia, brisk symmetrical tendon reflexes with bilateral ankle clonus. Full blood count, serum electrolytes, liver enzymes, bilirubin, blood sedimentation, and routine urinanalysis were normal. Analyses of cerebrospinal fluid (CSF) (traumatic puncture with bloody appearance) showed white blood cells 0·11 × 109/L, total protein 3870 mg/L, glucose 3·3 mmol/L, IgG 0·23 g/L, and no oligoclonal bands detected with isoelectrofocusing. Brainstem auditory-evoked potentials showed increased bilateral I–III interpeak latency. Other evoked potentials showed prolonged latencies. Electroencephalography showed frontal and central low-frequency activity. MRI showed T2 hyperintensity that extended from the medulla oblongata to C1–C2, with areas of contrast enhancement. The first diagnosis was that of brainstem tumour. A course of steroid treatment was ineffective. In 1999, dysphagia became permanent and the patient developed diplopia due to right VIth nerve palsy. Yearly MRI showed slowly progressing medullary atrophy and A

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persistent contrast enhancement. A thin rim of periventricular signal abnormalities in fluid-attenuated inversion recovery (FLAIR) and T2-weighted images were also noted (figures 1–4). MRI showed slight elevation of choline and the presence of lactate. On admission to hospital in October, 2005, neurological examination showed diplopia with convergent strabismus in the right eye, gaze-evoked nystagmus, dysphonia, dysphagia, slight spastic paresis of the right leg, brisk symmetrical tendon reflexes with bilateral ankle clonus, bilateral extensor plantar response, positive Romberg’s sign, and bladder dysfunction manifested by urinary urgency. The patient had reduced vibratory sensation in the arms and legs. However, all symptoms and signs were mild and the main complaint remained diplopia. The patient did not show mental and cognitive impairment, and was able to have a job and attend university. Lyme serology and testing for the presence of autoantibodies (ie, antinuclear, antimitochondrial, antismooth muscle, antigastric parietal cells, antidoublestranded DNA, anticardiolipin, lupus anticoagulant, antiHu, antiRi, antiYo, and antiglutamic acid decarboxylase) were negative. There were no urogenital or cutaneous ulcerations and no evidence of ocular pathology. Blood concentration of lactic acid and pyruvic acid were normal, and genetic testing for mitochondrial encephalopathies (ie, myoclonus epilepsy associated with ragged-red fibres; and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke) was negative. Analysis of very-long-chain fatty acids showed no abnormalities. A second examination of CSF showed a normal white cell count and total protein concentration, with absent oligoclonal bands. Total-body CT was normal. Repeat MRI confirmed atrophy of the medulla oblongata and upper spinal cord with persistent mild postcontrast enhancement.

Clinical diagnosis

Figure 1: First MRI, 1998 T2-weighted (A) and postcontrast T1-weighted (B) midline sagittal sections on brainstem and cervical spinal cord show T2 signal hyperintensities in medulla oblongata and C1 segment of spinal cord, which maintain normal size (A). Patchy enhancement at lower pons and brainstem–spinal cord junction (arrows, B). Normal cervical enlargement is not appreciable.

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The involvement of several cranial nerves and the clinical history of the patient are consistent with brainstem dysfunction without systemic symptoms. Brainstem lesions might involve different cranial nerves, the corticospinal and corticobulbar tracts, and the reticular formation. The patient might have vertigo, dizziness, no coordination, nausea, and vomiting because of impaired vestibular and cerebellar connections. Although most neurological diseases that involve the brainstem might occur in other parts of the brain, some tumours, demyelinating diseases, inflammatory, and granulomatous disorders show preferential brainstem involvement. http://neurology.thelancet.com Vol 6 June 2007

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Figure 2: MRI in December, 2003 Axial T2-weighted sections (A–C) at cranio–cervical junction show patchy areas of hyperintensity (arrows) at ponto–medullary junction (A), in central and dorsal medulla and inferior cerebellar peduncles (B), and in lateral columns at C1 level (C).

Brainstem tumours In a young patient, brainstem glioma is the first tumour to be suspected. Brainstem gliomas typically arise in the first two decades of life (ie, they are substantially less common in adults than in children), and can cause cranial nerve palsy and long tract signs. The most common tumour type is that of diffuse intrinsic glioma (80% of patients), usually arising in the pons1 as an enlarging tumour with involvement of an entire crosssection of the brainstem; it may slightly, inhomogeneously enhance on postcontrast studies. Some focal gliomas (eg, posterior exophitic or focal tectal) might present with clinical symptoms because of hydrocephalus and increased intracranial pressure. The clinical presentation of the patient and the slow progressive disease course are consistent with a diagnosis of brainstem glioma. However, MRI stability and onset of atrophy are inconsistent with this diagnosis. Other rare tumours such as lymphomas and ependymomas need to be considered. Lymphomas commonly do not have substantial mass effect, as shown by MRI, and are distinguished by uniform enhancement after gadolinium administration. In the early stage of the disease, patients with lymphoma usually respond well to corticosteroid treatment. Ependymomas might mimic clinically an intrinsic tumour of the brainstem as a result of compression and infiltration around the lateral recess of the fourth ventricle where they commonly originate. However, ependymomas frequently have an extra-axial component on MRI and surgery that might extend caudally between the tonsils. Clinical and MRI work-ups of the patient rule out the presence of these tumours.

White-matter diseases Acquired demyelinating diseases are the second possible diagnosis. Multiple sclerosis is the most common chronic inflammatory demyelinating disease of the CNS that affects young adults. Clinical manifestations from brainstem lesions vary among patients. Bilateral http://neurology.thelancet.com Vol 6 June 2007

internuclear ophthalmoplegia from involvement of the medial longitudinal fasciculus is a frequent manifestation. MRI might show lesions of the periventricular white matter, brainstem, cerebellum, and spinal cord at different levels to a varying extent. Lesions associated with multiple sclerosis are unlikely to group in the medulla oblongata and C1 segment and to present a uniform periventricular distribution rather than the radially oriented Dawson’s fingers.2 Moreover, postcontrast enhancement in patients with multiple sclerosis does not last for years,3 and the lack of oligoclonal bands and the slow progressive disease course do not lend support to this diagnosis for the patient. Behçet’s disease and systemic lupus erythematosus are inflammatory diseases that might mimic multiple sclerosis and involve the brainstem. Behçet’s disease is a vasculitis with a chronic course. It is more common in men than in women, and has variable geographical prevalence, which in Turkey ranges from eight to 42 people per 10 000.4 Postmortem studies show that 20% of patients with Behçet’s disease have neurological involvement.5 Although the characteristic mucocutaneous ulcers of the mouth and perineum usually precede or accompany neurological symptoms, they occasionally occur later and thus prevent the possibility of diagnosis. Brainstem manifestations seem to be the most common CNS presentation of Behçet’s disease, which include cranial nerve palsies, cerebellar signs, and sensory and motor long-tract signs.6 On MRI, midbrain is the most common location of signal abnormalities, with frequent diencephalic or basal ganglia extension.6 Analysis of the CSF of patients with Behçet’s disease shows pleocytosis, neutrophilic or lymphocytic, and elevated protein levels; a few patients might have oligoclonal bands.7,8 Clinical or laboratory findings are not consistent with a diagnosis of Behçet’s disease for the patient. Systemic lupus erythematosus is an autoimmune disorder that involves the skin, mucous membranes, musculoskeletal system, heart, lungs, or kidneys. Up to 563

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Figure 3: MRI in December, 2003 Supratentorial sections at two different levels of lateral ventricles. T2-weighted images (A–C) show narrow bands of slightly increased signal intensity with garlandlike aspect (arrows, C, detail of B). FLAIR images (D,E) show more conspicuous signal-intensity changes (arrows). On postcontrast T1-weighted image (F), irregular profile of lateral ventricle is visible (arrows).

60% of patients have neurological and psychiatric symptoms; however, brainstem localisations are rare.9,10 Optic neuritis and myelopathy have been described occasionally. For some patients, the clinical presentation of systemic lupus erythematosus is indistinguishable from that of multiple sclerosis.11 The lack of systemic symptoms and normal antibody titres without involvement of other organs rule out this diagnosis for the patient. We considered Bickerstaff’s encephalitis—a rare inflammatory disease. An autoimmune pathogenesis has been suggested for this disease because of presence of serum anti-GQ1b IgG. These antibodies are present in Miller Fisher syndrome—a localised variant of GuillainBarré syndrome.12 Bickerstaff’s encephalitis manifests clinically as a postviral illness that preferentially involves the midbrain, and is characterised by progressive ophthalmoplegia, ataxia, and disturbed consciousness. Analysis of CSF in these patients shows pleocytosis and increased protein concentration. The clinical course of the patient was not consistent with this diagnosis. 564

Brainstem involvement can be seen in several leucoencephalopathies or leucodystrophies. Of the inherited leucodystrophies, brainstem lesions are found most frequently in X-linked adrenoleucodystrophy, leucoencephalopathy with brain stem and spinal cord involvement and high lactate,13 and Alexander’s disease. Adrenoleucodystrophy is an X-linked disease caused by accumulation of very-long-chain fatty acids in neural tissue and the adrenal glands because of a defect of peroxisomal β-oxidation. Accumulation of fatty acids in plasma is identified easily by screening of serum, which was normal in the patient. Moreover, common findings such as adrenal insufficiency and posterior white-matter lesions that involve the splenium of the corpus callosum were absent in the patient. Leucoencephalopathy with high concentration of lactate in the brain is a rare white-matter disease.13 Cerebral MRI shows inhomogeneous signal abnormalities in the periventricular and deep white matter, brainstem, cerebellar connections, and dorsal http://neurology.thelancet.com Vol 6 June 2007

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Figure 4: MRI in September, 2004 Contiguous sagittal T2-weighted sections (A,B) show signal changes and progression of atrophy of medulla oblongata and upper spinal cord (arrows in B). Coronal postcontrast T1-weighted section (C) confirms persistence of enhancement (arrows) at the level of ponto–medullary junction.

columns of the spinal cord. Proton magnetic resonance spectroscopy (MRS) of patients with this disease is characterised by decreased N-acetylaspartate and increased lactate in white matter.14 The patient did not have the distinctive MRI features described above. Brainstem involvement in Alexander’s disease, which is commonly present in infants with the disease who have frontal preponderance of white-matter abnormalities, might be the predominant feature in the juvenile or adult variants.15,16

Granulomatous disease Because the patient had a persistently abnormal blood–brain barrier on MRI, we considered the possibility of granulomatous disorders. CNS involvement in sarcoidosis—an inflammatory multisystem disease of unknown cause—is rare. Neurosarcoidosis preferentially occurs in the hypothalamic region, starting in the leptomeninges; however, any part of the CNS can be involved, resulting in a wide range of clinical syndromes. Involvement of the VIIth cranial nerve and diabetes insipidus are the most common presenting signs.17 Systemic signs include hilar lymphoadenopathy; diffuse pulmonary infiltration; and lesions of skin, liver, and eyes. In neurosarcoidosis, examination of CSF is not specific and shows a chronic inflammatory pattern with mild lymphocytic pleocytosis and elevated protein concentration. Increased concentration of angiotensin-converting enzyme in the serum and CSF should be expected. Diagnosis of sarcoidosis is unlikely in the patient, considering the lack of systemic involvement, MRI findings, normal concentration of angiotensin-converting enzyme, and normal CSF examination. Langerhans’ cell histiocytosis and Erdheim-Chester disease (a non-Langerhans histiocytosis) might affect the http://neurology.thelancet.com Vol 6 June 2007

brainstem, and are commonly characterised by patchy areas of enhancement and minimum mass effect. Both disorders might involve several organs and, rarely, the CNS. Langerhans’ cell histiocytosis (previously called histiocytosis X) is a reactive, granulomatous disease rather than a neoplastic condition. Erdheim-Chester disease is generally regarded as a neoplastic, monoclonal proliferation of histiocytes with macrophage differentiation.18 These disorders are identified by use of immunochemistry and electron microscopy; Birbeck granules confirm Langerhans’ cell histiocytosis.18,19 Diabetes insipidus or cerebellar and brainstem signs indicate CNS involvement.20 When the brainstem is affected, lesions are found more frequently in the pons than in the medulla oblongata. Associated features that may aid diagnosis of Langerhans’ cell histiocytosis and Erdheim-Chester disease are age (Langerhans’ cell histiocytosis in children and ErdheimChester disease in adults), and the presence of lytic bone lesions (especially in the flat bones of the cranium) in Langerhans’ cell histiocytosis.21 Erdheim-Chester disease is characterised by symmetric, patchy, diametaphyseal sclerotic lesions in the long bones of the legs.18,22 However, a particular feature of this disease may aid diagnosis: persistence of postcontrast enhancement in lesions for days or weeks after injection of contrast medium due to the phagocytic properties of the histiocytes that characterise this disease.23 Such longlasting enhancement was not found in the patient. Furthermore, shrinkage of the brainstem without previous radiotherapy or chemotherapy, and the association with periventricular abnormalities, rule out this diagnosis.

Neuroradiological differential diagnosis This 27-year-old man first had a brain MRI in July, 1998, at age 20 years, because of dysphagia and dysphonia. 565

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From 1998 to 2005, he had MRI studies about once a year, most of which were available for review. The first MRI study of the brain and cervical spinal cord showed a minimal or questionable enlargement of the lateral ventricles, normal cisterns, and normal sulci. A narrow band of periventricular hyperintensity in FLAIR images that were slightly larger around the frontal horn of the left ventricle had been overlooked initially. These signal abnormalities were barely visible in spin-echo T2-weighted images. The medulla oblongata presented very marked and inhomogeneous hyperintensities in T2-weighted images, extending cranially to the lower pons and caudally into the lateral columns of the spinal cord down to C1–C2 level. Below this level, the signal intensity of the spinal cord was normal, but there was no evidence of normal cervical enlargement. Postcontrast examination showed patchy enhancement of the medulla oblongata, mostly at the junction with C1 segment and at the ponto–medullary junction (figure 1). No swelling or any sign of mass effect were present on these MRI films; the discharge summary suggested “probable brainstemspinal cord tumour”. In the MRI films from 2002, atrophy involving the medulla oblongata and upper spinal cord is evident. Postcontrast examination confirmed the abnormal blood–brain barrier at the junction between the brainstem and the spinal cord, and showed a tiny area of enhancement in the chiasm. In 2003 and 2004, signal abnormalities in the lower brainstem and upper spinal cord did not change (figure 2), whereas atrophy slightly increased. Clearly visible in T1-weighted and T2-weighted images was involvement of periventricular white matter along the temporal horns, and irregularities of the profile of the superior segments of the lateral ventricles (figure 3). Postcontrast enhancement seemed less marked at the junction between the brainstem and the spinal cord, but increased at the ponto–medullary junction (figure 4). The enhancement in the chiasm was no longer present. The last MRI study in June, 2005, was unchanged, compared with those of 2003 and 2004, although the enhancement seemed milder than in previous studies. Magnetic resonance spectroscopy of the cerebral hemispheres in February, 2004, and January, 2005, (TR [repetition time] 2000 ms, TE [echo time] 272 ms, 250 mm field of view, and 32×32 phase-encoding steps) showed slight elevation of choline and presence of lactate in periventricular regions. Lactate was present in ventricular CSF. N-acetylaspartate was normal. A CT scan in June, 2005, confirmed the irregularities of the profile of the lateral ventricles, without calcifications. In conclusion, MRI showed that the patient had a disorder with various features: signal abnormalities of the periventricular white matter of the cerebral hemispheres, in a limited, ribbon-like extension, with irregularities of the ventricular profile; involvement of the lower part of the brainstem and upper cervical spinal 566

cord, with marked signal changes and persistent (although diminishing) patchy areas of abnormal blood–brain barrier; and development and progression of atrophy of the medulla oblongata and spinal cord. This last finding was the most striking feature. These MRI features, periventricular abnormalities, and lesions in the brainstem and upper spinal cord seem to orient the diagnosis in different directions. Abnormalities in periventricular white matter in a young person should immediately suggest a demyelinating disorder— specifically multiple sclerosis. However, their distribution and the persistent abnormal blood–brain barrier do not lend support to this diagnosis. The patient’s periventricular abnormalities are not associated with hydrocephalus and, therefore, interstitial oedema due to transependymal passage of fluid is unlikely. Moreover, the limited extension and the fairly neat definition of the band of periventricular signal abnormalities and their association with the peculiar distribution of brainstem lesions would be very unusual for a metabolic leucoencephalopathy. The enhancing lesions in the brainstem and upper spinal cord that evolved into atrophy are also difficult to interpret. Two main factors militate against the initial tentative diagnosis of brainstem tumour. First, the normal brainstem size and the pattern of enhancement would be very unusual for a brainstem glioma. Second, to unify diagnoses, the periventricular abnormalities should be interpreted as an expression of either a multicentric glioma or a dissemination through the CSF on the walls of the lateral ventricles from the brainstem tumour. To our knowledge, there is no tumour that can disseminate to such an extent in the ventricular system. Diffuse leptomeningeal gliomatosis from benign24 or malignant tumours might occur rarely, but diffuse dissemination on the ventricular walls is probably never seen. Moreover, ventricular dissemination in this patient would require countercurrent seeding—ie, against the flow of CSF exiting the fourth ventricle. We occasionally observe ependymal seeding in the frontal horns (manifested by a thin layer of enhancement) only in germinomas, either pineal or suprasellar. We did not consider a diagnosis of germinoma; however, atrophy has been described in germinomas of the basal ganglia or thalamus, mostly in Japanese or other oriental populations.25,26 We have observed only two such cases, and are not aware of a brainstem presentation. Atrophy of the ipsilateral brainstem has been noted in a few cases of basal ganglia germinoma, but was considered secondary to Wallerian degeneration.27 We considered mitochondrial disorders; however, brainstem involvement in mitochondrial diseases, particularly that of Leigh syndrome, is found more frequently in the midbrain and pontine tegmentum than in the lower brainstem.28,29 Furthermore, to our knowledge, persistent enhancement has never been reported with mitochondrial diseases. http://neurology.thelancet.com Vol 6 June 2007

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In conclusion, the 7-year stability of the supratentorial and infratentorial lesions, the persistent disruption of the blood–brain barrier, and the development of brainstem and spinal cord atrophy in the absence of steroid treatment, radiotherapy, or chemotherapy make a tumour and any kind of inflammatory or granulomatous lesions very unlikely. Therefore, an uncommon presentation of a leucodystrophic process should be reconsidered. The narrow periventricular rim of signal change is not compatible with a series of leucoencephalopathies, such as metachromatic leucodystrophy, Canavan disease, organic acidurias, and hypomyelinating disorders.30–32 Furthermore, in these disease settings the abnormalities that extend to the brainstem are not confined to the medulla oblongata. The periventricular changes are also not consistent with the pattern observed in the adult variant of some of these diseases such as Krabbe’s disease33–35 or adrenomyeloneuropathy (the adult milder form of adrenoleucodystrophy)36 that should be considered because of the patient’s age. Most leucodystrophies have no postcontrast enhancement. However, Alexander’s disease is a leucodystrophy in which enhancement occurs.15 This disease usually presents in infants or young macrocephalic children, and leads to rapid neurological deterioration and early death. It can have a juvenile onset, between 2-years-old and 12-years-old, in which megalencephaly might be mild or absent and the course less rapid.15 CT or MRI studies of the most common infant form of Alexander’s disease show striking abnormalities. In addition to megalencephaly, abnormal densities and signal abnormalities are recognisable in the white matter of the cerebral hemispheres, and are prominent in the frontal regions where convolutions might appear swollen with effacement of the sulci. The white matter is hypodense on CT and hyperintense in T2-weighted MRI images up to its most peripheral extension under the cortical ribbon. Density and signal intensities tend to return to normal in posterior parietal and occipital regions. Various degrees of swelling and abnormal signal intensities might involve basal ganglia and the brainstem, sometimes with a tumour-like aspect.16 The putamen and head of the caudate nucleus are almost always involved; in the brainstem, the midbrain and medulla oblongata are frequently affected. Ventricles are initially normal or thin, enlarging during the disease course when atrophic changes or cystic degeneration of white matter arise. Consistent with several leucoencephalopathies associated with megalencephaly, a cyst of the septum pellucidum is commonly found in Alexander’s disease, sometimes extending posteriorly in a dilated cavum vergae. MRI abnormalities associated with this disease have been codified by van der Knapp and colleagues.15 In addition to the abnormalities mentioned above, they emphasised the presence of a periventricular rim of variable width with high signal intensity in T1-weighted images, hypointensity in T2-weighted images, hyperhttp://neurology.thelancet.com Vol 6 June 2007

density on CT,37 and contrast enhancement in these areas and in other grey-matter and white-matter structures. Distribution of contrast enhancement correlates with that of Rosenthal fibres—the histological hallmark of Alexander’s disease.15,38 These fibres, proteinaceous astrocytic inclusions with hyaline appearance on light microscopy, are particularly abundant in the subependymal, perivascular, and subpial areas. They accumulate most at astrocyte endfeet (ie, the astrocytic processes that abut endothelial cells).39 Therefore, their accumulation may impair the blood–brain barrier and cause the contrast enhancement that is observed on MRI. There have been reports of adults who have presented with mild neurological impairment usually consisting of weakness, ataxia, dysfunction of lower cranial nerves, and palatal myoclonus: diagnosis of Alexander’s disease was made upon histological identification of Rosenthal fibres at postmortem or cerebellar biopsy.40 Mutations in GFAP, which encodes glial fibrillary acidic protein, are associated with Alexander’s disease.41 Studies of transgenic mice with copies of human GFAP showed presence of hypertrophic astrocytes with inclusion bodies identical to the Rosenthal fibres of Alexander’s disease.42 Mutations in GFAP have been identified in children and adults with Alexander’s disease, which, from 2002, could also be diagnosed without biopsy, enabling the recognition of a peculiar MRI pattern.16,43-48 The MRI patterns described in children and adults with Alexander’s disease matches those of the patient and of four other confirmed cases we have seen recently. The first feature is atrophy of the medulla oblongata and upper spinal cord. The second feature is signal abnormalities in the atrophic brain stem, spinal cord, and commonly in the hilus of the dendate nuclei. The third feature is patchy postcontrast enhancement, mostly in the lower brainstem and dendate nuclei, sometimes with minimum postcontrast enhancement in periventricular areas. The fourth feature is a periventricular, symmetric band of abnormal signal intensity, sometimes with a garland-like aspect. Ventricular garlands might represent synechiae, but their nature has not yet been established.48 Periventricular signal abnormalities are usually more conspicuous in FLAIR images than in T2-weighted images. In a few patients, periventricular signal changes are absent: the MRI picture is limited to atrophy and signal changes in the medulla oblongata and upper cervical spinal cord without postcontrast enhancement. MRS findings are not specific. Increased myo-inositol is usually found in Alexander’s disease, but we could not confirm the presence of this glial marker in the patient because of the long TE used.49,50 In conclusion, the MRI pattern of the patient is peculiar, and does not fit with any other disorder that we know of, whereas it corresponds perfectly to the pattern now observed in a sufficient number of cases of Alexander’s disease. The transient, minimum enhancement observed 567

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in the chiasm of the patient is consistent with the adult form of Alexander’s disease because involvement of the chiasm and fornices has been reported.16 In our opinion, the neuroradiological diagnosis is Alexander’s disease, and the appropriate test for confirmation is DNA sequence analysis of GFAP.

Genetic test We did genomic DNA sequence analysis for presence of GFAP mutations. Exons one to nine of the gene, including the flanking intronic sequences, were investigated by direct sequencing. We identified a heterozygous missense mutation, 1076T→C, in exon 6 that results in Leu359Pro. A correlation between disease symptoms and this aminoacid substitution is consistent with the identification of another mutation, Leu359Val, in association with Alexander’s disease.51

Alexander’s disease Alexander’s disease is a very rare, genetically determined leucoencephalopathy that was first described in 1949 by W Stewart Alexander.52 The eponym of Alexander’s disease was proposed by R Friede in 1964.53 Three forms of Alexander’s disease have been identified according to age of onset: infant (ie, those younger than 2-years-old), juvenile (ie, from 2-years-old to 12-years-old), and adult (ie, 13 years or older).51 The infant form is the most severe and common, and presents with macrocephaly, seizures, spasticity, and retarded physical and mental development. Clinical and MRI pictures are sufficiently characteristic to enable diagnosis in the absence of biopsy and identification of Rosenthal fibres.15 Death occurs from 2 months to 7 years after onset of symptoms. Juvenile and adult patients do not present with macrocephaly, and are characterised clinically by lower brainstem signs including speech abnormalities, swallowing difficulties, frequent vomiting, spasticity, and ataxia. In adults, dysautonomia, sleep disturbances, and palatal myoclonus have been observed.43,45,47 Ocular palsies, as seen in the patient, are reported very rarely.40,43 The clinical course of the adult form is slow, and patients older than 60 years have been described.45 A few patients might remain asymptomatic.54 Genetic diagnosis is crucial, particularly for those who remain asymptomatic, because it will show the full clinical spectrum of the disease; biopsy of the brainstem in the search of Rosenthal fibres cannot be proposed. Histologically, the hallmark of Alexander’s disease is the presence of Rosenthal fibres—eosinophilic astrocytic cytoplasmic inclusions that form elongated tapered rods up to 30 μm long. These structures contain GFAP, ubiquitin, heat shock protein 27, and αβ-crystalline; they are most numerous in astrocytes localised in subpial, perivascular, and subependymal sites.39,55 Rosenthal fibres are also commonly found in pilocytic astrocytomas and in states of chronic reactive gliosis (eg, glial scars, syringomyelia).39 568

GFAP is a member of the intermediate-filament superfamily, and its fairly specific expression in mature astrocytes might play an important part in the stability and functional integrity of the cytoskeleton. GFAP is formed by four α-helical segments (called 1A, 1B, 2A, and 2B) that are linked and flanked by a non-helical N-terminal head and C-terminal tail domains.51 Most mutations have been reported in the conserved central rod domain that participates in interfilament interactions. Transgenic mice engineered to overexpress wildtype human GFAP develop a fatal encephalopathy and form identical aggregates in astrocytes, suggesting that elevated GFAP in addition to mutant protein might contribute to the pathogenesis of Alexander’s disease. Moreover, GFAP-null mice show subtle effects on development.56,57 The mice are viable, with a seemingly normal life span, reproduction, and gross motor behaviour. However, the absence of GFAP does seem to lead to a defect in the fine distal processes of the astrocyte, but the nature of this defect has not been defined. Moreover, null mice showed apparantly normal responses to several types of injury, except blunt head trauma, ischaemia, and hypotonic stress.56 These data, according to lack of human null mutations, might confirm that the dominant effect of mutations in Alexander’s disease is caused by a gain of function rather than loss of function. To date, the number of adults with confirmed mutations in GFAP is too small to make distinctive correlations between genotype and phenotype. Most reported cases are sporadic, caused by de novo heterozygous mutations in GFAP, but families with dominantly inherited disease have been reported.44,45,54 Sex-dependent modulation of disease progression has been suggested by heterogeneous clinical presentations between males and females who have identical mutations. Moreover, modifier genes and other factors might have a role in disparate clinical presentations among affected members in the same family.58 Particular mutations seem to be associated with a typical phenotype. For instance, mutations that affect Arg239 might contribute to a severe phenotype; other mutations (eg, Lys63Gln, Glu207Lys, and Leu331Pro) seem to be associated with less severe forms.51 To our knowledge, we have reported the first patient with adultonset Alexander’s disease with a mutation (Leu359Pro) located in the 2B rod domain of the gene. Most mutations reported in this region lead to a severe phenotype with a fulminating course. However, a patient with a different mutation at codon 359 (Leu359Val) had a milder disease progression.51 We did not observe cognitive defect in the patient, which has been described in juvenile Alexander’s disease with Leu359Val.51 The clinical course of the patient suggests a possible correlation between mild phenotype and mutations at the codon 359. Allogeneic bone-marrow transplantation, which has demonstrated efficacy in some metabolic leucoencephalopathies,59 is ineffective for those with Alexander’s disease.60 The only treatment available is symptomatic. http://neurology.thelancet.com Vol 6 June 2007

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Conclusion Genetic testing of GFAP will enable recognition of an increasing number of juvenile, adult, or atypical cases of Alexander’s disease, and may show the full clinical and MRI spectrum of this leucoencephalopathy. A young individual or adult with unexplained lower-brainstem symptoms and signs who has brainstem atrophy on MRI, with or without postcontrast enhancement, should be investigated for Alexander’s disease. Contributors SR and MS were involved in the clinical care of the patient, and were the primary source of clinical information. MS analysed and discussed neuroradiological studies. IC did the genetic testing, and was involved in genetic consultation. TDS prepared illustrations and contributed to the literature search. SR and MS were principally responsible for writing the article. Conflicts of interest We have no conflicts of interest. Acknowledgments We thank P O Behan (Institute of Neurological Sciences, University of Glasgow, UK) for reading the Grand Round and for helpful advice, and L M Fantozzi (S Andrea Hospital, University La Sapienza, Rome, Italy) for the MRI studies. References 1 Guillamo JS, Doz F, Delattre JY. Brain stem gliomas. Curr Opin Neurol 2001; 14: 711–15. 2 Barkhof F, Filippi M, Miller DH, et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997; 120: 2059–69. 3 Cotton F, Weiner HL, Jolesz FA, Guttmann CR. MRI contrast uptake in new lesions in relapsing-remitting MS followed at weekly intervals. Neurology 2003; 60: 640–46. 4 Azizlerli G, Kose AA, Sarica R, et al. Prevalence of Behçet’s disease in Istanbul, Turkey. Int J Dermatol 2003; 42: 803–06. 5 Lakhanpal S, Tani K, Lie JT, Katoh K, Ishigatsubo Y, Ohokubo T. Pathologic features of Behçet’s syndrome: a review of Japanese autopsy registry data. Hum Pathol 1985; 16: 790–95. 6 Koçer N, Islak C, Siva A, et al. CNS involvement in neuro-Behçet syndrome: an MR study. AJNR Am J Neuroradiol 1999; 20: 1015–24. 7 Akman-Demir G, Serdaroglu P, Tasci B. Clinical patterns of neurological involvement in Behçet’s disease: evaluation of 200 patients. The Neuro-Behçet Study Group. Brain 1999; 122: 2171–82. 8 Kidd D, Steuer A, Denman AM, Rudge P. Neurological complications in Behçet’s syndrome. Brain 1999; 122: 2183–94. 9 Tan CH, Rahman A. Systemic lupus erythematosus presenting with brainstem lesions. Hosp Med 2002; 63: 115–17. 10 Kunavarapu C, Kesavan RB, Pevil-Ulysee M, Mohan SS. Systemic lupus erythematosus presenting as “one-and-a-half syndrome”. J Rheumatol 2001; 28: 874–75. 11 Ferreira S, D’Cruz DP, Hughes GR. Multiple sclerosis, neuropsychiatric lupus and antiphospholipid syndrome: where do we stand? Rheumatology 2005; 44: 434–42. 12 Garcia–Rivera CA, Zhou D, Allahyari P, et al. Miller Fisher syndrome: MRI findings. Neurology 2001; 57: 1755. 13 van der Knaap MS, van der Voorn P, Barkhof F, et al. A new leukoencephalopathy with brainstem and spinal cord involvement and high lactate. Ann Neurol 2003; 53: 252–58. 14 Linnankivi T, Lundbom N, Autti T, et al. Five new cases of a recently described leukoencephalopathy with high brain lactate. Neurology 2004; 63: 688–92. 15 van der Knaap MS, Naidu S, Breiter SN, et al. Alexander disease: diagnosis with MR imaging. AJNR Am J Neuroradiol 2001; 22: 541–52. 16 van der Knaap MS, Salomons GS, Li R, et al. Unusual variants of Alexander’s disease. Ann Neurol 2005; 57: 327–38. 17 Nowak DA, Widenka DC. Neurosarcoidosis: a review of its intracranial manifestation. J Neurol 2001; 248: 363–72.

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