THE SPECTRUM OF DISORDERS MIMICKING MULTIPLE SCLEROSIS
Multiple sclerosis is the commonest demyelinating disease affecting the central nervous system of young adults living in the Western world. The diversity of symptoms and signs which may occur, and the unpredictable course, afford almost unlimited opportunities for misdiagnosis. That said, whilst there are very many disorders with which multiple sclerosis might be confused, these fall into several distinct categories in which the sources of error can be systematized.
The classification of demyelinating diseases (Table 8.1 ) is based on clinical features, pathological and imaging appearances, and aetiological considerations. The clinical suspicion of demyelination, as a pathological process, is high when a young adult develops one or more neurological episodes consistent with damage to white matter tracts within the central nervous system, especially when these affect the optic nerves, brainstem or spinal cord. However, more or less identical episodic symptoms are also caused by vascular or structural lesions, albeit less frequently. Although there are more likely explanations for intermittent neurological symptoms in children or the elderly, multiple sclerosis can affect people in these age groups. Demyelination is also suspected clinically when neurological syndromes indicating widespread involvement of the central nervous system follow within a few days or weeks of an infectious illness or vaccination (acute disseminated encephalomyelitis). Patients developing clinical evidence for extensive brainstem damage in the context of hyponatraemia, or more usually following its over zealous correction, may develop large confluent areas of pontine or extrapontine myelinolysis. In some young patients with progressive neurological disease, widespread demyelination results from genetically determined disorders of myelin formation (the leucodystrophies). Symptoms as a result of demyelination may also occur following direct viral infection of the central nervous system, especially in immunocompromised individuals. Thus, demyelinating disease may develop abruptly or slowly; unannounced or in the context of a precipitating event; early or late in life; as a sporadic condition; triggered by preceding infection or metabolic circumstances; and as part of a familial disorder.
Table 8.1.
Classification of demyelinating disease
|
|
|
|
Pathologically, a simple approach is to distinguish those disorders of myelination associated with perivascular inflammatory cell infiltration from the noninflammatory forms of demyelination (see Chapter 12). Inflammation initially characterizes the focal and multifocal lesions associated with demyelination occurring in optic neuritis, transverse myelitis, multiple sclerosis, Devic's disease, acute disseminated encephalomyelitis and the more specific syndromes that follow vaccination and exanthematous illnesses. Extensive noninflammatory confluent areas of demyelination are seen in the leucodystrophies, progressive multifocal leucoencephalopathy and central pontine myelinolysis. However, even within these two main subdivisions, important differences exist which suggest that several mechanisms of myelin injury contribute to the location, course, prognosis and extent of demyelination. Furthermore, the possibility of inflammation occurring secondary to tissue injury cannot be ignored (see Chapters 12 and 14).
Acute postinfectious encephalomyelitis, acute haemorrhagic leucoencephalitis (Hurst's disease), postvaccinial encephalomyelitis and some cases of subacute necrotizing myelitis, transverse myelitis and optic neuritis can legitimately be included within the syndromes of acute disseminated encephalomyelitis. Balo's concentric demyelination, Devic's disease, and Marburg type or mixed peripheral and central forms of demyelination are usually considered within the context of multiple sclerosis. The commonest forms of leucodystrophy encountered in clinical practice are metachromatic leucodystrophy, adrenoleucodystrophy and Krabbe's disease. The nosological status of Schilder's disease is increasingly insecure. As originally described, it probably included cases of leucodystrophy and subacute sclerosing panencephalitis. It is doubtful that Schilder's disease exists as a distinct disorder, either within or without the spectrum of multiple sclerosis. Accordingly, it is not discussed further here although we retain a brief description of the neuropathology in Chapter 12.
Brain imaging provides a further means of classifying demyelinating disease. Magnetic resonance imaging (MRI) studies show that isolated areas of demyelination actually occur rather infrequently. Thus, many patients with symptoms and signs attributable to a single anatomically placed lesion show multiple central nervous system abnormalities, typically affecting the periventricular white matter. To some extent, the characteristic imaging appearances of acute disseminated encephalomyelitis differ from those seen in multiple sclerosis, primary progressive inflammatory demyelination and the leucodystrophies. However, as pointed out in Chapter 7, these differences do not in themselves provide a reliable means for distinguishing the various conditions. Approaches to classification of the demyelinating diseases and the strategies for distinguishing the separate conditions recognized in clinical practice are somewhat merged in the accounts that follow.
From the clinical perspective, the importance of syndromes that can be attributed to focal demyelination (usually of the optic nerve, brainstem or spinal cord) lies in the fact that these are sometimes genuinely monophasic and do not recur or lead to widespread clinical manifestations. Other cases represent the inaugural episode of multiple sclerosis and many strategies have been developed for assessing the risk of conversion to multiple sclerosis following each type of episode, based on clinical features and laboratory (mainly imaging) investigations. These rates vary with the different syndromes, and ages at presentation. Self-evidently, they increase with duration of follow-up, although the number of new individuals developing recurrent demyelination reduces with time. Since imaging studies have established that a high proportion of patients with clinically isolated demyelinating syndromes have anatomically disseminated lesions at presentation, laboratory markers provide one potential means for stratification and prediction of the long-term outcome. For this reason, particular importance is attached to the concept of temporal dispersion of lesions in the assessment of individual patients. Multiple sclerosis can reliably be diagnosed on clinical grounds only when more than one demyelinating episode, separated by at least 1 month and with clear evidence for recovery between attacks, has occurred and not merely on the basis of anatomically disseminated lesions. Even under these circumstances, many clinicians would reserve judgement until symptoms have been intermittently present for at least 6 months. However, imaging evidence for temporal dispersion following a clinically isolated episode is increasingly being accepted as an alternative way of securing the diagnosis of multiple sclerosis at an earlier stage and in advance of the second clinical event (W.I. McDonald et al 2001). The distinction between anatomical and temporal dissemination of lesions is clearly illustrated by the multifocal but monophasic nature of acute disseminated encephalomyelitis by comparison with multiple sclerosis.
With prudence, most potential diagnostic errors can be avoided, and only the more exacting problems need be considered here. Sources of diagnostic difficulty may conveniently be summarized as:
-
•
diseases that may cause multiple lesions of the central nervous system and also often follow a relapsing–remitting course
-
•
systematized diseases causing lesions in separate parts of the central nervous system but usually with symmetrical manifestations and a progressive course
-
•
isolated or monosymptomatic central nervous system syndromes often suggesting a single white matter lesion
-
•
nonorganic symptoms which mimic the clinical manifestations and course of multiple sclerosis.
DISEASES THAT MAY CAUSE MULTIPLE LESIONS OF THE CENTRAL NERVOUS SYSTEM AND ALSO OFTEN FOLLOW A RELAPSING–REMITTING COURSE
Diseases in which multiple lesions affect the central nervous system, and the illness follows a relapsing course, may appear to fulfil the strictest clinical and paraclinical diagnostic criteria, and so are easily confused with multiple sclerosis (Table 8.2 ). Modern techniques, including brain imaging, are helpful but not necessarily decisive in making the distinction from multiple sclerosis. The ambiguity may only be resolved if positive evidence for the specifically different condition becomes available – usually from laboratory or histological investigations.
Table 8.2.
Diseases causing multiple lesions sometimes with a relapsing–remitting course
|
Acute disseminated encephalomyelitis
In its classical form, acute disseminated encephalomyelitis is an illness of childhood that is of acute or subacute onset, in which an inflammatory and demyelinating process simultaneously affects multiple parts of the central nervous system, often shortly following an exanthematous or infectious illness Although an acute and fulminant presentation may be similar to acute (non-inflammatory) encephalopathy in children or young adults (Reye's syndrome), also occurring as part of several specific metabolic and infectious illnesses, the latter condition is distinguished by the presence of specific laboratory abnormalities, including hyperammonaemia, hepatic dysfunction and hypoglycaemia.
In acute disseminated encephalomyelitis, the cerebrum usually bears the brunt of the illness. Headache, fever and drowsiness sometimes progress to coma within a few days. Convulsions may occur, although these are seen in <20% of cases (Dale et al 2000; Hynson et al 2001). Focal neurological abnormalities typically include motor, sensory, visual and cognitive syndromes. These usually indicate multiple lesions of the brain but there may be associated brainstem involvement (Figure 8.1 ). Optic neuritis is common and often bilateral (Figure 8.2 .). Occasionally, the peripheral nervous system is also involved. In other cases, the clinical picture is restricted to focal involvement of the brainstem, optic nerves or spinal cord – alone or in combination – and without much in the way of cerebral features. Patients with post-infectious focal inflammation of the central nervous system may be systemically ill with pyrexia and marked meningism. These features occur both in the encephalitic and myelitic forms of the disease. The cerebrospinal fluid shows a mixed polymorphonuclear and lymphocytic or predominantly mononuclear pleocytosis with raised protein and slight reduction in glucose. Oligoclonal bands are often present but, unlike multiple sclerosis, these may subsequently disappear (see below: Kesselring et al 1990).
Figure 8.1.
Macroscopic appearance of the brain in a patient aged 31 years who died from acute disseminated encephalomyelitis after an illness lasting 10 days; there is diffuse midbrain damage from a combination of demyelination and tentorial herniation as a result of cerebral oedema. Kindly provided by Dr Janice Anderson.
Figure 8.2.
Optic disc appearance in a patient with acute optic neuritis associated with Mycoplasma pneumoniae infection.
The symptomatology, course and prognosis of acute disseminated encephalomyelitis in adults do not differ significantly from the classical post-exanthematous condition of childhood (McHugh and McMenamin 1987). Although a wider range of causative organisms has been implicated, the individual adult case more usually develops spontaneously or in the context of a non-specific respiratory infection. But even in children, a presumptive diagnosis of acute disseminated encephalomyelitis is often made in the absence of an identified provocative cause, especially in cases of acute cerebellar ataxia. Despite surviving the acute illness, patients may be left with persistent neurological deficits. The prognosis correlates inversely with the rate of onset of disability and overall severity. There is some evidence that outcome is influenced by the early use of high dose corticosteroids but this has not been formally evaluated. Fulminant cases of central nervous system inflammatory demyelination have been treated with plasma exchange (Bennetto et al 2004; Keegan et al 2002; 2005; Weinshenker et al 1999b), and with improvement reported in about 45%.
First described in 1790 (see Chapter 1), the classical accounts of acute disseminated encephalomyelitis and post-vaccinial encephalitis were written several decades ago (Miller and Evans 1953; Miller et al 1956). Several hundred cases were reviewed from personal experience or reports in the literature but no attempt was made to separate diffuse from anatomically restricted forms of para-infectious neurological disease, including polyradiculitis. Some cases were probably due to direct viral infection of the nervous system and related disorders that were not then recognized. The Newcastle experience indicated that about 1:1000 children with exanthematous disorders develop acute disseminated encephalomyelitis, the risk being slightly higher with pertussis and scarlet fever than with measles and rubella. The majority of those cases in these series were encephalopathic or multifocal. The encephalomyelitis that complicates rubella does not differ materially from the acute disseminated encephalomyelitis of measles except that it is less frequent and perhaps more severe. There is a late progressive variant, analagous to subacute sclerosing panencephalitis. Post-varicella infectious encephalomyelitis is often indistinguishable from other forms of the disorder but almost 50% of cases show a pure cerebellar syndrome sometimes associated with involuntary movements. This carries a relatively good prognosis with a low rate of persistent disability (Brumlik and Means 1969). Many other specific causes of acute disseminated encephalomyelitis have been described including a large number of bacterial and viral infections (Table 8.3 ). Toxic causes include injection of herbal extracts (Schwarz et al 2000), bee sting (Boz et al 2003) and anti-tetanus toxin (Hamidon and Raymond 2003). Prominent basal ganglia involvement, both clinically and with imaging, is often a feature in children with post-streptococcal acute disseminated encephalomyelitis and may be related to a high frequency of anti-basal ganglia antibodies associated with this infection (Dale et al 2001).
Table 8.3.
Infections associated with acute disseminated encephalomyelitis
| Childhood exanthematous illnessesa | H.G. Miller and Evans 1953; H.G. Miller et al 1956; Brumlik and Means 1969 |
| ECHO and coxsackievirus | Tyler et al 1986 |
| Adenoviridae | Kesselring et al 1990 |
| Herpes simplex 1 | Kusuhara et al 2002; An et al 2002 |
| Varicella zoster and human herpes virus-6 | An et al 2002 |
| Mycoplasma | Riedel et al 2001; Pfausler et al 2002 |
| Borrelia burgdorferi | van Assen et al 2004 |
| Campylobacter | Orr et al 2004 |
| Pasteurella multocida | Proulx et al 2003 |
| Plasmodium vivax | Koibuchi et al 2003 |
| Streptococcus | Dale et al 2001 |
| HIV | Narciso et al 2001 |
| Rocky Mountain spotted fever | Wei and Baumann 1999 |
| Influenza virus | Nakamura et al 2003 |
| Parainfluenza virus | Au et al 2002; Voudris et al 2002 |
| Puumala virus | Toivanen et al 2002 |
| Hepatitis C virus | Sacconi et al 2001 |
| Hepatitis A virus | Alehan et al 2004; H. Tan et al 2004 |
| Coronavirus | Yeh et al 2004 |
Including measles, rubella and varicella.
Since an illness consistent with acute disseminated encephalomyelitis may later convert to multiple sclerosis, the natural history of childhood onset demyelinating disease has particular clinical poignancy. The natural wish is for a monophasic disorder and the initial preference is usually to diagnose acute disseminated encephalomyelitis. But the reality is that the monophasic nature of acute disseminated encephalomyelitis, defined in its typical form by the absence of subsequent relapse, can only be established with confidence after prolonged observation. Early judgement is invariably difficult. When acute disseminated encephalomyelitis clearly follows specific viral infection or innoculation, particularly in a child, the distinction from multiple sclerosis can be made with some confidence. There are no secure guidelines for distinguishing the encephalopathic presentation of multiple sclerosis from acute disseminated encephalomyelitis developing without preceding infection, especially in adults. Despite following what is essentially a monophasic course, separate sites may be involved sequentially in the acute phase giving the appearance of a temporally disseminated illness. Our position is that the clinical features of acute disseminated encephalomyelitis may evolve over a reasonably short period without it becoming necessary to change the diagnosis to that of multiple sclerosis. For this reason, we remain to be convinced by the claim for co-occurrence of acute disseminated encephalomyelitis and multiple sclerosis in two cases (Ravaglia et al 2004). Rather, we prefer the interpretation that these were the encephalitic and myelitic presentations of relapsing–remitting multiple sclerosis, respectively. The relationship of acute disseminated encephalomyelitis to clinically isolated demyelinating lesions – bilateral optic neuritis and acute transverse myelitis in children and adults, or cerebellar ataxia following childhood varicella – is particularly ambiguous (Tselis and Lisak 1995).
The use of paraclinical investigations often does not resolve the distinction between acute disseminated encephalomyelitis and multiple sclerosis (Dale et al 2000; Hahn et al 2004; Hartung and Grossman 2001; Hynson et al 2001). The recent literature focuses on the role of MRI but this investigation is also not decisive. Although extensive multifocal white matter and grey matter lesions are characteristic of acute disseminated encephalomyelitis (Figure 8.3 ), the appearances may be indistinguishable from those seen in multiple sclerosis and occasionally MRI can be normal even when the patient presents in an obtunded state (Hollinger et al 2002; Murray et al 2000). It has been proposed that an abnormal electroencephalogram can aid the diagnosis when the MRI findings are unhelpful (Hollinger et al 2002). Kesselring et al (1990) studied six adults and six children, developing optic nerve, cerebral, brainstem and cord disease, alone or in combination, following infection by mumps, varicella, Mycoplasma, adenovirus and non-specific respiratory infections. Clinical features alone were unhelpful. Oligoclonal bands were found to be transiently present in acute disseminated encephalomyelitis, a finding that contrasts with their persistence in multiple sclerosis. Although multifocal asymmetric white matter abnormalities were not discriminating, some cases of generalized and clinically isolated post-infectious demyelinating syndromes showed extensive and rather symmetric changes in the cerebral or cerebellar white matter and in the basal ganglia (Figure 8.4 ). Many lesions show gadolinium enhancement in the acute phase (Singh et al 1999). This may be homogeneous or ring shaped (Lim et al 2003), with individual lesions exhibiting a mixture of enhancing and non-enhancing properties (Tenembaum et al 2002) or no enhancement at all (Hynson et al 2001). Rarely, the lesions of acute disseminated encephalomyelitis appear cystic on MRI, thus mimicking brain abscess (de Recondo and Guichard 1997; Go and Imai 2000; Lim et al 2003), but large ring enhancing lesions with a cyst-like appearance can also occur in multiple sclerosis. In short, the pattern is not distinguishable with certainty from multiple sclerosis on a single scan.
Figure 8.3.
Acute disseminated encephalomyelitis. T2-weighted brain MRI reveals (A) multifocal white matter and (B) grey matter lesions.
From Confavreux and Vukusic (2002). © 2002, reproduced with permission of Lippincott Williams & Wilkins (lww.com).
© 2006 Lippincott Williams & Wilkins
Figure 8.4.
T2-weighted brain MRI in acute disseminated encephalomyelitis. (A) The rather symmetrical appearances characteristic of the acute phase. (B) Marked resolution 10 years later.
Rather more useful is the information provided by serial or gadolinium-DTPA (diethylenetriamine pentetic acid) enhanced scans. These suggest that, whereas lesions persisting on T2-weighted images long after the clinical manifestations have resolved do not provide useful information, the development of new T2 lesions or the demonstration of new areas with gadolinium enhancement indicates ongoing disease activity typical of multiple sclerosis (Brex et al 2001a). If a sufficient follow up interval – probably at least 3 months – has elapsed, the occurrence of new gadolinium enhancing lesions excludes the diagnosis of acute monophasic demyelination (Brex et al 2001a; McDonald et al 2001). O'Riordan et al (1999) showed that only 1/11 patients with acute disseminated encephalomyelitis patients followed up for 8 years exhibited new lesions. This individual was aged 52 years at follow-up and the small cerebral white matter lesion observed might have been due to small vessel disease. There was also a striking tendency for resolution of the T2 lesions originally detected following the acute monophasic disease: the resolution was partial in seven cases and complete in three (Figure 8.4). In three other examples of monophasic central nervous system demyelination in childhood presenting as hemiparesis (which seem most likely to be cases of acute disseminated encephalomyelitis), the cerebral lesions were extensive and exhibited mass effect during the acute phase but subsequently displayed marked resolution with follow up (Yapici and Eraksoy 2002).
How long to wait before concluding that the diagnosis is one of monophasic demyelination is difficult to establish. The 6 months suggested by Kesselring et al (1990) in children may be adequate for purposes of definition but the interval before relapse after an initial attack of multiple sclerosis is clearly often much longer. It has been suggested that new episodes of central nervous system damage may occur 18 months after the initial episode in acute disseminated encephalomyelitis but this freedom of interpretation depends on the erroneous assumption that multiple sclerosis does not occur in childhood, and cases of this type would not now be included in a series of patients with acute disseminated encephalomyelitis. The matter is further complicated by the proposal that a syndrome of multiphasic disseminated encephalomyelitis occurs both in childhood (Dale et al 2000; Dale et al 2000) and in adults (Khan et al 1995).
The situation may nevertheless be clearer in children where the a priori expectation of multiple sclerosis as the eventual explanation for a first episode of demyelination is lower. Dale et al (2000) described 48 children in whom the diagnosis of central nervous system inflammatory demyelination was made through a tertiary referral centre. Of these, 28 were classified as having acute monophasic disseminated encephalomyelitis, 13 had multiple sclerosis and seven were considered to have multiphasic disseminated encephalomyelitis. By comparison with multiple sclerosis, cases of acute disseminated encephalomyelitis showed younger age at onset; a higher likelihood of preceding infection (74% vs. 38%); a greater frequency of encephalopathy (69% vs. 15%), pyramidal tract signs (71% vs. 23%) and poly-symptomatic features at presentation (91% vs. 38%); a greater likelihood of blood leucocytosis (64% vs. 22%) and cerebrospinal fluid pleocytosis (64% vs. 42%); a lower frequency of cerebrospinal fluid oligoclonal bands (29% vs. 64%) and MRI periventricular white matter lesions (44% vs. 92%; Figure 8.5 ) and more basal ganglia lesions (28% vs. 8%). On follow-up MRI, there was partial or complete resolution of lesions in 90% with acute disseminated encephalomyelitis and no new abnormalities were seen. Whereas partial lesion resolution was also seen in those with multiple sclerosis, all of the latter subjects displayed new lesions at follow-up. Although only 23% of subjects in both groups had optic neuritis, this was always bilateral in cases of acute disseminated encephalomyelitis, and unilateral in multiple sclerosis. The seven cases of multiphasic encephalomyelitis normally had only a single relapse. This occurred within a few months of the original episode and often while treatment with corticosteroids was being electively withdrawn.
Figure 8.5.
T2-weighted brain MRI. (A) Acute disseminated encephalomyelitis. (B) Multiple sclerosis. In the former there are more discrete cerebral white matter lesions whereas periventricular abnormalities predominate in the latter.
From Dale et al (2000) with permission.
© 2006
A retrospective report on 31 children diagnosed with acute disseminated encephalomyelitis reported a high frequency of prodromal illness (71%) with an impaired conscious state (68%) and ataxia (65%) at presentation. There was a low frequency of cerebrospinal fluid oligoclonal bands (3%) and, although MRI white matter lesions were seen in 90%, there was less frequent periventricular and callosal involvement (both 29%; Hynson et al 2001). Grey matter lesions were seen in 61%, including the basal ganglia in 39% and thalamus in 32%. It is notable that gadolinium enhancing lesions were seen in only 29% of children in this study. This rather challenges the notion that enhancement is the rule for acute inflammatory/demyelinating central nervous system lesions. Four children had relapses – in two cases within weeks of the original episode and 2 years after the initial event in the others.
Another recent study reported on 84 children with a diagnosis of acute disseminated encephalomyelitis who were followed for a mean of 6.6 years (Tenembaum et al 2002). There was a preceding viral illness or vaccination in 74%. The most common presenting features were acute hemiparesis (76%), unilateral or bilateral long tract signs (84%), and mental changes (69%). None of 54 children who had cerebrospinal fluid examination exhibited oligoclonal bands. Brain MRI revealed multifocal grey and white matter lesions, of varying size, in 86% of cases. These were sometimes large and with a mass effect. The thalamus was involved bilaterally in 12%. In two cases (2%), some lesions were haemorrhagic. Of the 27 who had gadolinium enhanced scans, 30% showed open ring enhancing lesions, and in two cases these was a mixture of enhancing and non-enhancing lesions. Follow-up revealed a generally good prognosis with 89% having minimal or no disability (EDSS 0–2.5). MRI revealed marked resolution of abnormalities and no evidence for new lesions. Ten children experienced a single relapse at a median of 2 years after the initial attack. However, MRI did not reveal new lesions at the time of these relapses, nor did the cerebrospinal fluid contain oligoclonal bands. The authors called these cases biphasic disseminated encephalomyelitis.
In a further series of 18 children with a diagnosis of acute disseminated encephalomyelitis (Gupte et al 2003), the most common presentations were ataxia (10 cases), headache (8) and weakness (5). MRI lesions were seen in white and grey matter. The cerebrospinal fluid contained oligoclonal bands in only 4/13 (31%). Most children recovered although five had residual deficits. Two had a relapse, on both occasions within weeks of the original episode and shortly after discontinuation of steroid treatment. The authors suggest that the term multiphasic disseminated encephalomyelitis should only be used if there has been a single relapse following close after cessation of steroid treatment for the first attack. Another recent series of 18 children with a diagnosis of acute disseminated encephalomyelitis reported a high frequency of preceding upper respiratory tract illness (72%), onset in winter or spring (88%), motor deficits (77%), asymmetrical cortical grey matter lesions (80%), and subcortical white matter lesions (93%; Murthy et al 2002). A large series of children with acute disseminated encephalomyelitis following rubella and varicella has recently been reported from Moscow (Idrissova et al 2003). Cases complicating rubella had an explosive onset with seizures, coma and moderate pyramidal tract signs, whereas those following varicella were characterized by cerebellar ataxia and mild pyramidal dysfunction.
Brass and colleagues (2003) also reported that a number of clinical and MRI features helped to distinguish the acute disseminated encephalomyelitis from multiple sclerosis in childhood. They compared seven children diagnosed with acute disseminated encephalomyelitis (mean age 8.7 years) with 17 diagnosed as multiple sclerosis (mean age 12.4 years) and found the following differences: fever (43% vs. 6%), headache (57% vs. 24%), fatigue (71% vs. 29%), vomiting (57% vs. 0%), encephalopathy (71% vs. 6%), corpus callosum lesions (17% vs. 64%) and periventricular lesions (50% vs. 91%).
The results of a large study organized by the French Neuropaediatric Society and involving 296 children <16 years having a first neurological episode consistent with inflammatory demyelination of the central nervous system between January 1985 and December 2001 has recently challenged this idea (Mikaeloff et al 2004a; 2004b). An initial diagnosis suggestive of acute disseminated encephalomyelitis was made in 119 (40%) cases, multiple sclerosis in 96 (33%) and a monofocal episode in 81 (27%). During a median follow-up of 1.9 years, 72/200 (36%) individuals with isolated demyelination at presentation had a second neurological episode qualifying them for the diagnosis of multiple sclerosis: 34/119 (29%) cases initially diagnosed as acute disseminated encephalomyelitis and 38/81 (47%) classified as having an isolated and monofocal episode. Median time from disease onset to the second neurological episode, as estimated by the Kaplan Meier technique, was 1.9 years. It was 6 years for the patients with an onset ≤10 years, and 1 year for those with onset at >10 years. Therefore, the final diagnosis was multiple sclerosis in 168 cases (57%), monophasic acute disseminated encephalomyelitis in 85 individuals (29%), and single monofocal episode in 43 patients (14%). Among the 168 children with multiple sclerosis, median age at onset was 13.1 years and the sex ratio 2.1 F:M. Age at onset in the 85 children finally classified as having acute disseminated encephalomyelitis was 6.4 years and the sex ratio 0.8 F:M. Even with a relatively short period of follow-up, the results of this representative study suggest that multiple sclerosis appears to be more frequent than acute disseminated encephalomyelitis, and half of the cases initially considered to have monophasic demyelination do in fact experience a second neurological episode within 2 years. Monophasic acute disseminated encephalomyelitis occurs predominantly before the age of 10 and in males, whereas multiple sclerosis predominantly develops later and in females. However, these statistics do not help in making a more accurate prognostic evaluation in the individual, at presentation.
Can consensus be reached on whether acute disseminated encephalomyelitis is a disease entity quite distinct from multiple sclerosis, as opposed to a spectrum of syndromes with overlapping transitional cases? Although the pathological hallmark of the former condition is considered to be multifocal lesions of a similar age that exhibit perivenous inflammation with adjacent demyelination and oedema, Lumsden (1970) could find no meaningful pathological distinction between the two conditions. Bauer and Hanefeld (1993) cited cases of relapsing disease following viral or vaccinial encephalomyelitis (see below), arguing against a rigid subdivision. A child who sustained three separate attacks of unilateral optic neuritis in the 3 years following acute disseminated encephalomyelitis induced by influenza vaccine remained symptom free >15 years after the last attack (Matthews 1991). In a recent editorial, Hartung and Grossman (2001), reviewing several recently published series, suggested that acute disseminated encephalomyelitis and multiple sclerosis fall within a common spectrum of inflammatory demyelinating diseases. However, efforts to make this distinction have sometimes foundered through allowing too liberal criteria for acute disseminated encephalomyelitis that include a number of the isolated clinical syndromes typically associated with conversion to multiple sclerosis in young adults. Not surprisingly, when such criteria have been employed many patients have subsequently been re-classified as having multiple sclerosis once further manifestations of demyelination are observed (Schwarz et al 2001). The situation is even more problematic when criteria are proposed for distinguishing multiphasic disseminated encephalomyelitis from multiple sclerosis. It has been suggested that relapses involve the same location in the further episodes of acute disseminated encephalomyelitis (Cohen et al 2001) but those familiar with multiple sclerosis will recognize that relapses manifesting as recurrence of previously experienced symptoms are not uncommon.
Our view is that monophasic acute disseminated encephalomyelitis exists as an entity separate from multiple sclerosis, although it is only rarely encountered beyond childhood. We recognize that, although there is a combination of clinical and radiological features that favour the diagnosis of acute disseminated encephalomyelitis over multiple sclerosis (Table 8.4 ), no single manifestation is completely specific. We do not recognize an entity of multiphasic disseminated encephalomyelitis that is distinguishable from multiple sclerosis in adults. When this has been suggested as the diagnosis, there have usually been atypical features for multiple sclerosis (such as encephalopathy or tumour-like lesions on MRI), and we take the view that unusual presentations of a common disease are a more likely explanation than another condition of doubtful nosological status.
Table 8.4.
Features of a monophasic illness that are more characteristic of acute disseminated encephalomyelitis than multiple sclerosisa
|
No single feature is pathognomonic of acute disseminated encephalomyelitis and on occasions may be seen in multiple sclerosis.
Acute haemorrhagic encephalomyelitis
The hyperacute form of acute disseminated encephalomyelitis (Hurst's disease) is usually preceded by a nonspecific respiratory infection about 10 days before the onset of neurological symptoms. In some cases, there are no prodromal complaints. Young adult males are most commonly affected, complaining initially of headache or dizziness and progressing over hours through stages of disorientation, confusion and drowsiness to coma (Hurst 1941). The rate of progress is such that events usually overtake the detection of focal signs and this form of the disease is frequently fatal, although affected individuals may remain in a persistent vegetative state for several weeks, and some survive with severe disability following treatments which reduce intracranial pressure (C-C. Huang et al 1988). The combination of pyrexia and a marked cerebrospinal fluid pleocytosis with a predominantly neutrophil response mimics pyogenic infection of the central nervous system but the course is not influenced by antimicrobial treatment. Pathologically, the disorder is characterized by fibrinoid necrosis and inflammatory infiltration of vessels, oedema, perivenular petechial haemorrhage and macrophage infiltration around vessels in both grey and white matter but without demyelination (Figure 8.6 ; Hart and Earle 1975; Russell 1955; see Chapter 12). In some cases, the clinical and pathological features of acute haemorrhagic leucoencephalitis are focal, suggesting a rapidly growing tumour or herpes simplex encephalitis. These transitional forms are important in establishing that Hurst's disease is part of the spectrum of acute disseminated encephalomyelitis and they provide evidence for the sequence of events involved in the pathogenesis of multifocal demyelination of the human nervous system. The widespread use of MRI has also revealed that a small percentage of cases with otherwise typical acute disseminated encephalomyelitis exhibit haemorrhagic lesions (Dale et al 2000; Tenembaum et al 2002).
Figure 8.6.
Acute perivascular infiltration in the same patient as in Figure 8.1. Haematoxylin and eosin; magnification ×30. Kindly provided by Dr Janice Anderson.
Postvaccinial encephalomyelitis
Postvaccinial encephalomyelitis has become a rare disorder (Fenichel 1982) and the definitive series was collected several decades ago following the need to vaccinate large numbers of individuals against smallpox as part of public health measures. The 62 cases studied clinically and pathologically by de Vries (1960) were collected over 34 years and were necessarily severe. In all, the neurological illness developed within 21 days after vaccination and, where fatal, death occurred at or soon after 13 days. In these hyperacute cases, the pathological findings resemble transitional forms of acute haemorrhagic or disseminated encephalomyelitis and the general principle that demyelination occurs secondary to blood–brain barrier permeability is again borne out. The clinical illness starts with a vaccinial skin reaction and systemic symptoms which merge with the neurological manifestations, typically affecting the cerebrum but sometimes presenting as a myelitic disorder. One of us (DHM) has observed Devic's disease following smallpox vaccination. Despite having a high mortality, subjects with postvaccinial encephalomyelitis may recover spontaneously and completely. It was thought that the risk had gone with the global eradication of smallpox infection and consequent cessation of vaccination programmes. However, a vaccination programme has been reintroduced recently for certain groups in view of concerns about global bioterrorism, raising the possibility that there may be further cases, although they can be largely prevented by administering antivaccinia gammaglobulin at the time of vaccination (Miraville and Roos 2003). It is to be hoped that the series reported from south Wales following the vaccination of 800 000 individuals at risk will never be repeated. Eleven patients developed generalized or restricted forms of encephalomyelitis and several other postinfectious manifestations of neurological disease, affecting either the central or peripheral nervous systems (Spillane and Wells 1964).
One reason for believing that acute disseminated encephalomyelitis arises from immune sensitization to brain antigens is that it may follow the use of rabies vaccine containing central nervous system tissue (Uchimura and Shiraki 1957). This form of the disease behaves much like other cases of acute disseminated encephalomyelitis and the pathological features are also indistinguishable. However, cases have not been seen since the method for preparing this and other vaccines was altered.
Systemic lupus erythematosus
Although the nervous system is involved in a high proportion of individuals with systemic lupus erythematosus, diagnostic confusion does not arise in the great majority either because there is obvious evidence for systemic disease or the neurological symptoms are unlike those commonly encountered in multiple sclerosis (J.T. Sibley et al 1992). The diagnosis of systemic lupus erythematosus should take account of established diagnostic criteria (Table 8.5 ; Hochberg 1997; E.M. Tan et al 1982). A standard nomenclature system for neuropsychiatric involvement has also been developed, but this was more to aid accuracy in clinical research rather than to replace clinical judgement in diagnosing individual patients (Table 8.6 ; ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature 1999). In a recent report, the most common neuropsychiatric manifestations amongst 128 unselected patients with lupus were neuropsychological impairment (80%, most often mild), headache (57%), depressive mood disorder (47%), poly- or mononeuropathy (30%), anxiety (24%) and seizures (16%; Brey et al 2002).
Table 8.5.
American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus 1982a with updating 1997b
|
A person is considered to have systemic lupus erythematosus if four or more of the 11 criteria are present. NB: this table is an abbreviated summary and the original publications should be referred to for further information.
E.M. Tan et al (1982);
Hochberg (1997).
Table 8.6.
Neuropsychiatric syndromes observed in systemic lupus erythematosusa
|
|
From ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature (1999).
Disseminated relapsing–remitting disease, with symptoms indistinguishable from those of multiple sclerosis, has occasionally been reported (M. Hutchinson and Bresnihan 1983) – a substantial and persistent elevation in erythrocyte sedimentation rate or acute phase protein concentration providing an initial clue to the correct diagnosis.
The presentations most likely to be confused with multiple sclerosis are the various combinations of optic neuritis and myelopathy. Optic neuritis, which is not recognizably different from that seen in multiple sclerosis, may be the initial symptom (Schwartzberg et al 1981). Optic neuropathy in systemic lupus erythematosus may, however, take different forms – acute retrobulbar neuritis, ischaemic neuropathy or progressive visual failure (Jabs et al 1986). Symptoms of spinal cord disease may be slowly progressive (Fulford et al 1972; Provencale and Bouldin 1992), recurrent (Tola et al 1992; M. Yamamoto 1986) or, more commonly, acute or subacute (Barile and Lavalle 1992; Lavalle et al 1990). Optic neuritis can accompany acute transverse myelitis (S. Oppenheimer and Hoffbrand 1986; Simeon-Aznar et al 1992) or precede the onset of paraparesis and ataxia (Tola et al 1992). Such presentations are inevitably suggestive of Devic's disease or multiple sclerosis, and the results of diagnostic tests do not always reliably allow these distinctions to be made.
Internuclear ophthalmoplegia, even as an initial sign (Cogan et al 1987; Hammondeh and Kahn 1982; Jackson et al 1986), and unilateral tonic spasms (M. Hutchinson and Bresnihan 1983), both characteristic features of multiple sclerosis, have been described in systemic lupus erythematosus.
When the central nervous system is involved in systemic lupus erythematosus, the cerebrospinal fluid has been found to contain oligoclonal immunoglobulin G (IgG) in 42% of cases (Winfield et al 1983). Routine examination of the cerebrospinal fluid occasionally shows levels of total protein and cell counts that are outside the ranges expected in multiple sclerosis (Provencale and Bouldin 1992). However, these distinctions are not necessarily reliable and brain MRI can also show discrete and periventricular white matter lesions, not immediately distinguishable from those of multiple sclerosis (Figure 8.7 ; Ormerod et al 1987). One clue to a vascular rather than demyelinating aetiology is a predominance of subcortical and white matter lesions that extend beyond the periventricular region. Small cortical T2 hyperintensities or foci of cortical atrophy may indicate previous small areas of infarction (D.H. Miller et al 1987b). When larger vessels are involved, the areas of abnormal signal conform to the classical territories of arterial distribution (Figure 8.8 ). Abnormalities are reported using MR spectroscopy and single photon emission computed tomography (SPECT) as the basis for studies of brain metabolites and perfusion, respectively, in patients with a clinical diagnosis of neuropsychiatric lupus – sometimes even in the absence of visible MRI abnormalities (Handa et al 2003).
Figure 8.7.
T2-weighted image in systemic lupus erythematosus showing the predominantly peripheral distribution of the focal lesions.
Figure 8.8.
T2-weighted image in systemic lupus erythematosus showing an extensive area of infarction.
In cases with acute transverse myelitis, swelling of the cord may extend over many segments in association with increased signal on T2-weighted MRI and gadolinium enhancement (Figure 8.9 ; D.H. Miller et al 1992b). Such extensive cord lesions are rarely seen in multiple sclerosis. Visual evoked potentials may be delayed (Jabs et al 1986). Serological tests for systemic lupus are also not wholly discriminating and anti-nuclear factor – usually but not invariably in a low titre – has been found in approximately 30% of people with multiple sclerosis (Barned et al 1995; Dore-Duffy et al 1982). In a prospective survey, 22% patients with multiple sclerosis had circulating anti-nuclear autoantibodies, usually in the range of titres 1 : 80 to 1 : 160 (Collard et al 1997). These were undetectable in cerebrospinal fluid and had no systemic clinical associations. Concomitant drug treatment might have induced autoantibody production in some patients. Most consider that the occasional presence of autoantibodies in patients with multiple sclerosis is an epiphenomenon indicative of an underlying autoimmune process rather than being directly involved in the pathogenesis (de Andres et al 2001). Transverse myelitis in systemic lupus is, however, strongly associated with anti-phospholipid antibodies (Lavalle et al 1990; J.H. Kim et al 2003).
Figure 8.9.
T2-weighted image of the spinal cord in systemic lupus erythematosus showing diffuse high signal with swelling.
While transverse myelitis may be the presenting symptom of systemic lupus erythematosus, in the majority of reported cases the onset of neurological symptoms is preceded or accompanied by evidence for systemic disease, even though this may only be recognized in retrospect (Andrianakos et al 1976). It is the concomitant systemic features that often prove crucial in establishing the diagnosis. That said, the distinction between systemic lupus erythematosus and multiple sclerosis sometimes remains in doubt. Pender and Chalk (1989) reported the combination of relapsing spinal cord disease and optic neuritis. The patient described by Devos et al (1984) and the three reported by Kinnunen et al (1993) almost certainly had both systemic lupus erythematosus and multiple sclerosis. A further intriguing suggestion of a relationship between the two diseases is the occurrence of multiple sclerosis in one identical twin and systemic lupus erythematosus, without nervous system involvement, in the other (F.F. Holmes et al 1967). A brother and sister had multiple sclerosis and the former had three children with systemic lupus erythematosus (Sloan et al 1987). A woman with multiple sclerosis is described whose mother had systemic lupus erythematosus (Hietaharju et al 2001).
Introduction of the term lupoid sclerosis (Fulford et al 1972) does not assist greatly in clarification, although any physician experienced in the management of demyelinating disease will recognize the convenience of that description for the patient with relapsing symptoms, at least some of which are unusual for multiple sclerosis, and in whom there is suggestive serological evidence for systemic lupus erythematosus. This combination may be sufficient to prompt the use of immunosuppressive treatments (such as oral cyclophosphamide) not used routinely in patients with conventional forms of multiple sclerosis.
Anti-phospholipid antibody syndrome
Although closely related to systemic lupus erythematosus – and indeed some patients with the latter condition manifest the same immunological abnormalties – there is an identifiable group of patients, usually with a multisystem clinical syndrome, in whom anti-phospholipid antibodies are thought to play a specific pathogenic role. Usually known as the primary anti-phospholipid syndrome, it has also recently become known in some circles as Hughes syndrome in deference to the physician who first reported this association (G.R.V. Hughes 1983). The most characteristic and classical clinical features reflect a disturbance of the blood coagulation system with an increased frequency of both venous and arterial thromboses. Young women are usually affected, presenting with deep vein thromboses, pulmonary embolism or recurrent spontaneous abortion. The most common neurological manifesations are migraine, often with aura, or transient ischaemic attacks affecting the carotid, vertebral or ophthalmic artery territories. The association with migraine may be coincidental, bearing in mind the high prevalence overall of the latter condition in the young adult population. Stroke as a result of cerebral infarction can occur, and is potentially the most significant neurological complication. The typical features are hemiplegia, hemianopia, dysphasia and a variety of posterior circulation syndromes. Movement disorders, especially chorea, are also relatively frequent. In general, presentation with acute neurological episodes suggestive of demyelination is uncommon. Ischaemic optic neuropathy may occur but the clinical features – optic disc swelling and altitudinal field defect with poor recovery – suggest a vascular rather than demyelinating mechanism. Transverse myelitis is reported and, as in cases of systemic lupus erythematosus, the syndrome is often severe with major sensorimotor deficits and limited neurological recovery. Rarely, multiple cerebral infarcts in the anti-phospholipid antibody syndrome can result in a relapsing clinical picture and MRI findings similar to those of multiple sclerosis (T.F. Scott et al 1994). B.J. Kelly et al (1989) described (unfortunately only in abstract), two patients with the anti-phospholipid syndrome manifesting as venous thromboses and spontaneous abortion who developed clinical features highly characteristic of multiple sclerosis – optic neuritis, transverse myelitis, Lhermitte's symptom, paroxysmal tonic spasms and internuclear ophthalmoplegia.
The diagnosis is based on a characteristic clinical syndrome in combination with typical laboratory abnormalities. Consensus efforts have been made to achieve a uniform set of criteria for achieving a firm diagnosis (Table 8.7 ; W.A. Wilson et al 1999). In some patients there is thrombocytopaenia. Anti-nuclear antibodies may be detectable, especially in patients with coexisting systemic lupus erythematosus, but their presence is not required to make the diagnosis. Disorders of clotting include prolongation of the partial thromboplastin time and the presence of lupus anticoagulant detected using the dilute Russell's viper venom time. The most specific serological association is the presence of a raised titre of anti-phospholipid antibodies directed against cardiolipin. In active disease, these will normally be markedly elevated. Both IgG and IgM antibodies are found and a sustained increase in the IgG form is suggestive of disease activity. Patients with neurological involvement may demonstrate abnormal imaging. Infarction is the basis for cases of ischaemic stroke and can involve either the anterior or posterior circulation. Other patients display multiple and mainly small cerebral white matter lesions, predominantly in subcortical rather than periventricular regions. The low specificity of this imaging appearance must also be emphasized, especially with increasing age, where asymptomatic white matter lesions are a frequent manifestation of arteriosclerotic small vessel disease. Patients with acute transverse myelitis may exhibit extensive lesions involving multiple segments of the spinal cord and accompanied by swelling in the acute stage.
Table 8.7.
Proposed preliminary criteria for the diagnosis of anti-phospholipid syndromea
|
|
In abbreviated form fromW.A. Wilson et al (1999); one or more clinical and one laboratory criteria must be present for a patient to be considered as having definite anti-phospholipid syndrome.
From the neurological perspective, the diagnosis is often considered but rarely made. There is potential for this disorder, which has a vascular prothrombotic pathogenic mechanism, to produce multifocal relapsing central nervous system involvement such that the diagnosis of multiple sclerosis is considered. A practical difficulty is that mild elevation in the IgG anti-cardiolipin antibody titre is occasionally found in the normal population (Tanne et al 1999). It has been suggested that the clinical phenotype in patients with demyelinating disease and anti-phospholipid antibodies selectively affects the optic nerves and spinal cord (Karussis et al 1998). In a sample derived from attendance at a rheumatology clinic, 23/26 patients with clinical features suggesting multiple sclerosis (especially transverse myelitis or optic neuritis) had anti-phospholipid antibodies compared with 166/296 of those without these neurological features (Ijdo et al 1999). Others have not found a correlation between anti-phospholipid antibodies and a distinct clinical phenotype in groups of patients with multiple sclerosis (Heinzlef et al 2002; Roussel et al 2000; Sastre-Garriga et al 2001). A firm conviction that the neurological syndrome is the result of anti-phospholipid syndrome requires robust clinical and laboratory evidence, and the exclusion beyond reasonable doubt of other potential neurological causes. The proposal that patients with multiple sclerosis should routinely be tested for anti-phospholipid antibodies (Cuadadro et al 2000) runs the risk of incorrectly reversing a definite clinical and laboratory diagnosis of multiple sclerosis on the basis of a modest elevation of anti-cardiolipin antibody titre. The abrupt onset and duration of the neurological deficits often suggest a vascular disorder resulting from transient ischaemia rather than demyelinating disease. Non-neurological features indicating a systemic thrombotic disorder, and the history of recurrent sponaneous abortions, should alert the physician to this potential diagnosis. The importance of making the correct diagnosis lies in the fact that, although not without its risks, anticoagulant treatment with warfarin reduces the future risk for stroke and other thrombotic events. When previous thrombotic events have occurred, it has been recommended that anticoagulation should aim to reach an International Normalized Ratio (INR) of 3–4 to obtain an optimal therapeutic effect and reduce the risk of further thromboses (G.R.V. Hughes 2003).
Primary Sjögren's syndrome
Sjögren's syndrome is a relatively common multisystem disorder, most often characterized by a triad of keratoconjunctivitis sicca, xerostomia and another connective tissue disease – usually rheumatoid arthritis. Classification criteria for the condition have been published recently (Table 8.8 ; Vitali et al 2002). It has previously been held that neurological complications are relatively rare. When they occur, they usually affect the peripheral nervous system or trigeminal nerve, often manifesting as sensory neuropathy or ganglionopathy, sometimes confined to the trigeminal territory. It is, however, noteworthy that severe myelopathic syndromes can also be encountered. From the histological perspective, the lesions of Sjögren's disease are not demyelinating but resemble those of paraneoplastic syndromes (Bakchine et al 1991). In 1986, however, E.L. Alexander et al (1986) re-emphasized earlier reports (Atwood and Poser 1961) that the clinical features of central nervous system involvement might mimic those of multiple sclerosis. They described 20 patients, all of whom had been regarded as having multiple sclerosis. In only four had Sicca syndrome been recognized before the onset of neurological symptoms. In the majority, the course was relapsing and remitting, including internuclear ophthalmoplegia and signs of spinal cord and cerebellar disease. Once the suspicion of an alternative diagnosis had been raised, confirmatory evidence was obtained from the obvious systemic abnormalities, involvement of the peripheral nervous system and detection of autoantibodies (anti-Ro and anti-La). Visual evoked potentials were frequently abnormal and oligoclonal IgG usually present in the cerebrospinal fluid. MRI showed small numbers of white matter lesions indistinguishable from those of multiple sclerosis in some patients (E.L. Alexander et al (1986). The resemblance to multiple sclerosis was heightened by clear descriptions of optic neuritis (Figure 8.10 ) as an early or initial symptom of Sjögren's syndrome (Wise and Angudelo 1988). Tesar et al (1992) described three patients with optic neuropathy, indistinguishable from optic neuritis, but in whom other neurological and systemic features eventually drew attention to the correct diagnosis. Other case reports emphasize the occurrence of transverse myelitis in Sjögren's syndrome (Manabe et al 2000; Wakatsuki et al 2000) and a recent study described nine female patients with a previous diagnosis of primary progressive multiple sclerosis in whom the combination of sicca complex symptoms and investigative findings fulfilled the criteria for Sjögren's syndrome (Pericot et al 2003).
Table 8.8.
Classification criteria for Sjögren's syndromea
|
In abbreviated form from Vitali et al (2002).
Figure 8.10.
Optic disc appearance in a young female with recurrent optic neuritis and other manifestations of demyelination having anti-Ro autoantibodies, skin changes, and a positive family history of Sjögren's syndrome.
These reports naturally give rise to concern that many patients thought to have multiple sclerosis are wrongly diagnosed. However, reassessment of large clinic series has, in general, been reassuring with no increase in the frequency of Sjögren's syndrome. Complaints of dry eyes and mouth are almost invariably attributable to medication (Metz et al 1988; Noseworthy et al 1989a; Sandberg-Wollheim et al 1992), although Miró et al (1990) revised the diagnosis of multiple sclerosis to Sjögren's syndrome in two of 64 patients on the basis of clinical suspicion and salivary gland biopsy.
Two recent series from a single centre slightly alter this perspective on the easy separation of Sjögren's syndrome from multiple sclerosis. De Séze et al (2001b) performed detailed laboratory investigations looking for evidence of Sjögren's syndrome in 60 patients with a presumptive diagnosis of primary progressive multiple sclerosis. Their investigations included a Schirmer test, salivary gland scintigraphy, salivary gland biopsy and investigation for anti-Ro and anti-La antibodies. There was a remarkably high frequency of abnormalities for many of these investigations and, using previously proposed European diagnostic criteria (Vitali et al 1996), the authors diagnosed Sjögren's syndrome in ten (16.6%) patients. These findings are difficult to interpret, given that it is unusual to perform such extensive investigations in an older adult population – the mean age was about 50 years – and an age-matched control group was evidently not studied. Delalande et al (2004) subsequently reported 82 individuals with Sjögren's syndrome, selected for neurological involvement. Fifty-six of the 82 had disease of the central nervous system – affecting the spinal cord (29 cases), cerebrum (33 cases) or optic nerves (13 cases). Abnormalities of the visual evoked responses (61%) and the presence of oligoclonal bands (31%) were relatively frequent. Seventy per cent of the 58 cases who had MRI scans showed cerebral lesions and 40% met radiological criteria for multiple sclerosis; 75% of the 29 with symptomatic spinal cord disease had discrete cord lesions but MRI was normal in the absence of clinical evidence for spinal involvement. Reassuringly, despite these clinical similarities, most patients (51/82) also had involvement of the peripheral nervous system, and anti-Ro/SSA autoantibodies were detected (sometimes only with serial testing).
Taken together, it would seem that misdiagnosis is rare but that Sjögren's syndrome can occasionally cause relapsing– remitting disease of the central nervous system before onset of the classical sicca syndrome (Ménage et al 1993) although usually with simultaneous involvement of the peripheral nervous system. A previous lack of agreed diagnostic criteria for Sjögren's syndrome (Anon 1992), the serum anti-Ro/La antibodies being neither constant nor specific (as is also true for the diagnostic criteria in multiple sclerosis), has not helped rational debate on this aspect of the differential diagnosis (P.M. Moore and Lisak 1990).
Behçet's disease
Involvement of the central nervous system in Behçet's disease has frequently been reported since the 1950s but, in the majority of cases, the clinical features do not closely resemble those of multiple sclerosis. The more usual manifestations are, for example, meningoencephalitis (O'Duffy and Goldstein 1976), progressive pseudobulbar palsy (Motomura et al 1980) or intracranial hypertension (Pamir et al 1981). There are rare instances of spinal cord disease, with progressive or partially remitting weakness and sensory change. Brainstem syndromes including ophthalmoplegia and cranial nerve palsies, accompanied by hemiplegia, are not infrequent. The large study by Siva et al (2001) – reporting from Turkey, where Behçet's disease is relatively common – provides a particularly useful indication of the frequency of various neurological manifestations. Of 164 patients in whom neurological abnormalities were present, features at presentation included: headache (61.6%), motor symptoms (53.7%), cerebellar symptoms apart from dysarthria (29.9%), brainstem symptoms other than dysarthria (29.3%), dysarthria (22.6%), behavioural symptoms (12.2%), sensory symptoms (11%), alteration of consciousness (7.3%), cognitive symptoms (2.4%) and other symptoms (9.8%, including seizures, peripheral neuropathy and optic neuritis). The final diagnoses – after imaging and cerebrospinal fluid studies – were: a parenchymal syndrome (neuro-Behçet's disease, 75.6%), venous sinus thrombosis (12.2%), optic neuritis (0.6%), psycho-Behçet's syndrome (0.6%) and indefinite (11%).
The presentation with spinal cord or brainstem features may not be clinically distinguishable from multiple sclerosis (Shakir et al 1990). Paraplegia may be sudden in onset (Bergerin et al 1980). Optic neuropathy, either in isolation (Kansu et al 1989) or associated with disseminated symptoms (Bergerin et al 1980), is rare and probably the result of ischaemia. In acute attacks, fever, headache, meningism and a raised sedimentation rate and C-reactive protein are common (Chajek and Fainaru 1975). Motomura et al (1980) found that, in contrast to multiple sclerosis, Lhermitte's sign, internuclear ophthalmoplegia and tonic spasms do not occur.
Fifty patients with Behçet's disease who had attended the National Hospital in London over a 10-year period were discussed by D. Kidd et al (1999b). The most frequently observed neurological findings were brainstem syndromes, followed by spinal cord or hemisphere lesions, and meningoencephalitis. Optic nerve, vestibulo-cochlear and peripheral nerve involvement was less common. Over an average of 3 years’ follow-up, most had only a single neurological episode and made a good recovery. The prognosis was less good in those with recurrent episodes (one-third) or a high cerebrospinal fluid pleocytosis at presentation. Four patients experienced progressive neurological deterioration.
Siva et al (2001) also studied prognosis in their large cohort with neurological manifestations. After 10 years, 45% had accumulated severe disability (Expanded Disability Status Scale >6), with early cerebellar features and progressive symptoms each predicting a poor prognosis. A better prognosis was seen in patients whose presentation was with headache or venous sinus thrombosis.
Investigations can be of value in distinguishing these conditions. In Behçet's disease, the cerebrospinal fluid may show a pleocytosis beyond the range seen in multiple sclerosis (Shakir et al 1990). Conversely, oligoclonal IgG is rarely present in Behçet's disease. In one study, although seven patients had matching bands in serum and cerebrospinal fluid, none of 35 had oligoclonal bands restricted only to the cerebrospinal fluid (D. Kidd et al 1999b). Disseminated white matter lesions are sometimes shown on cerebral MRI (Figure 8.11 ; Morrissey et al 1993b), although such changes are rarely extensive (D. Kidd et al 1999b). On the other hand, there may be striking involvement of the brainstem, thalamus and internal capsules (Figure 8.12 ; Akman-Demir et al 2003). Acute lesions in these regions may be large, and accompanied by swelling and gadolinium enhancement resembling the appearances of a tumour. Mass effect may be observed with slow enlargement over months followed by resolution following the use of corticosteroids (Erdem et al 1993a; Kermode et al 1989). Atrophy can develop later in previously affected regions (Figure 8.13 ; Akman-Demir et al 2003).
Figure 8.11.
T2-weighted MRI in Behçet's disease showing an area of high signal in periventricular white matter.
Figure 8.12.
(A) T2-weighted and (B) Gadolinium enhanced T1-weighted MRI in Behçet's disease showing an extensive lesion of the brainstem.
From D. Kidd et al (1999) with permission.
© 2006
Figure 8.13.
Behçet's disease. Serial MRI of an adult female with a brainstem syndrome. (A) T2-weighted scan during the acute phase shows high signal and swelling of the midbrain. (B) T1-weighted scan 5 years later shows midbrain atrophy.
Reproduced with permission from D.H. Miller et al (1997).
© 2006
Since there is no specific test for Behçet's disease, the diagnosis has to be based on the association of aphthous oral ulceration with genital ulcers, intra-ocular inflammation or defined skin lesions (Table 8.9 ; International Study Group for Behçet's Disease 1990). A positive pathergy test – in which a small papule or pustule develops at the site of a sterile needle prick – provides additional support for the diagnosis in an appropriate clinical context, although it is neither completely specific nor sensitive. Neuro-Behçet's disease can, however, develop before the appearance of mucosal ulceration (Kozin et al 1977) or even in its absence (Lueck et al 1993).
Table 8.9.
Diagnostic criteria for Behçet's diseasea
|
From International Study Group for Behçet's Disease (1990).
Central nervous system vasculitis
Vasculitis can affect the central nervous system as part of a systemic disorder or as an isolated manifestation. Central nervous system involvement can be multifocal and multiphasic and the lesions are inflammatory in nature. There is potential for the clinical and laboratory manifestations of central nervous system vasculitis to overlap with those seen in multiple sclerosis, although it is uncommon that there is serious difficulty in making the distinction. Here, the differential diagnosis of vasculitis has to be considered.
Systemic vasculitis with central nervous system involvement
Involvement of the central nervous system by vasculitis occurs as part of a systemic vasculitic disorder or as an isolated condition. The former category includes polyarteritis nodosa, Churg–Strauss syndrome (in which there is eosinophilia and pulmonary involvement) and Wegener's granulomatosis (in which renal and pulmonary involvement are common). When it occurs, neurological involvement is most often, but not exclusively, confined to the peripheral nervous system: a rapidly evolving and progressive mononeuritis multiplex or symmetrical polyneuropathy is characteristic. Nevertheless, transient ischaemic episodes or strokes can occur in a multifocal pattern in patients with a systemic vasculitis. Oculomotor palsies or visual impairment are seen with the orbital involvement that not uncommonly occurs in Wegener's granulomatosis. Many patients with an active polyarteritis will be systemically unwell and will exhibit a raised erythrocyte sedimentation rate and the presence of anti-neutrophil cytoplasmic antibodies. Such a clinical picture, along with peripheral nerve and systemic non-neurological involvement, means that multiple sclerosis will rarely arise in the differential diagnosis of systemic arteritis. Prompt diagnosis is crucial because vigorous immunosuppression with pulsed corticosteroids and cyclophosphamide have a major beneficial effect in a group of disorders that previously had a high mortality rate.
Isolated central nervous system vasculitis
Isolated or primary central nervous system vasculitis is much more difficult to diagnose since the characteristic serological abnormalities that accompany systemic vasculitic disorders are typically absent. The illness usually evolves over months although more protracted courses spanning years, with fluctuating or even relapsing and remitting symptoms, are occasionally seen. The manifestations often include features not expected in multiple sclerosis: headache, obtundation, meningism, seizures, and stroke-like episodes. In some cases the occurrence of optic neuropathy, myelopathy (which can be acute or chronic) or brainstem involvement may raise the possibility of multiple sclerosis. MRI findings are largely nonspecific, often with multifocal white matter and grey matter lesions, some of which may display enhancement or haemorrhagic features. A rare but characteristic finding is of large numbers of punctate foci of gadolinium enhancement in the white matter (Figure 8.14 ; Campi et al 2001). Such lesions often persist for many months. Intrinsic cord lesions are seen in patients with myelopathic presentation. The cerebrospinal fluid will normally show evidence of inflammation, with a mononuclear pleocytosis, an elevated protein and the presence of intrathecal oligoclonal bands. Cerebral angiography has long been advocated but is rarely useful in diagnosis – segmental narrowing of smaller arteries proving neither specific nor sensitive for isolated central nervous system vasculitis. The crucial diagnostic test is brain and leptomeningeal biopsy to provide a pathological diagnosis.
Figure 8.14.
(A) T2-weighted MRI in isolated cerebral vasculitis showing multiple lesions. (B) Gadolinium enhanced T1-weighted scan showing multiple areas of enhancement.
Reproduced with permission from D.H. Miller et al (1997).
© 2006
The diagnostic difficulties associated with central nervous system vasculitis – whether systemic or part of an isolated process – are emphasized by Scolding et al (1997) who described eight patients with vasculitis in whom cerebral manifestations dominated the clinical presentation, often without systemic features. Seizures (focal and generalized), stroke-like episodes, acute and subacute encephalopathy, cognitive impairment, movement disorders and cranial nerve palsies were all observed. Many of these syndromes would not ordinarily be confused with multiple sclerosis, but three patients had an illness with relapses and remissions and optic nerve and brainstem involvement, entirely consistent with the symptoms and signs of multiple sclerosis. Of these, two had oligoclonal bands and one had typical MRI abnormalities. Multiple sclerosis was the preferred diagnosis at presentation in all three patients and the correct explanation only emerged when atypical features were analysed in more detail, supplemented by investigations looking for an underlying vasculitis, including the presence of anti-neutrophil cytoplasmic antibodies. Against a clinical background suggestive of multiple sclerosis, the clues in these three cases were seizures, headache, encephalopathy, stroke-like episodes, fever, arthralgia and skin rash. The importance of diagnosing central nervous system vasculitis lies in the prospect that it can be effectively treated in most instances with cyclophosphamide. Corticosteroids are also frequently used, especially to treat acute neurological events.
Systemic sclerosis
Multiple sclerosis has been described in association with systemic sclerosis (Trostle et al 1986), but a causal connection was not suggested. The typical case with calcinosis, Raynaud's phenomenon, dysphagia, sclerodactyly and telangiectasia will not cause confusion. When the nervous system is involved, peripheral nerves are more usually affected, but vasculitic lesions affecting the central nervous system can mimic episodes of demyelination. Averbuch-Heller et al (1992) decribed four patients with myelopathy indistinguishable from spinal demyelination.
Susac syndrome
This rare syndrome is defined by the clinical triad of retinal disease, sensorineural deafness and encephalopathy. The pathological basis is a microangiopathy of small vessels in the brain, retina and cochlea. It usually presents in young women and is often monophasic and self-limiting (Meca-Lallana et al 1999). Multiple white matter and grey matter lesions may be seen on MRI and confusion with multiple sclerosis or acute disseminated encephalomyelitis occurs if there is clinical evidence for multifocal white matter disturbance (Murata et al 2000). A high frequency of central corpus callosum lesions was reported in a recent review of 27 cases along with another 51 described in the literature (Figure 8.15 ; Susac et al 2003); gadolinium enhancement in the parenchyma and leptomeninges was also reported. Essential clues to the diagnosis are deafness (which is an unusual feature of multiple sclerosis) and retinal vascular disease. For this reason, Susac syndrome is discussed more in the ophthalmic than the neurological literature. Recurrences have been described up to 18 years after the original episode (G.W. Petty et al 2001).
Figure 8.15.
(A) Sagittal and (B) axial T2-weighted MRI in Susac's syndrome shows white matter lesions and corpus callosum involvement.
From Susac et al (2003). © 2003, reprinted with permission of Lippincott Williams & Wilkins (lww.com).
© 2006 Lippincott Williams & Wilkins
Noninflammatory cerebrovascular disease
Less confusion may arise in making the distinction between vascular disease affecting the central nervous system when this does not have the added twist of biomarkers indicating inflammatory brain disease, but the noninflammatory vascular disorders may mimic the clinical features and imaging appearances of multiple sclerosis.
Multiple cerebral emboli in a young adult, notably arising from subacute bacterial endocarditis or atrial myxoma, can present with clinical features resembling those of multiple sclerosis. A more common problem is that of the young woman taking an oral contraceptive who experiences the rapid onset of focal neurological signs – weakness and sensory loss in one upper limb, for example. Unless MRI shows multiple lesions, investigation is unlikely to distinguish between infarction and demyelination. Visual evoked potentials seldom show changes of diagnostic value in the initial attack of multiple sclerosis and cerebrospinal fluid oligoclonal IgG may be present in acute cerebrovascular disease (Roström and Link 1981). In doubtful circumstances, it may seem best to discontinue the contraceptive pill and await events. However, in other circumstances where MRI shows multifocal lesions characteristic for demyelination, and the cerebrospinal fluid exhibits oligoclonal bands, a more confident diagnosis of demyelinating disease will be made and contraception allowed to continue.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)
In the last decade, the autosomal dominant disorder known as cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) has become recognized as a significant cause of stroke and migraine in young adults (Dichgans et al 1998). There is usually a positive family history of strokes occurring at a relatively young age. Dementia may develop with disease progression. MRI reveals multifocal or symmetrical white matter lesions that are sometimes very extensive. Brain imaging is often already abnormal in the pre-symptomatic phase. Distinctive radiological features of CADASIL are prominent involvement of the anterior temporal white matter and external capsules (Figure 8.16 ; O'Sullivan et al 2001). This imaging pattern will suggest the correct diagnosis in cases where a multifocal relapsing and remitting or progressive central nervous system syndrome have erroneously led to the suspicion of multiple sclerosis (O'Riordan et al 2002). The cerebrospinal fluid does not contain oligoclonal bands. The characteristic small vessel arteriopathy may be diagnosed from a skin biopsy. The disorder is the result of a mutation of Notch3 located at chromosome 19q12 (Joutel et al 1996).
Figure 8.16.
T2-weighted MRI in CADASIL. There are extensive white matter abnormalities. Characteristic involvement of (A) the external capsules and (B) anterior temporal white matter. Kindly provided by Professor Tarek Yousry.
Sarcoidosis
Sarcoidosis is a multisystem granulomatous disorder, with the most frequent clinical manifestations related to intrathoracic disease (especially pulmonary involvement with mediastinal lymphadenopathy). It is generally estimated that about 5% of cases develop evidence for central nervous system involvement. A recent study reported neurological involvement in an unusually high proportion of cases (26%; R.K. Allen et al 2003), although many of these patients had peripheral nerve or muscle involvement that would not be confused with multiple sclerosis. The prognosis seems poorer for central than peripheral nervous system involvement (Ferriby et al 2001). Diagnosis of neurosarcoidosis is most challenging when there is no evidence for disease outside the nervous system, and it is sometimes only diagnosed definitively following biopsy of central nervous system or meningeal tissue (Bode et al 2001; F.G. Moore et al 2001). The manifestations and management of sarcoidosis affecting the nervous system have been recently reviewed (Hoitsma et al 2004; Nowak and Widenka 2001; Vinas and Rengachary 2001). These reviews highlight the frequency of nervous system involvement (seen in 5–15% of patients with sarcoidosis); the most frequent clinical manifestations (cranial nerves, meninges, optic nerves and spinal cord); the role of neuroradiological and other laboratory investigations in supporting the diagnosis (whilst noting that there is no pathognomonic noninvasive investigation and that the diagnosis is often only made after granulomatous lesions are demonstrated from biopsy of affected conjunctiva, muscle, lymph node, liver or central nervous system tissue); and the approach to treatment (for which corticosteriods are the mainstay but often associated with adverse effects because of the need for long-term maintenance therapy). Nowak and Widenka (2001) propose the following differential diagnosis when sarcoidosis involves the central nervous system parenchyma: multiple sclerosis, cerebral metastasis, cerebral lymphoma, tuberculosis, fungal infections and high- and low-grade glioma. When there is meningitis, the differential diagnosis proposed is: bacterial meningitis (such as Borrelia sp.), tuberculous or carcinomatous meningitis, meningioma, leukaemic infiltration, meningeal lymphoma and meningeal plasmacytoma. To either list could be added isolated angiitis of the central nervous system.
Most forms of neurosarcoidosis do not resemble multiple sclerosis but where the spinal cord and optic nerve are involved the distinction can be extremely difficult. Since sarcoid myelopathy typically presents as chronic progressive paraparesis, resulting from compression, ischaemia or parenchymal disease (Day and Sypert 1976), but occasionally has a rapid or subacute onset (Bogousslavsky et al 1982; Nathan et al 1976), confusion can arise with both the relapsing–remitting and progressive variants of multiple sclerosis. Lhermitte's symptom has been reported in neurosarcoidosis (Sauter et al 1991).
The clinical features of sarcoid optic neuropathy (Figure 8.17 ) often closely resemble those of demyelinating neuropathy (Beardsley et al 1984; Piéron et al 1979; Rush 1980), although E.M. Graham et al (1986) found that visual loss is usually more gradual. Recovery may follow treatment with corticosteroids but can occur spontaneously (Galetta et al 1989). E.M. Graham et al (1986) also noticed that although there is improvement with corticosteroid treatment, patients may subsequently become steroid dependent with relapses occurring as the dose is reduced. A particular diagnostic challenge arises when optic neuritis presents as the first symptom of systemic sarcoidosis (DeBroff and Donahue 1993). It was noted by L.P. Frohman et al (2003) that characteristic ophthalmic features suggesting a granulomatous optic neuropathy (periphlebitis, uveitis and optic disc granuloma) were only found in a minority of patients whose sarcoidosis presented as an anterior visual pathway disturbance. However, their study did report a high frequency of abnormalities on chest X-ray (72%), gallium scan (93%), cerebrospinal fluid (88%) and anterior visual pathway imaging (70%), and angiotensin-converting enzyme was elevated in 76% (L.P. Frohman et al 2003). Whilst this emphasizes the value of such investigations when sarcoid optic neuropathy is suspected, the frequency of abnormalities reported in this study is higher than that observed by other experienced clinicians (J.P. Lynch 2003).
Figure 8.17.
Bilateral optic disc appearances showing infiltration in a patient with histologically proven neurosarcoidosis.
Sarcoid meningoencephalitis inevitably results in symptoms attributable to multiple lesions, including cranial nerve palsies and signs of brainstem disease, which present diagnostic difficulties. However, features such as headache, papilloedema and diabetes insipidus steer the clinical diagnosis away from multiple sclerosis.
Overt systemic sarcoidosis is usually present before the onset of neurological involvement, or is readily found on routine investigation. When there is diagnostic doubt, histological confirmation must be sought from biopsy of accessible suspect lesions or tissue commonly affected by sarcoidosis – gum, conjunctiva, lymph node, muscle and other sites. The Kveim test is unreliable (positive tests have been observed in clinically definite multiple sclerosis) and is no longer available in the United Kingdom given concern about the potential for prion transmission. In about 10% of patients with neurosarcoidosis, there may be no evidence for systemic sarcoidosis (Oksanen et al 1985) and, rarely, autopsy indicates that there is no involvement outside the nervous system (Beardsley et al 1984).
The cerebrospinal fluid total protein may be greatly raised and oligoclonal IgG is sometimes present (Kinnman and Link 1984; Zajicek et al 1999). The cell count is often increased with an excess of neutrophils and eosinophils. Glucose is occasionally reduced. There may be elevation of angiotensin-converting enzyme in the cerebrospinal fluid and serum. Whilst initially this appeared to be a promising diagnostic test (T.F. Scott 1993), further experience suggests that it is a rather nonspecific finding that may also be seen in other inflammatory neurological disorders. Genetic mutations may also be associated with elevated serum levels of angiotensin-converting enzyme (Linnebank et al 2003). Tahmoush et al (2002) suggest that a level of cerebrospinal fluid angiotensin-converting enzyme >8 nmol/mL/min is suggestive of neurosarcoidosis.
Cerebral MRI sometimes shows white matter and periventricular lesions similar to those of multiple sclerosis (Figure 8.18A ; D.H. Miller et al 1988d; Lexa and Grossman 1994) but involvement of the cortex or hypothalamus is not expected in the latter condition. The lesions of sarcoidosis can be demonstrated as areas of increased signal and swelling in the optic nerves (Bode et al 2001; Engelken et al 1992) and spinal cord. Enhanced MRI is especially valuable. It often shows meningeal involvement (Pickuth et al 2000), most commonly involving the basal cisterns, pituitary and hypothalamic regions, but also involving meninges overlying the cortex, brainstem, spinal cord and cauda equina (Figure 8.19 ). Parenchymal granulomatous lesions in the cortex, white matter, brainstem, optic nerves, other cranial nerves, spinal cord, cauda equina and nerve roots may all enhance (Sauter et al 1991). Enhancement of meningeal, parenchymal or periventricular lesions was detected in 15/17 (88%) cases in one study where gadolinium enhanced MRI was performed (Lexa and Grossman 1994). Lesions in the brain or spinal cord sometimes exhibit a mass effect, simulating the appearance of a tumour. Hydrocephalus can also occur. Enhancement of parenchymal lesions in sarcoidosis generally lasts longer than the 4–6 weeks that characterizes the evolution of the enhancing phase of multiple sclerosis lesions, although corticosteroid treatment for sarcoidosis often leads to the resolution of enhancement (Lexa and Grossman 1994). In a minority of cases, the distribution of white matter abnormalities is indistinguishable from that seen in multiple sclerosis, and this observation is in keeping with the post-mortem findings (Figure 8.18).
Figure 8.18.
(A) T2-weighted MRI in neurosarcoidosis showing multifocal and periventricular abnormalities indistinguishable from those seen in multiple sclerosis. (B) Post-mortem specimen showing involvement of the ventricular lining by sarcoid tissue (arrow). Kindly provided by Dr Trevor Hughes.
Figure 8.19.
Gadolinium enhanced T1-weighted image in neurosarcoidosis. Note the widespread meningeal enhancement. (A) Coronal section and (B) sagittal section showing the optic tract (arrow).
Zajicek et al (1999) reviewed 68 patients with definite or probable neurosarcoidosis, a definite diagnosis (seen in 12/68 cases, 18%) being dependent on finding sarcoid granulomas on nervous system histology. Twenty-six (38%) patients presented with uni- or bilateral optic nerve disease. This had often first been diagnosed as optic neuritis but carried a worse prognosis for vision – although referral patterns may have inflated the apparent frequency of visual involvement. Nineteen (28%) of the 68 subjects had significant spinal cord disease with neurological involvement at other sites in about half these cases. The spinal cord syndrome produced a picture similar either to subacute transverse myelitis or chronic spinal cord demyelination. However, this and other reports (Prelog et al 2003; Zajicek 1990; Kaiboriboon et al 2005) illustrate the coexistence of spinal cord and cauda equina involvement in neurosarcoidosis – a clinical syndrome that also occurs in multiple sclerosis as a result of the involvement of the conus medullaris. Neurosarcoidosis presented with brainstem or cerebellar symptomatology, not easily distinguished from multiple sclerosis, in 14/68 (21%) cases. Twenty of 54 (37%) patients had oligoclonal bands and a further ten (18%) showed isoelectrophoretic abnormalities of proteins both in serum and cerebrospinal fluid. White matter abnormalities were present on MRI in 16/37 (43%) patients. Meningeal enhancement with gadolinium best discriminated the appearances from those of multiple sclerosis and was seen on 11/29 (38%) scans (Zajicek et al 1999).
A subsequent systematic analysis of spinal fluid samples from patients diagnosed with neurosarcoidosis, based on a stringent set of criteria that required a neurological syndrome compatible with neurosarcoidosis and histological verification of granulomas, suggests that local intrathecal production of oligoclonal bands is a relatively uncommon feature – being seen in only one of 19 cases (Ed Thompson, personal communication). This finding suggests that some cases reported in earlier series – where oligoclonal bands were positive but histological confirmation of the diagnosis was not mandatory – did in fact have multiple sclerosis. A definitive answer is not possible and the chance concurrence of two relatively common disorders cannot absolutely be excluded. Nevertheless, in making the distinction between sarcoidosis and multiple sclerosis, the status of oligoclonal bands (usually negative in neurosarcoidosis and positive in multiple sclerosis) is of some diagnostic value.
Although peripheral nerve involvement is seen less commonly than central nervous system involvement, there should be no confusion with multiple sclerosis when it does occur. Focal, multifocal and diffuse neuropathies were reported in a review of 11 cases with sarcoid neuropathy confirmed on nerve biopsy (Said et al 2002). Nine also had histological evidence for muscle involvement and there was pulmonary or mediastinal involvement in eight. The biopsies revealed necrotizing vasculitis in addition to granulomas in seven cases.
Infections
A number of specific infections can reproduce the typical presenting features of multiple sclerosis and this potential area of diagnostic confusion becomes even greater with the development of chronic infections – not least because some may trigger autoimmune processes as part of the complex interplay between pathogen and host response.
Lyme borreliosis
In an endemic area (Figure 8.20 ), acute Lyme disease will usually be recognized from the rash and from the constitutional disturbance, although the history of tick bite may not be forthcoming. Neurological involvement at this acute or subacute, essentially monophasic, stage can resemble multiple sclerosis, with cranial nerve lesions, particularly facial palsy, widespread paraesthesiae due to radicular involvement and signs of spinal cord disease (Bateman et al 1987; Pachner and Steere 1985; Pachner et al 1989). Optic neuritis has rarely been described (Winyard et al 1989). After reviewing published cases, D.M. Jacobson et al (1991) concluded that the relationship between optic neuritis and Lyme borreliosis remains ambiguous. However, they make a case for serological testing in isolated optic neuritis in endemic areas, with antibiotic treatment in patients showing a rise in antibody levels on paired sera. Acute transverse myelitis (Rousseau et al 1986) and meningoradiculomyelitis (Tullman et al 2003) have also been reported. Myelitis may reflect primary infection or an early immune-mediated postinfectious response (Lesca et al 2002).
Figure 8.20.
Lyme disease: a global map showing the geographic distribution of the disease.
Far more difficult diagnostic problems are posed when chronic progressive or relapsing neurological disease develops in what is regarded as tertiary Lyme disease, many years after infection or long after clinical evidence for infection has waned (Ackerman et al 1988). Syndromes that have been considered to represent chronic neuroborreliosis include progressive spastic paraparesis (Kohler et al 1986), transverse myelitis (Reik et al 1986; Weder et al 1987), cerebellar ataxia (Benoit et al 1986), recurrent cranial nerve palsies (Pachner and Steere 1985) and dementia (Logigian et al 1990). Optic neuritis was mentioned but not described by Ackerman et al (1988). Optic neuropathy in a case described by Schechter (1986) case was clearly ischaemic. More recent studies have suggested that chronic neurological syndromes may be related to borreliosis through an immunopathogenic mechanism (Hemmer et al 1999; Muraro et al 2003).
MRI may show disseminated white matter lesions (Logigian et al 1990), which result from focal vasculitis and demyelination (Oski et al 1996; Romi et al 2004), and the cerebrospinal fluid may contain oligoclonal IgG (Finkel and Halperin 1992). Positive serology for Borrelia burgdorferi merely indicates past infection and is unlikely to be relevant in the absence of other evidence for infection (Coyle 2002; Coyle et al 1993). Investigation of patients diagnosed as having multiple sclerosis in endemic areas has not revealed any excess of positive tests for Borrelia (Schmutzhardt et al 1988; Coyle 1989). Although the finding of antibodies in cerebrospinal fluid is a more reliable indication of central nervous system involvement (Ackerman et al 1988; Finkel and Halperin 1992), it is not possible easily to culture Borrelia burgdorferi and there is no reliable assay for active (as against past) infection (Coyle 2002). This creates difficulties of diagnosis in patients presenting with an atypical neurological syndrome and positive Borrelia serology. The diagnosis of borreliosis is most unlikely if the patient has not visited or lived in an area where the Ixodes tick (the vector that transmits the infection to humans) exists. Conversely, the diagnosis of Lyme disease can reasonably be considered if the patient lives in an endemic area. However, because Lyme disease is endemic in those parts of Europe and North America that are also areas of high prevalence for multiple sclerosis, it is also quite possible that the occurrence of positive Borrelia serology in a patient with otherwise typical multiple sclerosis is coincidental. In our view, a confident diagnosis of neuroborreliosis infection should only be made when the patient lives in or has visited an endemic area, has a neurological syndrome typical for borreliosis such as facial palsy, sensorimotor radiculitis or meningitis, and manifests positive Borrelia serology in the cerebrospinal fluid. We doubt that there is a chronic progressive or relapsing form of neuroborreliosis infection that genuinely represents part of the differential diagnosis of multiple sclerosis but recognize that this is an opinion not shared universally.
Meningovascular syphilis
Neurosyphilis is now a comparative rarity in countries where multiple sclerosis is prevalent and is therefore more likely to be overlooked on the few occasions when a patient does present with luetic disease. Oculomotor palsies, perhaps combined with hemiparesis, certainly bear a superficial resemblance to multiple sclerosis, but headache and epilepsy are often prominent manifestations and classical pupillary abnormalities may be present. Cerebrospinal fluid will usually exhibit a lymphocytic pleocytosis with raised protein and IgG and oligoclonal bands. Laboratory diagnosis is based on serological investigation of blood and cerebrospinal fluid (Reik 2002). Nonspecific serological abnormalities are the rapid plasmin reagin (RPR) and venereal disease research laboratory (VDRL) tests, but up to 20–40% of positive blood results are false positives and as many as 25% of subjects with late neurosyphilis may have a negative blood test. A positive cerebrospinal fluid VDRL provides definite evidence for neurosyphilis but again this test may be negative in 30% of cases. More specific and sensitive evidence for syphilitic infection is a positive test for treponemal antibodies, such as the serum fluorescent treponemal antibody absorption test, which is almost always informative but does not distinguish active from past infection.
Syphilitic optic neuritis is usually bilateral, with disc swelling, enlarged blind spots and peripheral constriction of the visual fields (Graveson 1950). Syphilitic myelopathy may be acute or slowly progressive (Siller 1989). Florid manifestations of neurosyphilis are now most often complications of human immunodeficiency virus (HIV) infection.
Human immunodeficiency virus (HIV)
Vacuolar myelopathy related to acquired immunodeficiency syndrome (AIDS) presents as progressive spastic paraparesis and sensory ataxia (McArthur 1987) but, both clinically and pathologically, it more closely resembles subacute combined degeneration than multiple sclerosis (Petito et al 1986). Confusion might arise, however, from the frequent association with AIDS-related dementia, the clinical evidence of multiple lesions being supported by MRI findings that can mimic those of multiple sclerosis (McArthur 1987). Oligoclonal bands are rarely present in the cerebrospinal fluid and the more usual MRI appearances of prominent atrophy with hazy or diffuse white matter signal changes, rather than distinct multifocal lesions, are points of distinction.
HIV is one of the many antecedent infections recognized in acute disseminated encephalomyelitis (Table 8.3; Narciso et al 2001) and meningoencephalitis may occur during acute seroconversion, within a few weeks of infection. Discriminating between AIDS and multiple sclerosis is rarely problematical. However, J.R. Berger et al (1989) described seven men, seropositive for HIV-1, with clinical disease indistinguishable from relapsing–remitting multiple sclerosis. In two, the histopathology at autopsy was that of multiple sclerosis and it is probable that their disease was not directly the result of the infection. More intriguing is the report of fulminating and rapidly fatal leucoencephalopathy as the first indication of HIV infection, with the histological changes of multiple sclerosis (Gray et al 1991). These cases suggest that a putatively T-cell-dependent autoimmune disorder like multiple sclerosis can occur in individuals with low or absent T-cell counts. On reflection, this is perhaps not surprising since additional pathogenic mechanisms are likely to be operating in chronic multiple sclerosis, including, tissue damage secondary to microglial and macrophage activation. Also, at least some of the clinical manifestations of HIV infection are now considered to be part of the immune reaction to infection, and HIV-induced macrophage activation in the central nervous system is likely to be a mechanism for the tissue damage that leads to HIV dementia (McArthur et al 2003). [Human T-cell leukaemia virus type 1 (HTLV-1) associated myelopathy presents as a chronic myelopathy and is discussed below.]
Progressive multifocal leucoencephalopathy
Progressive multifocal leucoencephalopathy normally manifests in immunosuppressed individuals. In the past it was commonly seen in patients with AIDS but now occurs rarely in HIV-positive individuals treated with combination antiretroviral therapies. It is the result of an infection of oligodendrocytes by activated JC virus, a papovavirus existing in a dormant state in many healthy individuals. Multiple large areas of myelin destruction develop subacutely in the cerebral white matter and less often in the posterior fossa. Clinical manifestations include hemiplegia, dysphasia, hemianopia, seizures and cognitive impairment. MRI reveals extensive and asymmetric lesions in the cerebral white matter, without mass effect, and usually (though not invariably) without gadolinium enhancement. The clinical presentation and radiological picture can be similar to that of the fulminant Marburg variant of multiple sclerosis and diagnostic biopsy may be undertaken that shows characteristic oligodendrocyte inclusions. However, the occurrence of such an illness in the context of immunosuppression should suggest progressive multifocal leucoencephalopathy, and JC virus DNA can be detected in the cerebrospinal fluid (Yiannoutsos et al 1999). The prognosis is poor unless the underlying immunosuppression can be reversed. Specific antiviral therapies have to date been largely ineffective. A contemporary focus on progressive multifocal leucoencephalopathy in the context of multiple sclerosis has been stimulated by the report of two cases developing in patients treated with the combination of IFN-β1a and Tysabri (Kleinschmidt-DeMasters and Tyler 2005; Langer-Gould et al 2005). One proved fatal whereas the other exhibited partial recovery after treatment was discontinued. Tysabri is a therapeutic humanized monoclonal anti-adhesion molecule antibody showing beneficial effects on the clinical course of relapsing multiple sclerosis (see Chapter 18). These cases raise questions of how the development of progressive multifocal leucoencephalopathy might be related to the impairment of lymphocyte trafficking, and whether such cases might be prevented by laboratory screening to detect preclinical JC virus activation that would lead to early discontinuation of treatment (Berger and Koralnik 2005).
Subacute sclerosing panencephalitis
This chronic measles infection of the central nervous system is rarely seen since the widespread introduction of measles vaccination. It presents mainly in childhood, and the usual picture is of a subacute and relentlessly progressive syndrome with behavioural and locomotor deterioration, leading to obtundation and periodic myoclonic jerks. Such a course is unlikely to be confused with multiple sclerosis. MRI has on occasion shown extensive white matter abnormalities and occasional patients present in late adolescence or as young adults. Usually, there is generalized brain atrophy and areas of focal signal change are not prominent (D.H. Miller et al 1990b). The EEG may show periodic high voltage complexes, and the cerebrospinal fluid contains oligoclonal bands specific for measles virus. Antiviral treatments that may be used include isoprinosine, interferon-β and intraventricular interferon-α, but the prognosis is poor.
Whipple's disease
This is an infectious disease caused by the weakly Gram-positive rod-shaped bacillus, Tropheryma whippelii. Gastrointestinal involvement leading to a malabsorption syndrome is a frequent manifestation but the central nervous system is also affected. The most common features are brainstem syndromes (oculo-masticatory myorhythmia – rhythmic myoclonic movements of the jaw, lower face, and eyes – is said to be almost pathognomonic of cerebral Whipple's disease), dementia and an akinetic-rigid syndrome. MRI may be normal but generalized atrophy and multifocal white matter and grey matter lesions in the cerebrum or lesions in the brainstem can all occur (Wroe et al 1991). Both homogeneous and ring-enhanced lesions have been described, as have multiple peripherally located space-occupying lesions (Figure 8.21 ). The cerebrospinal fluid may be normal or show pleocytosis (mononuclear cells) with a raised protein and oligoclonal bands. Positive polymerase chain reaction for T. whippelii is of diagnostic value but is only available as a specialized investigation in a limited number of laboratories. Whereas the gastrointestinal diagnosis of Whipple's disease is made from small bowel histology, confirmation of neurological involvement may require brain biopsy (Erdem et al 1993b; Wroe et al 1991). Although the importance of recognizing Whipple's disease lies in the potential for effective treatment, many neurologists will never see a case and, if they should, the most typical clinical presentations are unlikely to be confused with multiple sclerosis. Antibacterial treatments include tetracyclines, co-trimoxazole, cefixime and rifampicin. While stabilization of neurological status is to be expected, some patients appear to worsen despite antibacterial treatment.
Figure 8.21.
Adjacent T2-weighted images (A and B) in Whipple's disease showing multiple parenchymal abnormalities.
Primary lymphoma of the central nervous system
There is some evidence that lymphoma confined to the central nervous system has increased in prevalence over recent years. Primary central nervous system lymphoma can occur in immunologicaly competent individuals and may present as solitary or multifocal lesions (Kuker et al 2005). In the latter situation, multifocal lesions of various sizes – some large and with mass effect and others much smaller – may occur in the cerebral white matter. The picture may then resemble demyelination (Figure 8.22 ). A periventricular predilection is apparent but not universal. There have been infrequent instances when lesions involve the spinal cord. The clinical manifestations are subacute and progressive and include hemiparesis, hemianopia, seizures, obtundation and myelopathy. Lesions often display gadolinium enhancement and there may be initial clinical improvement accompanied by remarkable radiological resolution in response to a course of high-dose corticosteroids. This response may lead particularly to the early suspicion of multiple sclerosis. However, the lymphoma soon recurs and becomes progressive. Cerebral biopsy is required for definitive diagnosis.
Figure 8.22.
A case of biopsy-proven central nervous system B-cell lymphoma. (A) Multiple white matter lesions on T2-weighted images. (B) Some display gadolinium enhancement.
Mitochondrial disease
Some forms of mitochondrial disorder can cause multifocal and relapsing central nervous system syndromes. The best characterized is Mitochondrial Encephalopathy with Lactic Acidosis and Stroke (MELAS). Patients can present at any age with acute hemispheric events suggestive of cerebral ischaemia – typically, hemiplegia and hemianopia – but in addition there may be more generalized encephalopathic features with headaches, seizures and obtundation. The acute episodes tend to occur during times of increased metabolic stress, especially intercurrent infections. T2-weighted MRI reveals large areas of abnormal signal involving cortex and adjacent white matter that resemble infarction, but do not conform to a single arterial territory. Diffusion weighted MRI has been reported to show increased diffusion during the acute phase (Kolb et al 2003; Oppenheim et al 2000), and this protocol may therefore be useful in making the distinction from acute infarction in which context diffusion is decreased. Recovery is variable, but there is sometimes complete resolution of the imaging abnormalities. The cerebrospinal fluid and serum may show raised lactic acid. MELAS is the result of a pathological point mutation of mitochondrial DNA (most often at base point 3243). The main differential diagnosis is with cerebrovascular disease rather than multiple sclerosis. Individuals with Leigh's disease, or subacute necrotizing encephalomyelitis, develop a progressive brainstem syndrome with respiratory failure, dystonia, eye movement abnormalities and areflexia. Again, the episodes are usually triggered by intercurrent infection and the disease is more common in children. Thus, it may be considered as an alternative to childhood onset multiple sclerosis but should rarely cause diagnostic difficulties in adults.
SYSTEMATIZED CENTRAL NERVOUS SYSTEM DISEASES
Since multiple sclerosis is a disorder in which oligodendrocytes and their dependent myelin sheaths are primarily affected, its manifestations are mainly confined to white matter tracts. It will therefore occasionally be confused with other disorders which target myelinated pathways in the central nervous system but lack its characteristic clinical course (Table 8.10 ).
Table 8.10.
Systematized central nervous system diseases
|
Hereditary ataxias and paraplegias
The classical form of Friedreich's ataxia presents in the first or second decade with progressive ataxia, weakness of the limbs and extensor plantar responses, but absent tendon reflexes. To this picture may be added, in some families, optic atrophy, early dementia and deafness. However, even with such widespread signs, there is seldom a close resemblance to multiple sclerosis. More difficult is the atypical case of sporadic cerebellar ataxia.
The nosology and classification of these spino-cerebellar degenerations, and the group of hereditary paraplegias which are even more likely to be confused with multiple sclerosis, were the special expertise of Anita Harding (Harding 1984). A significant number of individuals within pedigrees having the pure form of hereditary spastic paraplegia show onset between the ages of 10 and 50 years (meeting one criterion for the diagnosis of multiple sclerosis), and there is a high prevalence of sensory and bladder symptoms, all of which can cause considerable diagnostic uncertainty. However, the gait is usually disproportionately spastic for the degree of weakness, there is often a pes cavus foot deformity, and distal amyotrophy. The muscle wasting, and associated neurological features, distinguish the more complicated forms of hereditary spastic paraplegia and make confusion with multiple sclerosis less likely, but difficulties may still arise from the coexistence of spastic paraplegia with optic atrophy and cerebellar signs, including dysarthria and nystagmus. The report of multiple sclerosis in two members of a family with hereditary spastic paraplegia caused by a frame shift of the spastin gene may be coincidental (S.H. Mead et al 2001).
Given the occasional familial clustering of multiple sclerosis, and the episodic clinical course of some inherited conditions, a vague history in near relatives of difficulty in walking is often impossible to confirm as evidence of hereditary disease but certain clinical features may be of diagnostic help. Marked asymmetry of physical signs is a strong indication of multiple sclerosis rather than a systematized degeneration, while moderate symmetrical spasticity with preservation of vibration sense is more suggestive of hereditary spastic paraplegia. The distinction from Mendelian inherited disorders of the nervous system (the hereditary ataxias and paraplegias) is made more difficult by the fact that affected sibling pairs with multiple sclerosis sometimes show course and clinical concordance. This is most likely in the context of primary progressive multiple sclerosis, thus making the distinction from hereditary spastic paraparesis particularly tricky (see Chapter 3). Conversely, there may be a poor correlation between onset, severity and clinical features in members of the same pedigree with one or other of the inherited ataxias and paraplegias, especially in those disorders showing genetic anticipation and juvenile forms resulting from triplet repeat expansion in succeeding generations.
The MRI findings in degenerative ataxic disorders are predominantly those of atrophy, although there are no intracranial changes in pure spastic paraplegia (Ormerod et al 1994). A variable degree of cerebellar and/or brainstem atrophy is present in all but the earliest stages of hereditary or idiopathic late onset cerebellar ataxia (Figure 8.23 ), the notable exception being Friedreich's ataxia where atrophy is largely confined to the spinal cord and medulla. Rarely, white matter signal changes are seen in disorders considered to be primarily neurodegenerative. This is not surprising given that gliosis is a pathological feature of these disease processes. Degenerations of grey matter may simulate primary progressive multiple sclerosis. Autosomal dominant cerebellar ataxia is distinguished by the presence of severe cerebellar atrophy and a paucity of white matter lesions (Burk et al 1996). Friedreich's ataxia may, however, show nonspecific white matter abnormalities in about 40% of patients (Ormerod et al 1994) but specific gene testing will establish the correct diagnosis.
Figure 8.23.
Sagittal T1-weighted MRI in a patient with hereditary spinocerebellar ataxia showing marked cerebellar atrophy.
Whilst oligoclonal IgG has occasionally been present in the cerebrospinal fluid, it is likely to be an incidental finding. The more usual absence can help to make the distinction from multiple sclerosis (Ormerod et al 1994). Visual evoked potentials are often abnormal in hereditary ataxia (L. Pedersen and Trojaborg 1981) but marked asymmetry would favour multiple sclerosis. In Friedrich's ataxia but not multiple sclerosis, sensory nerve action potentials are absent and ECG abnormalities may be present. Most importantly, identification over the last decade of the genetic basis for Freidreich's and many of the other hereditary ataxias allows specific molecular diagnoses to be made (Campuzano et al 1996).
The locations of genetic loci for many chronic progressive hereditary ataxias, including Friedreich's (spinocerebellar) ataxia, SCA1–8, SCA10–14, and dentato-rubro-pallido-luysian atrophy are summarized by Opal and Zoghbi (2002). Specific gene mutations for all of these conditions are recognized and mapped to a variety of chromosomes. In several, the mutation arises by a common mechanism of repeat expansion within the disease-causing gene (for example, in Friedreich's ataxia, there is a GAA repeat expansion in intron 1 of the X25 gene located on chromosome 9q13; in SCA1, −2 and −3, there are CAG repeat expansions within the relevant genes located on chromosomes 6p23, 12q24 and 14q32, respectively). The genetics of hereditary spastic paraplegia are complex; at least 20 loci have been implicated to date (Blumen et al 2003; Fink 2002). In eight, the loci encoding these genes are known. The most common cause is a mutation of the spastin gene (SPG4) located on chromosome 2p22. This accounts for 40% of cases of autosomal dominant hereditary spastic paraplegia (McDermott et al 2003). Both in the hereditary ataxias and paraplegias, there are sometimes distinctive clinical features – in addition to the core ataxia or paraplegia – that associate with abnormalities at specific genetic loci.
Leucodystrophies
The distinction between multiple sclerosis and dysmyelinating disease has long been argued. The changing classifications put forward by neuropathologists and the emerging position on whether or not multiple sclerosis ever occurs in children have informed this debate. Distinctions have now been made between a number of poorly understood developmental disorders of white matter, conditions such as subacute sclerosing panencephalitis with which they were originally confused, and multiple sclerosis occurring in children and young adults. These genetically determined white matter disorders are reviewed and beautifully illustrated by van der Knaap and Valk (1995; see Figures 8.24 and 8.25 ). New syndromes continue to be identified, in part aided by the identification of genetic mutations (Schiffmann and van der Knaap 2004). Many of these disorders – including adrenoleucodystrophy, metachromatic leucodystrophy and Pelizaeus–Merzbacher disease – show diffuse white matter changes that are extensive and may reach an extreme degree in advanced cases, extending far out into the gyral white matter (D.H. Miller et al 1997). Few are of importance in the differential diagnosis of multiple sclerosis in adults, although some, such as Pelizaeus–Merbacher disease, are disorders of myelination and therefore relevant to a full understanding of demyelinating disease. Even those leucodystrophies which routinely have adult onset forms, or may occasionally present outside childhood, have clinical phenotypes that are unlikely to cause confusion. Table 8.1 provides a classification of leucodystrophies that includes conditions which will be not confused with multiple sclerosis. Table 8.10 provides a smaller list of leucodystrophies that deserve special mention in the context of multiple sclerosis and its differential diagnosis. These are now discussed in more detail.
Figure 8.24.
(A) T2-weighted MRI of adrenoleucodystrophy in childhood. (B) Gadolinium enhanced T1-weighted image of same patient. Note the extensive enhancement around the trigones. (C) T2-weighted images of metachromatic leucodystrophy.
Figure 8.25.
T2-weighted MRI in Pelizaeus–Merzbacher disease.
Adrenoleucodystrophy
This group of disorders is characterized by the accumulation of very long chain saturated fatty acids in all lipid-containing tissues and body fluids, including plasma. They arise from defective very long chain fatty acyl-CoA synthetase activity in peroxisomes (Wanders et al 1988) and lead to the accumulation of membrane-like cytoplasmic inclusions in brain tissue (Schaumburg et al 1974; 1975). The gene responsible for adrenoleukodystrophy, ABCD1, maps to Xq28, close to that for glucose-6-phosphate dehydrogenase deficiency and colour blindness (Aubourg et al 1990). It codes for a peroxisomal membrane protein that is a member of the ATP-binding cassette transporter superfamily (Mosser et al 1993). All racial groups are affected and the incidence in the United States is about 1 : 16 800 (Bezman et al 2001).
The diagnosis is confirmed by detecting markedly elevated very long chain fatty acids in plasma or cultured skin fibroblasts (A.B. Moser et al 1999). Three X-linked clinical syndromes share this biochemical abnormality:
-
•
childhood onset adrenoleucodystrophy
-
•
adult onset adrenomyeloneuropathy
-
•
mild adult onset adrenomyeloneuropathy that affects 50% of women who are heterozygous for the X-linked gene.
The adult syndromes presenting with progressive spastic paraparesis are those most likely to be confused with multiple sclerosis. The clinical phenotype of childhood and adult disorders, while usually quite distinct within individuals, may both be seen in the same family (Elrington et al 1989).
X-linked childhood adrenoleucodystrophy usually presents between the ages of 4 and 8 years with behavioural disturbance, dementia and epilepsy followed by involvement of special senses and motor systems. Although a significant proportion of children later develop adrenal insufficiency, Addison's disease may precede the neurological manifestations by several years (Menkes 1990; Sadeghi-Nejad and Senior 1990) or may occur without nervous system involvement (Josien et al 1993; O'Neill et al 1982). The cerebrospinal fluid is usually normal (Ménage et al 1994), although oligoclonal IgG bands have been described (Dooley and Wright 1985). White matter lesions are usually seen on MRI in childhood adrenoleucodystrophy. These often begin in the posterior hemispheres and advance forwards as the disease progresses (Figure 8.24A). The lesions sometimes display gadolinium enhancement at the advancing edge of the lesion (Figure 8.24B), in keeping with the post-mortem finding of inflammation (H.W. Moser 1997). The MRI white matter lesions become more extensive over time, mirroring the progressive clinical deterioration.
MRI findings vary with age at presentation and to some extent predict the future course (Loes et al 2003). If the patient is young and there is initial parieto-occipital or frontal white matter involvement with gadolinium enhancement (the former distribution being more commonly seen than the latter), rapid progression of MRI abnormalities is likely. If abnormalities are confined to the corticospinal tract or cerebellar white matter, a slower evolution occurs: such a pattern is usually seen in adolescents or adults. A reduced N-acetyl aspartate to choline ratio in normal-appearing cerebral white matter on MR spectroscopy is also associated with progression of MRI abnormality (Eichler et al 2002).
Adrenomyeloneuropathy typically presents in adult men with a slowly progressive spastic paraparesis, impaired vibration and other sensory modalities in the lower limbs, and bladder dysfunction. Clinicians may be alerted to unusual causes for this otherwise common neurological problem by the presence of peripheral nerve involvement (J.W. Griffin et al 1977), but the specific diagnosis is often overlooked if the very long chain fatty acids are not assayed. Less common clinical manifestations include Klüver–Bucy syndrome, dementia, spinocerebellar degeneration and olivopontocerebellar atrophy (H.W. Moser et al 1984; Nakazato et al 1989); overall, about 40% who present with the adrenomyeloneuropathy phenotype show various degrees of cerebral involvement (van Geel et al 2001). The typical myelopathic presentation can easily be misdiagnosed as a progressive spinal form of multiple sclerosis. Important clues to the correct diagnosis will be a positive family history in brothers or other male relatives in the maternal line, and a previous or concurrent diagnosis of Addison's disease from clinical and/or biochemical manifestations (Rees et al 1975). Brain MRI is abnormal in 50% of men with adrenomyeloneuropathy (Ménage et al 1994): the most common findings are symmetrical parieto-occipital abnormalities (Figure 8.26 ), although frontal or cerebellar white matter lesions may be observed. However, none of these epidemiological, clinical, biochemical or imaging clues to the diagnosis may be present and we recommend that plasma very long chain fatty acids are checked in all patients with an unexplained progressive myelopathy.
Figure 8.26.
T2-weighted MRI of a 40-year-old male with adrenomyeloneuropathy showing symmetrical parieto-occipital white matter abnormality.
From D.H. Miller et al (1997) with permission.
© 2006
Female heterozygotes may develop relatively mild, and occasionally remitting, spastic; limb weakness and sensory loss, but cerebellar involvement is rare (Dooley and Wright 1985; Marsden et al 1982; Ménage et al 1994; H.W. Moser et al 1991). Although adrenal disease is almost never present in carriers, very long chain fatty acids are usually elevated. Brain imaging (in rare instances showing abnormalities of the corticospinal tracts or cerebral white matter resembling those found in males with adrenomyeloneuropathy) or measurement of the auditory evoked brainstem responses may help in diagnosis of the carrier state (Moloney and Masterson 1982; O'Neill et al 1983). However, although decreased N-acetyl aspartate is demonstrated on MR spectroscopic examination of corticospinal projection pathways in cerebral white matter, indicating axonal damage or loss, brain MRI is normal in a large majority of female heterozygotes (Fatemi et al 2003).
Autosomal recessive adrenoleucodystrophy presents in infancy with seizures, hypotonia, retardation, retinal degeneration and hepatic involvement (H.W. Moser 1997; H.W. Moser et al 1984; 1991). Females are more commonly affected than males. The pattern of organ involvement and mode of inheritance are similar in neonatal adrenoleucodystrophy and Zellweger's syndrome, the distinction being that the latter is more severe and usually leads to death within 2 years. Both conditions are recognized as disorders of peroxisomal assembly or biogenesis (Raymond 2002), and should be seen as entirely distinct from the X-linked adrenoleucodystrophies.
Metachromatic leucodystrophy
Most autosomal recessive leucodystrophies predominantly affect children. The early adult form of metachromatic leucodystrophy is rare, or perhaps seldom diagnosed, and tends to present with intellectual or emotional abnormalities (Cerizza et al 1987). As with many other inherited disorders, onset at >60 years has been described. Presentation with dementia and behavioural disorders is usual (Alves et al 1986). Ataxia, paralysis and optic atrophy only develop in the later stages, although the presentation is occasionally with paraparesis or cerebellar ataxia (Hageman et al 1995) and the condition can then more easily be mistaken for multiple sclerosis. Clinical evidence for peripheral neuropathy may be revealed by slowed nerve conduction although instances are reported of normal nerve conduction in adult patients (Cengiz et al 2002; Marcao et al 2005). The full range of clinical manifestations has probably not yet been fully explored. For example, although typically the course is progressive with steady decline into dementia or persistent vegetative state, Sadeh et al (1992) describe an apparently unique case with relapsing–remitting metachromatic leucodystrophy. The diagnosis may be confirmed by demonstrating increased urinary sulphatide excretion with a deficiency of aryl-sulphatase A in urine, peripheral blood leucocytes and skin fibroblasts, or by the demonstration of metachromatic material in peripheral nerve biopsies.
Globoid cell leucodystrophy (Krabbe's disease)
Krabbe's disease is an autosomal recessive disorder arising from reduced galactocerebrosidase activity as a result of mutation of the GALC gene at 14q24. The late onset of globoid cell leucodystrophy is very rare – almost all cases present at before the age of 5 years and so are almost never confused with (childhood) multiple sclerosis. Grewel et al (1991) describe the onset in a 14-year-old boy, not finally diagnosed until the age of 24 years. We know of one case presenting in the third decade and another is recently described who presented with a gait disorder aged 43 years (Brockman et al 2003). Four additional cases (two sibling pairs) are described aged 24–35 years, in whom the clinical presentation resembled hereditary spastic paraplegia with prominent MRI signal abnormality in the corticospinal tracts (Figure 8.27 ; L. Farina et al 2000), although in one sibling pair there was striking asymmetry of the clinical and MRI findings. Presentation with spastic paraparesis and brain MRI abnormalities in adults may be associated with a T1835C point mutation (De Stefano et al 2000; Satoh et al 1997). One of us (DASC) has recently been criticized for failing to make the diagnosis of adult onset Krabbe's disease in a female with a family history both of myotonic dystrophy and ‘hereditary spastic paraparesis’ in whom a mild spastic gait disorder was associated with a demyelinating peripheral neuropathy and marked asymmetric wasting of the shoulder girdles producing one flail upper limb: here, the confusion was not with multiple sclerosis but in failing to explore all possible causes for familial spastic paraplegia. The clinical picture in Krabbe's disease is typically dominated by progressive intellectual and motor decline with pyramidal, extrapyramidal and cerebellar involvement, together with epilepsy, visual failure and peripheral neuropathy. Visual evoked potentials are delayed but there are no oligoclonal bands in the cerebrospinal fluid. MRI usually shows periventricular and other white matter abnormalities although it can be normal (Bajaj et al 2002). MR spectroscopy reveals decreased N-acetyl aspartate and increased myoinositol and choline containing compounds in cerebral white matter (Brockmann et al 2003) although such findings are not specific for the condition. Examination of peripheral blood leucocytes or skin fibroblasts confirms the deficiency of β-galactocerebrosidase.
Figure 8.27.
Serial sagittal T2-weighted MR images in an adult with Krabbe's globoid leucodystrophy. Kindly provided by Dr Nagui Antoun.
Adult onset dominant leucodystrophy
Forms of dominantly inherited leucodystrophy also occur exclusively in adults and may closely resemble chronic progressive multiple sclerosis (Baumann and Turpin 2000; Eldridge et al 1984; Schwankhaus et al 1994). A report of a large kindred that included 21 affected individuals from four generations emphasized the occurrence of prominent and early abnormalities of the autonomic nervous system including orthostatic hypotension, a finding that would not be expected in multiple sclerosis (Eldridge et al 1984). Also unlike multiple sclerosis, MRI shows diffuse, nondiscrete, white matter disease and oligoclonal IgG is not present in the cerebrospinal fluid (Schwankhaus et al 1988). It remains uncertain whether all the adult onset dominant leucodystrophies are one and the same disorder, and many are difficult to distinguish from the complicated hereditary spastic paraplegias. An addition to this group is a family with spastic paraparesis, ataxia and mild dementia, presenting in adulthood but with onset in childhood. Diffuse white matter abnormalities were present on MRI, whereas pathognomonic features of the other leucodystrophies were absent (Fukazawa et al 1997b). In another recently described family, the prominent manifestations were cerebellar ataxia and dementia associated with extensive MRI white matter abnormalities (Tagawa et al 2001). In one of the subjects studied at post mortem, vacuolar changes were observed in the cerebral and cerebellar white matter and brainstem. In another pathologically confirmed case of dominantly inherited adult onset leucodystrophy, MRI showed minimal abnormality of the white matter although there was frontal and corpus callosum atrophy (Letournel et al 2003).
A new leucodystrophy has been recently described that is thought to have an autosomal recessive inheritance and presents in childhood or adolescence with progressive pyramidal, cerebellar and dorsal column dysfunction (van der Knaap et al 2003). MRI reveals cerebral and cerebellar white matter abnormalities and striking involvement of specific brainstem and spinal cord tracts along with an elevated lactate in white matter.
Vanishing white matter disease
This leucodystrophy has an unusual characteristic in that the clinical presentation is frequently with acute episodes of neurological deterioration. It is an autosomal recessive disorder that most often presents during childhood although onset in young adults is also described (van der Knaap et al 1998). Episodes of neurological deterioration, consisting of obtundation, seizures, weakness and ataxia, may occur spontaneously or, more characteristically, in association with an intercurrent infection or minor head trauma. Examination may reveal signs of cognitive, pyramidal and cerebellar dysfunction. MRI shows extensive symmetrical abnormality of cerebral white matter often with marked tissue destruction such that large areas of cavitation are apparent, thus accounting for the diagnostic term that has been assigned. Vanishing white matter disease is attributable to a mutation in any one of the five subunits making up the eukaryotic translation initiation factor gene mapping to 3q27 (van der Knaap et al 2002). It is thought that abnormal protein synthesis leading to cell damage occurs at times of increased metabolic demand, such as a rise in body temperature during intercurrent infections. Given the usual age of onset in childhood, and the characteristic radiological appearance, vanishing white matter disease is not likely to be confused with multiple sclerosis. That said, the presentation with acute episodic deterioration may mimic the relapses of multiple sclerosis and it should be borne in mind that episodes at onset do not automatically exclude the possibility of leucodystrophy.
Hereditary adult onset Alexander's disease
Although this leucodystrophy, characterized pathologically by Rosenthal fibres, is more common in childhood, occasional cases are seen in adults. The latter typically present with a progressive spastic paraplegia, pseudobulbar palsy, ataxia, palatal myoclonus and a positive family history suggesting dominant inheritance (R.S. Howard et al 1993; Schwankhaus et al 1995). MRI reveals profound atrophy of the medulla oblongata and upper spinal cord, but with sparing of the pons. Two recent cases were identified with a mutation in the gene for glial fibrillary acidic protein (Namekawa et al 2002). The clinical and MRI picture should not be confused with multiple sclerosis.
Oculodentodigital dysplasia syndrome
This is a rare autosomal dominant disorder in which central nervous system white matter is sometimes involved (Loddenkemper et al 2002). The clinical diagnosis is made on the basis of characteristic morphological abnormalities affecting the face, eyes, dentition and digits. The specific findings are a depressed nasal bridge, thin nose with hypoplastic alae and thin, anteverted nostrils, microphthalmos with abnormalities of the iris and microcornea, syndactyly and camptodactyly of the fourth and fifth digits, and hypoplasia of the tooth enamel (Loddenkemper et al 2002). Neurological findings include spastic paraparesis, gaze palsy, bladder and bowel disturbance, visual loss, deafness, ataxia and nystagmus. Diffuse or subcortical high signal in the white matter has been reported on MRI as has basal ganglia hypointensity.
Vitamin B12 deficiency
Confusion between subacute combined degeneration of the spinal cord and multiple sclerosis should only arise in the rare examples with relatively early onset of spastic leg weakness but no signs of peripheral neuropathy. Cervical MRI reveals high signal confined to the posterior columns in a symmetrical manner in some but not all patients (Figure 8.28 ). A potential cause for confusion with multiple sclerosis is the high frequency of Lhermitte's symptom in subacute degeneration of the cord. This symptom can also result from cord compression (see Figure 6.14; Gautier-Smith 1973). Visual impairment is very uncommon but visual evoked potentials may be delayed in the absence of visual symptoms (Fine and Hallett 1980). Cognitive impairment and diffuse cerebral white matter MRI abnormality are occasionally encountered. In making the diagnosis, it should be noted that the serum vitamin B12 level is usually but not invariably reduced below the normal laboratory range in cases of subacute combined degeneration of the spinal cord. When the level is not reduced but the condition is still suspected on clinical grounds, other characteristic biochemical findings that can aid diagnosis are an increase in serum homocysteine and methylmalonic aciduria.
Figure 8.28.
T2-weighted MRI in a patient with subacute combined degeneration of the spinal cord showing extensive alteration in the T2-weighted signal from the posterior columns. Kindly provided by Dr Nagui Antoun.
Finally, the presence of a serum B12 level mildly below the normal range may sometimes be seen as an isolated and incidental laboratory abnormality during work up of patients with a neurological disorder. Interpretation of this finding requires liaison with laboratory staff and does not always indicate a causal relationship between the abnormal investigation and the neurological disorder.
Myelopathy due to nitrous oxide toxicity
A number of reports exist of subacute combined degeneration of the spinal cord and a low vitamin B12 level in patients in whom a history emerges of recurrent nitrous oxide inhalation for recreational purposes (Ng and Frith 2002). This has been seen in health-care professionals with access to the agent. Users of nitrous oxide for recreational purposes sometimes refer to the practice as ‘nanging’. Signal abnormalities may be seen in the posterior columns on spinal MRI. Nitrous oxide causes irreversible oxidation of the cobalt atom of vitamin B12, making the vitamin inactive. Patients with incipient vitamin B12 deficiency for other reasons are more susceptible to develop this adverse neurological effect of nitrous oxide. Treatment is immediate cessation of nitrous oxide and administration of vitamin B12. A progressive myelopathy affecting the lateral and posterior columns is also described in association with inhalation of heroin vapour, adding to the syndrome of acute myelopathy following insufflation, although the authors speculate that adulteration of the substance with contaminants may also have exposed this addict to nitrous oxide (Nyffeler et al 2003).
Cerebrotendinous xanthomatosis
This rare autosomal recessive metabolic disorder is caused by mutations of the sterol 27-hydroxylase gene. It normally has a non-neurological presentation with tendon xanthomas. Other features include cataracts, elevated serum cholestanol and urinary bile alcohols, and premature cardiovascular disease. The neurological presentation can be with a prominent progressive spastic paraplegia accompanied by symmetrical intrinsic signal abnormalities in the posterior and lateral columns of the spinal cord on MRI (Verrips et al 1999). Bartholdi et al (2004) describe progressive myelopathy in one of two sisters in whom cerebrotendinous xanthomatosis was eventually diagnosed many years after the proband had been treated with a variety of immunosuppressants on the assumption that she had primary progressive multiple sclerosis. Other neurological features include cerebellar signs, peripheral neuropathy, seizures and dementia. MRI may show cerebellar white matter abnormalities and abnormal signal within the dentate nuclei (Clemen et al 2005). Treatment with chenodeoxycholic acid and a statin may prevent further neurological deterioration.
Phenylketonuria
This inherited disorder of phenylalanine metabolism is diagnosed at neonatal screening and prompt institution of a strict diet to avoid hyperphenylalaninaemia will prevent future neurological complications. However, some individuals who do not comply fully with the diet may present with a progressive neurological disorder later in life. The main manifestation is a progressive spastic paraplegia. Patients occasionally have episodes of neurological deterioration that resemble the relapses of multiple sclerosis (A.J. Thompson et al 1990a; 1993b). Additional reported features include cognitive impairment and ataxia. MRI reveals a symmetrical increase in T2 signal of cerebral white matter with a predilection for periventricular and posterior hemispheric regions (A.J. Thompson et al 1990a). The past history and biochemical findings are, of course, distinctive even if the MRI appearances can be confused with multiple sclerosis (Figure 8.29 ). The MRI changes are thought to represent dysmyelination and are reversible with re-institution of the correct diet (A.J. Thompson et al 1993b), which also leads to clinical stability or improvement.
Figure 8.29.
T2-weighted MRI scans in a young adult with phenylketonuria showing periventricular abnormality with a posterior predominance.
From D.H. Miller et al (1997) with permission.
© 2006
Leucoencephalopathy related to glue-sniffing
Inhalation of volatile solvents can result in white matter damage. Toluene is probably the main cause of neurological injury, and people who chronically inhale volatile glues for recreational purposes may develop a progressive and diffuse clinical and radiological leucoencephalopathy (Yamanouchi et al 1995). Pathologically, there is diffuse white matter demyelination. Although visual evoked potentials can be delayed, the diffuse and nonfocal nature of MRI abnormalities together with absence of cerebrospinal oligoclonal bands will be strong pointers against a diagnosis of multiple sclerosis. Diagnostic confusion is more likely if the patient presents with acute and recurrent episodes of neurological disturbance (M.B. Davies et al 2000).
Multiple system atrophy
This progressive neurodegenerative disorder of adults from middle-age onwards should rarely be confused with multiple sclerosis given the typical manifestations of an akinetic-rigid syndrome and autonomic failure. However, cerebellar features are prominent in some patients, and there may also be eye movement abnormalities and pyramidal tract signs that superficially raise the possibility of demyelination. The evolving clinical course should soon establish the correct diagnosis and additional investigations are very helpful in making the distinction. MRI is not expected to display multifocal white matter lesions in multiple system atrophy (unless they are age related), but there may be prominent hypointensity of the putamen on T2-weighted images, atrophy of posterior fossa structures and a cross-like area of T2 hyperintensity in the pons (Figure 8.30 ). The cerebrospinal fluid does not contain oligoclonal bands.
Figure 8.30.
T2-weighted MRI of a patient with multiple system atrophy. The pons is atrophic and within it there is a cross-shaped area of hyperintensity. Kindly provided by Dr Katherine Miszkiel.
Paraneoplastic syndromes
Subacute paraneoplastic cerebellar degeneration, when associated with gynaecological cancers, presents a stereotyped pattern of severe, rapidly advancing, symmetrical ataxia of the trunk and limbs, and also should not be confused with multiple sclerosis. In other forms, particularly those related to small cell cancer of the lung, cerebellar signs are less prominent and are accom panied by more widespread evidence for cerebral and spinal cord disease (Chabriat et al 1994; Henson and Urich 1982; W.P. Mason et al 1997; Posner 1986). As the cancer is usually occult at this stage, diagnosis may be difficult, particularly when optic neuritis or other forms of retinal degeneration occur (Figure 8.31 ; Boghen et al 1988; P.R. Rudge 1973; Waterston and Gilligan 1986). Clinical evidence of peripheral nervous disease is often present and should alert clinicians to the possibility of an underlying malignancy.
Figure 8.31.
Optic disc appearance in a patient with paraneoplastic bilateral sequential visual failure in association with bronchial carcinoma.
The cerebrospinal fluid usually shows a lymphocytic pleocytosis and oligoclonal IgG. In pure cerebellar degeneration, imaging shows cerebellar atrophy but in the multifocal forms, MRI is either normal or suggestive of limbic encephalitis. Long lesions involving the spinal cord accompanied by gadolinium enhancement have been reported in cases with myelopathic presentation (Mokri et al 1998). Anti-neuronal antibodies are reliably detected in some forms of paraneoplastic disease and their presence often resolves the situation where demyelinating disease is amongst the differential diagnoses. 19Fluoro-deoxyglucose-labelled positron emission tomography may be useful in demonstrating the occult carcinoma (Younes-Mhenni et al 2004).
Coeliac disease
Occasionally, patients with coeliac disease may develop a number of neurological syndromes including spino-cerebellar degeneration, encephalopathy, myoclonus and peripheral neuropathy (Bhatia et al 1995; Chin and Latov 2005; W.T. Cooke and Smith 1966). Recently, cases of progressive cerebellar ataxia have been associated with anti-gliadin antibodies (Hadjivassiliou et al 1998). However, as an isolated laboratory finding, it may be difficult to evaluate the significance of these antibodies since they occur in 8–12% of healthy controls (Abele et al 2003; Hadjivassiliou et al 2003). Whilst it is generally unlikely that cases of multiple sclerosis will be confused with the neurological complications of coeliac disease, we have encountered patients in whom intermittent neurological symptoms, consistent with multiple sclerosis and designated as ‘demyelinating’ have later been attributed to coeliac disease on the basis of a positive test for anti-gliadin antibodies and in the absence of gastrointestinal symptoms. Referral to the gastroenterology service and small bowel biopsy may be needed to resolve the matter.
Myeloneuropathy from acquired copper deficiency
There have been several reports in recent years indicating an association of acquired copper deficiency with a progressive myeloneuropathy (Hedera et al 2003; Kumar and Low 2004; Kumar et al 2003; 2004; Schleper and Stuerenburg 2001). The neurological presentation is seen in adults and resembles that of vitamin B12 deficiency. In some cases, the copper deficiency has been considered secondary to zinc overload (Hedera et al 2003; Kumar et al 2004) and in others to a malabsorption syndrome, sometimes following gastric surgery (Kumar and Low 2004; Kumar et al 2003; Schleper and Stuerenburg 2001). There is a striking reduction in serum caeruloplasmin and copper levels and an associated anaemia or pancytopaenia. Electromyography may reveal an axonal neuropathy and MRI in some cases shows extensive signal change in the posterior cervical cord. Recognition of this disorder is important because copper therapy has been reported to prevent further clinical deterioration.
Cerebellar ataxia with anti-glutamic acid dehydrogenase antibodies
The association between stiff man syndrome and antibodies to glutamic acid decarboxylase (GAD) is well known, and it is unlikely that such a neurological presentation will be confused with multiple sclerosis. More recently, there have been reports of cerebellar ataxia associated with anti-GAD antibodies. In one series of 14 adult patients with ataxia (median age of onset was 51 years) and serum anti-GAD antibodies, 13 were female, 11 had late onset insulin-dependent diabetes mellitus, eight had evidence of autoimmune thyroiditis, 10 had oligoclonal bands, and five of six tested had anti-GAD antibodies in the cerebrospinal fluid (Honnorat et al 2001). The effect of ataxia was more pronounced on the gait than individual limbs and was slowly progressive in most cases. Brain MRI was normal or showed atrophy confined to the cerebellum.
Motor neuron disease and its variants
In a few patients who go on to develop the typical clinical picture of amyotrophic lateral sclerosis (with disseminated upper and lower motor neuron abnormalities), the early presentation may be with a clinically predominant or exclusive upper motor neuron syndrome that leads to the suspicion of demyelination. It is now recognized that focal areas of pathologically increased signal in the pyramidal pathways are seen in about 70% of patients with motor neuron disease, with increased signal in white matter of the precentral gyrus in a small number of patients (Thorpe et al 1994b; 1996c). Signal change in the cerebral peduncles is often traceable down through the brainstem to the spinal cord (Figure 8.32 ). It is important to distinguish these pathological features from the areas of relatively high signal seen in the region of the pyramidal tracts in the internal capsule – but not below this level – in about half of normal individuals. The symmetry of these changes and, in motor neuron disease, the absence of other MRI abnormalities characteristic of multiple sclerosis, serve to distinguish the conditions.
Figure 8.32.
(A–D) T2-weighted MRI in motor neuron disease showing high signal in the position of the corticospinal tracts. Scans at different levels showing that the abnormal signal can be traced from the centrum semiovale down to the spinal cord.
A diagnosis of primary lateral sclerosis is sometimes made in patients with a history of progressive spastic tetraparesis extending over several years that have no lower motor neuron degeneration, sensory involvement or family history. Atrophy of the precentral gyrus has been described in some of these patients (C.E. Pringle et al 1992). Central motor conduction is usually delayed (W.F. Brown et al 1992). The reported cases are somewhat heterogeneous and the true nosological status of the condition remains uncertain.
ISOLATED OR MONOSYMPTOMATIC CENTRAL NERVOUS SYSTEM SYNDROMES
In approximately 85% of patients, the first symptoms and signs of multiple sclerosis can be attributed to the effects of a single lesion of the nervous system (Table 8.11 ). Such symptom clusters are naturally extremely diverse and cannot all be considered individually. With transient symptoms, precise diagnosis may often be impossible. This is perhaps not always desirable in patients who find it difficult to cope with the possibility of further episodes of demyelination. Conversely, many patients who have been reassured during a first or previous episode of demyelination would in retrospect have wished to know at an earlier stage in the illness that multiple sclerosis was a possibility. (We discuss when and what to tell patients in Chapter 15.)
Table 8.11.
Isolated or monosymptomatic central nervous system syndromes
|
|
|
Some symptoms resulting from isolated demyelinating lesions are much more suggestive of multiple sclerosis than others. For example, an acute lower motor neuron facial palsy can be the initial symptom of multiple sclerosis, but other causes (idiopathic Bell's palsy) are more likely. Conversely, acute internuclear ophthalmoplegia in a young woman, without any other detectable cause, is highly suggestive. Symptoms induced or greatly aggravated by exercise or heat should also alert suspicion. Optic neuritis is described in Chapter 6. With the aid of modern imaging techniques it should be possible to avoid most of the diagnostic pitfalls presented by isolated lesions of the central nervous system, provided the indications for their use are recognized. The approach to investigation is described in Chapter 7.
The clinical course of many essentially progressive lesions is occasionally marked by fluctuations, particularly sudden exacerbation and, more rarely, partial or complete remission. A good example is the onset of symptoms as a result of an intracranial meningioma during pregnancy followed by remission in the weeks after delivery. For example, Bickerstaff et al (1958) described unilateral visual loss as a result of pressure on the optic nerve from a meningioma, with a central scotoma, occurring during pregnancy with subsequent recovery. This phenomenon can be linked to the presence of female hormone receptors in some forms of intracranial tumour (Poisson 1984). One of our patients (DASC) with olfactory groove meningioma and bilateral papilloedema (in whom the diagnosis of multiple sclerosis did not arise) presented in the puerperium with recurrent headache which developed only on breast feeding.
There is no obvious explanation for the occasional relapsing– remitting course of symptoms attributable to brainstem glioma where the initial symptoms, such as ocular palsies and focal weakness, may remit in a manner indistinguishable from multiple sclerosis (Sarkari and Bickerstaff 1969). A similar remitting course, including the marked day-to-day fluctuations characteristic of multiple sclerosis, has been described in extramedullary tumours located at the foramen magnum (L. Cohen and Macrae 1962).
Vascular anomalies, both arteriovenous malformations and cavernous angiomas, involving the brainstem may present with remitting symptoms and signs diagnosed for many years as multiple sclerosis (Figure 8.33 ; Sadeh et al 1982; Stahl et al 1980). Cavernous angiomas are not revealed by angiography but show a characteristic appearance on MRI, with mixed low and signal on T2-weighted images – the former as a result of local magnetic field inhomogeneity induced by haemosiderin (Requena et al 1991). Arachnoid cysts in the foramen magnum may also present with fluctuating symptoms, which often cannot easily be attributed to a single lesion (Lehman and Fieger 1978). Pain is a prominent symptom in reported cases. The symptoms of tumours involving the spinal cord may also fluctuate or remit. Again, vascular malformations provide the most striking examples. Although less often remarked upon, spontaneous remission is also described for the symptoms and signs of other spinal cord tumours (Hirschbiegel 1967). The presence of a structural lesion, amenable to surgical treatment or some other form of intervention, should be assumed until proved otherwise. Although these patients may turn out to have primary progressive multiple sclerosis (see Chapters 6 and 7), there is no excuse for failing to exclude the structural lesion and this error rightly exposes the unwary physician to medico-legal attention.
Figure 8.33.
T2-weighted brain MRI showing a cavernous haemangioma of the brainstem. The low signal regions are due to haemosiderin deposition. Kindly provided by Dr Katherine Miszkiel.
Structural and noninflammatory infectious spinal cord syndromes
The principles of how the clinical features and course of anatomically discrete syndromes can be confused with multiple sclerosis, and the issues that arise with respect to overlapping disorders, are well exemplified by consideration of conditions affecting the spinal cord.
Spinal cord compression
The highly important distinction between progressive spinal multiple sclerosis and compression of the spinal cord should now usually be possible without recourse to invasive procedures. Myelography is no longer required unless MRI is contraindicated or not available. In young adults where confusion can easily arise with multiple sclerosis, many causes of compression (neurofibroma, meningioma or prolapsed intervertebral disc) are benign and amenable to surgery if diagnosed in time. Although S. Poser et al (1978) attempted to determine whether the spinal form of multiple sclerosis can reliably be distinguished on clinical grounds from other forms of spinal cord disease, they could offer little guidance. In practice, features more suggestive of spinal cord compression than multiple sclerosis are a reproducible and crisp cutaneous sensory level, root pain and segmental muscle wasting. A high index of suspicion is the best safeguard against error.
Investigation must be directed to the site of the lesion (Figure 8.34 ), and spinal cord MRI is the essential diagnostic investigation (Figure 8.35 ). It is not permissible to diagnose multiple sclerosis on the basis of progressive paraplegia and delay of the visual evoked potentials, in the absence of clear clinical evidence for multiple lesions, and until a structural lesion has formally been excluded (Figure 8.36 ). The report of multiple cerebral white matter lesions on MRI, thought to be consistent with multiple sclerosis, in two patients subsequently shown to have thoracic extramedullary spinal tumours (Salvi et al 1992) will not surprise the experienced neurologist. We deal later with the tricky issue of double diagnoses.
Figure 8.34.
Diagnosis of multiple sclerosis corrected in a patient with a slowly progressive spinal syndrome (due to spinal meningioma). (A) Contrast radiology had not been carried up to the level indicated by the clinical history and signs. (B) The lesion was demonstrated once the appropriate level was studied on the myelogram. This is perhaps of historical interest, since nowadays this diagnosis would invariably be made using MRI, but nonetheless makes an important clinical and anatomical point.
Figure 8.35.
Erroneous diagnosis of multiple sclerosis made in the context of a slowly progressive spinal syndrome. (A) Investigation by myelography. (B) Corrected (to spinal meningioma) more easily by access to MRI.
Figure 8.36.
(A) T2-weighted and (B) gadolinium enhanced T1-weighted MRI of a meningioma causing compression of the thoracic spinal cord (arrows). Kindly provided by Dr Katherine Miszkiel.
Cervical spondylotic myelopathy
The cardinal feature of spondylotic myelopathy is spastic paraparesis, not differing in any important respect from that of multiple sclerosis. The distinction is made even more difficult by the undoubted fact that the two conditions may coexist (Figure 8.37 ). This was shown conclusively by Brain and Wilkinson (1957) who suggested that damage to the cord caused by spondylosis favoured the formation of plaques in that region. It was believed by D.Oppenheimer (1978) that traction through the denticulate ligaments was responsible for the localization of plaques in the lateral columns of the cervical spinal cord (see Chapters 4 and 12). However, while MRI studies confirm that spondylotic compression and intrinsic cord lesions of multiple sclerosis both have a predilection for the mid-cervical cord, the demyelinating lesions are usually not located at the precise level of the external compression (Kidd et al 1993; Thorpe et al 1993). Using modern diagnostic techniques, Burgerman et al (1992) identified six patients with both conditions, two of whom benefited from surgery.
Figure 8.37.
(A) Frequency of lesions due to multiple sclerosis adjacent to each vertebral body in the patient population alongside the incidence of degenerative changes (disc protrusion or osteophyte formation).
From D. Kidd et al (1993) with permission. (B) Narrowing of the cervical canal as a result of spondylosis in a patient with primary progressive multiple sclerosis. Kindly provided by Dr Nagui Antoun.
© 2006
In view of the known association, it is not entirely realistic to list features thought to differentiate one condition from the other. Patients with spondylotic myelopathy are apt to be older and disturbance of sphincter control is a late symptom. Pain and loss of tendon reflexes in the upper limbs are less helpful in diagnosis than might be expected.
Chiari malformation
Type 1 Chiari malformation, in which ectopic cerebellar tissue passes through the foramen magnum into the cervical canal, may present in adult life in the absence of skeletal deformity of the skull or neck (Figure 7.39). In the majority of individuals with cerebellar ectopia, the clinical syndrome does not resemble multiple sclerosis but is that of syringomyelia or hydrocephalus. In a proportion, however, the predominant signs are cerebellar ataxia, spastic weakness of the limbs and nystagmus, under which circumstances the diagnosis of multiple sclerosis may naturally be considered (Mohr et al 1977). The occurrence of trigeminal neuralgia and Lhermitte's symptom and sign increase the resemblance (Banerji and Millar 1974). There has been a report of delayed visual evoked potentials in cerebellar ectopia (W.I. McDonald and Halliday 1977). Internuclear ophthalmoplegia is a feature of the more severe type 2 Chiari malformation, which is unlikely to be mistaken for multiple sclerosis (A.C. Arnold et al 1990), but also occurs in type 1 malformations where it may cause diagnostic confusion (Rudick et al 1986). The nystagmus is often vertical, and most characteristically down beat – a distinct abnormality of eye movement alerting clinicians to lesions of the foramen magnum, paraneoplastic disease and multiple sclerosis (see Chapter 6). Definitive diagnosis can be established by MRI, and CT/myelography is no longer necessary.
Spinal dural arteriovenous malformation
This condition most often affects middle-aged males. The presentation is with a progressive, often asymmetric, spastic paraparesis, evolving over months to years. There may be some diurnal or exercise-related fluctuation in symptoms. Progressive signs are often preceded by transient episodes of weakness, sensory loss or sphincter disturbance, without accompanying pain (Aminoff and Logue 1974; Cardon et al 1992; Dhopesh and Weinstein 1977; Symon et al 1984). In addition to pyramidal tract signs, quadriceps wasting and loss of a knee or ankle jerk provides evidence for lower motor neuron involvement at the lumbosacral level. This combination of features is explained by the fact that dural arteriovenous malformations most often occur in the thoraco-lumbar region and involve the conus as well as upper motor neuron fibres. The report that three of 11 (27%) patients with spinal arteriovenous malformations had cerebrospinal fluid oligoclonal bands (O. Cohen et al 2000) indicates the potential for incorrect diagnosis if undue significance is attached to spinal fluid abnormalities. However, the crucial diagnostic investigation is a good quality MRI scan of the thoraco-lumbar region. In most instances, multiple small serpiginous signal voids are seen predominantly over the dorsal aspect of the cord (Figure 8.38 ). These dilated veins are virtually pathognomonic of arteriovenous malformation. Because they are sometimes subtle and not readily visualized, formal spinal arteriography is usually required to confirm the diagnosis (Figure 8.39 ). Other frequent MRI findings are swelling and increased T2 signal of the lower cord as a result of venous stasis and oedema, and gadolinium enhancement involving vessels or cord. The malformation is often effectively treated by angiographic embolization or in some instances by surgical removal.
Figure 8.38.
T2-weighted sagittal MRI showing a spinal dural arteriovenous malformation. (A,B) Dilated veins over the dorsal thoracolumbar cord are seen as areas of serpiginous signal void on two consecutive slices. Kindly provided by Dr Katherine Miszkiel.
Figure 8.39.
Spinal arteriography in a male aged 52 years with a progressive paraparesis and unstable bladder as a result of spinal arteriovenous malformation showing filling through the lower intercostal branches. Kindly provided by Dr Nagui Antoun.
Tropical spastic paraplegia: HTLV-1-associated myelopathy
The clinical features of HTLV-1-associated myelopathy do not resemble those of relapsing–remitting multiple sclerosis but can closely mimic the chronic progressive form of the disease. The age incidence of HTLV-1 myelopathy and the progressive myelopathic form of multiple sclerosis are similar. Mean age at onset of symtoms was 46 years in one series of patients with HTLV-1 myelopathy (J.K. Cruickshank et al 1989), whereas the mean age of onset in primary progressive multiple sclerosis is 40 years (A.J. Thompson et al 2000). Pain in the back and distally in the legs is common at onset and bladder symptoms occur early. Spastic weakness may initially be unilateral but is eventually symmetrical. Tendon reflexes are increased in the upper limbs but the ankle jerks are sometimes absent. Sensory symptoms in the lower limbs are constantly present. Abnormalities of the cranial nerves are exceedingly rare. There are no remissions but after slow progression the condition may arrest. The condition progresses quite rapidly in a few individuals (Lima et al 2005).
The cerebrospinal fluid contains oligoclonal IgG but, in contrast to multiple sclerosis, bands are also present in serum (Link et al 1989; C.M. Poser et al 1990). A positive serological test for syphilis is common. Adult T-cell leukaemia cells (a result of HTLV-1 infection) are occasionally seen in blood or spinal fluid. Visual evoked potentials are often symmetrically delayed (P. Rudge et al 1991). MRI shows white matter lesions in the cerebrum but the brainstem is relatively spared and no lesions are seen in the cerebellum (P. Rudge et al 1991). Spinal MRI reveals thoracic cord atrophy (A.K. Howard et al 2003). Antibodies to HTLV-1 are present in blood and cerebrospinal fluid.
Myelopathy occurs predominantly in people inhabiting or coming from areas where HTLV-1 is endemic, particularly the West Indies and Japan, but sporadic cases have been reported from many countries (Gessain and Gout 1992). The virus can be transmitted by sexual contact, blood transfusion and intravenous drug abuse (Janssen et al 1991), but only a small minority of those infected will develop myelopathy. A condition with some similarities to Devic's disease is described in eight HTLV-1 negative women from the West Indies with recurrent episodes of spinal cord or visual involvement and endocrinopathies. Imaging showed cavitation of the spinal cord with few cerebral lesions and autopsy revealed inflammation and demyelination (Vernant et al 1997).
Noncompressive progressive myelopathy
Chronic progressive paraparesis presents a common problem of differential diagnosis and causes such as cervical spondylotic myelopathy, tropical spastic paraplegia and spinal cord compression have been considered above. In countries where multiple sclerosis is prevalent, this is the commonest cause of progressive noncompressive paraparesis. Thus, of 223 Danish patients with spastic paraparesis, either isolated or as part of more widespread disease, 129 (58%) were diagnosed as having multiple sclerosis on first admission to hospital (Hübbe and Dam 1973). Conversely, only six of 32 undiagnosed cases (19%) were found to have multiple sclerosis on prolonged follow-up. Marshall (1955) reported multiple sclerosis at autopsy in 34% of a similar series of patients. A positive diagnosis at time of presentation is now possible in a higher proportion of patients as a result of the emergence of several key paraclinical investigations over the last 30 years: specifically, evoked potentials, cerebrospinal fluid examination for oligoclonal bands, and MRI.
When they were introduced, it was naturally hoped that the inexpensive and noninvasive techniques of evoked potential recording would reliably indicate disseminated disease in the context of a progressive spinal syndrome. Re-reading this literature shows that in the most extensive assessment of visual evoked potentials in undiagnosed spinal cord disease (Blumhardt et al 1982), abnormalities were found in 36% of 64 patients with chronic progressive paraparesis and in 33% of 38 with chronic relapsing myelopathy. It is not known, of course, how many patients actually had multiple sclerosis. Paty et al (1979) investigated 72 patients with chronic progressive myelopathy, using evoked potentials, spinal fluid examination and CT brain scanning. Oligoclonal bands were present in 44%, abnormal evoked potentials in 35% and imaging abnormalities (nearly all merely consisting of diffuse atrophy without focal lesions) in 50%. No firm conclusions on the distinction between the group with multiple sclerosis and those with other diseases seemed apparent.
As expected, MRI has proved more informative (Figure 8.40 ). D.H. Miller et al (1987a) showed that 18/29 patients with chronic progressive paraparesis had changes typical of multiple sclerosis on MRI of the head and a further three had single lesions. Of 33 patients with chronic relapsing myelopathy, 25 had typical changes of multiple sclerosis and one had a single lesion. The method was very much more sensitive than recording evoked potentials. It is of interest that of the 130 patients originally referred for this investigation, nine were found to have compressive lesions, including two with extramedullary tumours. As experience in the use of MRI has increased, criteria for the diagnosis of primary progressive multiple sclerosis have been proposed that incorporate specific brain and spinal cord imaging findings in patients presenting with progressive myelopathy (A.J. Thompson et al 2000).
Figure 8.40.
T2-weighted MRI in a 40-year-old with a clinically isolated progressive spastic paraplegia. There are multiple cerebral white matter and spinal cord lesions suggesting demyelination. (A) Brain and (B) spinal cord (lesions arrowed).
One other condition, first described in the 19th century, to emerge intact from the syndrome of progressive paraplegias is primary lateral sclerosis (Pringle et al 1992a). The late onset may prove sufficient to make the distinction from multiple sclerosis but there is overlap with primary progressive spinal demyelination. The absence of a family history or signs of upper motor neuron lesions dating from childhood (pes cavus) helps to distinguish this condition from the hereditary spastic paraplegias. Spastic weakness of the legs is soon associated with generalized spino-bulbar involvement, producing pseudobulbar palsy and mimicking motor neuron disease but without muscle atrophy or fasciculations. Smooth following eye movements are often lost and the bladder may be involved, further increasing the similarity to multiple sclerosis. MRI does not show white matter abnormalities, although focal atrophy of the precentral gyrus has been reported on sagittal T1-weighted images, and (as expected) central motor conduction times are prolonged (Pringle et al 1992a). Oligoclonal bands are not present in the cerebrospinal fluid.
The early manifestation of widespread lower motor neuron involvement, both clinically and on electromyography, will usually prevent confusion between the classical form of motor neuron disease, amyotrophic lateral sclerosis and multiple sclerosis. A few cases that evolve to typical motor neuron disease nevertheless have an initial phase in which the manifestations exclusively affect upper motor neurons. In about 70% of patients, MRI reveals symmetrical high signal confined to the corticospinal tracts in the centrum semiovale, internal capsule, cerebral peduncles, pons and upper cervical cord (Thorpe et al 1996c). Such findings are unlike those seen in multiple sclerosis and give a clue to the correct diagnosis.
Acute spinal cord compression
It is self evident that when a patient presents with an acute clinically isolated and hitherto unexplained spinal cord syndrome, the first and foremost priority must be to identify any surgically treatable compressive lesion – intervertebral disc protrusion, extradural abscess or haematoma. Immediate MRI should be performed, followed by neurosurgical referral if compression is found. The success of surgical decompression is inversely related to the period during which compression has been present. That said, patients presenting with the Brown-Séquard or conus medullaris syndromes in whom spinal cord compression or central lumbo-sacral disc prolapse are the presumed causes until proved otherwise, not infrequently turn out to have demyelinating lesions. However, to make that diagnosis without first formally excluding a structural lesion is inexcusable.
Spinal cord stroke
Infarction of the cord may result from overt cardiovascular disease – bacterial endocarditis, aortic aneurysm or rupture of an arteriovenous malformation, or a profound drop in blood pressure – but may also occur for no detectable reason, even at autopsy (H.L. Lipton and Teasdell 1973). A few cases are the result of fibrocartilaginous embolism after the nucleus pulposus of an intervertebral disc has herniated into an adjacent vertebra. The infarction can be confined to the territory of the anterior spinal artery on one side, resulting in a partial Brown-Séquard syndrome, with sparing of the posterior columns. Multiple sclerosis may also present with any one of these spinal syndromes (D.H. Miller et al 1987a), but the onset is usually less abrupt, the neurological deficit less severe and the prognosis for recovery from the episode in question rather better.
Transverse myelitis
An acute or subacute lesion of the spinal cord is a classic presentation of multiple sclerosis and yet this syndrome has other causes which, despite in some situations leaving the patient severely disabled, do not recur. The history of early accounts, starting with Charlton Bastian (1882; 1910), and subsequent clinical descriptions and ideas on the aetiology and pathogenesis are given by Krishnan and Kerr (2005). A comprehensive recent review discusses the presentation, investigation, diagnosis and management of transverse myelitis and offers a set of criteria to distinguish idiopathic cases from those with a recognized cause (Transverse Myelitis Consortium Working Group 2002). Another review considers the differential diagnosis and management of acute myelopathies including transverse myelitis (Kaplin et al 2005). The vexed question of Devic's disease is discussed in Chapters 5 and 6, and the ways in which modern imaging techniques have greatly assisted the recognition of compressive lesions is covered in Chapter 7. It is unusual, but not exceptional, for systemic disease manifesting as acute myelitis to occur in the absence of evidence for disease of other organs, although this may not be recognized before the onset of paraplegia. Systemic lupus erythematosus and the other systemic diseases discussed above, infarction of the spinal cord, and parainfectious myelitis (acute disseminated encephalomyelitis) can all present as myelitis. An association of transverse myelitis with primary biliary cirrhosis has also been reported (Papadopoulos et al 2005).
Onset may be acute or subacute in acute inflammatory demyelination of the spinal cord and, from the clinical perspective, the process often ascends or spreads transversely (J.T. Hughes 1978). The diagnosis of transverse myelitis is usually made by exclusion and, as with acute disseminated encephalomyelitis in adults, the precipitating cause is seldom identified. However, clinical and laboratory criteria can usefully distinguish the various causes. The relationship of isolated spinal demyelination to multiple sclerosis is complex, as with more generalized forms of inflammatory central nervous system disease. Cord lesions due to multiple sclerosis are usually partial, sometimes conforming to the Brown-Séquard syndrome, but acute or subacute cord lesions may occur that exactly mimic transverse myelitis. This term is usually reserved for patients in whom the spinal lesion does not recur but the distinction may not be easy in the acute stage. The most reliable indicator is the presence of spinal shock in the acute monophasic lesion (McAlpine 1931). T.F. Scott et al (1998) emphasize that symmetry of the motor and sensory manifestations of acute spinal cord disease usefully identifies the patient with transverse myelitis, whereas spinal involvement in multiple sclerosis is usually asymmetric. Defined in this way, they report a low conversion rate from transverse myelitis to multiple sclerosis. Even though a monophasic episode of cord inflammation may result in persistent disability, many patients, including those with severe myelitis, recover fully and without sequelae (Altrocchi 1963; Berman et al 1981; H.L. Lipton and Teasdell 1973). MRI of the brain sometimes shows asymptomatic areas of abnormal signal in the white matter. The predictive value of such changes for the later development of multiple sclerosis is discussed in Chapter 7. In transverse myelitis, the acute cord lesion is typically extensive, involving multiple cord segments (Figure 8.41 ), whereas in multiple sclerosis the cord lesions are usually small.
Figure 8.41.
Swelling and high T2-weighted signal in the cervical cord and medulla (arrows) from a patient with acute transverse myelitis. Kindly provided by Dr Nagui Antoun.
Acute necrotizing myelitis
The original description of necrotizing myelitis was in men, rather older than most cases of transverse myelitis, and with slowly progressive lumbar cord disease occurring in association with chronic respiratory disease (Foix and Alajouanine 1926). The term acute necrotizing myelitis can reasonably be applied to patients developing severe inflammation of the thoracic or spinal cord, in whom flaccid areflexic paraplegia with anaesthesia and loss of sphincter control progresses rapidly over hours (H.I. Hoffman 1955). Inflammation is sufficient to cause severe pain with meningism and systemic symptoms, including pyrexia. The clinical presentation suggests cord compression. Contrast radiology or imaging often reveal a swollen cord with spinal block. Since the cerebrospinal fluid shows a marked polymorphonuclear pleocytosis, raised protein and lowered glucose concentrations, these patients are frequently thought to have pyogenic or tuberculous infection of the central nervous system and are treated with appropriate antimicrobial therapy. In some cases surgical exploration is undertaken to exclude intraspinal abscess. Because of the possibility of infection, there is often a reluctance to use corticosteroids but the course of acute necrotizing myelitis may be significantly influenced by high-dose intravenous methylprednisolone. Acute necrotizing myelitis has an appreciable mortality but in survivors the systemic features resolve within weeks, leaving significant handicap and disability. One of our patients (DASC), a 14-year-old girl with acute necrotizing myelitis in whom complete functional cervical cord transection was associated with spinal block due to cord swelling, meningism, pyrexia and a marked polymorphonuclear pleocytosis with reduced glucose, eventually made a complete and stable recovery, apart from minor bladder instability, after treatment with high-dose intravenous methylprednisolone. She remains well more than 15 years later. Conversely, another adult female patient with signs of functional cord transection due to acute necrotizing myelitis, made no useful recovery and soon developed acute demyelination of the dominant hemisphere manifesting as aphasia with hemiplegia, followed by brainstem symptoms and other features of the Marburg variant of multiple sclerosis from which she died within a few years of presentation.
Many organisms have been implicated by association in the aetiology of acute necrotizing myelitis (Table 8.12 ). Acute necrotizing myelitis is also described after rabies vaccination, as a complication of acute lymphocytic leukaemias, lymphoma, hypernephroma and other forms of carcinoma, and in acquired immunodeficiency syndrome (Bassoe and Grinker 1930; Britton et al 1985; Grisold et al 1980; Lester et al 1979; Mancall and Rosales 1964; Ojeda 1984). When acute necrotizing myelitis has occurred in association with tuberculosis (R.A.C. Hughes and Mair 1977), along with pleocytosis and glycorrhaccic changes that often occur in cerebrospinal fluid, it is not surprising that these patients are usually treated with antituberculous therapy, at least until bacteriological results are available.
Table 8.12.
Infections associated with acute necrotizing transverse myelitis
| Herpes zoster virus | Hogan and Krigman 1973 |
| Herpes simplex virus type II | Wiley et al 1987; Ahmed 1988 |
| Tuberculosis | Hughes and Mair 1977 |
| Coxsackie B4 virus | Ku and Lee 1998 |
| Tuberculin skin testing (PPD0 cytomegalovirus) |
|
| Mycoplasma pneumoniae | Parisi and Filice 2001; Goebels et al 2001 |
| Burkholderia pseudomallei | Haran et al 2001 |
| Coxiella burnetii | Waltereit et al 2002 |
| Cladophialophora bantiana | Shields and Castillo 2002 |
| Group B streptococcus | Schimmel et al 2002 |
| Pneumococcus | Ben-Dov et al 2002 |
| Dengue 2 virus | Leao et al 2002 |
| Acinetobacter baumaniia | Ubogu et al 2003 |
| Borrelia burgdorferi | Lesca et al 2002 |
| Babesia microti | Oleson et al 2003 |
| Hepatitis C virus | Zandman-Goddard et al 2003 |
Inadvertently delivered through an intrathecal pump.
A syndrome of progressive necrotic myelopathy has been recently described by J.D. Katz and Ropper (2000). Nine adult patients were reported in whom acute or subacute episodes of worsening occurred every few months leading to paraplegia or tetraplegia. There was evidence of flaccid, areflexic weakness, denervation over several spinal segments, and atrophy or cavitation of the cord in the chronic stage (although during acute episodes the cord was swollen and displayed gadolinium enhancement over several segments). In six patients, there were neither cerebrospinal fluid oligoclonal bands nor brain MRI abnormalities but two had prolonged visual evoked potentials. The condition worsened in spite of immunomodulatory therapy, and in two patients in whom pathological data were obtained there was evidence for cord necrosis. The authors suggest that these cases were indistinguishable from a limited form of Devic's disease.
Other forms of myelitis
The majority of patients with transverse myelitis are not systemically ill and the neurological disorder usually evolves over a few days. Onset with back pain and an ascending level is more frequent than in patients considered to have multiple sclerosis (Jeffrey et al 1993). Although the premonitory symptoms are often sensory or sphincter disturbance, in the severe case these are followed by devastating loss of mobility. With time, the weakness increases and may spread to involve one or both arms, usually in an asymmetric pattern and showing the flaccid areflexia characteristic of spinal shock. Sensory loss replaces the paraesthesiae and there is often a band of unpleasant hyperaesthesia at the upper sensory level. As in other cases of incomplete focal spinal disease, this may not accurately reflect the site of spinal affection because of lamination of fibres in the spinothalamic pathways. Sphincter control is lost but unlike those with multiple sclerosis, the patient usually has acute bladder retention rather than urgency or urge incontinence.
The need to exclude a structural cause for subacute cord injury occurring as a manifestation of transverse myelitis means that many patients undergo radiological investigation. Jeffrey et al (1993) reported that swelling of the cord was sometimes present in patients categorized as having parainfectious myelitis, but not in multiple sclerosis. However, focal cord swelling can undoubtedly occur in multiple sclerosis, usually limited to only one or two segments and diminishing with follow-up, although complete resolution may take several months. Austin et al (1992) found MRI of the cord to be abnormal in only seven of 18 adults with transverse myelitis and the abnormality did not correlate with the cause of the myelitis. When the onset is subacute and accompanied by focal swelling of the spinal cord, the distinction from an intrinsic tumour may be impossible without biopsy (Reznik et al 1994), although the overwhelming preference, if myelitis is thought most likely, would be to await follow-up and demonstrate resolution of swelling noninvasively by repeat MRI.
D.H. Miller et al (1987a) showed cranial MRI abnormalities typical of multiple sclerosis in 15/30 patients with acute myelitis <50 years and although, on a single scan, acute disseminated encephalomyelitis could not be excluded, the majority of patients had a partial cord syndrome that was more suggestive of multiple sclerosis. In a series of 31 patients from the Middle East with no specific cause identified, there was no radiological evidence for involvement outside the spinal cord and none of the patients developed episodes suggesting more widespread demyelination over the ensuing 9 years (Al Deeb et al 1997), suggesting that these were examples of restricted postinfectious encephalomyelitis. It is important to analyse the spinal fluid if myelography is used to exclude cord compression, since spurious changes may later be detected. Lumbar puncture should also be carried out in cases investigated by MRI. The spinal fluid shows an increased mononuclear cell count, numerically intermediate between the marked pleocytosis of acute necrotizing myelitis and the abnormalities seen in patients with multiple sclerosis. The total protein is raised and oligoclonal bands may be present but the glucose is usually normal. Multiple sclerosis and transverse myelitis cannot reliably be distinguished on the basis of changes in cerebrospinal fluid but a cell count >100 lymphocytes/cm3 is less likely in the former, and cerebrospinal fluid oligoclonal IgG is found inconsistently in patients thought to have parainfectious myelitis (Jeffrey et al 1993).
The clinical diagnosis of multiple sclerosis will often only be established by subsequent clinical events. However, to complicate matters, there have been reports of recurrent transverse myelitis without other central nervous system manifestations (Kim 2003; Tippett et al 1991). Kim (2003) compared 21 patients with recurrent cord relapses in whom a diagnosis of multiple sclerosis had been made with 15 patients having no evidence clinically or on MRI for involvement outside the spinal cord (called idiopathic recurrent transverse myelitis). Compared with the group with multiple sclerosis, the latter differed by having a male preponderance, an absence of oligoclonal bands, and a higher frequency of relapses and episodes of transverse myelitis. The cases of recurrent transverse myelitis have a number of features in common with Devic's disease apart from the absence of visual involvement, and one can argue that they should fall within the rubric of multiple sclerosis, albeit with an unusual clinical and immunopathogenic phenotype. The eight cases described by Fukuzawa et al (2003), in whom there were recurrent episodes of transverse myelitis associated with additional inflammatory episodes involving the cerebrum and brainstem, are – in our view – best regarded as cases of multiple sclerosis.
Unlike acute disseminated encephalomyelitis, transverse myelitis is more common in adults than children, and in women than men. Since the diagnosis is often made by exclusion, with somewhat unhelpful laboratory abnormalities and bacteriological findings, the probability arises that a heterogeneous collection of cases has been included in most large series. Berman et al (1981), working from a population base in an attempt to avoid selection bias, found that a high proportion of cases originally designated as transverse myelitis had to be excluded from their study. In the remainder, incidence peaked in the second and third decades with a further bimodal increase in patients aged over 70 years. Infection was reported more frequently in younger than older patients. For these two reasons, patients with spinal stroke are sometimes erroneously diagnosed as having transverse myelitis, and this is especially problematic in patients with sensory signs indicating an anterior cord lesion. Formerly, meningovascular syphilis was regarded as an important cause of acute myelitis whereas the more recent literature is replete with examples of transverse myelitis complicating collagen vascular disease.
De Séze et al (2001c) reviewed the clinical and laboratory features and outcome profiles of 79 patients presenting with an acute myelopathy. The patients were classified into six diagnostic categories: multiple sclerosis (34 examples), systemic disease (13, including cases of systemic lupus erythematosus and Sjögren's syndrome), spinal cord infarction (11), parainfectious myelopathy (5), delayed radiation myelopathy (3), and cases of unknown origin (13). A motor deficit was more frequent and spinal cord MRI lesions were more extensive in the systemic disease and spinal cord infarction groups when compared with multiple sclerosis. The five patients with parainfectious myelopathy all had extensive cord lesions and four exhibited swelling and gadolinium enhancement. All three patients with delayed radiation myelopathy had a long lesion associated with gadolinium enhancement and – in two cases – swelling of the cord. Brain lesions were predictably more common in multiple sclerosis (68%) but were also seen in 31% with a systemic disease. Whereas 88% with multiple sclerosis had oligoclonal bands in their cerebrospinal fluid, these were present in only 17% of the systemic disease group and in none of the patients with spinal cord infarction. Clinical outcome at 12 months was classified as good in 88% with multiple sclerosis, but poor or fair in 91% with spinal cord infarction and 77% with systemic diseases.
A further study compared MRI findings in nine patients with acute transverse myelitis and 13 with myelitis as a manifestation of multiple sclerosis (Bakshi et al 1998). In the former group, long lesions involving multiple cord segments were characteristic whereas in the latter group the lesions involved on average only one or two segments of cord. Swelling of the cord was seen equally in both groups. Brain MRI was normal in 78% with acute transverse myelitis but in only 15% with multiple sclerosis.
The series reported by Berman et al (1981) is probably representative with respect to prognosis in acute transverse myelitis. Sixty-eight per cent of patients in whom follow-up information was available made an adequate recovery over the ensuing 3 months. Three died and 14 were left with significant persistent disability. Only one patient subsequently developed multiple sclerosis. Preceding infection was reported in only one-third of patients, the majority of whom had upper respiratory infection, other causes being herpes zoster or simplex virus infection, hepatitis and smallpox vaccination. Kalita et al (1998) reported that a poorer outcome of acute transverse myelitis was associated with severe weakness and denervation on electromyography. Devinsky et al (1991) described the clinicopathological findings in nine fatal cases of herpes zoster myelitis resulting from direct infection of oligodendrocytes and occurring in association with immune suppression. They emphasized the 12-day interval between appearance of the cutaneous rash and the onset of neurological symptoms, with vertical and horizontal spread producing motor involvement and a tendency to spare the posterior columns. Tyler et al (1986) listed the following viral causes of transverse myelitis in man: picornaviruses, togaviruses, retroviruses, orthomyxoviruses, paramyxoviruses, bunyaviruses, arenaviruses, rhabdoviruses, hepatitis viruses, herpes viruses and poxviruses. Isolated case reports emphasize the occurrence of transverse myelitis after infection with hepatitis A, hepatitis C (Annunziata et al 2005), cytomegalovirus, herpes simplex type 2, toxoplasmosis, schistosomiasis, Borrelia and Coxiella (see also Lesca et al 2002; Waltereit et al 2002). Epstein–Barr virus infection has resulted in cases of myeloradiculitis and encephalomyeloradiculitis with the presence of viral DNA in cerebrospinal fluid suggesting a direct infectious mechanism. The clinical outcome for four such recently reported cases was variable (Majid et al 2002).
Visual failure
There are innumerable infective, toxic or physical causes of optic nerve disease that are unlikely to be confused with multiple sclerosis. Several rare causes due to systemic disease resulting in diagnostic difficulty have already been discussed above under a number of headings.
Anterior ischaemic optic neuropathy
Although anterior ischaemic optic neuropathy is generally held to be easily diagnosed, it may in fact be difficult to distinguish from optic neuritis in the absence of arteritis (Figure 8.42 ; Rizzo and Lessell 1991) found a considerable degree of overlap between the clinical features of these conditions. Ischaemic optic neuropathy generally affects older people and the sex incidence does not show the female preponderance characteristic of multiple sclerosis and optic neuritis. Pain in the eye is more frequent in optic neuritis, and disc swelling is almost invariable in ischaemic neuropathy. The onset of visual loss is usually abrupt, with little progression in ischaemic optic neuropathy, but the initial severity of visual loss is highly variable and not dissimilar in both conditions. A central scotoma is more often found in optic neuritis whereas a sector defect, often altitudinal and with an arcuate component, characterizes ischaemia. That said, the two conditions cannot reliably be distinguished by their visual field defects (W.I. McDonald and Barnes 1992). Much greater improvement of visual acuity is usual after the acute event in cases of optic neuritis.
Figure 8.42.
(A) Acute optic disc swelling in ischaemic optic neuropathy. (B) Late nerve fibre bundle atrophy following acute embolic ischaemic optic neuropathy.
Leber's hereditary optic neuropathy
Leber's hereditary optic neuropathy occurs predominantly in men. Typically, visual loss evolves synchronously in each eye, progressing more slowly than in bilateral demyelinating optic neuritis. In some patients with Leber's disease, visual loss in each eye occurs consecutively after a brief interval. Pain on eye movement and Uhthoff's phenomenon may each occur but these features are less frequent than in demyelinating optic neuritis (Riordan-Eva et al 1995). A centro-caecal scotoma is characteristic (Nikoskelainen et al 1977). Retinal microangiopathy and swelling of the optic disc may be observed in the acute stages of visual failure but are far from constant and seldom persist (Riordan-Eva et al 1995), and fluorescein angiography does not show leakage at the disc. Inheritance is strictly maternal and descendants of male patients are not affected. The molecular defect is a pathological point mutation in mitochondrial DNA (Wallace et al 1988). Several are described, one in particular (the 14484 point mutation) being associated with relatively good visual recovery: 71% with this mutation had a final visual acuity of at least 6/24 in one large series (Riordan-Eva et al 1995). Harding's disease (see McAlpine's Multiple Sclerosis 3rd edition, page 135; Harding et al 1992) and its relationship to multiple sclerosis are described in Chapters 3 and 6.
Central serous choroidoretinopathy
Optic neuritis may be closely mimicked by central serous choroidoretinopathy. This affects young adults, especially males, causing unilateral blurred vision but only slight loss of acuity and no impairment of colour vision. There is often distorted perception of straight lines, which gives the clue that the problem is of retinal not optic nerve origin. The pupillary light reflex is not affected. Changes at the fovea may be difficult to identify ophthalmoscopically and fluorescein angiography is often helpful. Multiple sclerosis is wrongly diagnosed on the basis of presumed optic neuritis and unreliable soft neurological signs (Krauscher and Miller 1982). The probability that this condition has been confused with optic neuritis in some series, accounting for the lower than expected conversion rate to multiple sclerosis after an episode of visual loss, is described in Chapter 6.
Neuroretinitis
The presentation of neuroretinitis resembles optic neuritis even more closely than central serous choroidoretinopathy. Rapid visual loss is accompanied by pain in the eye or headache. The optic disc is swollen. Some patients report vague sensory or bladder symptoms. The clue to diagnosis is the presence of a macular star, either at onset or within 2 weeks. This condition has been thought not to be related to multiple sclerosis (Parmley et al 1987) but the rarity of the disorder is such that there have been no large studies of its natural history.
Chronic relapsing inflammatory optic neuropathy (CRION)
Some patients who present with recurrent episodes of optic neuritis appear, on closer inspection, to have a distinct inflammatory disorder that has recently been designated chronic relapsing inflammatory optic neuropathy (CRION; Hickman et al 2002b; D. Kidd et al 2003). Characteristic features are acute severe visual loss associated with particularly severe and persistent orbital pain that requires powerful analgesia. The optic neuritis may be unilateral or simultaneously bilateral. Gadolinium enhanced MRI may reveal extensive swelling and enhancement of the optic nerve although this can also be seen in typical cases of optic neuritis. Brain MRI is normal. Spontaneous recovery is unusual but visual recovery may occur with early institution of high-dose intravenous methylprednisolone followed by a tapering dose of oral corticosteriods. Relapse sometimes occurs as the dose is reduced. Long-term immunosuppression is often used to prevent these relapses and modify the course of the disorder. The clinical picture is reminiscent of that encountered in granulomatous optic neuropathy but, in cases diagnosed as CRION, there is no clinical or laboratory evidence for systemic sarcoidosis even after prolonged follow-up (Kidd et al 2003).
Paraneoplastic optic neuritis
Both optic neuritis and retinitis occur as paraneoplastic syndromes. Presentation of optic neuritis is with subacute visual loss and disc swelling, accompanied by evidence of retinitis and vitreous cells (Figure 8.31). The disorder is associated with IgG antibody to collapsin response mediator protein-5 (CRMP-5) and most patients are smokers with an underlying small cell lung carcinoma (S.A. Cross et al 2003). There is a cerebrospinal fluid pleocytosis with oligoclonal bands, and a variety of associated neurological features indicating a more diffuse encephalo-myelo-radiculo-neuronitis.
Progressive visual failure
Progressive visual failure as the initial and sole manifestation of multiple sclerosis should be accepted only with the greatest reservation (see Chapter 6). Potential pitfalls for the neurologist who assumes that demyelinating disease is the correct explanation for progressive loss of vision are considerable (Ormerod and McDonald 1984). High resolution imaging of the optic nerves and chiasm with CT and/or MRI is mandatory to exclude a compressive lesion. Occasional instances of progressive bilateral (Ormerod and McDonald 1984) or unilateral (Eidelberg et al 1988) optic neuropathy do nevertheless occur, albeit uncommonly, in multiple sclerosis. These constitute unusual variants of primary progressive multiple sclerosis.
Sensory symptoms
Patients with the harmless condition of migrant sensory neuritis (named eponymously after Wartenberg) are usually diagnosed as having multiple sclerosis on the basis of disseminated, remitting, sensory changes, but the symptoms are quite distinctive (Matthews and Esiri 1983). They apparently arise from the stretching of cutaneous nerves. The characteristic sequence is of a brief searing pain, clearly perceived as superficial, in a strictly localized area of an extremity, occurring during rapid movement of the limb. This is followed by blunting of cutaneous sensation in the same area. This always involves the distribution of a cutaneous nerve and is never segmental or extensive. The frequently involved nerves are digital, sural, terminal radial and ulnar and the patellar plexus. Remission occurs within a few weeks but further episodes, affecting different nerves, are common and may be interpreted as confirming an erroneous diagnosis of multiple sclerosis. Our former colleague and author of this book let it be known that he was a martyr to this complaint (Bryan Matthews, personal communication).
Surprisingly, it seems that the prodromal sensory symptoms of migraine, undoubtedly relapsing–remitting, can be mistaken for those of multiple sclerosis (T.J. Murray and Murray 1984).
Central pontine myelinolysis
This is a noninflammatory demyelinating disorder that involves the central pontine tegmentum. It is entirely unrelated to multiple sclerosis. Central pontine myelinolysis usually presents in the context of a major electrolyte disturbance, most often hyponatraemia that has been rapidly corrected. There may be evidence of poor nutrition or alcohol abuse and it has been seen in association with hyperemesis gravidarum. Within 10–14 days of over zealous correction of the serum sodium, the patient develops a severe neurological deficit over a few days with quadriparesis and pseudobulbar palsy. This can proceed to the locked-in state. In other instances there are few or no symptoms, the diagnosis being made on the basis of a characteristic MRI abnormality, high signal on T2-weighted and low signal on T1-weighted images of the central pons without gadolinium enhancement or mass effect (Figure 8.43 ). The demyelination is thought to result from rapid osmotic shifts. With appropriate support, including intensive care and assisted ventilation, most patients will make a good recovery. The MR abnormality also resolves. The characteristic clinical and radiological picture should rarely be confused with an acute episode of brainstem demyelination due to multiple sclerosis.
Figure 8.43.
(A) T2-weighted and (B) T1-weighted MRI in central pontine myelinolysis show characteristic signal changes in the central pons.
NON-ORGANIC SYMPTOMS
People who fear that they might have multiple sclerosis and who have read or heard of the symptoms to be expected often complain of fluctuating vision, clumsiness and tingling in the extremities. The time course of these symptoms rarely resembles the relapses and remissions of multiple sclerosis. Blurred vision clears on rubbing or resting the eyes, and the ataxia does not usually result in self injury. The sensory symptoms are sometimes unilateral, and, although it has often been thought that they are more likely to affect the left arm and leg, either side may be involved (J. Stone et al 2002). More widespread sensory disturbance may also occur. The sensory symptoms often disappear on re-positioning of the limbs. Tingling persists for periods of a few minutes to half a day and recurs at irregular intervals. Sometimes these symptoms are recognizable as the effects of hyperventilation.
Another type of presentation is the persistent and usually multiple non-organic symptoms and signs found in people who think they have multiple sclerosis, sometimes in response to physical or mental trauma, but in whom no neurological diagnosis is made after thorough examination and investigation. It is sometimes stated that urinary or faecal incontinence are reliable indications of organic disease but this has not been our experience. The physical signs, in addition to the usual collapsing limb weakness as a result of fluctuating effort and simultaneous contraction of agonists and antagonists, can be highly elaborate, including spasmodic involuntary movements. The gait is often profoundly ataxic but with inconsistencies and a bizarre appearance that actually requires considerable athleticism to maintain an upright posture. In those with medical knowledge, the extensor plantar reflexes can deceive even the most experienced neurologist (Hankey and Stewart-Wynne 1988). Unilateral loss of vibration sense over the forehead is a particularly useful sensory finding in some patients with a non-organic disorder. The diagnosis of non-organic or functional disorder requires thorough investigation to provide mutual reassurance that there is no associated neurological disorder. The diagnosis of multiple sclerosis becomes unlikely in the presence of normal brain and spinal cord MRI, especially if combined with the absence of oligoclonal bands. But multiple sclerosis will sometimes be diagnosed with confidence and conviction in the absence of laboratory support if the clinical features are considered genuine and appear to have no better explanation. When multiple sclerosis has to be ‘un-diagnosed’, the situation can be formulated as a somatization disorder and explained to the patient as an abnormality of function with intact structure in the nervous system. These conversations are not easy and often end in distress for the patient apparently denied the prop of an organic explanation for symptoms that are genuinely experienced and seem real enough. Management is difficult, and may involve referral to liaison psychiatry but with uncertain benefits. Prolonged (12-year) follow-up has been recently reported on 60 patients in whom a diagnosis of unilateral functional weakness or sensory disturbance was made (J. Stone et al 2003). Of the 42 from whom information was obtained, 35 (83%) reported continued weakness or sensory symptoms and most had limitation of physical function, distress and other somatic symptoms. Patients with sensory symptoms at presentation had a better outcome than those with weakness. Accuracy of the original diagnosis was vindicated and a discrete neurological diagnosis (multiple sclerosis) emerged in only one instance. Assessment is especially difficult in patients who do have multiple sclerosis but in whom the major complaints and disabilities are dominated by elaboration and non-organic manifestations.
HOW ACCURATE IS THE DIAGNOSIS OF MULTIPLE SCLEROSIS?
In the accounts of diseases discussed above are many reports of overlap between the clinical and paraclinical features relied on for the diagnosis of multiple sclerosis. Before the ready availability of MRI it was estimated that approximately 10% of referrals to specialist multiple sclerosis clinics harboured an incorrect diagnosis, with considerable ambiguity in a further 5–10% (Herndon and Brooks 1985). Engell (1988) found that the diagnosis was correct in 485/518 (94%) patients diagnosed as having clinically definite multiple sclerosis in whom necropsy was subsequently performed, but the sample is not free from selection bias. In that series, mistakes included the Chiari malformation (one case), subacute combined degeneration of the spinal cord (one case), spinocerebellar degeneration (two cases), arteriovenous malformation (three cases), stroke or diffuse vascular disease (three cases) and intracranial tumour (seven cases).
Rudick et al (1986) describe in detail a series of patients, all satisfying stringent criteria for multiple sclerosis, in whom investigation eventually disclosed a different diagnosis. One patient had been followed for 15 years in a specialist multiple sclerosis clinic. Three were found to have unusual forms of vascular disease and two had spino-cerebellar degeneration. There were single cases of the Chiari malformation, arteriovenous malformation, hysteria, intrinsic spinal cord tumour and benign extramedullary tumour. These authors suggest warning signals (red flags) demanding reconsideration of the diagnosis – for example, absence of eye signs; failure of remission in young patients; and localized disease or atypical clinical features, particularly absence of sensory change or bladder disturbance in the presence of considerable motor disability.
As Herndon (1994) has emphasized, MRI and refined methods of spinal fluid analysis, if correctly applied, have largely eliminated the classical mistake of diagnosing tumours involving the nervous system as multiple sclerosis. Errors are now more frequent in the reverse direction – massive demyelinating lesions of the hemisphere, with resulting oedema, being mistaken for malignant tumours. Uncritical use of MRI may also lead to the erroneous diagnosis of multiple sclerosis in patients aged over 40 years, with inappropriate symptoms and a few (presumed) vascular white matter lesions shown on the scan mainly in a nonperiventricular location. In the context of a disease which, at any one time, affects 1 : 800 of the population, it is self-evident that double diagnoses will occasionally occur. These can be diagnostically taxing, especially when multiple sclerosis has already been accurately diagnosed and the second disorder produces symptoms which reliably mimic the manifestations of focal demyelination (Figures 8.44 and 8.45 ).
Figure 8.44.
CT myelography in a young man with a previous episode of optic neuritis developing a progressive cord lesion as a result of a coincidental spinal neurofibroma.
Figure 8.45.
(A, B) Adjacent T2-weighted MRI in a patient with white matter abnormalities as a result of central demyelinating disease (arrow) who also has a sphenoid ridge meningioma producing facial pain and ophthalmoplegia. (C) Patient with multiple sclerosis who became drowsy after a fall and had a chronic subdural haematoma (arrow).
In contrast, multiple sclerosis may not have been considered during the life of patients with chronic neurological disease who are subsequently proven histologically to have pathological features of the disorder. Phadke and Best (1983) describe four such cases, three of whom were elderly and thought to have unusual symptoms and signs of cerebrovascular disease. Six much younger patients are listed by H.J. Bauer and Hanefeld (1993), all of them dying from multiple sclerosis within a brief period from onset, in whom quite different diagnoses had been entertained. Multiple sclerosis can surprise even the most experienced neurologist.