Postgrad Med J 2001;77:379–382 379

Multiple system atrophy Postgrad Med J: first published as 10.1136/pmj.77.908.379 on 1 June 2001. Downloaded from

H U Rehman

Multiple system atrophy (MSA) is a degenera- tive disease of the central . “Red flags”—clinical features raising Dejerine and Thomas in 1900 were the first to doubts about the diagnosis of use the term olivopontocerebellar atrophy idiopathic Parkinson’s disease (OPCA) in two sporadic cases,1 although x Poor or absent levodopa response. Lack of typical levodopa induced Menzel described the first case in 1891. Shy x . and Drager in 1960 described four cases of a x Atypical levodopa induced dyskinesias— “neurological syndrome with orthostatic hypo- 2 for example, sustained dystonic spasm of tension”. They defined the full syndrome facial muscles, torticollis, antecollis. comprising of , urinary x Pyramidal signs. and rectal incontinence, loss of sweating, iris x Cerebellar signs. atrophy, external ocular palsies, rigidity, x Autonomic failure. , loss of associated movements, impo- x Early falls and instability. tence, atonic bladder, loss of rectal sphincter x Rapid clinical deterioration despite tone, , wasting of distal muscles, dopaminergic treatment. evidence of a neuropathic lesion in the electro- x Myoclonic jerks. myogram suggesting involvement of the ante- x Severe . rior horn cells, and the finding of a neuropathic x Pains not relieved by levodopa. lesion in the muscle biopsy. Adams et al first described a syndrome designated striatonigral degeneration in the early 1960s.3 These of the patients. Akinesia and rigidity predomi- patients had mild autonomic failure and nate and is usually asymmetric. Tremor may be and were shown to have lesions in the at rest, jerky irregular, or a classic pill rolling. olivopontocerebellar system. Graham and Op- Autonomic symptoms are present in 97% of penheimer first proposed the term multiple patients. They may precede the motor distur- system atrophy in 1969 and suggested that bance by months or even years. Impotence is OPCA, idiopathic orthostatic hypotension, the almost universal in male patients. Postural Shy-Drager syndrome, and striatonigral degen- hypotension is usually mild to moderate. It may eration “are merely the expression of neuronal cause recurrent syncopal attacks. Urinary urge atrophy in a variety of overlapping combina- incontinence and may also

tions”.4 occur. http://pmj.bmj.com/ MSA is a sporadic disease. MSA was consid- Cerebellar signs occur in about half the ered a rare disease but many patients with patients. MSA of OPCA type most commonly MSA are misdiagnosed as suVering from idio- presents with gait ataxia. Pyramidal signs, a mixed dysarthria with combination of hypoki- pathic Parkinson’s disease. It is clear from a 7 large postmortem series of parkinsonian netic, ataxic and spastic components, nystag- that cases of MSA are more common than pre- mus, saccadic pursuit, hypometric saccades, limitation of gaze, , and impaired viously thought. Between 4% and 22% of the distal vibration sense and joint position sense on September 28, 2021 by guest. Protected copyright. brains in parkinsonian banks have MSA.5 are sometimes seen. Dysphagia may become According to one estimate the prevalence of significant in the later part of the illness. Respi- MSA is 16.4 per 100 000 population. Mean ratory may also occur. This is caused by age of disease onset is 53 years (range 36–74) atrophy of the posterior cricoarytenoid muscles and the median disease duration to death is five resulting in failure of abduction of the vocal years (range 1–11). Both sexes are aVected 8 6 cords and narrowing of the airway. equally. In the fully developed disease they are permanently bedbound, almost mute and Clinical features severely dysphagic with an indwelling catheter, MSA can cause any combination of parkinso- yet with retained intellect and awareness. nian, autonomic, pyramidal, and cerebellar The cause of death in MSA is commonly signs. When parkinsonian features predomi- related to development of bulbar dysfunction nate, the term striatonigral degeneration is and dysphagia, predisposing to aspiration often used. When cerebellar features predomi- pneumonia. nate, sporadic OPCA is often used. When autonomic failure predominates, the term Shy- DiVerential diagnosis Hull Royal Infirmary, Drager syndrome is often used. These manifes- Anlaby Road, Hull MSA is most commonly misdiagnosed as idio- HU3 2JZ, UK tations may occur in various combinations and pathic Parkinson’s disease. Asymmetry, rest evolve with time. tremor, and a good levodopa response are sug- Correspondence to: Most patients with MSA are initially consid- gestive of idiopathic Parkinson’s disease, but do Dr Rehman ered to have Parkinson’s disease (see box for not exclude MSA. A poor or absent levodopa Submitted 12 July 2000 features that raise doubts about the diagnosis). response is the rule in MSA patients, although Accepted 28 November 2000 Parkinsonian features are documented in 91% transient but excellent benefit may occur.9

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Many patients, however, may appear to be vagus, vestibular nuclei, , and Postgrad Med J: first published as 10.1136/pmj.77.908.379 on 1 June 2001. Downloaded from deriving no benefit from their therapy, yet anterior horns may also be aVected. Other deteriorate hours or days after stopping it.10 medullary nuclei aVected include catecho- Patients with MSA on chronic levodopa treat- laminergic cells in the ventrolateral reticular ment lack typical, or display atypical, levodopa formation21 and cells in the arcuate nucleus. induced dyskinesias. These can take form of The absence of Lewy bodies distinguishes it sustained dystonic spasms of facial muscles,11 from idiopathic Parkinson’s disease. A useful torticollis, or a relatively fixed and dispropor- macroscopically diagnostic clue is a grey- tionate antecollis.12 greenish discoloration of the atrophic puta- Although a few patients may display inap- men. The and locus coeruleus propriate laughter or crying, intellect is strik- are pale as a result of loss of pigment. ingly preserved.6 Therefore is not a There are five histological features, which 13 feature of MSA. Presence of pyramidal or characterise MSA: glial cytoplasmic inclusions, cerebellar signs or autonomic failure should neuronal cytoplasmic inclusions, neuronal nu- raise a suspicion of MSA. Instability and falls clear inclusions, glial nuclear inclusions, and early in the course of the disease should also neurophil threads. Glial cytoplasmic inclusions suggest a cause other than idiopathic Parkin- (GCIs) are the most important. GCIs have son’s disease. Rapid clinical deterioration been recently described in MSA with various despite dopaminergic treatment is another combinations of striatonigral degeneration, clue. Myoclonic jerks, often stretch sensitive, OPCA, and Shy-Drager syndrome.22 These usually aVecting the fingers is rare in idiopathic 14 inclusions are not specific, although they are Parkinson’s disease. Speech is more severely characteristic of MSA. This also confirms the aVected in MSA than in idiopathic Parkinson’s notion that the three clinical syndromes of disease. Deep aching limb pains occur in both striatonigral degeneration, OPCA, and Shy- idiopathic Parkinson’s disease and MSA, but Drager syndrome are various manifestations of unlike the pain of idiopathic Parkinson’s the same disease. GCIs have become a disease, it is not relieved by levodopa in MSA.15 diagnostic hallmark of MSA. GCIs are found Another important diVerential diagnosis is in the primary motor and higher motor areas of pure autonomic failure. Other than clinical the cerebral cortex, pyramidal, extrapyramidal, manifestations, plasma noradrenaline (nore- pinephrine) concentrations in the supine rest- and corticocerebellar systems and in the ing condition may help to diVerentiate the two supraspinal autonomic systems and their tar- conditions. Plasma noradrenaline, an index of gets. These inclusions occur in oligodendro- peripheral sympathetic activity, is often normal cytes and may precede neuronal alteration, in patients with MSA, reflecting intact periph- implying that oligodendroglial degeneration eral sympathetic neurones, but abnormally low and not the degeneration of axons or neuronal in patients with pure autonomic failure, cell bodies is a prerequisite for the development indicating abnormal peripheral sympathetic of GCIs and that GCIs are unlikely to have 23 16 developed as a reaction to axonal injury. neurones. However, the distinction on the http://pmj.bmj.com/ basis of plasma noradrenaline has been unreli- Immunohistochemical studies have shown that able.17 Kaufmann et al therefore proposed that GCIs contain á-synuclein, a synaptic protein plasma arginine vasopressin (AVP) measure- also found in Lewy bodies in Parkinson’s 24 ments in upright tilt are a more sensitive way to disease. It has been suggested that a reduction diVerentiate the two conditions.18 In patients in the solubility of á-synuclein may induce this with MSA upright tilt produced a marked fall protein to form filaments that aggregate into in blood pressure, but plasma AVP increased cytoplasmic inclusions thus contributing to the only slightly and inappropriately for the degree dysfunction or death of glial cells. on September 28, 2021 by guest. Protected copyright. of hypotension. In patients with pure auto- nomic failure, however, a similar degree of Neurochemistry hypotension to that in MSA patients, elicited a Various changes in the dopaminergic, nor- marked rise in circulating AVP. adrenergic, serotoninergic, and cholinergic systems have been described. Changes in the Pathology dopaminergic system include loss of Macroscopically, changes in MSA are generally dopamine; its synthetic enzyme, tyrosine hy- related to the clinical pattern of the disease.19 doxylase; and a cofactor for tyrosine hydroxy- There may be variable cortical atrophy, al- lase, tetrahydrobiopterin. Noradrenaline con- though in most cases this is not marked. Atro- centrations have been reported to be low in the phy of , middle cerebellar pedun- locus coeruleus and hypothalamus. Severe cles, and the pons are most marked in patients (>75%) loss of catecholaminergic neurones in with the OPCA variant of the disease. There the ventrolateral medulla, particularly in the are varying degrees of cell loss and , rostral ventrolateral medulla, which contains without Lewy bodies in the substantia nigra, the Cl adrenergic neurones that provide tonic locus coeruleus, striatum, inferior olives, pon- vasomotor input to the sympathetic pregangli- tine nuclei and cerebellar Purkinje’s cells, and onic neurones, has been reported.21 in the intermediolateral cell columns and Concentrations of homovanillic acid, the Onuf’s nucleus in the ventral horn of the spinal major metabolite for dopamine, 3-methoxy-4- cord at second and third sacral levels.19 Loss of hydroxyphenylglycol, the major metabolite for neurones in the intermediolateral column of noradrenaline and 5-hydroxyindoleacetic acid, the relates to the autonomic distur- the major metabolite of serotonin is low in the bances in MSA.20 Dorsal motor nucleus of cerebrospinal fluid.25

www.postgradmedj.com Multiple system atrophy 381

Investigations Postgrad Med J: first published as 10.1136/pmj.77.908.379 on 1 June 2001. Downloaded from Cardiovascular autonomic function tests can Questions (answers on p 382) demonstrate various aspects of autonomic fail- 1. The following statements are true about ure. The plasma noradrenaline concentrations multiple system atrophy: are normal or slightly raised in MSA patients (A) MSA is a sporadic disease. diVerentiating it from pure autonomic failure (B) Between 4% and 22% of the brains in in which plasma noradrenaline is usually 1ow.17 parkinsonian brain banks have MSA. However, the clinical usefulness of plasma nor- (C) The prevalence of MSA is 8.6 per adrenaline concentrations as a diagnostic tool 100 000 population. in individual cases has not been demonstrated. (D) Mean age of disease onset is 68 years Computed tomography is usually normal in and the median disease duration to death is patients presenting a predominantly a parkin- two years. (E) Both sexes are aVected equally. sonian syndrome. In subjects with a predomi- 2. The following statements are true: nantly cerebellar presentation, cerebellar (A) Autonomic symptoms are present in and/or brainstem atrophy may be seen but this 60% of patients. is non-specific. Striatal computed tomography (B) Autonomic symptoms may precede the images are normal in all forms of MSA. Com- motor disturbance by months or even puted tomography is only of limited usefulness years. in the diagnosis of MSA unlike magnetic reso- (C) Cerebellar signs occur in 80% of the nance imaging which may show altered signal patients. in striatum, particularly in putamen, thus (D) Dysphagia is an early feature of the diVerentiating it from idiopathic Parkinson’s illness. disease. Magnetic resonance imaging may (E) Akinesia and rigidity is usually sym- show putaminal atrophy on T2 weighted metric. images and a hyperintense rim at the lateral 3. Which of the following statements are true? putaminal edge, often accompanied by putami- (A) A poor or absent levodopa response is nal hypointensity.26 the rule in MSA patients. Electrophysiological monitoring of indi- (B) Intellect is impaired early in the course vidual motor units from the striated compo- of MSA. nent of urethral sphincter has shown consistent (C) Deep aching limb pains are not abnormalities in MSA patients, reflecting loss relieved by levodopa in MSA. of anterior horn cells in Onuf’s nucleus in the (D) Instability and falls early in the course sacral cord and is highly specific (0.92) but less of the disease are characteristic of idio- pathic Parkinson’s disease. sensitive (0.62).27 Although occasional patients (E) Patients with MSA and idiopathic Par- with incontinence have normal studies, sub- kinson’s disease on chronic levodopa treat- clinical abnormalities can also be detected. ment are equally likely to have sustained

dystonic spasms of facial muscles, torticol- http://pmj.bmj.com/ Treatment lis, or a relatively fixed and disproportion- Treatment is mainly supportive. Levodopa ate antecollis. preparations may transiently improve the 4. The following are true about the histological 28 symptoms but usually are ineVective. and biochemical features of MSA: Head-up tilt of the bed at night, elastic support (A) The absence of Lewy bodies distin- stockings, fludrocortisone, and desmopressin guishes it from idiopathic Parkinson’s dis- (DDAVP) may help the postural hypotension.29 ease. Octreotide inhibits release of vasodilator pep- (B) A reddish-blue discoloration of the on September 28, 2021 by guest. Protected copyright. tides and may be useful in postural hypoten- atrophic putamen. sion, although it must be given subcutane- (C) GCIs are specific for MSA. ously.25 A number of vasoconstrictors can also (D) Changes in the dopaminergic system be used. These include , a peripher- include loss of dopamine. (E) Noradrenaline concentrations are high ally acting á1-agonist, as well as ephedrine and phenylpropanolamine.25 in the locus coeruleus and hypothalamus. Anticholinergics can help to reduce urinary 5. Which of the following statements about frequency but may precipitate urinary reten- investigations of MSA are true? tion. Retention with overflow may require (A) The plasma noradrenaline concentra- bethanecol chloride, a cholinergic muscarinic tions are normal or slightly raised in MSA. (B) Magnetic resonance imaging is of no agonist,30 intermittent self catheterisation, or use in the diagnosis of MSA. an indwelling catheter. may be (C) Electrophysiological monitoring of helped by a high fibre diet and bulk laxatives or individual motor units from the striated may require suppositories or enemas. component of urethral sphincter have a low Impotence may be treated with intracavern- specificity in the diagnosis of MSA. osal injections of papaverine, prostaglandin E, (D) Computed tomography is only of lim- 31 or implantation of a penile prosthesis. Silde- ited usefulness in the diagnosis of MSA. nafil has not been systematically evaluated in (E) Striatal CT images are normal in all patients with MSA. Tracheostomy or laser cri- forms of MSA. coarytenoidectomy may be considered for stri- dor, but wishes of the patient and ethical con- siderations will influence the decision.31

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Physiotherapy, occupational therapy, and autonomic failure and multiple system atrophy with Postgrad Med J: first published as 10.1136/pmj.77.908.379 on 1 June 2001. Downloaded from autonomic failure. 1992;42:590–3. speech therapy can prove very useful and can 19 Oppenheimer DR. Neuropathology of progressive auto- provide substantial benefit in activities of daily nomic failure. In: Bannister R, ed. Autonomic failure. A text- book of clinical disorders of the . 2nd living. Ed. Oxford: Oxford University Press, 1988: 267–83. 20 Kennedy PG, Duchen LW. A quantitative study of interme- Summary diolateral column cells in motor disease and the Shy-Drager syndrome. J Neurol Neurosurg Psychiatry 1985; MSA is a of the central 48:1103–6. nervous system. It is now recognised that MSA 21 Benarroch EE, Smithson IL, Low PA, et al. Depletion of catecholaminergic of the rostral ventrolateral encompasses a variety of clinical syndromes medulla in multiple system atrophy with autonomic failure. and OPCA, idiopathic orthostatic hypotension, Ann Neurol 1998;43:156–63. 22 Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions the Shy-Drager syndrome, and striatonigral in the CNS of patients with multiple system atrophy (stria- degeneration are merely the expression of neu- tonigral degeneration, olivopontocerebellar atrophy and ronal atrophy in a variety of overlapping Shy-Drager syndrome). J Neurol Sci 1989;94:79–100. 23 Lantos PL, Papp MI. Cellular pathology of multiple system combinations. MSA can cause any combina- atrophy: a review. J Neurol Neurosurg Psychiatry 1994;57: tion of parkinsonian, autonomic, pyramidal, 129–33. 24 Tu PH, Galvin JE, Baba M, et al. Glial cytoplasmic and cerebellar signs. Treatment is mainly sup- inclusions in white matter oligodendrocytes of multiple sys- portive, as no curative therapy is known. Mul- tem atrophy brains contain insoluble alpha-synuclein. Ann Neurol 1998;44:415–22. tiple system atrophy is most commonly con- 25 Mathias CT, Williams AC. The Shy-Drager syndrome (and fused with idiopathic Parkinson’s disease. multiple system atrophy). In: Caine DB, ed. Neurodegenera- tive diseases. Philadelphia: WB Saunders, 1994: 743–67. Knowledge of the distinguishing features of the 26 Olanow CW. Magnetic resonance imaging in . two conditions is important for an accurate Neurol Clin 1992;10:405–20. diagnosis and from a prognostic point of view. 27 Eardley I, Quinn NP, Fowler CT, et al. The value of urethral sphincter electromyography in the diVerential diagnosis of parkinsonism. BrJUrol1989;64:360–2. 1 Dejerine J, Thomas AA. L’atrophie olivo-ponto- 28 Lees AJ. The treatment of multiple system atrophy: striato- cerebelleuse. Nouv Iconog de le Salpetriere 1900;13:330–70. nigral degenerationand olivopontocerebeller degeneration. 2 Shy GM, Drager GA. A neurologic syndrome associated In: Bannister R, ed. Autonomic failure. A textbook of clinical with orthostatic hypotension. Arch Neurol 1960;2:511–27. disorders of the autonomic nervous system. 2nd Ed. Oxford: 3 Adams RD, Van Bogaert L, Van der Eecken H. Striato- Oxford University Press, 1988: 596–604. nigral degeneration. J Neuropathol Exp Neurol 1964;23:584– 29 McLeod JG, Tuck RR. Disorders of the autonomic nervous 608. system: part 2. Investigation and treatment. Ann Neurol 4 Graham JG, Oppenheimer DR. Orthostatic hypotension 1987;21:519–29. and nicotine sensitivity in a case of multiple system atrophy. 30 Fazzini E. Multiple system atrophy associated with progres- J Neurol Neurosurg Psychiatry 1969;32:28–34. sive autonomic failure. The Shy-Drager syndrome: a new 5 Quinn N, Wenning G. Multiple system atrophy. BrJHosp classification scheme. In: Stem MB, Koller WC, eds. Parkin- Med 1994;51:492–4. sonian syndromes. New York: Marcel Dekker, 1993: 69–78. 6 Quinn N. Multiple system atrophy—the nature of the beast. 31 Quinn N. Multiple system atrophy. In: Marsden CD, Faun J Neurol Neurosurg Psychiatry 1989;S suppl:78–89. S, eds. Movement disorders 3. Oxford: Butterworth- 7 Karen J, Kinin MS, Gilman S, et al. Characteristics of the Heinemann, 1994: 262–81. dysarthria of multiple system atrophy. Arch Neurol 1996;53: 545–8. 8 Guindi GM, Michaels L, Bannister R, et al. Pathology of the Answers intrinsic muscles of the larynx. Clin Otolaryngol 1981;6:101– 1. (A) true; (B) true; (C) false: the true prevalence of MSA is 9. 16.4 per 100 000 population; (D) false: the mean age of onset is 9 Wenning GK, Ben Shlomo Y, Magalhaes M, et al. Clinical 53 years (range 36–74) and the median disease duration to features and natural history of multiple system atrophy. An death is five years (range 1–11); (E) true. analysis of 100 cases. Brain 1994;117:835–45.

2. (A) false: autonomic symptoms are present in 97% of cases; http://pmj.bmj.com/ 10 Hughes AJ, Colosimo C, Kleedorfer B, et al. The dopamin- (B) true; (C) false: cerebellar signs occur in about half the ergic response in multiple system atrophy. J Neurol patients; (D) false: dysphagia may become significant in the later Neurosurg Psychiatry 1992;55:1009–13. part of the illness; (E) false: akinesia and rigidity is usually 11 Quinn NP. Unilateral facial in multiple system asymmetric. atrophy. Mov Disord 1992;7(suppl 1):79. 3. (A) true; (B) false: intellect is strikingly preserved, therefore 12 Quinn N. Disproportionate antecollis in multiple system dementia is not a feature of MSA; (C) true; (D) false: instability atrophy. Lancet 1989;i:844. 13 Robbins TW, James M, Lange KW, Cognitive and falls early in the course of the disease should also suggest a et al. cause other than idiopathic Parkinson’s disease; (E) false: these performance in multiple system atrophy. Brain 1992;115: 271–91. features suggest a diagnosis of MSA. 14 Obeso JA, Rodriguez ME, Artieda J, et al. Focal reflex 4. (A) true; (B) false: a grey-greenish discoloration of the atrophic putamen; (C) false: GCIs are not specific, although myoclonus: a useful sign in the diVerential diagnosis of par- on September 28, 2021 by guest. Protected copyright. kinsonism. Ann Neurol 1989;26:164–5. characteristic for MSA; (D) true; (E) false: noradrenaline 15 Caplan LR. Clinical features of sporadic (Dejerine- concentrations have been reported to be low in the locus coeru- Thomas) olivopontocerebellar atrophy. Adv Neurol 1984;41: leus and hypothalamus. 217–24. 5. (A) false: the plasma noradrenaline concentrations are normal 16 Ziegler MG, Lake CR, Kopin IJ. The sympathetic nervous or slightly raised in MSA patients diVerentiating it from pure system defect in primary orthostatic hypotension. N Engl J autonomic failure in which the plasma noradrenaline concentra- Med 1977;296:293–7. tions are usually 1ow; (B) false: magnetic resonance imaging 17 Polinsky RJ. Neurotransmitter and neuropeptide function in may show altered signal in striatum, particularly in putamen, autonoruic failure. In: Bannister R, ed. Autonomic failure. A thus diVerentiating it from idiopathic Parkinson’s disease; (C) textbook of clinical disorders of the autonomic nervous system. false: electrophysiological monitoring of individual motor units 2nd Ed. Oxford: Oxford University Press, 1988: 321–47. from the striated component of urethral sphincter has shown 18 Kaufmann H, Oribe E, Miller M, et al. Hypotension- consistent abnormalities in MSA patients and is highly specific; induced vasopressin release distinguishes between pure (D) true; (E) true.

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