Postgrad Med J (1991) 67, 509 - 531 i) The Fellowship of Postgraduate Medicine, 1991 Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from

Reviews in Medicine Neurology A.N. Gale, J.M. Gibbs, A.H.V. Schapira and P.K. Thomas Department ofNeurological Science, Royal Free Hospital School ofMedicine, RowlandHill Street, London NW3 2PF, UK

Introduction The past few years have seen a significant improve- gitis, Tunkel et al.' point out that the mortality has ment in our ability to diagnose and treat neuro- not changed significantly over the last 30 years but logical diseases. New imaging techniques such as the prognosis for Gram-negative meningitis has computed tomographic (CT) scanning and magne- been markedly improved by the introduction of tic resonance imaging (MRI) have had a major third generation cephalosporins. impact on the practice ofneurology. Whilst techni- In adults and older children the commonest ques such as positron emission tomography (PET) causative organisms are Neisseria meningitidis and are mainly research orientated at present, they may Streptococcus pneumoniae and the treatment of soon find wider clinical application. New electro- choice in the UK is intravenous benzyl penicillin, physiological examinations such as magnetic brain with chloramphenicol as a second line agent. In stimulation have found use in the investigation of children aged 4 months to 6 years the most likely

central motor conduction pathways. The applica- organism is Haemophilus influenzae type b which copyright. tion of the techniques of molecular biology to the may be resistant to ampicillin. Initial treatment in study of neurological disease is having a profound this age group has been chloramphenicol and effect on our understanding of the mechanisms ampicillin until sensitivities are known, but Peltona underlying these diseases. The clinical application et al.2 found that the third generation cephalos- of this knowledge is being seen in genetic counsell- porins cefotaxime and ceftriaxone were as effective ing and the diagnosis of neurodegenerative dis- as ampicillin and possibly better than chloram- orders. phenicol in a randomized comparison ofthese four The past few years have also seen major drugs in the treatment ofbacterial meningitis in 197 advances in the treatment of such diseases as children aged 3 months to 15 years. They found http://pmj.bmj.com/ epilepsy, Parkinson's disease, Guillain-Barre synd- that ceftriaxone sterilized the cerebrospinal fluid rome and migraine. Considerable work is now more rapidly than the others and discuss the being directed to effective treatment of disorders advantages and disadvantages ofeach agent rather such as Alzheimer's disease and multiple sclerosis. than expressing any firm preference. In this review, we have sought to provide an update Schaad et al.3 conducted a randomized, prospec- on selected topics chosen to cover a wide spectrum tive study comparing ceftriaxone (100 mg/kg/day ofneurological practice. They have been written to as a single daily dose) with cefuroxime (240 mg/kg/ on October 1, 2021 by guest. Protected emphasize recent advances in our understanding of day in four divided daily doses) for the treatment of the mechanisms of these diseases as well as in their bacterial meningitis in 106 children aged 6 weeks to management. 16 years. H. influenzae was the commonest infect- ing organism and N. meningitidis the next most frequent. Both drugs were clearly effective but Neurological emergencies results were better with ceftriaxone. Cerebrospinal fluid cultures were still positive at 24 hours in 6 out Thirdgeneration cephalosporins in treatment of of 52 patients treated with cefuroxime compared meningitis with one out of 52 in the ceftriaxone group, and moderate to profound hearing loss was found in 9 In a comprehensive review ofrecent advances in the of the cefuroxime treated patients and 2 of the pathophysiology and treatment ofbacterial menin- ceftriaxone group at 8 and 10 weeks after dis- charge. Moderate to severe sensorineural deafness is thought by some to be due to bacterial invasion of the cochlea. It occurs in about 10% of children Correspondence: A.H.V. Schapira, B.Sc., M.R.C.P. treated with ampicillin or chloramphenicol and is 510 A.N. GALE et al. Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from no less common following cefuroxime. If this the authors conclude that angiography is not complication can be reduced by ceftriaxone its necessary if both CSF and CT brain scan are place in treating this serious infection can be normal. Patients who delay presentation so that recommended. these investigations cannot be done within 2 weeks of the headache may need angiography. Encephalitis Nimodipine in subarachnoid haemorrhage Herpes simplex encephalitis is uncommon, affect- ing 2 to 4 per million of the adult population per The value ofnimodipine in improving the outcome year, but it should be considered in encephalo- in patients with subarachnoid haemorrhage has pathic patients particularly if there is accompany- been confirmed by Pickard et al.7 in a randomized, ing fever, behavioural changes, focal disturbances double blind comparision of nimodipine, 60 mg or seizures. The mortality untreated is around 70% four hourly, orally, for 21 days, against placebo. and survivors are often severely impaired, but in Treatment was commenced within 96 hours of the patients treated early with acyclovir nearly 40% ictus. Cerebral infarction occurred in 61 out of 278 recover with no or little residual deficit. This (22%) patients given nimodipine, compared with subject was reviewed recently by Whitley.4 92 out of 276 (33%) patients given placebo. Poor Laboratory confirmation may be difficult and outcome, including death, vegetative state, or waiting for a demonstrable rise in antibody titres is severe residual disability at 3 months, occurred in oflittle practical help in the acute situation. Rowley 55 patients (20%) treated with minodipine and 91 et al.,5 in a preliminary report, detected herpes (33%) on placebo and the death rate was lower in simplex virus DNA in cerebrospinal fluid (CSF) by the nimodipine treated group (43 compared with using the polymerase chain reaction, in all 4 60). patients with biopsy proven herpes simplex ence- Nimodipine is a calcium-channel blocker which phalitis and in none of their 6 control patients with readily crosses the blood-brain barrier and has a other neurological diseases. This method amplifies vasodilator effect on cerebral vessels, but little

very small amounts of DNA, not otherwise detect- effect on the peripheral vasculature. It was thought copyright. able, and the results are available within 2 to 3 days. that it would reduce vasospasm which is often seen It is likely to be much more reliable than CSF on angiograms following subarachnoid haemorr- culture, which is rarely informative, and is less hage. It is interesting that in this study there was no invasive than brain biopsy, particularly as CSF is apparent reduction in vasospasm, angiographic- required anyway in the emergency investigation of ally, in patients on nimodipine, and the incidence of these patients to exclude other conditions. rebleeding was slightly lower in the nimodipine group. It seems likely that nimodipine provides Subarachnoid haemorrhage andstroke some benefit directly by blocking calcium entry

into neuronal cells. http://pmj.bmj.com/ Thunderclap headache Nimodipine in acute stroke Patients with proven subarachnoid haemorrhage often report recent symptoms suggesting a pre- Gelmers et al.8 reported benefit from nimodipine in vious haemorrhage - the 'warning bleed' - and in acute ischaemic stroke in a prospective controlled most cases either the patient or the doctor has not trial of 186 patients in whom treatment was started appreciated the significance ofthe symptoms at the within 24 hours of onset, but a more recent, larger, time. Conversely, it is not uncommon for patients placebo-controlled, double blind trial of oral on October 1, 2021 by guest. Protected to present with sudden severe headache where nimodipine, 120 mg/day for 21 days, has provided appropriate investigation reveals no evidence of no support for the administration of this agent subarachnoid haemorrhage. Harling et al.6 report- following acute stroke.9 Treatment was allocated ed a small but useful prospective study of 49 randomly and commenced within 48 hours ofonset patients presenting with symptoms suggesting sub- in 1215 patients over the age of 40 who were arachnoid haemorrhage. Thirty-five had haemorr- hemiparetic, conscious and able to swallow, and hage confirmed by CSF examination, CT brain had been functionally independent beforehand. scan or both. Eight of the 14 patients with both There was no difference between the nimodipine normal CSF and CT scan had angiography and this and placebo treated groups in terms ofsurvival and was negative in every case. In all 14 patients degree of independence at 7 days, 21 days and 24 follow-up for 18 to 30 months revealed no subse- weeks in the trial as a whole and no difference quent subarachnoid haemorrhage or serious between the groups in 441 patients commencing disease. Even in retrospect, it was not possible to treatment within 24 hours. identify the patients who had bled on clinical The results ofclinical trials correlate with experi- grounds alone, so investigation is important, but mental studies10 which suggest that nimodipine NEUROLOGY 511 Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from minimizes ischaemic damage if given before or with lobar haemorrhages where hypertension was within minutes of the onset of ischaemia, but once less common. They found that at each site the an infarct has become established little benefit can prognosis was better in non-hypertensive patients be expected. or in hypertensive patients with evidence ofchronic vascular disease than in hypertensive patients with- Surgeryforprimary intracerebral haemorrhage out evidence of chronic vascular disease. The value of surgical treatment for primary intra- Acute spinal cord compression cerebral haemorrhage generally has not been considered helpful, but improvements in imaging Acute spinal cord compression requires urgent techniques, intensive care and surgical methods recognition and appropriate referral if permanent prompted a reassessment ofthis topic by Fujitsu et paraplegia with loss of sphincter control is to be al." They report a retrospective study comparing avoided. In their retrospective review of 76 con- medical treatment and microsurgical evacuation of secutive patients, Maurice-Williams and Richard- hypertensive putaminal haemorrhage in 180 son"3 found that avoidable delays in referral to patients admitted within 3 hours ofthe ictus. All 69 neurosurgical units were common and only 45% of patients with haemorrhages greater than 2 cm in patients reached the referring hospital within 14 largest diameter admitted to the Yokohama City days of their first visit to a doctor, and in 33% it University Hospital were treated surgically. The 20 took longer than 14 days from the first hospital patients with haemorrhages smaller than 2 cm and admission to reach a neurosurgical unit. At first all 91 patients with larger haemorrhages admitted consultation 68% were able to walk unaided but to two affiliated hospitals were treated medically. only 10% were able to do so on arrival at the Patients were graded at 6 hours or immediately neurosurgical centre. preoperatively according to a modified Glasgow The commonest cause of acute spinal cord coma scale into fulminant, rapidly progressive, compression is an extradural metastatic lesion and slowly progressive, or non-progressive groups. Kim et al."4 in a prospective study of 59 patients

Only in the rapidly progressively deteriorating with extradural spinal cord compression due to copyright. patients, under the age of 65, but with no signs of malignant disease, found that of all factors ana- tentorial herniation, was any benefit from surgery lysed, only pretreatment motor function correlated evident. All these patients had large haematomas with functional prognosis after treatment. Similarly, (> 5 cm in diameter). Of the 18 'rapidly progres- Sorensen et al."5 in a retrospective analysis of 345 sive' patients treated conservatively, by 6 months, cases treated by emergency decompression and/or 13 were dead or 'totally disabled' and 5 were radiotherapy, concluded that the main factor partially disabled, i.e. partially self-sufficient. Of determining short term outcome was the degree of the 24 surgically treated patients 7 were dead or disability at the time of treatment.

'totally disabled' 15 were partially disabled, one A particularly treacherous, though fortunately http://pmj.bmj.com/ was minimally disabled, and one was well and rare, cause of spinal cord compression is spinal capable of full employment at 6 months and epidural abscess which has been the subject of two improvement in the surgically treated group was recent reports. Hlavin et al.'6 carried out a retro- apparent in the first 7 days. In the study as a whole, spective analysis of 40 patients with this condition all patients over the age of 65 had died or were treated in their unit between 1980 and 1989. In 16 totally disabled at 6 months. patients, categorized as chronic, symptoms had Bearing in mind the limitations ofa retrospective been present for more than 2 weeks. Thirty out of study, the selection criteria and possible differences 33 patients, in whom an adequate history could be on October 1, 2021 by guest. Protected in care at the different institutions, it is possible that obtained, complained of back pain. Fever, sweats surgery may be of some benefit if undertaken early and rigors were present in three quarters of the enough in some patients under 65 years with large series, 13 had a radicular sensory disturbance, 14 haemorrhages who are deteriorating rapidly but do noted weakness, and 9 had sphincter dysfunction. not have tentorial herniation. This study lends no The rate of neurological progression varied from support to the routine evacuation of primary hours to weeks; 14 patients deteriorated while in intracerebral haematomas. hospital and 9 ofthose were already on appropriate The aetiologies and prognosis of non-traumatic antibiotics. Of the 39 patients treated surgically, 9 intracerebral haematomas are discussed in depth died, 2 remained paralysed despite surgery within by Weisberg et al.'2 who review 358 cases cate- 12 hours ofonset ofparalysis, 10 had some residual gorized according to site of haemorrhage. The neurological deficit and 18 were normal neurologi- commonest sites were putamen (100 patients), cally. The organism responsible was Staphylococ- thalamus (50 patients), pons (40 patients) and cus aureus in 24 out of 37 in whom identification cerebellum (29 patients) and hypertension was the was established and 13 patients were diabetic. major risk factor. They also discuss 98 patients In another report"7 of 29 patients, findings were 512 A.N. GALE et al. Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from similar in that 10 were diabetic, and the infecting Skyhoj-Olsen and Lassen"9 investigated 11 organism was S. aureus in 13, streptococci in 5, and patients using intra-carotid '33Xe injection during Gram-negative aerobes in 5. The outcome was a attacks of classical migraine. They found that little better: 2 died, 6 had mild to moderate rCBF was focally decreased to around 20 ml/100 g/ disability; and the neurological outcome in 21 was min (normal 54 ml/100 g/min), which is probably good. The authors emphasize the importance of low enough to produce an ischaemic effect. They thinking of this condition in a febrile patient with a point out, however, that, although the territory of painful spinal syndrome. hypoperfusion appeared to spread, this effect could be produced by a gradual decrease in flow in a fixed area, because of the scattering effect of nearby brain tissue on the radiation emitted (Compton Migraine effect). These observations, therefore, are compati- ble with, but not specific for, a primary vascular Classical migraine is a recurring syndrome of mechanism. stereotyped attacks, in which an aura of focal Kobari et al.20 utilized a sophisticated method of neurological symptoms, lasting less than one hour, measuring local cerebral bloodflow (LCBF) by is followed by headache, usually unilateral, accom- combining the high resolution of CT brain scann- panied by nausea and/or vomiting, which resolves ing with '33Xe inhalation in migraine sufferers. Six within 72 hours. Common migraine is a similar patients with common migraine and 4 with classical recurring syndrome without the aura. migraine had normal LCBF when free from head- ache. LCBF was increased, however, during the Pathophysiology headache phase in cerebral cortex and subcortical grey matter, most markedly in the thalamus, but The vasogenic hypothesis proposed by Graham also in basal ganglia and white matter of both and Wolff in 1938, that the aura is caused by focal hemispheres, in the 6 patients with common migra- ischaemia due to vasoconstriction and the head- ine and 6 patients with classical migraine. Further- ache is due to dilatation ofextracranial has more, the increase in LCBF was symmetrical and

vessels, copyright. been repeatedly challenged in favour of a primary the findings in patients with common migraine neurogenic mechanism. The migraine aura extends were similar to those with classical migraine. These to contiguous parts of the cerebral cortex and does findings are not consistent with either a spreading not seem to be restricted by arterial boundaries. It oligaemia or spreading cortical depression as the has been estimated to spread across the cortex at a primary cause, but suggest a neurogenic or chemi- rate of 2 to 3 mm/minute, a rate which intriguingly cally mediated cause for the vasomotor changes. approximates to the rate ofprogress ofthe 'spread- The absence of differences between results in ing depression of Leao'. Spreading depression is a common and classical migraine patients supports a

wave of reduced neuronal activity which can be common aetiology, and the authors suggest that http://pmj.bmj.com/ induced by a variety ofinsults to the cerebral cortex the lack of asymmetry between the right and left of experimental lissencephalic animals. hemispheres supports the view originally proposed by Wolff that the headache is likely to be due to Studies ofcerebral bloodflow dilatation of extracranial vessels. Over the last decade, estimations of regional cere- bral blood flow (rCBF) using radioactive xenon Magnetoencephalography ('33Xe) have become more reliable. It is evident that on October 1, 2021 by guest. Protected a migraine attack is associated with reduction in The question of whether the observed changes in cerebral blood flow followed by hyperperfusion. cerebral blood flow are primary or secondary to a The oligaemia does appear to spread across the primary neurogenic mechanism, remains unresolv- cortex at a rate of 2 to 3 mm/minute and is not ed, but the new non-invasive techniques ofmagnet- constrained by the borders of main arterial terri- oencephalography (MEG), for recording magnetic tories. These observations, however, have not signals from the brain, has recently been used to try reestablished the vascular hypothesis, because the to clarify the pathophysiology of migraine. observed oligaemia precedes and outlasts the focal Barkley et al.2 have detected three types ofsignal neurological features and persists well into the from migraine sufferers which they have not found headache phase of classical migraine. Further- in controls. The first type - large amplitude waves - more, Andersen et al."8 using '33Xe inhalation and was detected in 4 out of 9 migraine patients during single photon emission tomography (SPECT) ana- attacks and 5 out of 12 migraine sufferers between lysis in spontaneously occurring classical migraine attacks, but was not found in any of the 12 attacks, have shown that hyperperfusion persists headache-control subjects during non-migrainous for some hours after the headache has subsided. headaches nor in any of the 12 normal control NEUROLOGY 513 Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from subjects. The second feature was the observation of appear promising. It is well tolerated, and no 'long-duration decrements in spontaneous cortical serious adverse reactions have been reported. It activity', in 6 out of 9 migraine sufferers during seems to relieve headache, nausea and vomiting attacks but in none ofthe headache-controls. There and to be effective if taken even at a late stage of a is evidence from animal studies that this pheno- migraine attack which, if confirmed, would be an menon may be due to spreading cortical depres- advantage over alternative therapies. sion. The decrements in spontaneous cortical activity were not seen between attacks except in one Flunarizine case after a failed attempt to induce an attack in a patient prone to exercise-induced migraine. The Flunarizine is a class 4 calcium channel blocker third observation was of long duration, large which appears to be helpful in treating migraine. amplitude field changes in three migraine patients Previous reports (see review by Andersson and and in none of 6 control studies. This is the first Vinge26) have been supported by recent studies in report of MEG studies in migraine attacks and confirming the efficacy offlunarizine in prophylaxis clearly requires independent confirmation, but it and in treating the acute attack. may be the first demonstration ofspreading depres- Ludin27 found that, in a double blind, multicen- sion in migraine. tre study of 71 adult patients, both propranolol (40 mg thrice daily) and flunarizine (10 mg once Advances in treatment daily) were similarly effective in reducing the frequency of migraine attacks in about half of the Sumatriptan patients over a 4 month period, compared with the preceding month, during which placebo was admi- The effectiveness of the 5HT agonist ergotamine in nistered in a single blind manner. the treatment of a migraine attack is well known, Soyka et al.28 reported a response in 23 out of 31 but there are many unwanted side effects of this patients given 20 mg of flunarizine intravenously, drug, such as nausea and vomiting, as well as the compared with 8 out of29 patients given placebo in more serious dangers of peripheral vasoconstric- a double blind trial, and Pfaffenrath et al.,29 also in copyright. tion. Sumatriptan (previously GR 43175) is a a double blind study, observed a response in 19 out highly selective 5HT ID agonist.22'23 which may be of 32 patients within one hour of receiving 20 mg valuable in the treatment of a migraine attack and flunarizine compared with 10 out of 33 receiving may have fewer side effects than ergotamine placebo. Serious adverse effects were not observed because of its greater selectivity. in either of these trials. Perrin et al.24 report that clinical studies with This calcium channel blocker looks promising intravenous sumatriptan in a dose of 64 pg/kg and might prove to be valuable in preventing body weight, given to 31 patients during the cerebral infarction, which is a rare complication of headache phase of an attack of classical migraine a migraine attack. http://pmj.bmj.com/ or common migraine, was effective in 27 cases. In a small double blind study, 14 out of 15 patients responded to sumatriptan within 20 minutes, com- Multiple sclerosis pared with 2 out of 15 responding to placebo. The same authors also report the successful use of a The cause of multiple sclerosis (MS) remains dispersible oral preparation of 70 mg or 140 mg in unknown although intensive research efforts are an open study of 45 patients. By two hours, 14 providing valuable insights into the possible patients were completely free of headache, and mechanism(s) that underlie this disorder. It seems on October 1, 2021 by guest. Protected marked improvement occurred in all but 3 of the most likely that an environmental exposure (e.g. rest. Oral treatment of a migraine attack is often virus) in a genetically susceptible individual leads ineffective because of the failure of intestinal to an abnormality of immune regulation. absorption, particularly in the presence of nausea Evidence for an environmental influence in the or vomiting, but absorption of oral sumatriptan aetiology of MS has come from epidemiological seems adequate and plasma levels of sumatriptan data. A recent study has demonstrated a geo- taken during the attack were similar to those found graphic variation within Australia, with high when the drug was taken outside an attack. southern and low northern prevalence as well as a The same group25 reported results from a multi- genetic resistance amongst aborigines.30 A genetic centre trial of sumatriptan administered subcut- predisposition is suggested by the association of aneously to 111 patients during 125 migraine certain HLA types with MS - linkage with DR2 attacks. Six out of 18 patients had responded to and DQWI in particular. Twin studies have also 1 mg and 21 out of 22 patients had responded to shown a higher concordance rate in identical than 4 mg after 30 minutes. non-identical twins, supporting a genetic influence Preliminary results with sumatriptan, therefore, in the aetiology of MS. 514 A.N. GALE et al. Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from

The basis for the diagnosis of MS remains 500 mg for 5 days or 1 g alternate days for 3 doses. clinical and requires the demonstration of neuro- Preventing the progression of MS has been the logical deficits related to white matter lesions object of a multitude of trials and treatments. separate in time and anatomical distribution. Optic Azathioprine and cyclophosphamide have each neuritis is a common mode of presentation of MS. been used as immunosuppressants in MS.33 3The The development of clinically definite MS is esti- minimal beneficial effect of azathioprine is out- mated to occur in 75% ofpatients who present with weighed by its side effects. The initial report on the optic neuritis.3' This risk increased in patients who use ofcyclophosphamide is encouraging; results of were HLA-DR3 positive and further enhanced in a formal double blind clinical trial are awaited with those who were both HLA-DR3 and DR2 positive. interest. The use of cyclosporin A in MS has also Visual evoked potentials are very useful in been shown to have some benefits, but again these identifying lesions of the optic nerve even in seem to be outweighed by toxicity. Ifcyclosporin A patients who give no previous history of visual is used, benefit does not appear for 15-18 months deficit. Brainstem and somatosensory evoked and so its use is not appropriate for rapidly potentials can also be helpful in identifying lesions. progressive MS.3s Plasmapheresis, total lymphoid Central motor conduction times have been used to irradiation, transfer factor and interferon a are identify defects in motor tracts but rarely add other treatments attempted but which have not significant information to a detailed clinical shown any great promise. examination. Lumbar puncture with CSF exam- Following a report of the benefit of amantidine ination for oligoclonal bands is a useful adjunct to in MS,36 three studies have now shown that aman- evoked potentials in a patient thought to be tadine improves the fatigue associated with MS in suffering from MS. Oligoclonal bands are immuno- just over half the patients treated.37 Amantadine globulins synthesized locally with the CNS to as yet administration was associated with an increase in unidentified antigens. These immunoglobulins are P-endorphin-13-lipotropin, higher levels of which present in CSF but not in serum, and are found in were observed in responders.38 Ataxia in MS may 90% of patients with clinically definite MS, and improve with carbamazepine.39 Pain is common in approximately 40% of patients with isolated optic MS, dysaesthetic pain being the most frequent. neuritis. Oligoclonal bands are not specific for MS Behavioural therapy, anticonvulsants or tricycliccopyright. and are found in other inflammatory or infective antidepressants may be of some benefit. diseases affecting the CNS. The application of magnetic resonance imaging (MRI) to the study of MS has produced significant Epilepsy advances in our understanding of this disease. It must be emphasized that MRI is not a 'diagnostic Epilepsy is one of the most common neurological test' for MS. The results obtained from imaging disorders that present to the medical profession.

must be interpreted in the context of the patient's Incidence rates are 20-70/100,000 per year and http://pmj.bmj.com/ clinical history and examination. The lesions seen point prevalence rates 4-10/1000.4 Five per cent on MRI in MS can be mimicked by several other ofthe population suffer an epileptic seizure at some diseases. Ten per cent ofnormal adults over the age time in their life. of 50 years have multiple small abnormal areas The main classification of epilepsy is localiza- (presumably ischaemic) on MRI. With this in tion-related, i.e. into partial or generalized seizures. mind, 60% of patients with optic neuritis have Partial seizures may be simple (without altered cranial lesions compatible with MS. Fifty-six per consciousness) or complex (with altered conscious- cent ofacute and 82% ofchronic spinal syndromes ness), either of which may evolve to generalized on October 1, 2021 by guest. Protected have abnormal MRIs consistent with MS. Thomp- seizures. Generalized seizures may include absence son et al.32 found no relationship between the attacks, tonic, clonic, or tonic-clonic seizures and extent of lesions as demonstrated by MRI and the myoclonus. Complex partial and secondary gener- patient's disability. MRI scanning is not therefore alized seizures are the most common, accounting useful in predicting clinical disability in individual for more than half of cases. Tonic-clonic gener- patients. alized seizures account for about one third ofcases. The treatment of MS remains a difficult area. No specific cause for epilepsy is found in almost Although the temptation for therapeutic nihilism three quarters of patients. Cerebrovascular acci- should be avoided, therapeutic intervention dents, tumours (primary or secondary) and alcoho- requires carefully balanced judgement. Steroids lism account for most of the identified causes (see remain the most popular and effective means of ref.4). controlling exacerbations of MS. Steroid courses The diagnosis of epilepsy remains clinical and is should be limited to those relapses that are disabl- often very dependent on accurate witness accounts. ing. Intravenous methyl prednisolone has become The patient's description of an aura, especially the most favoured method of delivery either as involving gustatory or olfactory hallucinations, is NEUROLOGY 515 Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from often helpful in establishing the diagnosis of tem- alized tonic-clonic and partial seizures. The use, poral lobe epilepsy. If no witness account of side effects and interactions of the commonly used tonic-clonic movements is available, complaints of anticonvulsants have recently been excellently re- muscle aches, pains and bruises often suggest viewed.42 Vigabatrin has recently been introduced involuntary movements have occurred. Post-ictal as add-on therapy for seizures that have not confusion, drowsiness and headache are also responded to first line drugs. Vigabatrin is a important pointers to the diagnosis. In general, it is structural analogue of gamma-aminobutyric acid always best not to diagnose epilepsy if doubt (GABA), an inhibitory neurotransmitter inacti- remains, and to simply await the evolution of vated by GABA transaminase. Vigabatrin is an events. The role of the EEG after the first seizure is irreversible inhibitor of this enzyme and so in- still debated. Most feel this investigation will at creases GABA concentrations in the brain. Two to least provide a valuable 'baseline' ifnot support the three grams ofvigabatrin daily have been shown to diagnosis, whereas others would await further improve seizure control in about half of patients. seizures before performing an EEG. A single The drug is well tolerated but can be associated routine EEG is estimated to show epileptiform with drowsiness, fatigue and, rarely, confusion. abnormalites in about half of patients with Psychotic reactions may occur in patients with epilepsy. pre-existing psychiatric disorders. The drug is Similar debate centres on the use of CT brain excreted unchanged and plasma levels are no guide scans in patients presenting with epilepsy. Some to efficacy. neurologists perform CT scans on all newly diag- Surgery is likely to play an increasingly impor- nosed epileptics over the age of 20 years. Others tant role in the treatment of intractable epilepsy.43 consider CT scans are only indicated if the history The selection of patients suitable for surgery is suggests focal epilepsy, if there are abnormal crucial and depends upon clinical data suggesting physical signs or if there is a focal abnormality on partial attacks, neuropsychological assessment and EEG. A further case for scanning can be made for demonstration of an abnormality by CT, MRI or those patients unresponsive to anticonvulsants. positron emission tomography and neurophy- Abnormal CT scans are found in 20% of patients siology. The temporal lobe is resected most fre- copyright. with first seizures - most of the abnormalities are quently in those found suitable for surgery. The atrophic.4' mortality (0.5%) and substantial morbidity (5%) Data on recurrence of seizures after a single rates are low in experienced centres. More than half episode are variable and are influenced by several of patients operated on can be expected to have factors including the population base, diagnostic their seizures relieved completely. criteria, timing of entry into trial and study base. Most studies have shown a recurrence rate of 70-80% after the first seizure, most within weeks Muscle disease or months of the first. However, many patients http://pmj.bmj.com/ (-40%) will have prolonged remission from recur- Muscular dystrophies rent seizures. There is some suggestion that early treatment X-linked Duchenne muscular dystrophy (DMD) with anticonvulsants can improve the prognosis has been the focus of much attention since the and increase remission rates. At present, it is complete cloning of the DMD complementary standard practice to begin treatment only when the DNA (cDNA).4 The cDNA is 14 kb long and

diagnosis is certain and the patient has had two or encodes a 3685 amino acid protein Mr 400 kDa on October 1, 2021 by guest. Protected more seizures. However, in view of the high risk of called dystrophin. Dystrophin has been localized to a second seizure within the first 3 months or so of the sarcolemmal region of muscle fibres by the first, some neurologists are now prescribing immunocytology. This localization ofthe defective anticonvulsants for a period of 6 months after the gene product is consistent with the 'membrane first documented seizure. This strategy is clearly theory' of the disease. It has been suggested that intended to reduce recurrence rate. Continuation dystrophin is a binding molecule that anchors the of treatment is then dependent on whether the cytoskeleton to the plasma membrane. Abnormal patient relapses. function of such a binding protein would predis- Once the decision to begin treatment has been pose muscle fibres to disintegration and necrosis. made, the choice of which anticonvulsant is to be The sites of deletion within the DMD gene can used must be made. Absence attacks in childhood vary although most tend to occur within two and adolescence are best treated with ethosuxi- regions of the gene. However, patients with iden- mide, which may be supplemented with sodium tical deletions but markedly different clinical valproate if necessary. Absence attacks in adult- phenotypes have been described.45 Becker mus- hood are best treated with sodium valproate. cular dystrophy (BMD) is a milder form of DMD Carbamazepine or phenytoin are useful in gener- but is determined by the same gene. It is possible 516 A.N. GALE et al. Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from that the difference in clinical severity between Parkinson's disease DMD and BMD depends on whether the gene deletion disrupts (DMD) or maintains (BMD) the The last two years have seen important advances in open reading frame for protein translation. clinical, pathological, therapeutic and aetiological Whatever the position of the deletion within the aspects of Parkinson's disease (PD). DMD gene, it is clear that all DMD patients have greatly reduced amounts of dystrophin in their Clinical muscle. Immunocytochemical staining with dys- trophin antibodies, the analysis of dystrophin by PD is characterized clinically by bradykinesia, protein separation and immunoblotting and the rigidity and tremor. Onset is asymmetrical but use of genomic DNA probes which recognize usually becomes symmetrical as the disease pro- restriction fragment length polymorphisms within gresses. Dementia is now recognized to be more the DMD gene have all proved invaluable in the common in PD patients and its appearance is correlated to the severity of PD symptoms and diagnosis of DMD patients and carriers. 48 Two new approaches to the treatment of DMD signs. have resulted from the recent advances in our There are geographic variations in the preva- understanding of the molecular mechansism lence ofPD: 59 per 100,000 in Nigeria compared to underlying this disease. The first is based on the 341 and 352 per 100,000 in American blacks and observation that injected myoblasts are capable of whites respectively. This geographical variation fusing with host myoblasts with expression of the together with other epidemiological data suggest- donor genes in the resulting hybrid multinucleated ing clustering ofPD around wood mills and among cell. A study using myoblast transplants in the well-water drinkers supports the proposition that mouse muscular dystrophy model resulted in ex- environmental factors play some part in the pression of dystrophin in up to 40% of muscle development of PD. The recent description of a fibres examined. The second approach involves the kindred with autosomal dominant PD49 together introduction of the intact or modified dystrophin with the reappraisal ofthe twin data on PD, suggest that there may be a significant hereditary element gene into affecting cells. This latter approach is at copyright. present only theoretical. to the development of this disease. Pathology Mitochondrial myopathies The presence of Lewy bodies in surviving nigral The mitochondrial myopathies are a heterogen- neurones is regarded as the morphological hall- eous group of disorders most frequently due to mark of PD. The Lewy body is an intracytoplas- defects of the mitochondrial respiratory (electron mic, eosinophilic round inclusion, 5-25 jAm in transport) chain. Patients may present at any age diameter and is composed of aggregated filament from the neonatal period to late adulthood. with a high ubiquitin content. The relevance of the http://pmj.bmj.com/ Involvement may be confined to the ocular muscles Lewy body to the pathogenesis of idiopathic PD with ophthalmoplegia and ptosis, or widespread has been discussed in an excellent review by Gibb with an encephalomyopathy often dominated by and Lees.' The Lewy body is not specific to PD and features of CNS disease such as dementia, ataxia, is found in elderly individuals with no evidence of seizures, stroke-like episodes, deafness and retinal PD during lifetime, and also in neurodegenerative pigmentation. The proteins that comprise the res- diseases such as olivopontocerebellar atrophy as piratory chain are the products of both the nuclear well as in anterior horn cells ofpatients with motor and mitochondrial genomes. Mitochondrial DNA neurone disease. on October 1, 2021 by guest. Protected is maternally inherited and so any disease resulting The discovery of nigral Lewy bodies in approx- from a defect ofa mitochondrially encoded protein imately 10% of elderly control brains lead to the should be passed from the mother to all offspring suggestion that these patients had pre-clinical PD, but with subsequent transmission through the dying before the development ofclinical features. A female line alone. Such maternal inheritance has pre-clinical period seems likely as PD is probably been observed in certain families with mitochon- the end result of a long period of neuronal fallout drial myopathy; however, most cases appear and dopamine depletion. However, the proposition sporadic. Deficiencies of specific nuclear encoded that this Lewy body positive group does indeed respiratory chain polypeptide have been observed represent pre-cinical PD awaits further biochem- in some patients, whilst deletions ofmitochondrial ical and pharmacological confirmation. DNA have been observed in about one third of cases. Point mutations of mitochondrial DNA Therapy have been associated with the myoclonic epilepsy with ragged red fibres (MERRF) syndrome' and L-Dopa together with a dopa decarboxylase inhib- with Leber's hereditary optic neuropathy.47 itor remain the mainstay of the symptomatic NEUROLOGY 517 Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from treatment ofPD. Recent advances have been made death through its specific inhibition of NADH in the method of delivery of L-dopa with the CoQ reductase (complex I) the first protein of the introduction of slow release preparations. These mitochondrial respiratory chain. The discovery of still have to be given 4 times a day and often have to complex I inhibition in the substantia nigra of be supplemented with short acting standard L-dopa patients with PD provided a remarkable link preparations at the beginning of the day. Never- between the idiopathic disease and the animal theless, the slow release tablets can lead to better model. This biochemical defect is confined to the control of motor fluctuations in PD, reducing 'off' substantia nigra in PD and is not present in periods in particular. multiple system atrophy, another degenerative The use ofcontinuous subcutaneous infusions of disease affecting the substantia nigra. the dopamine agonist apomorphine has lead to a The re-evaluation ofa possible genetic contribu- substantial improvement of fluctuations in some tion to PD and the mitochondrial link to the MPTP patients. The infusion requires an insulin type model suggests that idiopathic PD may be the pump and the injection site has to be changed result of an interplay between hereditable and regularly so many PD patients find this system environmental factors. difficult to cope with. One alternative is the 'Pen- ject' system of apomorphine delivery used during 'off' periods to supplement standard L-dopa treat- The chronic fatigue syndrome: neurological aspects ment. Such use of apomorphine requires the administration of domperidone to prevent nausea Despite the recent interest in the chronic fatigue and vomiting. Recent attention has also been syndrome which has attracted considerable atten- focused on the use oflow dose L-dopa in combina- tion both in medical circles and elsewhere - tion with direct dopamine agonists such as lysuride including practitioners of 'alternative medicine', or bromocriptine. There is increasing evidence that the lay press and self-help associations - this is by such combinations may decrease the incidence of no means a new complaint. Nevertheless, substan- dyskinesias and response fluctuations associated tial problems still exist as to its nature and with long term L-dopa monotherapy.5' The use of nosological status. The renewed interest that has copyright. adrenal autografts and human fetal nigral grafts in developed over the past three decades or so stems the treatment of PD are still under evaluation. The from the outbreak of a paralytic disorder at the original success with implanting adrenal gland Royal Free Hospital in 195554 although similar tissue into the head of the caudate has not been outbreaks had occurred before. Subsequently the replicated at other centres. The risks of this oper- emphasis shifted more to sporadic cases in which ation in terms ofmortality and morbidity are high the symptomatology has been dominated by sub- and the benefits limited or non-existent. Fetal jective fatigue. The symptom complex seen in most nigral grafts are injected stereotactically and so the current patients bears considerably greater resem- risk of this procedure is much lower. blances to 'neurasthenia' or 'nervous exhaustion' http://pmj.bmj.com/ One of the most exciting advances in the treat- as recognized in the latter part of the last century" ment of PD came with the results of two studies than to that of the Royal Free epidemic. It is which showed that 10 mg/day of the mono-amine important to appreciate the heterogeneity of the oxidase-B inhibitor selegiline was able to delay the syndrome. requirement for L-dopa in newly diagnosed PD patients by approximately one year.52'53 This result Clinical manifestations and terminology suggests a protective effect against nigral neuronal degeneration and thus represents the first attempt 1. Acute epidemics on October 1, 2021 by guest. Protected at disease modification in the treatment ofPD. It is now common practice to begin all newly diagnosed In the outbreak of'encephalomyelitis' at the Royal PD patients on this drug. Free Hospital in 195554 the patients were described as usually beginning with constitutional symptoms, Aetiology including malaise, headache, and pains in the neck, back and limbs. Enlargement of posterior cervical The discovery that the neurotoxin MPTP is cap- lymph glands was noted in some individuals. These able of inducing Parkinsonism in man and other symptoms were succeeded by widespread muscle primates was a major advance in our understan- weakness without wasting or reflex depression, ding of the possible mechanisms underlying idio- accompanied by tremulous or jerky voluntary pathic PD. Recent work has shown that the muscle contraction and prolonged painful muscle specificity of MPTP for the dopaminergic neurones spasms. Paraesthesiae and sensory loss were re- of the substantia nigra is the result of selective ported but were less consistent than the motor uptake and conversion pathways. MPP+, the features. These symptoms were accompanied by active metabolite of MPTP, induces nigral cell considerable emotionality, including prolonged 518 A.N. GALE et al. Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from periods of uncontrollable weeping. nent. The second component comprises emotional Recovery from the acute illness was protracted changes. Mild depression, accompanied by anx- and relapses often occurred. It was dominated by iety, hypochondriasis and 'intense introspection' extreme fatiguability, often produced by relatively are listed as the most consistent psychiatric fea- minor exertion, such as being subjected to neuro- tures,63 but disturbances in sleep patterns and logical examination. Affected individuals contin- appetite also occur. The third component com- ued to complain of muscle aches and pains, often prises a wide variety ofsomatic symptoms, referred aggravated or precipitated by exertion, and the particularly to the cardiovascular and gastrointes- jerky pattern of muscle contraction tended to tinal systems. Mild anomia is also often reported. persist. It is generally agreed that physical signs indica- The majority of those affected were female, tive ofneurological disorder are absent and that, if predominantly nursing staff. Haematological and present, their explanation should be sought in other biochemical screening tests were negative and the directions. In recent years, cases seen by the author cerebrospinal fluid was consistently normal. Elec- (PKT) in which a presumptive diagnosis of the tromyography was believed to show characteristic chronic fatigue syndrome had been made have changes which will be considered later. It was included instances of hypothyroidism, myasthenia proposed that the disorder represented an en- gravis, the Lambert-Eaton myasthenic syndrome cephalomyelitis, although no viral agent was and multiple sclerosis. Metabolic myopathies may detected. The term 'benign myalgic encephalomye- also give rise to confusion. Particular attention litis' was introduced to designate the syndrome, towards seeking such disorders should be given if later abbreviated to 'myalgic encephalomyelitis' or the psychiatric components described above are 'ME'. lacking. Other acute outbreaks have occurred, both The variability of symptomatology between antedating and following the Royal Free epidemic. patients labelled as having the chronic fatigue The clinical picture was similar and muscle weak- syndrome poses considerable problems for case ness was again the predominant symptom. In some, definition, although progress towards a consensus the manifestations were considered to resemble agreement is being made.',67 Part of the problem copyright. poliomyelitis, as in Icelandic or 'Akureyri dis- stems from difficulty in interpreting the descrip- ease',56-58 whereas others were designated epidemic tions given by the patients to describe their symp- neuromyasthenia.59 61 toms. Fatigue may be reported as 'weakness' or 'tiredness' and, as pointed out elsewhere,68 the distinction between unpleasant fatigue and pain is not easy. In the study reported by Wessely and 2. Sporadic cases Powell69 on patients with fatigue from a variety of causes, it did not prove possible to distinguish As already stated, the majority ofpatients now seen between the various synonyms used by patients to http://pmj.bmj.com/ are sporadic and arise in the community. Although describe fatigue. the term myalgic encephalomyelitis is often used for such cases, the label 'chronic fatigue syndrome' is more satisfactory. This emphasizes the dominant Neurophysiological investigations symptom and makes no unsubstantiated aetiological attributions. The same criticism app- 1. The epidemic disorder lies to the designation 'postviral fatigue syndrome'. The sense of fatigue is assumed to be muscular. Electromyographic studies on patients during the on October 1, 2021 by guest. Protected Ramsay,62 one of those most closely involved with Royal Free outbreak identified a pattern of the original Royal Free outbreak, has stated that abnormality characterized by 'grouped motor unit 'This phenomenon of muscle fatiguability is the activity' during voluntary contraction. This equa- dominant and most persistent feature ofthe disease ted with the jerky muscle contraction observed and in my opinion a diagnosis should not be made clinically and which was subsequently recognized without it'. Behan and Behan"3 have stated that the to be typical of simulated weakness with poorly chief organ affected is skeletal muscle. The 'mus- sustained intermittent muscle contraction.70 Per- cular fatigue' is frequently accompanied by myal- sonal (PKT) electromyographic observations on gia that tends to develop with a latent interval after cases from the original epidemic have shown low physical activity. The symptom complex usually and intermittent motor unit firing rates on maximal also includes exhaustion on mental effort.6'65 The volition and simultaneous activation of agonist sense of fatigue is therefore not purely muscular. and antagonist muscles,7" again typical of simu- Tbe chronic fatigue syndrome can be considered lated weakness. The findings are similar to those as comprising a triad of manifestations, fatigue, obtained in patients with 'pseudomyasthenia'72 or :nuscular and mental, constituting the first compo- the 'asthenic syndrome'.73 NEUROLOGY 519 Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from

2. Sporadic cases patient with persistent fatigue and myalgia after chicken pox was reported by Arnold et al.8" to More extensive investigations have been under- develop early and abnormally severe intracellular taken into the pathophysiology ofthe complaint of acidosis as measured by 31P nuclear magnetic muscle fatigue in sporadic examples of the chronic resonance spectroscopy during exercise. It was fatigue syndrome. Muscle fatigue can be defined as suggested that the patient's sense of fatigue could a failure to maintain a required force or output of have been the result of lactic acid accumulation power during sustained or repeated muscle con- from excessive glycolytic activity. The muscle traction. Fatigue is subdivisible into peripheral and biopsy showed type II fibre preponderance which central types.'75 Peripheral fatigue results from could have contributed to the result, which cannot disturbances at or distal to the neuromuscular be accepted without careful controls for the effects junction. Central fatigue implies a failure of neural ofdisuse.82 Furthermore, this finding is not present drive reflected in an inability to maintain motor in all patients with the chronic fatigue syndrome unit firing frequency. This could result from a and also has been observed in schizophrenia.83'84 defect in motor axons or from a decrement in the The conclusion to be derived from the physio- activation of anterior horn cells from supraspinal logical studies on muscle performance in patients levels, including reduced motivation. A helpful with the chronic fatigue syndrome is therefore that subdivision can also be made into subjective and there is no good evidence of muscle dysfunction. objective fatigue. Objective fatigue is a physio- The findings indicate that the fatigue is central in logically demonstrable failure in the maintenance type. of muscle force, seen after intense anaerobic exer- cise or prolonged aerobic exercise. With lesser What is the chronicfatigue syndrome? degrees offorce output, it is observable in a variety ofneurological disorders including some metabolic All the evidence indicates that this is not a unitary myopathies, myasthenia and multiple sclerosis.76 disorder. There can be little doubt that the acute Subjective fatigue involves a reduction in voluntary epidemics, such as the one that occurred at the effort secondary to the occurrence of uncomfor- Royal Free Hospital, represent mass illness behav- copyright. table sensations following exercise. iour.7085 Within these outbreaks, however, identi- Isometric muscle force production in quadriceps fiable neurological disorders may be concealed, was measured in patients with the chronic fatigue including postinfectious encephalomyelitis.7' syndrome by Stokes et al.75 All the males generated In a series of 47 patients with sporadic chronic and maintained normal force levels. About halfthe fatigue syndrome seen at a specialist neurological females failed to do so but when electrical stimula- hospital, Wessely and Powell69 found that 72% had tion of the muscle was interpolated, this yielded evidence of a psychiatric disorder using diagnostic normal force. This finding indicated submaximal criteria modified to exclude fatigue. No less than effort. Stokes et al. also studied muscle fatiguability 47% showed major depression and in 15% there http://pmj.bmj.com/ in adductor pollicis from repetitive contraction was somatization disorder. In only 1 of the 47 produced by electrical stimulation of the ulnar patients was conversion disorder present. There is a nerve. No abnormality was detected in the patients. considerable overlap in the symptomatology of Lloyd et al.77 studied endurance as assessed from depression and the chronic fatigue syndrome. measurements of repeated maximal isometric con- Complaints of 'decreased energy' and fatigue are tractions of the elbow flexors. Patients with the almost universal in depressed patients, as are postinfectious fatigue syndrome showed little ab- nonspecific symptoms of somatic dysfunction. normality as compared with healthy controls. Fatigue occurs in the majority of patients with on October 1, 2021 by guest. Protected Jamal and Hansen reported increased jitter on somatization disorder.86 In addition, post-exercise single fibre electromyographic recordings in about myalgia is a frequent complaint in depressed 75% of a series of 40 patients with the chronic patients.69 It is also experienced by individuals who fatigue syndrome. This result is difficult to interpret are physically unfit and who overexert themselves. as it has not been replicated by others79 (N.M.F. It is then related to eccentric muscle contraction Murray, personal communication). (when a muscle lengthens during work), this being potentially damaging to muscle fibres.87'88 Other investigations In the series of patients with the chronic fatigue syndrome studied by Wessely and Powell,69 no Muscle biopsies have revealed only minor and psychiatric disorder was identifiable in 28%. The inconsistent structural abnormalities63 and exten- explanation of the complaint of fatigue in these sive biochemical studies by Byrne and Trounce80 patients is uncertain, but it must be recognized that have shown no evidence of an abnormality in depression may manifest itself with a complaint of mitochondrial or glycolytic enzymes. Serum crea- fatigue before other features appear. tine kinase activity is consistently normal. A This brief review of the neurological aspects has 520 A.N. GALE et al. Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from

not addressed the possible role ofviral infection as A problem that immediately arises is the wide a trigger mechanism, or persistent viral infection as range of manifestations that are encountered in a cause of the chronic fatigue syndrome. Substan- diabetic neuropathy. The commonest clinical syn- tial epidemiological problems exist in relation to drome is a chronic distal symmetric sensory poly- the studies that have been undertaken, which have neuropathy, often with accompanying autonomic been reviewed recently by Wessely and Thomas." disturbances ofvarying severity.9' An acute painful neuropathy may also occur.92 Apart from such Conclusions symmetric polyneuropathies, patients with diabe- tes may develop focal and multifocal neuropathies, The available evidence indicates that the chronic including cranial, trunk and limb mononeuro- fatigue syndrome is heterogeneous. There can be pathies.93 Diabetic subjects are also more suscepti- little doubt that for the sporadic cases that are now ble to compression and entrapment neuropathies. encountered, the major explanation is depression. Finally, lower limb motor neuropathies occur Such patients are often characterized by a violent (diabetic amyotrophy), often, but not always, refusal to accept a psychiatric explanation. The mainly proximal in distribution, sometimes with sociological reasons for this have been discussed by asymmetric and at others with relatively symmetric Wessely and Thomas.68 In doing so, patients often involvement.94 Mixed syndromes are not infre- do themselves a disservice as they may deny quent. themselves appropriate treatment. It is also essen- tial for the physician to be aware of this aspect so Metabolic hypotheses that psychiatric disorder does not go unrecognized. The chronic fatigue syndrome is not a manifesta- The salient metabolic abnormality in diabetic nerve tion ofencephalomyelitis. The carry-over from the is the accumulation ofsorbitol. This is the result of supposed cause of the Royal Free epidemic is increased flux through the polyol pathway in which unfortunate and is encapsulated in the use of the glucose is converted to sorbitol by an aldose label 'ME' which is favoured both by the lay press reductase and sorbitol to fructose by a polyol and by patients. Yet despite the failure to demon- dehydrogenase. A as to proposal the way in whichcopyright. strate any inflammatory disorder affecting the this might lead to neuropathy was developed central nervous system, reports still attribute com- largely from observations on experimental diabetes plaints such as mental fatiguability and anomia to in rats. The accumulation of sorbitol was linked encephalitic manifestations.M,65 to a depressed intraneural concentration of the It is evident that fatigue in this syndrome is ofthe cyclic hexitol, myo-inositol and this, via reduced subjective type. Little is known about the underly- synthesis of phosphoinositides, to diminished in- ing neural mechanisms. The identification of the traneural sodium-potassium adenosine triphos- relevant pathways and the neurotransmitters that phathse (Na+K+-ATPase) activity.95 The reduced are involved could in the future to lead improved Na+K+-ATPase activity was believed to have a http://pmj.bmj.com/ treatment for this troublesome and highly un- variety of effects, such as the impairment of nerve pleasant symptom. conduction velocity, altered axonal transport and defective amino acid uptake into sensory and autonomic ganglion cells, that ultimately resulted Diabetic neuropathy: a metabolic, vascular or in neuropathy. It proved possible to prevent the degenerative disorder? reduction in nerve conduction velocity either by the administration of aldose reductase inhibitors that Satisfactory therapy for diabetic neuropathy will reduced the accumulation of sorbitol, or by giving on October 1, 2021 by guest. Protected depend upon establishing its cause. It is possible to dietary myo-inositol supplementation. This was so, prevent the deterioration ofneuropathy once it has despite persisting hyperglycaemia. Both these mea- appeared either by continuous subcutaneous insu- sures restored nerve Na+K+-ATPase activity. lin infusion89 or by pancreatic transplantation' but This appeared to be an attractive formulation neither ofthese forms oftreatment is applicable for but a number of lines of evidence now make it the majority of patients. Accepting that adequate unlikely that the hypothesis accounts for diabetic control is not achieved in a high proportion of neuropathy. Further animal studies have revealed patients by conventional therapy, knowledge as to a poor correlation between nerve myo-inositol the particular consequences of the diabetic state concentrations and Na+K+-ATPase activity. Firs- that result in neuropathy could lead to the adop- tly, as distinct from nerve trunks, in sensory ganglia tion of measures that specifically protect the Na+K+-ATPase activity is not correlated with peripheral nerves even in the face of glycaemic myo-inositol concentrations in streptozotocin-in- control that is less than ideal. The causation of duced diabetes in rats.9' Moreover, in galactose- peripheral nerve damage is therefore currently the induced neuropathy in rats where flux in the polyol central question relating to diabetic neuropathy. pathway is also increased, leading to accumulation NEUROLOGY 521 Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from

of galactitol instead of sorbitol in nerve, nerve be a secondary event, perhaps related to capillary myo-inositol concentrations are reduced but Na+- wall hyperplasia. The persistence of the basal K+-ATPase activity is increased.97'98 The most laminal material in diabetes could be the conse- cogent piece of evidence is that in nerve biopsies quence ofabnormal collagen cross-linkage produc- from human patients with diabetic neuropathy, ed by non-enzymatic glycation."2 although sorbitol concentrations are increased, The pattern of nerve fibre loss in nerve biopsies those for myo-inositol are not reduced.9 from patients with diabetic neuropathy has been Nevertheless, sorbitol accumulation is still a found to be patchy, which was taken to support an contender for the causation of nerve damage. The ischaemic basis."3 Yet a similar patchy pattern of severity ofnerve fibre loss is directly correlated with nerve fibre loss is seen in hereditary motor and the amount of sorbitol accumulation.' Moreover, sensory neuropathy, a disorder in which a vascular there is some evidence that aldose reductase inhibi- causation has not been entertained."4 The explana- tion leads to increased regenerative sprouting in tion for this is still uncertain. Sugimura and patients with diabetic neuropathy when assessed in Dyck,"5 Dyck et al. 116 and Johnson et al."7 have serial nerve biopsies."° But if sorbitol accumula- found multifocal fibre loss in lower limb nerves in tion is the culprit, its mechanism of action has still autopsied cases that suggested ischaemia. On the to be elucidated in man. other hand, these patients were elderly and concur- rent vascular disease would not have been un- Vascular hypothesis expected. Direct measurements of intraneural oxygen ten- Early views as to the causation of diabetic neuro- sion in patients with diabetic neuropathy have pathy implicated large vessel disease'0 1"02 but this is revealed reduced values in comparison with control no longer entertained. Fagerberg'03 noted the subjects."8 This conclusion cannot yet be accepted occurrence of thickening of the walls of the small without reservation as the age of the control neural vessels by PAS-positive material, later subjects was significantly less than that of the shown to be reduplicated basal lamina. The view diabetic patients. It is important that this study be

was therefore advanced that diabetic neuropathy is repeated with age-matched controls. copyright. related to microangiopathy. This view, which had Thus, although an impressive body of evidence fallen into disfavour because of a poor correlation favouring a vascular cause for diabetic neuropathy between neuropathy and the vascular changes,104,105 has been assembled, none of it is yet conclusive. has recently been strongly revived by a number of laboratories. It seems probable that many of the Diabeticpolyneuropathy as a degenerative focal nerve lesions that occur in diabetic subjects neurological disorder are related to ischaemia, but the pathological verification for this is still limited and rests mainly Degenerative disorders constitute a major compo- on postmortem observations on patients with acute nent of the spectrum of neurological disease. In http://pmj.bmj.com/ third cranial nerve lesions."'0 What is now suggest- these conditions there is a progressive disturbance ed is that the totality of diabetic neuropathy may related to loss of neurones, as in motor neurone have a vascular basis. disease, to a 'dying-back' distal axonopathy, as in Observations on streptozotocin-induced dia- Friedreich's ataxia, or to demyelination. Such betic rats have documented reduced neural blood disorders are often characterized by the fact that flow and reduced intraneural oxygen tension.'07 particular sets ofneurones are affected and they are The reduction in nerve conduction velocity can thus referred to as system atrophies. They

clearly on October 1, 2021 by guest. Protected partially be prevented by maintaining the animals represent an aetiologically heterogeneous group, in hyperbaric oxygen.'08 Yet the relevance ofobser- but the common theme is a failure to maintain vations in the diabetic rat model to human neuro- cellular integrity or a failure of the processes pathy is still uncertain. Rats do not develop the involved in the maintenance of cell structure, as in degenerative changes in nerve seen in man. the distal axonopathies. In earlier times, the occur- It was reported that the numbers of 'closed' rence of these events led to the use of the term capillaries in nerve biopsies was greater in patients 'abiotrophy'. with diabetic neuropathy than in controls and that For diabetic polyneuropathy it is perhaps their number was correlated with the severity of surprising that the precise pattern of pathological neuropathy."'0 This observation has not been con- change is still not fully established. But there are firmed by others."0°"" The causal role of the many features that suggest a system degeneration. thickening of the walls of endoneurial capillaries There is a predominant involvement ofsensory and has been questioned. Vessel wall thickening may be autonomic neurones with relative sparing ofmotor observed in other neuropathies such as in heredi- function. It is possible that the pathology will prove tary motor and sensory neuropathy'l' and the to be a central-peripheral distal axonopathy."9 A reduplication of the basal lamina could therefore distally-accentuated degeneration of axons in the 522 A.N. GALE et al. Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from peripheral nerves has been shown.'20"2' Although Neuroimaging degeneration is known to occur in the posterior columns of the spinal cord,'04'05 it is not yet known Introduction whether this shows a rostral accentuation. The elucidation of the pattern of change that occurs is In the field of clinical neuroimaging, the develop- vital to the understanding of diabetic neuropathy. ment of magnetic resonance (MR) scanning un- In neurones, virtually all protein synthesis occurs doubtedly represents the greatest technical advance in the cell bodies. Structural proteins, enzymes, of recent years. Computerized X-ray tomographic etc., are then translocated down the axons to the scanning (CT) has changed very little in technical periphery in the antegrade transport systems. terms but its wider availability in district general There is no major disturbance of fast axonal hospitals has altered and in most respects improved transport, at least in experimental diabetes. Slow the diagnostic process for patients with neuro- component a, in which the structural proteins are logical and neurosurgical disorders. Vascular transported, is mildly impaired in streptozotocin- imaging has advanced and diversified with the diabetic rats'22 but, as already stated, this is not development of digital subtraction technology and accompanied by a degenerative neuropathy. In this more widespread application of ultrasonography, model, retrograde transport is also affected.'23 although the precise clinical role of these techni- Whether a more profound disturbance in slow ques remains rather poorly defined. Sophisticated axonal transport occurs in human diabetic neuro- functional imaging and measurement by means of pathy is unknown, but it seems unlikely as axonal emission tomography continues to make a major atrophy is not observed. contribution in the research field, with relatively Insulin, apart from its action on glucose homeo- little in the way ofpractical application in everyday stasis, has important effects on protein metabolism. clinical neurology. These various techniques will be These could conceivably be involved in the degen- reviewed and discussed in more detail. erative changes that occur in diabetic neuropathy. The uptake ofamino acids into dorsal root ganglia Magnetic resonance scanning is known to be reduced in streptozotocin-diabetic rats'24 and is accompanied by reduced protein As an imaging technique in brain and spinal cord,copyright. synthesis. Peripheral nerve, like the central nervous MR is superior to CT in almost every respect, both system, is not dependent on insulin for acute for showing normal anatomical structure and metabolic exchanges. Nevertheless, peripheral pathological tissue. For many cerebral lesions, nerve, including the sensory ganglia, possesses however, MR will simply show the same abnor- insulin receptors,'25"26 as does the central nervous mality rather more clearly than CT, and there are system. Their function is obscure, but they could be relatively few common clinical disorders for which involved in longer term neurotrophic effects in the indication for MR scanning can be regarded as nervous tissue. If this is so, a disturbance of their absolute. Nevertheless, the development of less http://pmj.bmj.com/ function could underlie the degenerative neuronal expensive and cumbersome magnetic scanners and changes that characterize diabetic neuropathy. the increasing requirement for cost effective investi- These, so far, are speculative concepts, but they gation, preferably avoiding invasive inpatient pro- deserve further exploration. cedures, will eventually lead to greater availability A further possibility is related to nerve growth and use of MR scanning for routine clinical use.'29 factor (NGF). Sympathetic and sensory neurones The option of buying time on a mobile MR unit is require NGF both for their development and for particularly attractive in this respect. their maintenance in adult life. Endogenous levels The investigation of suspected demyelinating on October 1, 2021 by guest. Protected of NGF have recently been shown to be altered in disease is a prime example for which CT scanning is streptozotocin diabetic rats.'27 It was suggested rarely helpful and MR often diagnostic. Lesions that this may be implicated in some of the func- are usually most obvious in the peri-ventricular tional deficits that occur in the peripheral nervous white matter of the cerebral hemispheres but system in diabetes. plaques can also be shown in the cerebellum, brainstem, spinal cord and optic nerves, structures Conclusion which only very rarely appear abnormal on CT scans. The appearances are not pathognomonic of The variegated clinical picture presented by the MS, however: like the finding of oligoclonal diabetic neuropathies128 strongly suggests the oper- immunoglobulins in the CSF, multifocal white ation ofmultiple causal factors. Thus it is probably matter lesions may also be seen in various other a mistake to search for a single explanation but conditions which include sarcoidosis, systemic instead to think in terms of a variety of distur- lupus erythematosus, cerebral vasculitis, postviral bances of varying importance in different individ- encephalomyelitis and HIV-related disease. Uncer- uals. tainty may also arise in middle aged and elderly NEUROLOGY 523 Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from

subjects, in whom areas of high signal around the seems more likely to become clinically applicable, ventricles are often present in the absence of any and this would represent a major advance, parti- symptoms of disease, probably reflecting age- cularly for the diagnosis and follow-up of cerebral related vascular changes. The use and limitations of aneurysms. MR imaging in the diagnosis ofmultiple sclerosis is well reviewed in a study by Appel and colleagues.'30 X-ray CTscanning Because of the limitations imposed on X-ray CT by bone artefact arising from the skull base and the Apart from shortening ofscanning times and some use of only the transaxial imaging plane, MR improvements in image quality, relatively few scanning is also vastly superior for demonstrating advances have been made in X-ray CT technology structural lesions in the posterior fossa, particular- in the last 10 years. Functional applications of CT ly within the brainstem and at the cervico-medul- such as cerebral blood flow measurement with lary junction. Anatomical abnormalities at the stable xenon are expensive and time consuming foramen magnum and cervical syringomyelia are without having any of the versatility of emission particularly well shown by this technique. tomography. Imaging ofthe spinal cord in general is an area in Wider availability of CT in district general which MR may eventually replace the existing hospitals allows more patients to be scanned, which standard procedure, which is myelography with or is usually to their advantage. It also saves unneces- without CT scanning.'3' This is particularly true sary travelling to regional centres for many ill when inflammatory or other intrinsic spinal cord patients with stroke, head injury and undiagnosed pathology is suspected and visualization of the encephalopathy, although limited funding of dis- nerve roots is not a priority. For cervical and trict units in the present economic climate often lumbar radicular lesions, myelography with CT precludes out-of-hours emergency work. When 24 probably remains the investigation of choice hour scanning does become possible, it is critical because neither MR nor plain CT of the spine for the safe management of neurological emergen- shows the nerve roots clearly within their intra- cies that the availability ofneuroadiological exper- thecal course, particularly in the lumbar region.'3' tise should have developed in parallel with that of copyright. Intrameduallary vascular lesions are likely to be the scanning facilities. Another occasional source well shown by MR scanning but extramedullary of difficulty is the use of more readily available CT (dural) arteriovenous malformations may be miss- scanning as a substitute for careful neurological ed by this technique; these lesions are still most assessment of the patient. appropriately pursued by myelography as a prelim- The addition of CT scanning during myelo- inary screening procedure, followed by spinal graphy in selected cases has undoubtedly improved angiography if the diagnosis remains likely. diagnostic precision, although performance of this In the field of cerebrovascular disease, MRI has combined procedure may sometimes present logis- greater sensitivity than CT for detection of subtle tical difficulties in a busy X-ray department with http://pmj.bmj.com/ vascular lesions, particularly small lacunar infarcts limited scanning time. Plain CT scanning for spinal and the more confluent subcortical lesions that disease is a rapidly expanding use of the technique, result from diffuse small vessel disease. So sensitive albeit with some limitations. In the cervical region is the technique, however, that distinction between it is rarely helpful without intrathecal contrast clinically significant subcortical vascular lesions administration and concurrent myelography, but and apparently benign age-related changes may be disc lesions in the lumbosacral region are often well difficult. This lack ofspecificity becomes a problem shown without the need for spinal contrast injec- on October 1, 2021 by guest. Protected in the very age group most likely to be affected by tion. Laterally placed disc lesions causing compres- vascular disease ofthe brain. Magnetic resonance is sion ofnerves roots beyond their intrathecal course clearly superior to CT for the demonstration of may be missed by myelography alone and shown infarcts and very small haemorrhagic lesions in the better by CT. The reverse is also true: prolapsed brainstem, but in most other respects it has discs causing distortion of the theca and displace- relatively few advantages for the routine investiga- ment ofroots within it may be poorly shown by CT tion of cerebrovascular disorders. alone and only clearly visible on myelography.'3" '32 Various functional applications ofMR are being Any paraspinal soft tissue component of a malig- developed and these are likely to become clinically nant or inflammatory lesion is best shown by CT important in the future. For example, modification but again intrathecal contrast and conventional ofthe imposed magnetic field by means ofgradient myelographic views may also be necessary to pulses can produce a subtraction angiographic demonstrate the degree of spinal cord or cauda image of the brain or, with different sequences, equina compression. information about regional tissue blood flow. Quantitative blood flow measurements are still some way off but noninvasive MR angiography 524 A.N. GALE et al. Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from

Vascular imaging: angiography and neurotransmitter storage sites or receptor density ultrasonography within the brain. The distinctive twin photon radiation produced by positron-emitting isotopes Development of tomographic brain imaging - enables their concentration in the brain to be both CT and MR - has substantially reduced the measured in absolute units, since it is also possible requirement for intracranial angiography. The to measure tomographically and correct for the main indications for this procedure are now attenuating effect of the tissues. Positron emission subarachnoid haemorrhage, delineation ofarterio- tomography (PET) is therefore a quantitative tech- venous malformations when surgery is contemp- nique, the images being merely a convenient means lated, preoperative assessment of potentially vas- of displaying the data. Apart from the cost of the cular tumours and the diagnosis of rare conditions tomographic camera itself, one disadvantage of such as cortical thrombophlebitis, cerebral vas- PET is the very short half-life of most of the culitis and other unusual angiopathies. biologically useful positron emitting isotopes, The arrival of intravenous digital subtraction which therefore require a cyclotron for their pro- angiography (DSA) and vascular ultrasonography duction in or near the scanning unit. Single photon have reduced the risks and also the cost ofcervical emission tomography (SPECT) cannot be truly vascular imaging, which can now be carried out as quantitative but it does represent a less expensive an outpatient procedure. However, the relative and elaborate form of functional imaging. merits of these two techniques and the clinical The greatest initial impact of PET was in the indications for performing them remain the subject study of cerebrovascular disease, dementia and of much debate and a rather confusing body of epilepsy. Quite apart from the considerable con- literature.'33 As a broad generalization, carotid tribution on the research side, in these areas PET ultrasound is probably superior for looking at has produced information of some diagnostic and plaque morphology and for providing some func- practical value to clinicians. Its possible role in the tional information - flow velocity for example - management of cerebral tumours is less clearly whereas good quality DSA gives a clearer ana- established.'34 In recent years there has been further

tomical picture of the type that most vascular progress in the delineation of distinctive regionalcopyright. surgeons like to see before considering endarterec- patterns of disturbance in various dementia synd- tomy. There is, however, a general trend towards romes, and also in the field of movement dis- more conservative management of carotid artery orders. '35 Characteristic patterns ofsubcortical and disease and this has somewhat reduced the clinical cortical metabolic activity, striatal DOPA uptake demand for imaging of the extracranial vessels in and dopamine D2 receptor binding sites have been the last few years. Only the results ofthe European described in idiopathic Parkinson's disease, the less and North American endarterectomy trials can common parkinsonian syndromes and in Hunting- show whether or not this trend is justified. ton's disease.'35 The considerable interest in apply-

Although labour-intensive and strictly operator ing PET to identification ofindividuals with Hunt- http://pmj.bmj.com/ dependent, carotid ultrasound is particularly useful ington's disease in the presymptomatic stage has as a research technique: being noninvasive and been overshadowed to a large extent by develop- serially repeatable, it offers the best chance of ments in DNA technology in the last 5 years. following the natural history of carotid atheroma- Emission tomography remains predominantly a tous disease in patients not being subjected to powerful and expensive clinical research tool. surgical treatment. Examination of large intra- Whether there are any definite applications for the cranial arteries by means of transcranial Doppler technique in everyday clinical neurology is still has also remained predominantly a research techni- rather questionable. As one might expect, the on October 1, 2021 by guest. Protected que up to now, and the possible clinical applica- concept of a clinical PET centre is more highly tions suggested by some authors are not generally developed in the United States and there is some agreed upon. difference ofopinion about the clinical role ofPET on each side ofthe Atlantic.'3 "35 These two reviews Emission tomography by Brooks'35 and Kuhl M4 are a good starting point for further reading about PET and its applications. The principles oftomographic detection and recon- struction can be applied to the distribution of radioisotopes within the brain or cerebral vascular Dementia compartment to produce emission, rather than transmission, tomographic images. Depending on Introduction the isotope and its handling within the tissues, these functional images can display regional blood flow, Deterioration of intellect in the middle aged and blood volume, metabolic consumption of oxygen elderly is not only a common clinical problem but or glucose, cerebral pH, or the distribution of also a major public health issue, made all the more NEUROLOGY 525 Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from acute by the combined pressures of an ageing an otherwise typical parkinsonian patient or from population and the increasingly competitive fun- widespread involvement of the cerebral cortex by ding of community health care. The difficult diffuse Lewy body disease.'39 challenge ofmanaging young people with dementia Epidemiological evidence suggests that, partic- has been brought sharply to our attention by the ularly amongst patients developing symptoms at AIDS epidemic. Much progress has been made in an early age, Alzheimer's disease is often acquired the last 20 years, both in the clinical assessment and by autosomal dominant inheritance, whereas classification of dementia syndromes and in our patients presenting later in life are more likely to knowledge of their underlying neurochemistry, have the sporadic form ofthe disorder. The familial pathology and molecular biology. The patho- Alzheimer gene has been located to the proximal physiological basis of dementia resulting from long arm ofchromosome 21. This was ofinterest in vascular disease has been the subject of more relation to the frequent occurrence of Alzheimer critical analysis and periodic review. The wider pathology at a relatively early age in patients with availability of CT scanning and the emergence of Down's syndrome, but the site ofthe genetic defect magnetic resonance imaging have gone some way on chromosome 21 has been shown to be distinct in towards improving the precision of clinical diag- the two disorders. A specific P amyloid protein nosis, particularly the distinction between degen- found in the central core of senile plaques and in erative and multi-infarct disease. Nevertheless, cerebral blood vessels ofpatients with Alzheimer's more than one pathology may often coexist in the disease is also coded (via a precursor protein) from same patient and autopsy studies continue to reveal chromosome 21. However, there is new clear a higher than expected incidence of clinical mis- evidence that the gene sites for this 13 amyloid and diagnosis in patients with dementia. In certain familial Alzheimer's disease are not identical either, specific instances, prognostic information and and the precise nature of the genetic defect in genetic counselling can be immensely helpful to Alzheimer's disease has yet to be identified.'" patients and their families. Regrettably, however, The discovery of MPTP-induced parkinsonism the considerable mass of information accumulated has revived interest in environmental neurotoxins, from recent research has so far produced little of but none so far has been convincingly linked with copyright. immediate practical or therapeutic value to pa- Alzheimer's disease. The high aluminium content tients with dementing disorders. of neurofibrillary tangles and the fact that similar (but not identical) tangles are found in the brains of Alzheimer's disease patients with dialysis-related dementia has led to much speculation about aluminium as a possible The major clinical features ofAlzheimer's disease - aetiological agent. However, its presence in high memory loss, dysphasia, dyspraxia and visuo- concentration in the lesions of Alzheimer's disease spatial disturbance - reflect the predominantly could equally well be a secondary consequence of cortical nature of the disease, in contrast to so- some other primary pathophysiological mechan- http://pmj.bmj.com/ called subcortical dementias (see below). In the ism. Certain clinical and pathological similarities early stages the clinical syndrome may be remark- between Alzheimer's disease and the transmissible ably focal, consisting for example of dysphasia spongiform encephalopathies raise the possibility with little or no evidence ofmore global dementia. of a slow virus or prion as the causative agent. Depressive symptoms are common and often re- Although this is conceivable, the generally late age sponsive to treatment.'36 Disintegration of per- of onset in Alzheimer's would be rather difficult to sonality and behaviour later add to the already account for on this basis. The topical question of distressing consequences of the cognitive deficits. prion disease and spongiform encephalopathy has on October 1, 2021 by guest. Protected With progressive loss of insight, the impact of the recently been reviewed.'4' disease shifts away from the patient to some extent No treatment has so far been shown to improve and increasingly onto the carers, a point which has the cognitive impairment in patients with Alzhei- important implications in the management of the mer's disease. The discovery of a pronounced loss disorder. 137 ofcentral cholinergic neurones led to the hope that In most cases, there are few physical neurological there might be effective pharmacological treat- signs, although the presence of extrapyramidal ment, analogous to the use of dopaminergic agents features has been increasingly recognized in in Parkinson's disease. This was the basis for the patients with otherwise typical features of Alz- use of tetrahydroamino acridine (THA), a cen- heimer's disease. This clinical point remains the trally-acting anticholinesterase inhibitor, for which subject of some debate,'38 to which has been added dramatic claims were made in some of the pre- recently the wider acceptance of dementia as a liminary trials. However, subsequent studies have feature ofParkinson's disease. The combination of not so far borne out the impression that this agent classical parkinsonism and dementia may result has a useful therapeutic effect.'36"42 Earlier trials either from coexistent Alzheimer-type pathology in with physostigmine and other centrally-acting cho- 526 A.N. GALE et al. Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from linergic agents have been equally disappointing and reported pathological studies have shown features these drugs have a high incidence of unacceptable suggestive of localized Alzheimer's disease in some side effects.'36 Low doses of selegeline (Deprenyl) patients but not others.'46 have been said to reduce anxiety, depression and As indicated above, the combination ofprogres- agitation in some patients, implying that deficiency sive generalized dementia of cortical type with of central dopaminergic neurotransmission may apparently classical, dopa-responsive parkinson- contribute to some ofthe behavioural disturbances ism may be associated neuropathologically with ofAlzheimer's disease.'36 It was inherently unlikely the presence of widespread Lewy bodies in the that all the manifestations ofthis disorder could be cerebral cortex as well as in the nigrostriatal attributed to failure of a single neurotransmitter system.139",45 Nevertheless, the Lewy body should system and there is now evidence to implicate other not necessarily be regarded as a diagnostic marker monoamines, amino acid transmitters and neuro- for a single disease: like the Pick body, it is no more peptides in the pathophysiology of the disease.'43 than a cellular inclusion made up of degraded The prospects for effective pharmacological modi- intracellular proteins. The finding of diffuse Lewy fication of symptoms therefore remain poor at the bodies is not always accompanied by parkinson- present time. Management of patients with this ism'39 and the clinical features associated with this devastating disease still depends largely upon the pathology are quite variable, sometimes including provision of practical and emotional support for other movement disorders and pyramidal signs as the family with the help of a team of appropriate well as dementia and parkinsonism.'47 therapists and community workers.'37,1" The concept ofsubcortical dementia Non-Alzheimer degenerative dementias It has been suggested that in patients with dementia Progressive focal syndromes with cerebral atrophy resulting from certain disorders which include confined to the frontal or temporal lobes have often subcortical pathology - particularly Huntington's been lumped together in the past under a diagnostic disease, progressive supranuclear palsy and classi- label ofPick's disease. In recent years it has become cal Parkinson's disease without cortical

Lewycopyright. clear that patients in this clinical category do not bodies - there is a characteristic pattern of neuro- always have the characteristic pathological psychological disturbance which is distinct from changes ofPick's disease, namely localized cortical that of predominantly cortical disorders. Commu- neuronal loss with the presence of argyrophilic nicating hydrocephalus and diffuse periventricular inclusions (Pick bodies) in the neural perikaryon. A vascular disease might also be included in the group ofpatients with a frontal lobe syndrome and 'subcortical' group of dementing disorders. In pathological features apparently distinct from contrast to the dysphasia, dyspraxia, agnosia and either Alzheimer's or Pick's disease has been des- marked amnesia of Alzheimer's disease, the main

cribed by Neary and others under the heading of features of subcortical dementia are said to be a http://pmj.bmj.com/ 'dementia of frontal lobe type'.'45"146 A small general slowness of thought (bradyphrenia) and number of such patients have later gone on to impaired ability to retrieve and manipulate acquir- develop features of motor neurone disease. The ed knowledge rather than frank amnesia.'1""45 The results of neuropsychological assessment, func- subcortical disorders certainly have in common a tional tomography and pathological examination disruption of many aspects of motor function, the do follow a consistent pattern in many of these gait and stance being most obviously affected, and patients but there is still some uncertainty about the the presence of generalized psychomotor, retarda- existence of this disorder as a distinct nosological tion is likely to affect test performance in certain on October 1, 2021 by guest. Protected entity. 46 predictable ways. However, not all investigators A more localized unilateral disorder charac- have been able to support the concept ofa clear cut terized by progressive dysphasia has also been qualitative difference between dementia ofcortical recognized, in which the pathology is largely and subcortical disease.'49 confined to the sylvian region in the dominant hemisphere. Again there is some debate as to Huntington's disease whether this is a localized form of Alzheimer's disease or Pick's disease, or a completely separate The discovery of a DNA marker closely linked to entity.'" Another focal syndrome of 'posterior the locus for Huntington's disease on chromosome cortical atrophy' has been described on the basis of 4 has been one of the most important applications clinical and radiological features. These patients of molecular genetics in the field of neurological presented with severe dyslexia, dysgraphia, dyscal- disease. Much further progress has been made since culia, transcortical dysphasia, visual agnosia and the original publication in 1983150 and a number of disorientation, whilst memory and personality centres are now offering a predictive testing service were relatively well preserved. The small number of based on the analysis of blood samples from NEUROLOGY 527 Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from individuals at risk and their relatives, ideally using was the more diffuse type ofsubcortical small vessel material from three generations rather than two. disease that had been described originally in 1894 This is clearly a major advance but there are still by Binswanger. This was something of an over- many limitations to the reliability of such testing, simplification, since dementia due to vascular and also some difficult ethical problems to be faced disease can result from several pathophysiological by those providing the service.'5' mechanisms in a wide variety of clinical settings (see Table I). This classification includes some rare Dementia due to vascular disease causes of vascular dementia but it does emphasize the range of investigations that may be necessary, Vascular dementia has probably been overdiagnos- particularly in younger patients with unexplained ed in the past. In a recent autopsy study only 6 of65 dementia of possible vascular origin. Another demented patients were found to have only vas- important point is that in most of these disorders, cular disease as the likely cause for their symptoms, including the more common ones, the underlying while 38 had only Alzheimer pathology and 10 had mechanism may be amenable to therapeutic inter- a mixed picture.'52 Only 1 of 4 patients with a vention. Hypertension is by far the commonest confident clinical diagnosis of vascular dementia treatable factor, contributing particularly to local had isolated cerebrovascular disease at autopsy, and diffuse small vessel disease as well as carotid the other 3 having Alzheimer's disease as well. atheroma and cardiac abnormalities. Cerebral vas- Misdiagnosis in the other direction was infrequent. culitis is rare but probably underdiagnosed as a The traditional concept of chronic progressive cause ofpatchy small vessel disease in patients ofall 'cerebral arteriosclerosis' was replaced in the early ages. 1970s by the pronouncement that multiple discrete Some important pathophysiological aspects of infarcts were the cause of vascular dementia. vascular dementia are discussed in a recent review Multi-infarct disease could then be classified most by Brown and Hachinski,'5 including particularly simply into two broad categories: bilateral cortical the revival of interest in haemodynamic factors in lesions resulting from thromboembolism - usually patients with diffuse subcortical vascular disease. from the heart, rarely from the neck vessels - or To some extent this line of thought represents a copyright. multiple subcortical infarcts of lacunar-type, typ- return towards the additional and previously cially in patients with hypertensive small vessel rejected concept of progressive cerebral arterial disease. In a separate, rather ill-fitting category, insufficiency.

Table I Causes of vascular dementia Type and site of cerebral ischaemic lesion Underlying vascular disorder http://pmj.bmj.com/ Multiple discrete embolic infarcts (mainly cortical) Cardiac emboli (Bilateral carotid atheroma) (Fat or air embolism) Multiple subcortical lacunar infarcts Subcortical small vessel disease, often hypertensive Diffuse subcortical ischaemic lesions Confluent, symmetrical small vessel disease in periventricular white matter ('Binswanger disease')

Bilateral paramedian thalamic infarction Distal basilar occlusion or embolism on October 1, 2021 by guest. Protected Focal small vessel disease Watershed ('borderzone') infarcts of haemodynamic Severe bilateral occlusive carotid disease. origin (cortical and subcortical) Cardiac arrest and other major hypotensive insults Diffuse or multifocal lesions due to rare Cerebral angiitis of any cause. occlusive angiopathies Amyloid (congophilic) angiopathy. Hereditary multi-infarct dementia. Bilateral venous hemispheric infarction (cortical and Cortical thrombophlebitis. subcortical) Sagittal sinus thrombosis. Systemic causes of multiple cerebral vascular SLE, PAN, TTP Antiphospholipid syndrome, occlusions Sickle cell disease, Lymphomatous angiopathies

SLE - systemic lupus erythematosus; PAN polyarteritis nodosa; TTP- thrombotic thrombocytopenic purpura. 528 A.N. GALE et al. Postgrad Med J: first published as 10.1136/pgmj.67.788.509 on 1 June 1991. Downloaded from

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