J Neurol Neurosurg Psychiatry 1998;65:291–300 291 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.3.291 on 1 September 1998. Downloaded from

NEUROLOGY AND MEDICINE

Neurology and the gastrointestinal system

G D Perkin, I Murray-Lyon

The interrelation of neurology and the gas- that the two techniques are complementary, trointestinal system includes defects of gut acetylcholinesterase staining being particularly innervation, primary disorders of the nervous helpful when the biopsy material does not system (or muscle) which lead to gastrointesti- include submucosa, or in older infants or chil- nal symptoms—for example, dysphagia—and, dren in whom the population of distal submu- finally, certain gut disorders which include cosal ganglion cells may be less dense.6 neurological features in their clinical range. The first of this trio will be discussed only Gastrointestinal disorders due to briefly in this review, the second and third in neurological disease more detail. DYSPHAGIA A neurogenic mechanism for dysphagia, which Defects of innervation may have either sensory or motor components, ACHALASIA or both, can result from a disorder at the oral, Achalasia is characterised by an absence of pharyngeal, or oesophageal phase of swallow- peristalsis in the oesophageal body accompa- ing. In most patients, the neurological disorder nied by a failure of relaxation of the lower is evident, but in others, dysphagia is the oesophageal sphincter.1 Although the condi- presenting feature. Besides the dysphagia, tion can be secondary to other disease other symptoms suggesting a neurogenic copyright. processes—for example, Chagas’ disease—in mechanism include drooling of saliva, nasal Europeans it is usually a primary disorder. Dif- regurgitation, and episodes of coughing or fering opinions have been expressed as to choking during swallowing.7 Videofluoroscopy whether the problem of innervation rests in the has proved of particular value in the assessment dorsal motor vagal nucleus, the vagus itself, or of neurogenic dysphagia. The procedure allows in the intrinsic innervation of the oesophagus, identification of the site of maximal dysfunc- with most evidence favouring the last explana- tion, pinpoints areas of barium collection, and tion. By the time of oesophageal biopsy or indicates whether laryngeal penetration is resection, there is almost total loss of ganglion occurring.8 Neurogenic dysphagia may arise Department of cells with substantial destruction of myenteric from involvement of the cortical areas con- Neuroscience and nerves. The changes are accompanied by an cerned with swallowing, their eVerent pathway, http://jnnp.bmj.com/ Psychological Medicine, The inflammatory reaction both within and around the brain stem motor or sensory nuclei, the Hammersmith Trust the nerves. Neurochemical analysis has shown lower cranial nerves in their distal course, their Hospitals, Charing a reduction in the number of neurons in the neuromuscular junctions, or the striated mus- Cross Hospital, myenteric plexus containing immunoreactive cle components of the swallow pathway. London, UK vasoactive intestinal polypeptide.2 The way in G D Perkin which the disease evolves remains unclear. STROKE Department of Stroke is the commonest cause of neurogenic Gastroenterology, HIRSCHSPRUNG’S DISEASE dysphagia. Up to 50% of patients with stroke on September 24, 2021 by guest. Protected Chelsea and Hirschprung’s disease presents at, or soon have been estimated to have dysphagia, albeit Westminster after, birth. Constipation is accompanied by temporary in many. Dysphagia is a recognised Healthcare NHS Trust, gaseous abdominal distension. Typically a nar- feature of unilateral as well as bilateral Chelsea and rowed distal segment of bowel is demonstrable hemispheric stroke and is commonplace in Westminster Hospital, London, UK in which there is loss of parasympathetic brain stem stroke. Most studies of dysphagia in 3 I Murray-Lyon ganglion cells from the intramural plexus. The cases of unilateral hemispheric stroke have aganglionosis is the result of incomplete migra- been retrospective, but in one prospective Correspondence to: tion of neurenteric ganglion cells from the neu- study, swallow function was analysed with Dr GD Perkin, Department of Neuroscience and ral crest to the most distal part of the gut. respect to the size and distribution of ischaemic 9 Psychological Medicine, Increased acetylcholinesterase activity has been stroke in middle cerebral artery territory. Imperial College School of detected in the submucosal and myenteric Attempts to correlate swallow patterns with Medicine, Charing Cross Hospital, Fulham Palace plexus of the aVected bowel segment. Besides stroke site were hampered by the fact that Road,London, W6 8RF, UK. using histological criteria for diagnosis— stroke volumes for lesions in the anterior terri- namely, the presence or absence of ganglion tory of the middle cerebral artery were Received 11 February 1998 cells in rectal biopsy4—acetylcholinesterase substantially larger than those in the posterior and in revised form 15 May 1998 Accepted 15 activity can be measured in the same territory of the artery. Pharyngeal transit time May 1998 specimen.5 Further experience has established was prolonged, compared with controls, with 292 Perkin, Murray-Lyon J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.3.291 on 1 September 1998. Downloaded from

lesions in either hemisphere. Laryngeal pen- movements, a delayed swallowing reflex, aspi- etration and aspiration were much more ration, and reduced pharyngeal peristalsis. common in the right hemisphere group. In Videofluoroscopy has allowed a more detailed general, however, attempts to correlate charac- analysis, particularly necessary as patients’ teristics of unilateral lesions with impairment symptoms correlate poorly with the type of of swallowing have not produced consistent swallow problem.16 Silent laryngeal aspiration findings. Data from experimental animals has is commonly found. Alhough opinions diVer, suggested that stimulation of either cortex can recent studies indicate that, for some patients, initiate swallowing.10 Transcranial magneto- significant improvement in swallow function electric stimulation has been used to study the occurs with medication. Patients with Parkin- projections of the corticofugal fibres involved. son’s disease who deny swallowing diYculties The oral muscles are represented symmetri- have also been studied.17 In such a group of 16 cally between the two hemispheres, whereas patients, all had some abnormality and three muscles of the pharynx and oesophagus tend to had silent aspiration. Their mean Webster be represented asymmetrically, but without score (used as an assessment of their disability) regard to speech dominance.11 The technique was 11, indicating relatively mild disease, and has been applied to the analysis of patients with assessments were performed at the time of the unilateral hemispheric stroke, with or without midday meal. dysphagia.12 In patients with dysphagia, pha- Dysphagia is a prominent feature of progres- ryngeal responses from the unaVected hemi- sive supranuclear palsy18 and is a recognised sphere are smaller than those in non-dysphagic finding in both Huntington’s and Wilson’s dis- patients, irrespective of the side of the lesion, or ease. Dysphagia in patients with spasmodic whether it is cortical or subcortical. The mylo- torticollis partly relates to the variable head and hyoid responses (taken as representative of oral neck posture but, in addition, delay in reflex swallowing musculature) do not display such initiation and the finding of pharyngeal residue asymmetry. It has been suggested that this on videofluoroscopy suggests a neurogenic implies that pharyngeal function is represented component.19 asymmetrically in the cortex, and that with damage to the hemisphere containing the pre- dominant pharyngeal centre, swallowing func- OTHER NEUROGENIC DISORDERS tion cannot be maintained by the “non- Besides stroke and multiple sclerosis, other dominant” hemisphere. Clearly, if this brain stem pathologies are associated with dys- hypothesis is correct, an alternative mechanism phagia. In the Chiari type 1 malformation, her- copyright. for dysphagia must exist in the small niation of the cerebellar tonsils through the proportion of patients with a predominant oral foramen magnum results in traction of the phase disorder of swallowing after hemispheric lower cranial nerves, secondary compression of stroke. the brain stem, and, in some patients, hydro- Some degree of swallow diYculty is remark- cephalus. Dysphagia is common in such ably common after unilateral hemispheric patients and is associated with a global impair- stroke. It was reported in nearly 30% of one ment of all phases of swallowing on series, based on the bedside assessment of videofluoroscopy.20 In some patients, dysphagia swallowing liquid.13 Some evidence was found has been the presenting feature. Palatal hypo- for an adverse eVect on functional outcome if aesthesia has usually been the norm, however, dysphagia was present. By one month after when such patients have been carefully 21 22 onset of stroke, only 2% of patients with assessed. http://jnnp.bmj.com/ unilateral stroke are still dysphagic. Clearly any Disorders of the lower motor neuron or neu- hypothesis regarding the pathogenesis of dys- romuscular junction that often result in dys- phagia after unilateral stroke needs to explain phagia include the Guillain-Barré syndrome, the transient nature of the process in many amyotrophic lateral sclerosis, and myasthenia patients. gravis. In amyotrophic lateral sclerosis, swallow Bilateral hemispheric strokes are associated abnormalities are not infrequent even in those with a higher incidence and greater severity of patients presenting with limb problems but are 7 dysphagia than unilateral strokes. Generally, particularly prominent where bulbar involve- on September 24, 2021 by guest. Protected the neurogenic basis of the problem is evident ment is evident on clinical examination. An from the patient’s examination although case abnormal oral phase of swallowing encom- reports exist describing dysphagia in patients passes both a prolonged oral transit time and with occult bilateral hemispheric infarction.14 repetitive lingual pumping, probably reflecting Swallow problems are particularly common in reduced lingual force.23 Patients often employ brain stem stroke, and are likely to include changing head postures to facilitate swallow- aspiration. Although aspiration is more likely in ing. A prolonged delay time (duration from those with bilateral brain stem lesions, the arrival of the bolus at the midpoint of the velum presence of unilateral or bilateral infarction until initiation of maximal hyoid excursion) is does not correlate with outcome.15 As with strikingly apparent in the bulbar group, hemispheric stroke resulting in dysphagia, whereas the pharyngeal response time (from many dysphagic patients with brain stem initiation of maximal hyoid excursion to hyoid strokes are able to return to full oral nutrition. return to rest) shows no diVerence between patients with the bulbar and non-bulbar forms EXTRAPYRAMIDAL DISORDERS of the disease. Laryngeal aspiration can occur Abnormalities of swallowing described in before, during, or after the pharyngeal phase of Parkinson’s disease include defects of tongue swallowing. Neurology and the gastrointestinal system 293 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.3.291 on 1 September 1998. 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Oculopharyngeal muscular dystrophy is an autosomal dominant disorder which is pre- dominantly seen in French Canadians.31 The condition normally presents with bilateral pto- sis, with dysphagia following (fig 1). The ptosis is very variable and sometimes barely discern- ible. Pharyngeal contraction is typically de- pressed or absent with pooling in the hy- popharynx. Relaxation of the upper oesophageal sphincter is incomplete, late, or absent. Peristaltic activity in the oesophagus is often abnormal. Cricopharyngeal myotomy can result in a significant relief of symptoms. In some families, dysphagia precedes other mani- festations of the disease by months or years.32

Disorders of gastric and intestinal motility Both neurogenic and myopathic disorders are Figure 1 Bilateral ptosis in a patient with oculopharyngeal muscular dystrophy. associated with abnormalities of gut motility.

Dysphagia has been estimated to be a NEUROGENIC DISORDERS prominent symptom in at least one third of With neurogenic disorders involvement of the myasthenic patients. Both oral and pharyngeal autonomic innervation of the gut is the relevant phases of swallowing may be aVected and this mechanism. In this context, the most common despite a lack of subjective complaint of underlying disorder is diabetes mellitus. Gas- 24 dysphagia. In cases with severe bulbar in- troparesis leads to nausea, vomiting, abdomi- volvement, findings include ballooning of the nal pain, and distension. Alhough most pa- pharynx during repeated swallowing, residues tients with a diabetic gastroparesis display within the pharynx, nasopharyngeal regurgita- antral hypomobility,33 a proportion have peri- tion, and poor palatal elevation. ods of continuous, low amplitude, contractions in the antrum, in both the fasting and 34 PRIMARY MUSCLE DISEASE postprandial phases. Abnormalities of the copyright. Dysphagia is a recognised feature of inflamma- small bowel are common in patients with tory muscle disease, myotonic dystrophy, and diabetic gastroparesis. Typically, frequent long some of the muscular dystrophies. Fluoro- and short non-propagated bursts of phasic scopic features of both polymyositis and pressure activity occur in the jejunum with dermatomyositis include defective transfer to reduced frequency and amplitude of contrac- the oropharynx, retention of material in the tions in both the fasting and fed phases.34 The valleculae, and aspiration. Peristalsis is defec- phenomenon of long and short bursts has been tive in the upper oesophagus.25 An additional attributed to sympathetic denervation and the mechanism for dysphagia in inflammatory composite intestinal motility pattern in the muscle disease is failure of relaxation of a dys- fasting phase considered to represent dysfunc- functional cricopharyngeal muscle.26 Rarely, tion of both sympathetic and parasympathetic

inclusion body myositis presents with dys- supply. Both constipation and diarrhoea are http://jnnp.bmj.com/ phagia and, in some of these cases, biopsy of common in diabetic patients and indeed may cricopharyngeal muscle has disclosed charac- alternate. It has been suggested that the colonic teristic features of the disease.27 Cricopharyn- muscle of diabetic patients with constipation is geal myotomy can be therapeutically beneficial. able to respond to exogenous stimulation, in In an early manometric study, evidence was the form of parenteral injection of neostigmine presented of weakness aVecting the pharynx, or metoclopramide, but not to the stimulus of cricopharyngeal sphincter, and oesophagus in an ingested meal.33 Diarrhoea in diabetic

myotonic dystrophy, although doubt has been patients may be due to gluten induced on September 24, 2021 by guest. Protected cast on the accuracy of such recording enteropathy, pancreatic insuYciency, bacterial systems.28 In a barium study published in the overgrowth of the small intestine, or so-called same year, dilatation of the oesophagus (princi- idiopathic diabetic diarrhoea. The last has gen- pally its lower portion) was noted along with erally been considered a manifestation of auto- diminution and slowing of peristalsis.29 Further nomic neuropathy. Faecal incontinence is a video fluoroscopic studies have elaborated on common problem in patients with diarrhoea. these findings. Abnormalities described in- clude impaired pharyngeal contraction, myoto- PRIMARY MUSCLE DISEASE nia of the tongue and pharynx, stasis, and Abnormal gastric emptying has been identified pooling of the contrast in the pyriform sinuses in patients with polymyositis or and valleculae along with nasal regurgitation dermatomyositis,35 although in most patients it and tracheal aspiration.30 The earlier findings remains asymptomatic. An extensive literature in the oesophagus have been confirmed with, in exists on motility disorders associated with addition, descriptions of oesophageal spasm, myotonic dystrophy (table 1). Delayed gastric regurgitation, and antiperistaltic contractions. emptying is almost inevitable in the condition In some patients abnormalities of oesophageal but is seldom symptomatic.36 Diarrhoea and motility are unaccompanied by symptoms. abdominal cramps are common and steator- 294 Perkin, Murray-Lyon J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.3.291 on 1 September 1998. Downloaded from

Table 1 Gastrointestinal manifestations of myotonic synthesis of methionine and succinyl- dystrophy coenzyme A. The mechanism by which re- duced methionine causes demyelination in the Abnormalities of pharyngeal and oesophageal contraction 41 Gastric dilatation and diminished peristalsis CNS remains to be elucidated. Vitamin B12 Small bowel dilatation deficiency may arise from inadequate oral Megacolon Abnormal anal sphincter contractions intake, deficiency of intrinsic factor formation, various malabsorption disorders (for example, in association with jejunal diverticulosis), rhoea is recorded. Radiological studies of the resection of the stomach or terminal ileum, or large bowel have sometimes demonstrated from a disorder of the terminal ileum resulting 37 megacolon. Intestinal pseudoobstruction has in altered absorption of bound cobalamin. 38 also been reported and manometric abnor- Consequences include peripheral neuropathy, malities attributable to abnormal and sustained myelopathy, altered mental status, and optic contraction of the internal and external anal 42 39 neuropathy. Patients with pernicious anaemia sphincters. Despite this, constipation is rela- due to intrinsic factor deficiency are usually in tively uncommon. their 60s or 70s at presentation but the condi- Various gastrointestinal symptoms have been tion is recognised in juveniles and young recorded in patients with Duchenne’s muscu- adults. Most patients with pernicious anaemia lar dystrophy, including diarrhoea and consti- with neurological dysfunction present with a pation. Cases of intestinal pseudo-obstruction mixed myelopathic/neuropathic picture. The have been encountered with dilated and fluid 40 commonest initial neurological complaint is a filled small intestine and colon. It has been mixture of numbness and paraesthesia distrib- suggested that in such cases there is significant uted symmetrically and starting usually either atrophy and fibrosis of the intestinal smooth in the feet alone, or in the feet and hands muscle. together. In some patients, however, sensory symptoms are confined to the upper limbs. The Primary disorders of gut function or second commonest presenting complaint, ei- absorption ther in isolation or with sensory symptoms, is

VITAMIN B12 DEFICIENCY gait ataxia. Other forms of neurological presen-

Accounts of the manifestations of vitamin B12 tation are unusual. A small proportion of deficiency extend from the last century al- patients have symptoms suggestive of auto- though, inevitably, early accounts are less likely nomic dysfunction with urinary urgency, fre-

to have included a homogenous population. quency, or incontinence, faecal incontinence, copyright. Cobalamin in food is bound to protein. Pep- or impotence. Typically symptoms progress tic digestion releases free cobalamin which over weeks or months. then binds to R-binder, a cobalophilin found in The commonest neurological finding is saliva and gastric juice. Free cobalamin is again diminished lower limb vibration sense. Some- formed in the duodenum by the action of pan- times the hands or arms are aVected. Proprio- creatic enzymes but then binds to parietal cell ception is typically impaired in a similar distri- derived intrinsic factor. Absorption takes place bution. Cutaneous sensory change is less via intrinsic factor receptors in the terminal frequent. Lhermitte’s sign has been reported in ileum (fig 2).41The primary function of cobala- up to 20% of cases.43 Ataxia, commensurate min is to provide coenzymatic activity for the with the impairment of lower limb propriocep- http://jnnp.bmj.com/ Intestinal lumen Mucosa Blood

Food-Cbl + Peptic H digestion Stomach Cbl + R-binder on September 24, 2021 by guest. Protected

R-Cbl

Pancreatic enzymesCbl R-Cbl Duodenum (OH–) + IF

IF-Cbl

Distal IF-Cbl Cbl + TCII TCII-Cbl complex ileum Vla IF receptors

Figure 2 Enteric processing and absorption of cobalamin (Cbl). IF=intrinsic factor; R-binder=A cobalophilin with a rapid (compared with IF) electrophoretic mobility; TCII=transcobalamin II. (This figure is reproduced by kind permission of the author and publisher.41) Neurology and the gastrointestinal system 295 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.3.291 on 1 September 1998. Downloaded from

tion, is common. Weakness is sometimes Vertical nystagmus is rather less common than found, but always accompanied by sensory horizontal nystagmus, but still occurs in about abnormalities, and principally in the lower half of the cases. Gait ataxia is more common limbs. There may be lower limb hyperreflexia, than limb ataxia. Most patients have evidence or hyporeflexia, or a combination of the two. of a peripheral neuropathy. A failure to Hyporeflexia is more common. Visual impair- recognise atypical cases, without all the classic ment takes the form of bilateral centrocaecal features, undoubtedly leads to underdiagnosis scotomata. It is uncommon and even more so of the condition. In a postmortem series of 28 as an isolated phenomenon.44 Mental impair- cases, only four had presented with the classic ment usually takes the form of a global demen- triad of altered mental state, ophthalmoplegia, tia or simply a mild impairment of short term and ataxia.51 Most of the patients in the series memory with a reduced attention span. presented with an acute or chronic organic Neurological investigation provides some as- mental syndrome. Only nine of the 28 were sistance in making the diagnosis. Studies with recorded as having abnormal extraocular EMG when abnormal have shown evidence of movements and/or nystagmus. The degree of a predominantly axonal neuropathy. Somato- recovery in patients with Wernicke-KorsakoV sensory evoked potentials may be delayed or syndrome due to alcoholism is largely deter- absent, with recovery after successful mined by the duration of history before admis- treatment.45 Visual evoked potentials may be sion and the delay in initiating thiamine abnormal in the absence of visual symptoms or therapy. Vertical nystagmus and any ophthal- signs. moplegia recover completely, but horizontal It is well recognised that a lack of correlation nystagmus and gait ataxia often persist, and a exists between the haematological and neu- transition from a global confusional state to a

ropsychiatric manifestations of vitamin B12 KorsakoV psychosis is commonplace. deficiency. Indeed, severely anaemic patients may display no neurological impairment. Fur- NICOTINAMIDE DEFICIENCY thermore, some patients may display neuropsy- Endemic pellagra, linked to dietary deficiency

chiatric manifestations of B12 deficiency in the of nicotinamide and associated with a triad of absence of anaemia or macrocytosis.46 Most dermatitis, diarrhoea, and dementia, is no such patients will have evidence of a megalob- longer seen in developed countries. Nicotina- lastic bone marrow but reports of patients with mide deficiency has been described in some both normal peripheral blood and bone disorders of the alimentary tract. Bacterial marrow examinations yet with neuropsychiat- colonisation of the small intestine can lead to copyright. ric syndromes exist.47 the conversion of dietary tryptophan to in-

Generally, serum vitamin B12 concentrations doles. In a patient with jejunal diverticulosis are very substantially depressed, although it has associated with bacterial overgrowth, a clinical been argued that concentrations of 100–200 syndrome of stupor, neck stiVness, rigidity, and pg/ml are still consistent with the diagnosis, grasp reflexes showed a dramatic response to which is then supported by the finding of raised nicotinamide.52 Non-endemic pellagra tends to concentrations of serum methylmalonic acid lack dermatitis and diarrhoea. Its features then and total homocysteine and by the response to are similar to those encountered in alcoholic treatment.46 pellagra. Typically, patients are confused or display clouding of consciousness. Myoclonus Other vitamin B group deficiencies is common, principally involving the face and http://jnnp.bmj.com/ VITAMIN B1 DEFICIENCY shoulders. The third main element of the

Vitamin B1 deficiency leads to beriberi and encephalopathy is Gegenhalten, which tends to Wernicke-KorsakoV syndrome. Although the spare the neck and predominate in the limbs.53 latter has been intimately linked to chronic Less common signs include ataxia, pyramidal alcoholism, it is recognised to occur in other or cerebellar signs, primitive reflexes, seizures, settings. In a postmortem series of 29 cases, in and cranial or peripheral neuropathies. which chronic alcoholism had been excluded, gastrointestinal causes of the syndrome in- VITAMIN D DEFICIENCY

cluded peptic ulcer, acute pancreatitis, Muscle weakness has long been recognised to on September 24, 2021 by guest. Protected oesophageal metastasis, and carcinoma of the occur in patients with metabolic bone disease. stomach or oesophagus.48 A combination of In an early report,54 a patient with steatorrhoea ophthalmoplegia, nystagmus, and ataxia, con- associated with jejunal villous atrophy pre- sidered to reflect a Wernicke-KorsakoV syn- sented with a year’s history of diYculty in drome, has been described in a patient with walking. Examination disclosed a proximal anorexia nervosa.49 One of Wernicke’s three weakness of both upper and lower limbs patients, in his original description, had had associated with a myopathic gait. Metabolic intractable vomiting as a result of pyloric studies indicated osteomalacia. On a combina- stenosis induced by sulphuric acid poisoning.50 tion of a gluten free diet and vitamin D supple- The classic features of the condition include mentation her motor deficit showed substantial an altered mental state, often with a distur- improvement. In an analysis of 45 patients with bance of memory, coupled with a particular osteomalacia with proximal myopathy, there combination of neurological findings. Some- were 14 with gluten enteropathy, five with a times the mental state is normal, in other cases previous gastrectomy, and one with a history of the patient presents in coma. Oculomotor signs distal small bowel resection.55 Almost inevita- are almost inevitable, typically nystagmus cou- bly the symptoms began in the lower limbs pled with a lateral rectus palsy or gaze paresis. although examination often disclosed weakness 296 Perkin, Murray-Lyon J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.3.291 on 1 September 1998. Downloaded from

of shoulder abduction and external rotation Table 2 Clinical features of familial vitamin E deficiency with weakness of elbow extension even in the Ataxia absence of upper limb symptoms. In the legs, Dysarthria the weakness predominated in extension, Altered proprioception and vibration sense flexion, and abduction of the hips. Peripheral Absent deep tendon reflexes Babinski’s sign muscles, at least in cases secondary to vitamin Pes cavus D malabsorption, were spared with intact Kyphoscoliosis reflexes and preserved sensation. EMG shows Cardiomyopathy myopathic features with short duration poly- phasic potentials. Changes on light microscopy of the aVected muscles are not conspicuous. Coeliac disease This and later studies have failed to show any Coeliac disease is an intestinal disorder charac- terised by malabsorption, abnormal small correlation with the development of muscle bowel mucosa, and intolerance to the wheat weakness and the plasma calcium concentra- protein gluten.63 Neurological symptoms are tion. Indeed the exact mechanism of the mus- rare in children with coeliac disease. In adult cle weakness remains unknown. Generally the series, however, neurological manifestations muscle syndrome responds favourably to have been recorded in as many as 36% of vitamin D. patients,64 although figures of this magnitude have included cases of osteomalacic myopathy, VITAMIN E DEFICIENCY cases of peripheral neuropathy or spinal cord Vitamin E deficiency may result from chronic disease secondary to vitamin B12 deficiency, fat malabsorption, as a part of cholestatic liver and patients with episodic neurological dys- disease, in association with abetalipoproteinae- function secondary to hypokalaemia or hypoc- mia, or as a familial disorder of vitamin E alcaemia. absorption.56 In patients with peripheral neu- Neurological complications of less certain aetiology are recorded. A peripheral neu- ropathy secondary to vitamin E deficiency, ropathy, unrelated to B deficiency, produces peripheral nerve tocopherol (vitamin E) con- 12 predominant lower limb symptomatology with centrations are depressed, a finding which prominent ataxia, although some of this antedates histological evidence of axonal 57 includes a cerebellar component. The neu- degeneration. Abetalipoproteinaemia is an ropathy is usually progressive.65 Postmortem inborn error of lipoprotein metabolism leading examination, in addition to showing evidence copyright. to absence of apoprotein B. Neurological of peripheral nerve damage, has demonstrated manifestations include neuropathy, cerebellar cerebellar and spinal cord pathology, the latter ataxia, ophthalmoplegia, and muscle with some of the features of subacute com- weakness.58 The absence of all the low density bined degeneration of the spinal cord. In lipoproteins, consequent to the absence of general, the neuropathy is not influenced by the apoprotein B, results in failure of absorption of use of a gluten free diet. A detailed pathological vitamin E, concentrations of which are unde- study in a patient with coeliac disease who died tectable from birth in the serum of patients after a progressive neurological disorder resist- with the condition.59 A spinocerebellar disorder ant to all appropriate nutritional measures has occurs in patients with cystic fibrosis or multi- been published.63 The neurological features ple ileal resections associated with undetect- included a neuropathy, cerebellar ataxia, and

able serum concentrations of vitamin E and dementia. Eventually diVuse myoclonus http://jnnp.bmj.com/ shows some response to vitamin E replacement emerged. Although the ankle reflexes were therapy.60 diminished, the others were exaggerated. Com- A familial disorder of vitamin E deficiency paring this with previous studies, a pattern of has been described in the absence of any other neuropathological change emerges in which gastrointestinal disturbance or lipid maximal damage is found in the cerebellum, malabsorption.61 Patients absorb vitamin E brain stem nuclei and deep grey matter, and normally but poorly conserve plasma the spinal cord. Cerebellar findings are princi- 56 pally those of Purkinje cell loss with associated on September 24, 2021 by guest. Protected á-tocopherol in very low density lipoproteins. gliosis and loss of granule cells. Deep grey The syndrome that emerges bears a striking matter structures aVected include the thala- resemblance to Friedreich’s ataxia (table 2).62 mus, caudate nucleus, globus pallidus, puta- The patients have ataxia, cerebellar signs, dys- men, amygdala, anterior hypothalamic nuclei, arthria, bilateral extensor plantar responses, periaqueductal grey matter, corpora quad- pes cavus, and scoliosis. Deep tendon reflexes rigemina, the substantia nigra, and the red are absent in the lower limbs, where there is nuclei. Various cranial nerve nuclei are af- impaired proprioception. Some of the patients fected. In the spinal cord, the changes concen- have a cardiomyopathy. Genetic studies indi- trate in the posterior columns (mainly the fas- cate that the disease is inherited as a recessive, ciculi graciles) and the lateral columns. the locus for which is not in the chromosome 9 Cerebral cortical changes include focal neuro- region containing the gene for Friedreich’s nal atrophy and chromatolysis. The cause of ataxia, but rather, located on chromosome 8. this degenerative process has not been estab- Because of this overlap, all patients presenting lished. The pattern diVers from the changes with a clinical syndrome suggesting Friedre- seen in alcoholic cerebellar degeneration and ich’s ataxia should have vitamin E concentra- subacute combined degeneration or pellagra, tions measured. and is uninfluenced by nutritional therapy. Neurology and the gastrointestinal system 297 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.3.291 on 1 September 1998. Downloaded from

In some patients with coeliac disease who develop progressive neurological dysfunction, the cerebellum bears the brunt of the process.66 67 Imaging in such patients has shown diVuse cerebellar atrophy.67 There are usually some, although inconspicuous, signs of neurological disturbance outside the cerebel- lum. As with cases with a more global encephalopathic syndrome, neuropathological studies have shown profound Purkinje cell loss to be the most consistent finding. In cases with adult coeliac disease with a spinocerebellar pattern of degeneration, no evidence of vitamin E deficiency has been detected as a possible explanation for the neurological process.68 In an early study, episodes of unexplained loss of consciousness were encountered in five of 16 patients with adult coeliac disease who had developed a progressive neurological Figure 3 CT demonstrating bilateral parieto-occipital disorder.65 Subsequently a prevalence of epi- infarction in a patient with coeliac disease. (This figure was lepsy of 5.5% was recorded in a cohort of provided by Dr G Gobbi, Servizio di Neuropsichiatria patients with coeliac disease, most having par- Infantile Reggio Emilia, Italy.) tial seizures.69 Some studies have confirmed the association and explored it in more detail. In cerebral venous thrombosis are described in one, 43 patients were selected either because of patients with ulcerative colitis.72 In one post- the unexplained association of cerebral calcifi- mortem study of ulcerative colitis, thrombo- cation with epilepsy (31 cases) or because of embolic disease was found in 39% of patients, the existence of epilepsy in established coeliac predominating in the viscera and in the lungs.73 disease (12 cases).70 Among the first cohort of A similar predisposition to thromboembolic 31 patients, 24 were found to have unequivocal disease has been reported in patients with evidence of coeliac disease based on a full gas- Crohn’s disease.74 In one case both arterial and trointestinal evaluation including biopsy of the venous thrombosis occurred, resulting in spinal small intestine. Among the second group of 12 cord ischaemia, although this case was compli- copyright. cases of coeliac disease with epilepsy, five were cated by the concomitant presence of shown to have cerebral calcification on CT. hyperhomocysteinaemia.75 Cerebral arterial The cerebral calcification was usually bilateral occlusions have been described aVecting the and predominated in the parieto-occipital internal carotid and middle and posterior regions (fig 3) Epilepsy, in the previously cerebral vessels.76 Various factors have been known cases of coeliac disease, had antedated suggested as the underlying trigger for the the gastrointestinal disorder. In the whole thromboembolism including, in the case of group, the seizures were usually partial and Crohn’s disease, focal induction of tissue factor predominantly occipital. There were no procoagulant activity on endothelial cells and neurological signs in these cases. Some of the macrophages. cases of epilepsy had proved to be drug resist- Peripheral neuropathy is a recognised com-

ant but tended to show an improvement once a plication of Crohn’s disease. In two cases, a http://jnnp.bmj.com/ gluten free diet was introduced in the previ- sensory axonal polyneuropathy occurred, the ously undiagnosed cases. Alhough comparison severity of which waxed and waned according has been made with the Sturge-Weber syn- to the severity of the bowel disease.77 Neu- drome, significant diVerences exist. There is no ropathy is more commonly encountered in evidence of enlargement of the choroid plexus patients with ulcerative colitis, and usually and no evidence of cerebral atrophy. There is presents in the form of an acute or chronic no evidence of abnormal deep cerebral veins, inflammatory demyelinating polyneuropathy.78

the calcification is usually bilateral rather than Rarely, inflammatory bowel disease has been on September 24, 2021 by guest. Protected unilateral and neurological deficit has been associated with muscle disorders. The underly- found in a minority.71 Even in patients with a ing bowel disorder has usually been Crohn’s history of seizures and bilateral parieto- disease rather than ulcerative colitis. In one occipital calcifications but without abnormal such case, a patient with a 12 year history of intestinal biopsy, a diagnosis of coeliac disease Crohn’s disease, requiring previous bowel sur- may still be possible, based on the fact that the gery, developed typical clinical and investiga- mucosal lesions in such cases may be patchy or tive features of dermatomyositis.79 The condi- of late onset, and on evidence of low folate tion responded to a combination of prednisone concentrations of unknown cause in some of and azathioprine. In the other cases reported, them.70 The aetiology of the cerebral changes the muscle involvement has ranged from has not been established. non-specific changes on muscle biopsy to a florid picture of myositis with lymphocytic Inflammatory bowel disease infiltration and muscle cell necrosis. Granu- Thromboembolic complications are recog- loma formation has been reported. It has been nised features of both ulcerative colitis and suggested, at least for cases with dermatomy- Crohn’s disease. In some such cases, ositis, that immune complex formation, a neurological involvement may follow. Cases of known feature of inflammatory bowel disease, 298 Perkin, Murray-Lyon J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.3.291 on 1 September 1998. Downloaded from

might be the mechanism for the muscle clinical manifestations of the neurological changes. pathology were published in which dementia Neurological complications of inflammatory and oculomotor signs were prominent features. bowel disease may extend to the CNS. In a In one such case, in which the diagnosis was prospective study, brain MRI was performed in established by jejunal biopsy, the patient patients with Crohn’s disease or ulcerative became demented and complained of blurred colitis, and the findings compared with age vision with diplopia. His ocular examination matched controls. All the patients were under disclosed fixed pupils, minimal nystagmus, and the age of 40. Hyperintense focal white matter a fluctuating gaze paresis.88 The first report of a lesions on T2 weighted images were found in patient with Whipple’s disease confined to the 40%-50% of the patients with inflammatory CNS was published in 1977.89 The diagnosis bowel disease, but in only 16% of the control was established at postmortem examination. subjects.80 In most cases the lesions were single, The patient had presented with headache and and none enhanced. The distribution was not focal seizures. Investigations established the stated. None of the patients had neurological presence of a left anterior temporal lobe mass symptoms but the findings on neurological which was later resected. Subsequently he examination were not given. Although the became mute with primitive reflexes, Gegen- authors reported either cardiolipin IgG or IgM halten, and extensor plantar responses. Later antibodies in seven of the 72 patients with he developed nystagmus although no other eye inflammatory bowel disease, the incidence in signs were recorded. Cases with more overt the control population was not stated. At ophthalmoplegias have been presented.90 In present the pathogenesis of these changes, or one, a patient with drowsiness, impaired indeed their confirmation in other series, has memory, and ataxia was found to be disorien- not been established. Myelopathy has been tated and lacking short term memory. Examin- described with Crohn’s disease and, less ation of extraocular movements disclosed a commonly, with ulcerative colitis. defect of saccadic upgaze with preserved pursuit. There was limb and truncal ataxia, and Whipple’s disease bilateral extensor plantar responses. Subse- Whipple’s disease was first described 90 years quently paralysis of upgaze emerged with ago.81 Whipple noted the presence of rod absent doll’s head and caloric induced move- shaped structures in vacuoles and even cul- ments. Experience of these and other cases has tured a bacillus which he thought might be the established a particular pattern of CNS in- responsible agent. Subsequently, light and volvement. The findings, in decreasing order of copyright. electron microscopy studies confirmed the frequency, include dementia, ophthalmoplegia presence of rod shaped bacilli in the aVected (typically, at least initially, supranuclear in tissues, both, in the case of the bowel, lying free type), myoclonus, and various hypothalamic in the lamina propria of the small intestine and features including insomnia, hyperphagia, and also as partly degraded structures within mac- polydipsia.91 92 The combination of conver- rophage vacuoles.82 Subsequently, the same gence nystagmus with palatal, tongue, and structures were located in the CNS, the heart, mandibular movements called oculomastica- synovium, lymph nodes, lung, and liver. The tory myorhythmia has been considered pathog- demonstration of a distinctive pattern of bacte- nomonic. The parts of the brain particularly rial antigens in the foam cells of aVected aVected include the hypothalamus, cingulate patients served to confirm that only a single gyrus, basal ganglia, insular cortex, and cer-

bacterium was concerned in the pathogenesis ebellum. http://jnnp.bmj.com/ of the disease.83 Using nucleotide sequencing, Not surprisingly, diagnosis is diYcult if the it proved possible to demonstrate that the pathognomonic features are lacking. Magnetic organism was a gram positive actinomycete, resonance imaging identifies areas of reduced and a provisional title of Tropheryma whippelii intensity on T1 and increased intensity on T2 has been given to it.84 More recently the organ- weighted images which correspond with the ism has been successfully propagated in cell known sites of pathological involvement.90 93 culture although that propagation depended on Gadolinium enhancement of the lesions has 85 the presence of interleukin-4. been described as has evidence of ependymitis. on September 24, 2021 by guest. Protected Some of the epidemiological aspects of the The CSF typically shows an inflammatory cell disease remain unexplained. It is rare, and is response, often including polymorphonuclear largely confined to North America and Europe. leucocytes, and sometimes contains PAS posi- No specific immune defect has been detected tive macrophages. Chloramphenicol and in aVected people. On the contrary, it has been trimethoprim-sulphamethoxazole are capable suggested that the causative agent subverts the of arresting the course of CNS disease with immune system by promoting interleukin-4 gaze palsies and nystagmus being the most release or by blocking macrophage activating responsive signs. cytokines.82 Typically, the clinical manifestations of Summary Whipple’s disease include diarrhoea, abdomi- Both achalasia and Hirchsprung’s disease arise nal pain, weight loss, and joint pain. The from defects of innervation of the oesophagus disease presents in middle age.86 Evidence of and distal large bowel respectively. Their CNS involvement was first established with the consequences are confined to disorders of finding of PAS positive material in ventricular motility in the relevant part of the gastrointes- ependymal nodules and in perivascular tinal tract. Many neurogenic and primary mus- accumulations.87 Subsequently, cases with cle disorders are associated with abnormalities Neurology and the gastrointestinal system 299 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.3.291 on 1 September 1998. Downloaded from

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