1362 J Neurol Neurosurg Psychiatry 2004;75:1362–1366 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2003.029041 on 16 August 2004. Downloaded from

more dystonia in his hands while on his have been identified and hydroxygluaric LETTERS medications. aciduria has been proposed to have an His previous diagnostic evaluation autosomal recessive inheritence, occurring Dystonia, tremor, and included serological testing that had revealed in both D and L isoforms. Most of the cases a normal thyroid stimulating hormone con- reported in the literature are identified in parkinsonism in a 54 year old centration, normal liver function tests, nor- early childhood. The D isoform usually man with 2-hydroxyglutaric mal ammonia concentration, and normal presents with neonatal or early infantile aciduria reactive plasma reagent. Head magnetic encephalopathy, seizures, extrapyramidal resonance imaging (MRI) had been per- symptoms, and cardiomyopathy.34 In con- Glutaric aciduria is often considered to be a formed one year before presentation and the trast, the L isoform may present within the rapidly progressing dementing illness with flair images revealed prominent white matter 1st years of life with non-specific motor only occasional extrapyramidal symptoms, 1–7 hyperintensities in the frontal and parietal delay, and later cognitive and motor devel- usually described as dystonia. We present regions, with posterior ex vacuo dilatation of opmental delay. Gait ataxia may occur as a case of late onset 2-hydroxygluaric aciduria his lateral ventricles (fig 1), and mild early as the 2nd year.5 Additional findings and slowly progressive dystonia and parkin- cerebellar atrophy. Urine organic acids were sonism. include occasional pyramidal and extrapy- sent and revealed 2-hydroxyglutaric aciduria. ramidal features and dystonia, with a pre- dilection for the hands. Progressive mental Case report retardation is common in these patients. A 54 year old man was referred to the Discussion Most cases are diagnosed in childhood but University of Florida movement disorders This case demonstrates that older patients Clerc et al,6 in 2000, reported an adult patient center for management of ‘‘end stage with parkinsonism may have inborn errors of with tremor and excessive urinary excretion Parkinson’s disease’’. He was diagnosed with metabolism. Our patient was unique in that of L-2-hydroxyglutaric aciduria. Our case also developmental delay and mild cerebral palsy until his mid-20s and later when he lost his highlights the possibility of this disorder by his paediatrician, for a failure to meet job in his mid-30s, he was assumed to have presenting later in life with dystonia, tremor, mild cerebral palsy, and only after developing motor milestones. He had below average and parkinsonism. other parkinsonian features was he later grades in school and graduated high school Imaging and urine samples are very helpful misdiagnosed as having Parkinson’s disease. two years behind his age matched peers. At in making this diagnosis. Neuroimaging The important clues that were missed in this age 26, he noticed a mild intention tremor in findings in L-2-hydroxyglutaric aciduria patient were the developmental delay, the his right hand, a mild head tremor, and mild reveal subcortical leucoencephalopathy (as progression of symptoms leading to a mental unsteadiness in walking. These were seen in our case), and may also show atrophy assumed to be potentially parkinsonian fea- incapacity to hold his job, and the parkinso- 25 7 nian features that were unresponsive to of the cerebellum. Larnaout and colleagues tures, and later in his 30s he was given the performed a necropsy on a patient with assumed diagnosis of Parkinson’s disease. He levodopa and other agents. In addition, his MRI, which was carried with him to the childhood onset of cognitive and motor delay was treated with levodopa, dopamine ago- and epilepsy whose brother was diagnosed nists, a monoamine oxidase inhibitor, and appointment, had changes indicative of glutaric aciduria. A differential diagnosis in with L-2-hydroxyglutaric aciduria and they anticholinergics, which all failed to help his described the diffuse white matter changes as symptoms. He was gainfully employed by the this case should have included other non- levodopa responsive disorders that can pre- demyelination with spongiform, cavitating city in a maintenance department until being cystic lesions and cerebellar white matter fired in his mid-30s for incompetence. At the sent with movement disorders, such as copyright. proprionic acidaemia, methylmalonic acid- gliosis. This pattern of involvement was time of his clinic appointment, his mother consistent with the MRI results and was noted progressive difficulty with swallowing, uria, glutaric aciduria, and leucodystrophy. considered to be the typical spongiosis balance difficulties, and aggressive beha- Given his relatively benign course, he prob- encountered in disorders of amino acid viour. There was no history of exposure to ably has L-2-hydroxyglutaric aciduria and not metabolism. neuroleptics, and he did not smoke or drink D-2-hydroxyglutaric aciduria. Our patient The diagnosis of hydroxyglutaric aciduria is alcohol. His brother also had a tremor. unfortunately died as a result of an accident made by analysing urine samples with gas On neurological examination he was alert shortly after his evaluation, making confir- and oriented to person and place. His mation of the L isoform impossible. chromatography. The L isomer reveals a memory was tested (3/3 registration and 1/3 2-Hydroxyglutaric aciduria is a rare inborn solitary peak of 2-hydroxyglutaric acid, recall after five minutes). He had a hypo- error of metabolism that was first recognised whereas the D isomer may have other citric 1 phonic dysarthria with pallilalia. Gerstmann in the L isoform by Duran and colleagues acid cycle intermediates present in addition 2 3 features (right/left confusion, finger anomia, and later defined clinically by Barth et al. to D-2-hydroxyglutaric acid. In the USA, acalculia, and agraphia) were all impaired. There is less known about the molecular testing is available for the urinary detection He had frontal release signs including a root, biology and underlying biochemical defect of 2-hydroxyglutaric acid, but unfortunately http://jnnp.bmj.com/ snout, grasp, and glabellar tap. He had than in other amino acidurias. Further cases American laboratories are unable to distin- frontal lobe impairment including problems have been identified and have detailed guish between the L and the D isomer. with Luria 2 and 3 step command testing, clinical, biochemical, radiological, and patho- This case reminds us that inborn errors of anti-saccade testing, problems with crossed logical characteristics that have established a metabolism can be a cause of parkinsonism, response inhibition, and motor impersis- spectrum of the disease. Several subtypes and in selected cases an investigation should tence. Stereognosis and graphesthesia were intact. Cranial nerve examination revealed only saccadic pursuit. He had a tongue tremor. Power, reflexes, and sensory exam- on September 29, 2021 by guest. Protected ination were normal. On cerebellar examina- tion he was hypermetric on finger to nose testing, with past pointing and ataxia. Movement disorder examination revealed prominent parkinsonian features including rigidity, bradykinesia, shuffling gait, and balance problems. His hands were mildly dystonic. He had mild bilateral postural intention tremors. His posture was stooped and he had decreased arm swing and shuf- fling steps. He retropulsed on a pull test and could not perform tandem gait. In addition, he had a masked face, pallilalia, and severe micrographia. His off medication Unified Parkinson’s Disease motor scale (UPDRS) examination was 55. After taking his usual medications (trihexphenidyl and selegiline) he was re-examined one hour later and his Figure 1 Flair magnetic resonance images revealed prominent white matter hyperintensites in the UPDRS score was unchanged (55). He had frontal and parietal regions with posterior ex vacuo dilatation of his lateral ventricles.

www.jnnp.com J Neurol Neurosurg Psychiatry 2004;75:1362–1366 1363 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2003.029041 on 16 August 2004. Downloaded from be performed with urine organic acids so that detected on testing jaw opening against of eight seropositive subjects had a diagnosis this diagnosis can be quickly made. With the resistance, although her jaw hung slackly of ‘‘stroke’’ or ‘‘transient ischaemic attacks’’, emergence of new genetic therapies for open if not supported. Limb power and and the authors concluded that these biochemical diseases it may be important in reflexes were normal. patients might have been misdiagnosed. the future to make this diagnosis early in the Acetylcholine receptor antibodies (AchR- It is therefore possible that myasthenia course of the disease. abs) were strongly positive at 11 nmol/l gravis in the elderly is sometimes missed and (normal range 0 to 0.25 nmol/l). Other that the clinical course may in some cases be W E Owens, M S Okun autoantibodies were negative apart from a more benign than appreciated. University of Florida Movement Disorders Center, positive gastric parietal cell antibody. Department of Neurology, McKnight Brain Institute, Computed tomography of the mediastinum W W Y Wong, R J M Lane McKnight Brain Institute, PO Box 100236, Gainesville did not show any thymic abnormality. She West London Neurosciences Centre, Charing Cross FL 32610, USA; [email protected] was given pyridostigmine 60 mg twice daily, Hospital, London W6 8RF, UK doi: 10.1136/jnnp.2003.033571 and her symptoms gradually improved. On repeat assessment one month later, there was Correspondence to: Dr R J M Lane; r.lane@imperial. no evidence of ptosis and the jaw weakness ac.uk References seemed to be improving, though she still doi: 10.1136/jnnp.2003.034124 needed to hold her jaw when speaking for a 1 Duran M, Kamerling JP, Bakker HD, et al. L- few minutes. Repetitive nerve stimulation of Competing interests: None declared 2hydroxyglutaric aciduria: an inborn error of metabolism? J Inherit Metab Dis 1980;3:11–15. left frontalis and obicularis oculi showed no 2 Barth PG, Hoffman GF, Jaeken J, et al. L-2- decremental response. Electromyographic REFERENCES hydroxyglutaric acidaemia: clinical and examination of the right biceps, extensor digitorum communis, and left frontalis mus- 1 Oosterhuis HJGH. The natural course of biochemical findings in 12 patients and myasthenia gravis: a long term follow up study. preliminary report on L-2-hydroxyacid cles was also normal. J Neurol Neurosurg Psychiatry 1989;52:1121–7. dehydrogenase. J Inherit Metab Dis In view of the improving symptoms and 2 Authier FJ, De Grissac N, Degos JD, et al. 1993;16:753–61. the electrophysiological findings, it was Transient myasthenia gravis during HIV infection. 3 Van der Knaap MS, Jacobs C, Hoffmann GF. D- decided to continue pyridostigmine alone Muscle Nerve 1995;18:914–16. 2-hydroxyglutaic aciduria: biochemical marker or and steroid treatment was not initiated. Her 3 Roses AD, Olanow CW, McAdams MW, et al. clinical disease entity? Ann Neurol No direct correlation between serum 1999;45:111–19. symptoms continued to improve. By April 2003, she was completely asymptomatic. The antiacetylcholine receptor antibody levels and 4 Baker NS, Sarnat HB, Jack RM, et al. D-2- clinical state of individual patients with hydroxyglutaic aciduria: hypotonia, cortical pyridostigmine was gradually withdrawn myasthenia gravis. Neurology 1981;31:220–4. blindness, seizures, cardiomyopathy and over one month. She remained asympto- 4 Donaldson DH, Ansher M, Horan S, et al. The cylindrical spirals in skeletal muscle. J Child matic on follow up in September 2003. relationship of age to outcome in myasthenia Neurol 1997;12:31–6. Neurological examination was entirely gravis. Neurology 1990;40:786–90. 5 Barbot C, Fineza I, Diogo L, et al. L-2- normal although her AchR-abs remained 5 Vincent A, Clover L, Buckley C, et al. UK hydroxyglutaric aciduria: clinical, biochemical positive at 5.00 nmol/l. myasthenia gravis survey. Evidence of and magnetic resonance imaging in six underdiagnosis of myasthenia gravis in older Portuguese pediatric patients. Brain Dev people. J Neurol Neurosurg Psychiatry 1997;19:268–73. 2003;74:1105–8. 6 Clerc C, Bataillard M, Richard P, et al. An adult COMMENT

form of L-2-hydroxyglutaric aciduria revealed by To our knowledge, transient myasthenia copyright. tremor. Eur Neurol 2000;43:119–20. gravis has not been described previously in ‘‘Doctor, I can hear my eyes’’: 7 Larnaout A, Hentati F, Belal S, et al. Clinical and a patient of this age. It is known to occur in pathological study of three Tunisian siblings with 10–15% of infants born to mothers with report of two cases with different L-2-hydroxyglutaric aciduria. Acta Neuropathol myasthenia as a result of transplacental mechanisms (Berl) 1994;88:367–70. transfer of maternal antibodies, and there is An unusual but fascinating symptom is the a report of transient myasthenia in autoim- one described by patients complaining that 2 Transient myasthenia gravis in an mune disease resulting from HIV infection. they can hear their own eye movements. We In that study, seven HIV infected patients report two cases, with different postulated elderly woman presented with transient myasthenic symp- mechanisms. Myasthenia gravis is usually a chronic dis- toms. Four of them had positive AchR-abs. In one, myasthenia gravis and coincident auto- order, although remission rates of 25–30% Case reports can be expected with judicious interventions immune thrombocytopenia both resolved such as thymectomy and immunosuppres- following anti-retroviral treatment. Our Patient 1 sion in appropriate cases. Spontaneous remis- patient had no history of preceding infection, A 53 year old woman presented with a http://jnnp.bmj.com/ sion occurs rarely. Oosterhuis found a although there was a history of thyroid tendency to fall to the left. She did not remission rate of only 1% per annum over disease. experience hearing difficulties or tinnitus. 17 years among 180 patients with generalised The persistence of high levels of AchR-abs Clinical examination was unremarkable myasthenia gravis treated with anticholines- despite clinical resolution is of interest. There other than increased sway on Romberg. terases alone.1 We describe a case of ocular is no direct correlation between antibody titre Pure tone audiometry was normal other than and bulbar myasthenia in which there was and clinical state in individual myasthenic bilaterally mildly elevated thresholds of complete recovery over a matter of weeks patients.3 The resolution of clinical symptoms 30 dBHL at 8 kHz. However left sided ipsi- without immunosuppressive agents. and signs, despite persisting acetylcholine and contra-lateral stapedial reflexes were elevated, and auditory brain-stem evoked The patient, a 78 year old woman, devel- receptor antibodies, presumably reflects a on September 29, 2021 by guest. Protected oped acute, painless left sided ptosis in positive balance of acetylcholine receptor responses, while normal on the right, showed October 2002, while on holiday abroad. genesis to antibody mediated destruction. increased latency of wave V on the left. Serial There was no diplopia. She had developed Late onset myasthenia gravis differs from MRI scans demonstrated an enlarging left hypothyroidism one year before but was the typical form in several ways. The HLA vestibular schwannoma. Trans-labyrinthine euthyroid on replacement therapy. The ptosis DR3 haplotype is uncommon in late onset resection of the tumour was complicated by a resolved gradually over the next few days. disease, while thymomas are more common. left cerebellar infarct and hydrocephalus, and There was no family history of autoimmune It is said that late onset disease is more severe subsequently the patient continued to experi- diseases. Two weeks later she found she and less likely to remit, and that bulbar ence imbalance. Two years post-operatively, could not chew properly towards the end of a involvement is more common.4 Response to direct questioning about tinnitus led to the meal. The jaw weakness recovered the conventional treatment is also less satisfac- patient describing tonal tinnitus in the left following day but later recurred, to the extent tory than in younger patients. Our patient ear on looking to the left, in which up-gaze that she had to support her jaw while talking was therefore atypical of this older group. increased the pitch, while down-gaze lowered and eating. She had slight dysphagia but A recent cohort study suggested that the pitch. Notably she said ‘‘I feel I could play there was no history of choking, breathing myasthenia gravis might be underdiagnosed a tune with my eyes’’. problems, or limb weakness. in older people.5 In that study, 2000 asympto- On examination in January 2003, there matic individuals aged 60 and over, who Patient 2 was no definite ptosis or ophthalmoparesis. participated in the Oxford healthy aging A 32 year old man presented with visual No fatigability was demonstrated in the project, were screened for AchR-abs. instability and a tendency to fall forward and eyelids, and no weakness or fatigability was Surprisingly, 0.71% were seropositive. Four to the left provoked by loud sounds such as

www.jnnp.com 1364 J Neurol Neurosurg Psychiatry 2004;75:1362–1366 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2003.029041 on 16 August 2004. Downloaded from the telephone ringing in his left ear. His chewing loud enough to make understanding CASE REPORT auditory symptoms included being able to of conversations at mealtimes difficult. A 52 year old man complained of diplopia, hear his heart beats, bone taps, and footsteps. Supra-normal bone conduction thresholds, dizziness, vertigo, decrease of consciousness, Additionally he complained of a soft low or so-called ‘‘conductive hyperacusis’’, has memory impairment, and hyperphagia. These pitched sound in his left ear ‘‘rather like been reported in other patients with Tullio symptoms occurred abruptly while he was 4 moving a hard-pressed finger across a clean, phenomenon, and dehiscence of the superior painting the gate in his garden. wet china dinner plate’’ when he moved his semi-circular canals is thought to be the The diplopia and vertigo disappeared in 5 eyes. These symptoms could be reduced if the commonest associated pathology. It is pos- about 15 minutes, while hyperphagia and patient tensed his abdominal muscles. Pure tulated that the dehiscence may act as an memory impairment lasted for about 24 tone audiometry showed normal air conduc- alternative lower impedance pathway for hours and completely disappeared the follow- tion hearing thresholds bilaterally other than sound energy, enabling these patients to hear ing day on awakening. Instead, amnesia a mild elevation of 35 dBHL at 0.25 kHz on the movements of their eyeballs within the concerning the event is still present. the left. Bone conduction hearing levels were bony sockets, these sounds being conducted The decrease of consciousness consisted of normal, perhaps even supra-normal, with through the skull. It is interesting to note slight hypersomnolence (the patient could thresholds of 210 dBHL at 0.5 and 1 kHz that although our patient had dehiscence of easily be awakened by auditory and verbal bilaterally, giving rise to an ‘‘air-bone gap’’ at both superior semi-circular canals, he was stimulation) and was present only at the these frequencies. Clinical examination and only symptomatic on the left side. This could onset, while memory impairment was noted three-dimensional video oculography demon- be explained by the Tullio phenomenon being only later. The patient’s wife reported that he strated left beating torsional nystagmus multi-factorial in nature, and additional kept repeating the same questions to her, and provoked by the patient humming, and CT factors such as trauma or bone remodelling painted the garden gate incorrectly (using scanning of the petrous temporal bones need to be present as well as the dehiscence colours inappropriately). The patient was 5 revealed bilateral dehiscence of the superior before the clinical features become manifest. completely unaware of these symptoms, semicircular canals (fig 1). which were reported only by his wife. W Albuquerque Regarding the hyperphagia, his wife Department of Neuro-otology, National Hospital for reported that the patient compulsively ate Neurology and Neurosurgery, London, UK Discussion all the food he found in the refrigerator and Patient 1 has gaze-evoked tinnitus, a phe- A M Bronstein in the kitchen. Apart from the fact that he nomenon first described in 19821 that was Academic Department of Neuro-otology, Imperial was eating continuously all day long, when it initially thought to be rare, but subsequently College Faculty of Medicine, London, UK was time for his lunch and evening meal, he reported to be surprisingly common (preva- always felt hungry and ready to eat, as his lence 19–36%) in one study of patients post Correspondence to: Professor A M Bronstein, main concern was food, and his attention 2 vestibular schwannoma resection. It has also Academic Department of Neuro-otology, Division of could not be diverted during his meals. been described in patients with cerebello- Neuroscience and Psychological Medicine, Imperial The following day his wife took him to the pontine angle meningioma, meningeal College Faculty of Medicine, Charing Cross Hospital, hospital. Neurological examination on admis- Fulham Palace Road, London W6 8RF, UK; metastases of malignant melanoma, and sion revealed only retrograde amnesia about 2 [email protected] sudden sensorineural hearing loss. It may the events that had occurred in the previous develop months post-operatively, and is doi: 10.1136/jnnp.2003.030577 24 hours, along with fatuous behaviour. The usually heard in, and caused by moving the medical history was not significant. Cranial eyes towards, the diseased ear. The exact computed tomography and extracranial copyright. mechanism is not known, but it has been References Duplex ultrasonography were normal. Five postulated that neural plasticity mechanisms 1 Whittaker CK. Letter to the editor. Am J Otol days later, brain magnetic resonance imaging activated by unilateral deafferentation result 1982;4:188. (MRI) revealed an ischaemic lesion involving in cross-talk between neural elements con- 2 Biggs NDW, Ramsden RT. Gaze-evoked tinnitus the medial portion of the left thalamus in the trolling eye movements and the central following acoustic neuroma resection: a de- territory of the tubero-thalamic perforating auditory system. Indeed, functional imaging afferentation plasticity phenomenon? Clin artery (fig 1). MRI-angiography of extracra- studies of patients with gaze-evoked tinnitus Otolaryngol 2002;27:338–43. nial and intracranial cerebral arteries was have shown anomalous activation of the 3 Lockwood AH, Wack MA, Burkard RF, et al. The normal. auditory lateral pons and auditory cortex, functional anatomy of gaze-evoked tinnitus and sustained lateral gaze. Neurology A transthoracic echocardiogram was nor- enhanced by failure of cross-modality inhi- mal, while a transoesophageal echocardio- 3 2001;56:472–80. bitory mechanisms. 4 Colebatch JG, Day DL, Bronstein AM, et al. gram revealed an atrial septal aneurysm Patient 2 has Tullio phenomenon, a condi- Vestibular hypersensitivity to clicks is without a patent foramen ovale. Conven- tion in which sound and/or pressure stimu- characteristic of Tullio phenomenon. J Neurol tional vascular risk factors (hypertension, lates the vestibular system. These patients Neurosurg Psychiatry 1998;65:670–78. diabetes, hypercholesterolaemia, and smok- http://jnnp.bmj.com/ often complain of abnormal auditory sensa- 5 Minor LB, Solomon D, Zinreich JS, et al. Sound- ing) were absent. Routine laboratory studies tions such as ‘‘hearing footsteps vibrating and/or pressure-induced vertigo due to bone including coagulation profiles were normal. through the body’’, and finding the noise of dehiscence of the superior semicircular canal. Arch Otolaryngol Head Neck Surg During the hospital admission, the 1998;124:249–58. patient’s clinical condition progressively improved and he was discharged eight days later without any neurological symptoms. Transient compulsive Two weeks later he was submitted to a hyperphagia in a patient with a neuropsychological test battery to assess reasoning (Raven PM47), short term memory on September 29, 2021 by guest. Protected thalamic infarct (verbal and spatial span), learning (paired Eating disorders are associated with various associate and Corsi spatial learning), atten- psychiatric and neurological diseases. Patho- tion (visual search), and frontal executive logical eating behaviour ranges from reduced functions (Nelson card sorting test, trial to excessive appetite, dysregulation of hunger making B, category, and literal fluency). and satiation signals, and odd food prefer- Anxiety and depression were investigated by ences. Hyperphagia and anorexia are reported the state-trail anxiety inventory and the Beck in lesions (mostly tumours) involving the depression inventory. Results were within the ventromedial hypothalamus.1 Moreover, eat- normal range (,1 SD) for all the tests. ing disorders also occur in temporal lobe tumours, temporal lobe epilepsy, and advanced states of degenerative disease with COMMENT neuronal loss in the medial temporal lobe. The anatomical substrates of eating disorders Hyperorality is part of the Kluver-Bucy are conventionally the basal ganglia and the syndrome which occurs in patients with cortico-limbic areas. In our patient compul- Figure 1 Transverse computerised bilateral mesial temporal lesions.1 sive hyperphagia was associated with the tomography image showing bilateral We report a patient in whom compulsive clinical features of medial thalamic ischae- dehiscence of the superior semi-circular canals hyperphagia was associated with a medial mia. The patient presented with signs and (indicated by arrows). thalamic ischaemic stroke. symptoms of the so called ‘‘top of the basilar

www.jnnp.com J Neurol Neurosurg Psychiatry 2004;75:1362–1366 1365 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2003.029041 on 16 August 2004. Downloaded from

(IPD), has a mild stimulant effect and may cause agitation, restlessness, and euphoria even in normal subjects. It is associated with a well documented withdrawal syndrome consisting of confusion, muscular pain, and rigidity. This can progress to involve symp- toms comparable with neuroleptic malignant syndrome, including pyrexia and increased creatine kinase.1 There is now good evidence that L-dopa is addictive, and there are many case reports of patients with IPD who seek to increase their L-dopa dose to high levels because of psychological dependence rather than therapeutic benefit.2 The largest series of such patients3 suggested that L-dopa depen- dence results in paranoia, hypomania, hyper- sexuality, and euphoria associated with weight loss and severe dyskinesias. Many of the behavioural changes are similar to those seen in amphetamine or cocaine abusers and have been termed ‘‘hedonistic homeostatic dysregulation’’. Figure 1 Magnetic resonance imaging of the brain. (A) Coronal view, T2 weighted (time of repetition/time of echo/excitations: 3800/120/2). (B) Axial view, T2 weighted (3800/120/2). A CASE REPORT round hyperintense lesion is located in the paramedian portion of the left thalamus (A). The An 81 year old woman had been diagnosed ischaemic lesion involves the medial thalamus (B) in the territory of the thalamo-perforating with Parkinson’s disease 10 years before. She branches of the posterior cerebral artery. reported a five year history of extremely frequent but intermittent severe pain and syndrome’’ and of thalamic perforating artery embolic occlusion of the distal portion of stiffness in all her muscles, resulting in severe infarction. the basilar artery may have caused a transient disability and distress. Her general practi- Thalamo-perforating arteries usually arise bilateral thalamic ischaemia. The definite tioner had tried amitriptyline and baclofen from the posterior cerebral artery and supply infarct involved the left thalamus and was with no effect. The only effective treatment the posteromedial thalamus (PMT),2 which completely asymptomatic. was Madopar, a combination levodopa and contains the rostral interstitial nucleus of the In our patient we believe that transient benserazide hydrochloride, which she took in medial longitudinal fasciculus, the posterior thalamo-cortical dysfunction because of large doses every two hours. She admitted inferior portion of the dorsomedial nucleus, impairment of the connection between the taking in excess of 2.3 g every 24 hours. She the nucleus parafascicularis, the intralaminar medial thalamic nuclei and the frontal or even woke in the night to take Madopar

nuclei, and sometimes the mamillothalamic temporal lobes may have been the determi- tablets. She was obsessional about her drug copyright. tract. Unilateral infarcts of the PMT may nant of the compulsive hyperphagia. This regimen and would not allow even minor cause a decrease in consciousness and neu- compulsive hyperphagia may be the equiva- changes. Her husband said that she was ropsychological disturbance (patients will be lent of the utilisation behaviour described in hostile, paranoid, and very demanding. She disoriented, unconcerned, apathetic, and may bilateral PMT infarction,4 in which patients had never suffered from hallucinations or engage in behaviour involving the compulsive automatically and inappropriately handle dyskinesias. use of objects out of the behavioural context). and use objects placed before them, even Her previous records indicated ongoing A visual deficit (diplopia and vertical gaze though told not use them. problems with weight loss, investigated over functional impairment with up gaze palsy or several years but with no apparent cause. She combined up and down gaze palsy) are often P Cerrato, M Grasso, C Azzaro, C Baima, had undergone computed tomography of the reported because of the involvement of the M Giraudo, A Rizzuto, A Lentini, P Perozzo, brain in 2001, which showed multiple white upper mesencephalon.2 Neuropsychological B Bergamasco matter lesions secondary to chronic ischae- disturbances are more marked and long First Division of Neurology, Department of mic damage. lasting in patients with bilateral PMT infarc- Neuroscience, University of Turin, 10126 Turin, Italy She presented as a cachectic, frail, elderly tion. Except for visual dysfunction, similar women bent over in a wheelchair. She http://jnnp.bmj.com/ features are reported in anteromedial thala- G Sorrentino weighed 34 kg. She was unable to stand or mic infarction. University ‘‘Parthenope’’ of Naples, Naples, Italy walk owing to pain and stiffness. She was In diencephalic lesions hyperphagia may slightly confused, with a mini-mental state result from hypothalamic, thalamo-cortical, Correspondence to: Dr Paolo Cerrato; examination (MMSE) score of 24/30. She [email protected] or limbic dysfunction. Lesions involving the appeared to be in constant pain and was ventromesial hypothalamus, the amygdala, doi: 10.1136/jnnp.2003.027607 uncooperative with examination. Despite and the fibre bundle from the substantia Competing interests: none declared this, she had no evidence of tremor, rigidity, nigra to the basal ganglia alter the signal of or bradykinesia. There were no other sig- 1 satiation and food intake. Eating disorders nificant neurological findings. on September 29, 2021 by guest. Protected caused by hypothalamic dysfunction are References She was admitted to hospital for slow characterised by dysregulation of hunger 1 Herzoog MDB, Copeland PM. Eating disorders. supervised withdrawal of her Madopar. Blood and satiation signals and are associated with N Engl J Med 1985;313:295–303. tests including blood count, electrolytes, other endocrine dysregulations. 2 Bogousslavsky J, Caplan L. Stroke syndromes. creatine kinase, thyroid function, and inflam- Cortical lesions may cause eating disorders Cambridge: Cambridge University Press, matory markers were all in the normal range. if they involve the temporal and frontal 1995;29:276–83. She refused further investigation by magnetic association areas connected to the basal and 3 Papez JW. A proposed mechanism of emotion. resonance imaging or single photon emission diencephalic systems. Moreover, clinical Arch Neurol 1937;38:725–43. computed tomography. She was only able to observations and animal studies suggest that 4 Eslinger PJ, Warner GC, Grattan LM, et al. tolerate a very slow withdrawal of L-dopa ‘‘Frontal lobe’’ utilization behavior associated the limbic structures and their connections with paramedian thalamic infarction. Neurology owing to severe muscular pain, and it took are strongly involved in the regulation of 1991;41:450–2. two separate admissions over five months to appetite.3 complete the withdrawal. In our patient the acute occurrence of It was possible to keep her off L-dopa for a compulsive eating was part of a complex Case study: cerebrovascular period of four weeks, during which she behavioural and neuropsychological distur- parkinsonism with levodopa regained her appetite and weighed 40 kg. bance typical of medial thalamic dysfunction. She was clear in her mind and her MMSE Behavioural abnormalities may be more addiction score was 30/30. She was no longer para- easily explained by bilateral involvement of Levodopa (L-dopa), the mainstay of treat- noid and no longer wanted to take L-dopa the medial thalamic region. Indeed an ment for idiopathic Parkinson’s disease treatment. She became pain-free. Her

www.jnnp.com 1366 J Neurol Neurosurg Psychiatry 2004;75:1362–1366 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.2003.029041 on 16 August 2004. Downloaded from handwriting was large and legible. She was with ‘‘hedonistic homeostatic dysregulation.’’ informed cooperation and that of her hus- able to walk with a Zimmer-frame, but had a She became profoundly disabled as a result of band, who had given her drug treatment for wide based shuffling gait compatible with a L-dopa dependence, the manifestations of many years. Other patients simply refuse to diagnosis of small vessel cerebrovascular which were much worse than the symptoms comply with drug changes and may even disease. with which she had initially presented. change specialists to secure an L-dopa supply. Following that period she became The psychiatric effects of L-dopa depen- The successful outcome in this case is depressed and withdrawn. Paroxetine did dence are well documented, including severe probably the exception rather than the rule. not help but the reintroduction of Madopar, depression after withdrawal.3 However, the in a dose of 62.5 mg three times daily, helped characteristic severe muscle pain suffered by O Lily, A Al-Din to alleviate the depression. After one year of our patient has not been reported before. We Department of Neurology, Pinderfields General follow up she remained mobile with help. speculate that long term L-dopa treatment Hospital, Wakefield, UK She had not developed tremor, extrapyrami- causes changes in the expression of central dal rigidity, or significant bradykinesia. Her dopamine receptors such that withdrawal Correspondence to: Dr Oliver Lily; [email protected] appetite and alertness continued to be good. leads to unpleasant symptoms, even in people She refused any further reduction in the dose without Parkinson’s disease. A similar doi: 10.1136/jnnp.2003.029041 of L-dopa. mechanism may underlie the development of ‘‘dopaminergic malignant syndrome’’. Competing interests: none declared It is our suspicion that there may be other COMMENT patients without IPD who are dependent on Despite its high prevalence, IPD is often a L-dopa. It is important that L-dopa is not References challenging diagnosis. Up to 25% of patients considered a benign medication, and trials of 1 Friedman JH, Feinberg SS, Feldman RG. A considered to have this condition by a treatment with this agent should be carefully neuroleptic malignant-like syndrome due to neurologist may have an alternative diagno- supervised. Any patient taking L-dopa in levodopa therapy withdrawal. JAMA sis.4 In the community, the diagnosis may be large doses without dyskinesias should have 1985;254:2792–5. wrong in nearly 50% of cases.5 Where there is the diagnosis reconsidered. Any patient with 2 Nausieda PA. Sinemet ‘‘abusers’’. Clin difficulty in making a diagnosis, a trial of L- IPD in whom muscular pain is a prominent Neuropharmacol 1985;8:318–27. 3 Giovannoni G, O’Sullivan JD, Turner K, et al. dopa is often useful. However, it is possible symptom, especially associated with weight Hedonistic homeostatic dysregulation in patients that L-dopa dependency can occur even in loss and psychiatric problems, should have with Parkinson’s disease on dopamine patients without IPD. They can develop their use of L-dopa investigated. It is worth replacement therapies. J Neurol Neurosurg withdrawal symptoms of muscular aching noting that in the case of our patient, the Psychiatry 2000;68:423–8. and stiffness, which superficially resemble actual doses of L-dopa taken were nearly 4 Hughes AJ, Daniel SE, Kilford L, et al. Accuracy of worsening parkinsonism and obviously double those recorded in the medical notes. clinical diagnosis of idiopathic Parkinson’s respond well to L-dopa, giving the impression Finally, patients with L-dopa addiction, disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry of a helpful treatment. In our patient’s case, both with and without IPD, represent a great 1992;55:181–4. larger and larger doses of L-dopa were challenge in management. The prognosis is 5 Meara J, Bhowmick BK, Hobson P. Accuracy of prescribed over many years, leading to recognised to be poor. In our patient’s case, diagnosis in patients with presumed Parkinson’s physical and psychiatric effects compatible Madopar was withdrawn only with her disease. Age Ageing 1999;28:99–102. copyright. http://jnnp.bmj.com/ on September 29, 2021 by guest. Protected

www.jnnp.com